Postcodes as useful markers of income in 26,000 British households.
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Biomedical subjects
Publications and source records attributed to P Appleby.
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Cerebrovascular disease was a leading cause of death from 1955 to 1980 in Japan. The mortality rate from this disease has decreased sharply in recent decades. This downward trend seems to correspond to the dietary habits of Japanese. Data from a large prospective cohort study were analyzed to examine the association between dietary habits and cerebrovascular disease mortality in Japan. The subjects for this analysis were 223,170 men and women aged 40 to 69 at baseline in December 1965. There were 6,168 deaths in men and 4,862 deaths in women due to cerebrovascular disease (ICD7: 330-334) during the follow-up period from January 1966 to December 1981. Rate ratio (RR) and 95% confidence interval (95% CI) adjusted for sex, attained age, follow-up period, prefecture, cigarette smoking, alcohol drinking and occupation was used for comparison. In this study, the risk of mortality from cerebrovascular disease was inversely associated with dairy milk, meat and fish consumption. Therefore the joint effect of dairy milk, meat and fish (DMF) as animal fat and protein was of interest. In the binary analysis, DMF (D, M, F) means the combination of dairy milk (1-3 times/week or more), meat (1-3 times/week or more) and fish (4 times/week or more). Thus DMF (d, m, f) was the reference group having dairy milk (less than 1 time/week), meat (less than 1 time/week) and fish (less than 4 times/week). For the disease, the RR of DMF (D, M, F) was 0.68 with 95% CI of 0.63 to 0.74, relative to the reference group. Furthermore the joint effect of DMF was more strongly associated with cerebral haemorrhage (ICD7: 331, DMF (D, M, F); RR: 0.63, 95% CI: 0.55-0.70) than with cerebral embolism and thrombosis (ICD7: 332, DMF (D, M, F); RR: 0.79, 95% CI: 0.70-0.89). These findings suggest that the increasing intake of animal fat and/or protein may have played a key role in reducing cerebrovascular disease in Japan.
At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.
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CONTEXT: A large number of epidemiologic studies have reported on associations between various "inflammatory" factors and coronary heart disease (CHD). OBJECTIVE: To assess the associations of blood levels of fibrinogen, C-reactive protein (CRP), and albumin and leukocyte count with the subsequent risk of CHD. DATA SOURCES: Meta-analyses of any long-term prospective studies of CHD published before 1998 on any of these 4 factors. Studies were identified by MEDLINE searches, scanning of relevant reference lists, hand searching of cardiology, epidemiology, and other relevant journals, and discussions with authors of relevant reports. STUDY SELECTION: All relevant studies identified were included. DATA EXTRACTION: The following information was abstracted from published reports (supplemented, in several cases, by the authors): size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. DATA SYNTHESIS: For fibrinogen, with 4018 CHD cases in 18 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 1.8 (95% confidence interval [CI], 1.6-2.0) associated with a difference in long-term usual mean fibrinogen levels of 2.9 pmol/L (0.1 g/dL) between the top and bottom thirds (10.3 vs 7.4 pmol/L [0.35 vs 0.25 g/dL]). For CRP, with 1053 CHD cases in 7 studies, the combined risk ratio of 1.7 (95% CI, 1.4-2.1) was associated with a difference of 1.4 mg/L (2.4 vs 1.0 mg/L). For albumin, with 3770 CHD cases in 8 studies, the combined risk ratio of 1.5 (95% CI, 1.3-1.7) was associated with a difference of 4 g/L (38 vs 42 g/L, ie, an inverse association). For leukocyte count, with 5337 CHD cases in the 7 largest studies, the combined risk ratio of 1.4 (95% CI, 1.3-1.5) was associated with a difference of 2.8 x 10(9)/L (8.4 vs 5.6 x 10(9)/L). Each of these overall results was highly significant (P<.0001). CONCLUSIONS: The published results from these prospective studies are remarkably consistent for each factor, indicating moderate but highly statistically significant associations with CHD. Hence, even though mechanisms that might account for these associations are not clear, further study of the relevance of these factors to the causation of CHD is warranted.
OBJECTIVE: To assess effects of intravenous streptokinase, one month of oral aspirin, or both, on long term survival after suspected acute myocardial infarction. DESIGN: Randomised, "2 x 2 factorial," placebo controlled trial. SETTING: 417 hospitals in 16 countries. SUBJECTS: 17 187 patients with suspected acute myocardial infarction randomised between March 1985 and December 1987. Follow up of vital status complete to at least 1 January 1990 for 95% of all patients and to mid-1997 for the 6213 patients in United Kingdom. INTERVENTIONS: Intravenous streptokinase (1.5 MU in 1 hour) and oral aspirin (162 mg daily for 1 month) versus matching placebos. MAIN OUTCOME MEASURES: Mortality from all causes during up to 10 years' follow up, with subgroup analyses based on 4 year follow up. RESULTS: After randomisation, 1841 deaths were recorded in days 0-35, 991 from day 36 to end of year 1, 1478 in years 2-4, and 1230 in years 5-10. Allocation to streptokinase was associated with 29 (95% confidence interval 20 to 38) fewer deaths per 1000 patients during days 0-35. This early benefit persisted (death rate ratio 0.98 (0.92 to 1.04) for additional deaths between day 36 and end of year 10), so that there were 28 (14 to 42) and 23 (2 to 44) fewer deaths per 1000 patients treated with streptokinase after 4 years and 10 years respectively. There was no evidence that absolute survival benefit increased with prolonged follow up among any category of patient, including those presenting early after symptoms started or with anterior ST elevation. Nor did the early benefits seem to be lost in any category (including those aged over 70). Allocation to one month of aspirin was associated with 26 (16 to 35) fewer deaths per 1000 during first 35 days, with little further benefit or loss during subsequent years (death rate ratio 0.99 (0.93 to 1.06) between day 36 and end of year 10). The early benefit obtained with combination of streptokinase and one month of aspirin also seemed to persist long term. CONCLUSIONS: The early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seem to be maintained for at least 10 years.
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Experiments were performed to investigate the immunological site of action of an immunomodulatory factor (IMF), isolated from the gastrointestinal nematode Heligmosomoides polygyrus. IMF inhibited antibody production in murine and human 'T-helper (Th-2) driven' immunoassays. The effects were mediated via T lymphocytes as T cell-depleted cultures failed to respond to IMF, a result confirmed by prepulsing discrete cell subsets with the immunomodulant. Although the molecular nature and mode of action of IMF has yet to be determined, it would appear to be a relatively small non-proteinaceous molecule. From this data, we suggest that H. polygyrus secretes a systemically-active IMF from the intestinal lumen, to down-regulate Th-2 cell development in order to promote its survival in a potentially immunologically hostile environment.
Diverse gram-negative bacterial cells communicate with each other by using diffusible N-acyl homoserine lactone (AHL) signal molecules to coordinate gene expression with cell population density. Accumulation of AHLs above a threshold concentration renders the population "quorate," and the appropriate target gene is activated. In pathogenic bacteria, such as Pseudomonas aeruginosa, AHL-mediated quorum sensing is involved in the regulation of multiple virulence determinants. We therefore sought to determine whether the immune system is capable of responding to these bacterial signal molecules. Consequently the immunomodulatory properties of the AHLs N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) were evaluated in murine and human leukocyte immunoassays in vitro. OdDHL, but not OHHL, inhibited lymphocyte proliferation and tumor necrosis factor alpha production by lipopolysaccharide-stimulated macrophages. Furthermore, OdDHL simultaneously and potently down-regulated the production of IL-12, a Th-1-supportive cytokine. At high concentrations (>7 x 10(-5) M) OdDHL inhibited antibody production by keyhole limpet hemocyanin-stimulated spleen cells, but at lower concentrations (<7 x 10(-5) M), antibody production was stimulated, apparently by increasing the proportion of the immunoglobulin G1 (IgG1) isotype. OdDHL also promoted IgE production by interleukin-4-stimulated human peripheral blood mononuclear cells. These data indicate that OdDHL may influence the Th-1-Th-2 balance in the infected host and suggest that, in addition to regulating the expression of virulence determinants, OdDHL may contribute to the pathogenesis of P. aeruginosa infections by functioning as a virulence determinant per se.
More than 150 epidemiological or clinical studies have reported on associations between vascular disease and the presence of certain persistent bacterial and viral agents, or of clinical conditions (e.g., periodontal disease) that are associated with persistent infection. This article provides a review of such studies, particularly in relation to Helicobacter pylori, Chlamydia pneumoniae, dental disease and cytomegalovirus (CMV), as well as references to possible mechanisms. The association between coronary heart disease and H. pylori or between heart disease and dental disease may be accounted for by residual confounding. Although markers of C. pneumoniae infection are around twenty times more common in atherosclerotic plaques than in disease-free blood vessels, the sequence of infection and disease is uncertain. For CMV, a limited number of patients with classic atherosclerotic coronary heart disease have been investigated in seroepidemiological studies. For all such agents, better and larger seroepidemiological and pathology-based studies are needed to resolve these uncertainties, as well as - at some stage - large-scale, randomised intervention studies.
OBJECTIVE: To determine the quantitative importance of dietary fatty acids and dietary cholesterol to blood concentrations of total, low density lipoprotein, and high density lipoprotein cholesterol. DESIGN: Meta-analysis of metabolic ward studies of solid food diets in healthy volunteers. SUBJECTS: 395 dietary experiments (median duration 1 month) among 129 groups of individuals. RESULTS: Isocaloric replacement of saturated fats by complex carbohydrates for 10% of dietary calories resulted in blood total cholesterol falling by 0.52 (SE 0.03) mmol/l and low density lipoprotein cholesterol falling by 0.36 (0.05) mmol/l. Isocaloric replacement of complex carbohydrates by polyunsaturated fats for 5% of dietary calories resulted in total cholesterol falling by a further 0.13 (0.02) mmol/l and low density lipoprotein cholesterol falling by 0.11 (0.02) mmol/l. Similar replacement of carbohydrates by monounsaturated fats produced no significant effect on total or low density lipoprotein cholesterol. Avoiding 200 mg/day dietary cholesterol further decreased blood total cholesterol by 0.13 (0.02) mmol/l and low density lipoprotein cholesterol by 0.10 (0.02) mmol/l. CONCLUSIONS: In typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol.
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OBJECTIVES: Most randomised trials of anticoagulant therapy for suspected acute myocardial infarction have been small and, in some, aspirin and fibrinolytic therapy were not used routinely. A systematic overview (meta-analysis) of their results is needed, in particular to assess the clinical effects of adding heparin to aspirin. DESIGN: Computer aided searches, scrutiny of reference lists, and inquiry of investigators and companies were used to identify potentially eligible studies. On central review, 26 studies were found to involve unconfounded randomised comparisons of anticoagulant therapy versus control in suspected acute myocardial infarction. Additional information on study design and outcome was sought by correspondence with study investigators. SUBJECTS: Patients with suspected acute myocardial infarction. INTERVENTIONS: No routine aspirin was used among about 5000 patients in 21 trials (including half of one small trial) that assessed heparin alone or heparin plus oral anticoagulants, and aspirin was used routinely among 68,000 patients in six trials (including the other half of one small trial) that assessed the addition of intravenous or high dose subcutaneous heparin. MAIN OUTCOME MEASUREMENTS: Death, reinfarction, stroke, pulmonary embolism, and major bleeds (average follow up of about 10 days). RESULTS: In the absence of aspirin, anticoagulant therapy reduced mortality by 25% (SD 8%; 95% confidence interval 10% to 38%; 2P = 0.002), representing 35 (11) fewer deaths per 1000. There were also 10 (4) fewer strokes per 1000 (2P = 0.01), 19 (5) fewer pulmonary emboli per 1000 (2P < 0.001), and non-significantly fewer reinfarctions, with about 13 (5) extra major bleeds per 1000 (2P = 0.01). Similar sized effects were seen with the different anticoagulant regimens studied. In the presence of aspirin, however, heparin reduced mortality by only 6% (SD 3%; 0% to 10%; 2P = 0.03), representing just 5 (2) fewer deaths per 1000. There were 3 (1.3) fewer reinfarctions per 1000 (2P = 0.04) and 1 (0.5) fewer pulmonary emboli per 1000 (2P = 0.01), but there was a small non-significant excess of stroke and a definite excess of 3 (1) major bleeds per 1000 (2P < 0.0001). CONCLUSIONS: The clinical evidence from randomised trials dose not justify the routine addition of either intravenous or subcutaneous heparin to aspirin in the treatment of acute myocardial infarction (irrespective of whether any type of fibrinolytic therapy is used).
OBJECTIVES: To assess the effects of cigarette smoking on the incidence of non-fatal myocardial infarction, and to compare tar in different types of manufactured cigarettes. METHODS: In the early 1990s responses to a postal questionnaire were obtained from 13,926 survivors of myocardial infarction (cases) recently discharged from hospitals in the United Kingdom and 32,389 of their relatives (controls). Blood had been obtained from cases soon after admission for the index myocardial infarction and was also sought from the controls. 4923 cases and 6880 controls were current smokers of manufactured cigarettes with known tar yields. Almost all tar yields were 7-9 or 12-15 mg/cigarette (mean 7.5 mg for low tar (< 10 mg) and 13.3 for medium tar (> or = 10 mg). The cited risk ratios were standardised for age and sex and compared myocardial infarction rates in current cigarette smokers with those in non-smokers who had not smoked cigarettes regularly in the past 10 years. RESULTS: At ages 30-49 the rates of myocardial infarction in smokers were about five times those in non-smokers (as defined); at ages 50-59 they were three times those in non-smokers, and even at ages 60-79 they were twice as great as in non-smokers (risk ratio 6.3, 4.7, 3.1, 2.5, and 1.9 at 30-39, 40-49, 50-59, 60-69, 70-79 respectively; each 2P < 0.00001). After standardisation for age, sex, and amount smoked, the rate of non-fatal myocardial infarction was 10.4% (SD 5.4) higher in medium tar than in low tar cigarette smokers (2P = 0.06). This percentage was not significantly greater at ages 30-59 (16.6% (7.1)) than at 60-79 (1.0% (8.5)). In both age ranges the difference in risk between cigarette smokers and non-smokers was much larger than the difference between one type of cigarette and another (risk ratio 3.39 and 3.95 at ages 30-59 for smokers of similar numbers of low and of medium tar cigarettes, and risk ratio 2.35 and 2.37 at ages 60-79). Most possible confounding factors that could be tested for were similar in low and medium tar users, with no significant differences in blood lipid or albumin concentrations. CONCLUSION: The present study indicates that the imminent change of tar yields in the European Union to comply with an upper limit of 12 mg/cigarette will not increase (and may somewhat decrease) the incidence of myocardial infarction, unless they indirectly help perpetuate tobacco use. Even low tar cigarettes still greatly increase rates of myocardial infarction, however, especially among people in their 30s, 40s, and 50s, and far more risk is avoided by not smoking than by changing from one type of cigarette to another.
The effect of BTS 71 412, 4-acetyl-1-(4-chlorophenyl)-3-(2-methylthiophenyl)- 3-pyrazolin-5-one, has been determined on a variety of immune reactions in vitro in order to gain a further insight into the mechanisms whereby this novel immunosuppressive drug suppresses cell and antibody mediated immune responses in vivo. BTS 71 412 markedly inhibited [3H]thymidine incorporation by mouse splenocytes activated with concanavalin-A (IC50 = 20.1 microM), phytohaemagglutinin (IC50 = 4.6 microM), lipopolysaccharide (LPS) (IC50 = 3.2 microM), anti-IgM (mu-chain specific) (IC50 = 2.6 microM), or mixed lymphocyte culture (IC50 = 8.4 microM). Activity of BTS 71 412 was not associated with a reduction in cell viability. BTS 71 412 also prevented [3H]thymidine incorporation by the murine HT-2 helper T-cell clone when cultured with IL-2 (IC50 = 7.6 microM) or IL-4 (IC50 = 7.3 microM), enriched Thy-1+ T-lymphocytes stimulated with phorbol 12-myristate 13-acetate plus ionomycin (IC50 = 3.6 microM), and enriched B220- B-lymphocytes stimulated with LPS (IC50 = 3.0 microM). Splenocytes cultured with BTS 71 412 produced lower levels of interleukin (IL)-2, IL-10 and interferon-gamma when stimulated with concanavalin-A (IC50 values 42 microM, 22 microM and 60 microM, respectively). The compound suppressed in vitro antibody responses to keyhole limpet haemocyanin (IC50 = 2.3 microM), but did not reproducibly inhibit IL-6 or tumour necrosis factor alpha production by adherent peritoneal macrophages stimulated with LPS in vitro. These data indicate that BTS 71 412 specifically inhibits both B- and T-lymphocyte activation and proliferation but does not affect macrophage activation in vitro.
It is becoming increasingly clear that the clinical courses of a variety of autoimmune and infectious diseases are influenced by the balance of TH1 and TH2 cell subsets that are generated during the immune response. IL-10 is one of several cytokines which influences the differentiation of TH cell subsets and represents a target for therapeutic intervention. We have evaluated a variety of pharmacological agents for their ability to modulate IL-10 release by the murine D10.G4.1 TH2 cell line when stimulated with concanacavalin-A in the presence of IL-1 alpha. Several were inhibitory, and the concentrations which caused a 50% reduction in IL-10 production were 0.38 microM cyclosporin-A, 0.0073 microM dexamethasone, 0.045 microM prednisolone and 0.31 microM cycloheximide. Methotrexate and pentoxifyline caused a weak but statistically significant reduction in IL-10 production at a concentration of 10 microM (P < or = 0.05), whereas amrinone and azathioprine had no clear effect. The pharmacological agents tested are known to exert multiple effects and were evaluated with a view to their use as reference standards in an ongoing screening programme to identify novel compounds which specifically modulate Il-10 production.
STUDY OBJECTIVE: To compare the rates of reported emergency appendicectomies in a cohort study of vegetarians and non-vegetarians by participants' history of meat consumption. DESIGN: This was a prospective cohort study in which participants were asked about their lifetime history of meat consumption/avoidance and, separately, whether they had had an appendicectomy. Appendicectomy was described as either "emergency" or "non-emergency" according to details supplied by the participant. SETTING: The United Kingdom. PARTICIPANTS: These comprised more than 11000 people, of whom 4852 (44%) completed both an appendicectomy form and a dietary questionnaire giving details of their lifetime history of meat consumption. MAIN RESULTS: The percentage who reported an emergency appendicectomy was higher among lifelong meat eaters (10.7%) than either lifelong non-meat eaters (7.8%) or those who had stopped eating meat (8.0%); and the operations were performed at an earlier age in this first group (mean values 18.9, 26.0, and 19.6 years respectively). The overall age adjusted emergency participants who did not eat mean with those who ate meat was 0.47 (95% confidence interval 0.35, 0.65). CONCLUSION: The results suggests that people who do not eat meat have a 50% lower risk of requiring an emergency appendicectomy than those who do. The data do not, however, allow the reliable testing of other hypotheses, so meat consumption may simply be a marker for another dietary, lifestyle, or socioeconomic factor.
OBJECTIVE: To investigate the health consequences of a vegetarian diet by examining the 12 year mortality of non-meat eaters and meat eating controls. DESIGN: Prospective observational study in which members of the non-meat eating cohort were asked to nominate friends or relatives as controls. SETTING: United Kingdom. SUBJECTS: 6115 non-meat eaters identified through the Vegetarian Society of the United Kingdom and the news media (mean (SD) age 38.7 (16.8) years) and 5015 controls who were meat eaters (39.3 (15.4) years). MAIN OUTCOME MEASURES: Standardised mortality ratios for cancer, ischaemic heart disease, and total mortality in the two cohorts and death rate ratio in the non-meat eaters compared with meat eaters after adjustment for potentially confounding variables. RESULTS: Standardised mortality ratios (taking the value among the general population as 100) for ischaemic heart disease were 51 (95% confidence interval 38 to 66) for meat eaters and 28 (20 to 38) for non-meat eaters (P < 0.01). Values for all cancers were 80 (64 to 98) and 50 (39 to 62) for meat eaters and non-meat eaters respectively. After adjustment for the effects of smoking, body mass index, and socioeconomic status death rate ratios in non-meat eaters compared with meat eaters were 0.72 (0.47 to 1.10) for ischaemic heart disease and 0.61 (0.44 to 0.84) for all cancers. CONCLUSIONS: The reduced mortality from cancer among those not eating meat is not explained by lifestyle related risk factors, which have a low prevalence among vegetarians. No firm conclusion can be made about deaths from ischaemic heart disease. These data do not justify advice to exclude meat from the diet since there are several attributes of a vegetarian diet apart from not eating meat which might reduce the risk.