Showing papers by "Clinical Trial Service Unit published in 2009"

Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

Abstract: BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

Quantitative effects on cardiovascular risk factors and coronary heart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils

Abstract: Background/objectives Reduced consumption of trans-fatty acids (TFA) is desirable to lower coronary heart disease (CHD) risk. In practice, partially hydrogenated vegetable oils (PHVO) that contain both TFAs and other fatty acids are the unit of replacement and could be replaced with diverse alternative fats and oils. We performed quantitative estimates of CHD effects if a person's PHVO consumption were to be replaced with alternative fats and oils based on (1) randomized dietary trials and (2) prospective observational studies. Subjects/methods We performed meta-analyses of (1) the effects of TFAs on blood lipids and lipoproteins in controlled dietary trials and (2) associations of habitual TFA consumption with CHD outcomes in prospective cohort studies. On the basis of these results and corresponding findings for saturated fatty acids (SFA), cis-monounsaturated fatty acids (MUFA) and cis-polyunsaturated fatty acids (PUFA), we calculated the effects on CHD risk for replacing 7.5% of energy from three different PHVO formulations (containing 20, 35 or 45% TFAs) with butter, lard, palm or vegetable oils. Results In controlled trials, each 1% energy replacement of TFAs with SFAs, MUFAs or PUFAs, respectively, decreased the total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio by 0.31, 0.54 and 0.67; the apolipoprotein (Apo)-B/ApoAI ratio by 0.007, 0.010 and 0.011; and lipoprotein (Lp)(a) by 3.76, 1.39 and 1.11 mg/l (P Conclusions Effects on CHD risk of removing PHVO from a person's diet vary depending on the TFA content of the PHVO and the fatty acid composition of the replacement fat or oil, with direct implications for reformulation of individual food products. Accounting for the summed effects of TFAs on multiple CHD risk factors provides more accurate estimates of potential risk reduction than considering each risk factor in isolation, and approaches the estimated risk reduction derived from prospective cohort studies.

Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis

Abstract: While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5×10−8) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism—including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles—all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay.

WHO Scientific Update on trans fatty acids: summary and conclusions

Abstract: The purpose of the WHO scientific review on trans fatty acids (TFAs) was to examine the evidence generated since the 1993 Joint FAO/WHO Expert Consultation on Fats and Oils in Human Nutrition, and to inform member countries on the health consequences of TFAs consumption that have emerged since the last report was released. The new information was deemed sufficient to recommend the need to significantly reduce or to virtually eliminate industrially produced TFA from the food supply in agreement with the implementation of the 2004 WHO Global Strategy on Diet, Physical Activity and Health. This goal has been accomplished in some countries and cities, by the virtual elimination of partially hydrogenated vegetable oils in the human food supply, replacing them with healthy cis-unsaturated fatty acids. The document provides the evidence base to promote discussion between the international scientific community related to nutrition and health as well as between agriculturalists, food producers, relevant health professionals, national and international food regulatory agencies, civil society and the private sector to achieve the stated goal.

Does auditory rhythmical cueing improve gait in people with Parkinson's disease and cognitive impairment? A Feasibility study†

Abstract: Gait and balance problems resulting from Parkinson's disease (PD) are more common in people with PD and dementia (PDD), yet, it is unknown whether the benefits of cueing therapy for mobility generalize to them. We aimed to determine the feasibility and effectiveness of auditory cues to improve gait in PD and cognitive impairment (PD-CI). Nine participants with PD-CI walked with and without auditory cues using two different strategies: (1) Cue with temporal instruction to “step in time to the beat,” (2) Cue with spatiotemporal instruction to “take a big step in time to the beat.” Cues were delivered with a metronome at preferred stepping frequency while on medication during single and dual-task gait. Gait was assessed using GAITRite and walking speed, stride amplitude, step frequency, and variability (CV%) of step and double limb support time were measured. Data were analyzed in SPSS version 16 using fixed-effect linear mixed models. An adjusted, P value of 0.01 was considered significant. Participants were men, aged 74.89 (±6.45) years with median MMSE of 22 (range 20.5–25) and UPDRS III score of 44 (35.5–47.0). Participants complied with testing and instructions. The cue that focused attention on both temporal and spatial parameters of gait significantly improved single and dual-task walking speed and stride amplitude. This study provides evidence for the potential of cueing to improve gait in PD-CI. Only individuals with mild CI were included, and the effect with increased CI and different types of dementia requires further evaluation. © 2009 Movement Disorder Society

The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls.

Abstract: Aims Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A1, the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear. Methods and results Case–control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA1 than to HDL-C. The ratio apoB/apoA1 was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8–9.2)] and varied little with age. The ratio apoB/apoA1 was substantially more informative about risk ( χ 12 = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol ( χ 12 = 407, 334, 204, and 105, respectively). Given apoB and apoA1, the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk ( P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA1 and pre-onset HDL-C with risk in such retrospective case–control studies. Conclusion Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Estimating cardiac exposure from breast cancer radiotherapy in clinical practice.

Abstract: Purpose To assess the value of maximum heart distance (MHD) in predicting the dose and biologically effective dose (BED) to the heart and the left anterior descending (LAD) coronary artery for left-tangential breast or chest wall irradiation. Methods and Materials A total of 50 consecutive breast cancer patients given adjuvant left-tangential irradiation at a large U.K. radiotherapy center during 2006 were selected. For each patient, the following were derived using three-dimensional computed tomography (CT) planning: (1) mean dose and BED to the heart, (2) mean dose and BED to the LAD coronary artery, (3) MHD, (4) position of the CT slice showing the maximum area of the irradiated heart relative to the mid-plane slice, and (5) sternal and contralateral breast thickness (measures of body fat). Results A strong linear correlation was found between the MHD and the mean heart dose. For every 1-cm increase in MHD, the mean heart dose increased by 2.9% on average (95% confidence interval 2.5–3.3). A strong linear-quadratic relationship was seen between the MHD and the mean heart BED. The mean LAD coronary artery dose and BED were also correlated with the MHD but the associations were weaker. These relationships were not affected by body fat. The mid-plane CT slice did not give a reliable assessment of cardiac irradiation. Conclusion The MHD is a reliable predictor of the mean heart dose and BED and gives an approximate estimate of the mean LAD coronary artery dose and BED. Doses predicted by the MHD could help assess the risk of radiation-induced cardiac toxicity where individual CT-based cardiac dosimetry is not possible.

Life expectancy in relation to cardiovascular risk factors: 38 year follow-up of 19 000 men in the Whitehall study

Abstract: Objective To assess life expectancy in relation to cardiovascular risk factors recorded in middle age. Design Prospective cohort study. Setting Men employed in the civil service in London, England. Participants 18 863 men examined at entry in 1967-70 and followed for 38 years, of whom 13 501 died and 4811 were re-examined in 1997. Main outcome measures Life expectancy estimated in relation to fifths and dichotomous categories of risk factors (smoking, “low” or “high” blood pressure (≥140 mm Hg), and “low” or “high” cholesterol (≥5 mmol/l)), and a risk score from these risk factors. Results At entry, 42% of the men were current smokers, 39% had high blood pressure, and 51% had high cholesterol. At the re-examination, about two thirds of the previously “current” smokers had quit smoking shortly after entry and the mean differences in levels of those with high and low levels of blood pressure and cholesterol were attenuated by two thirds. Compared with men without any baseline risk factors, the presence of all three risk factors at entry was associated with a 10 year shorter life expectancy from age 50 (23.7 v 33.3 years). Compared with men in the lowest 5% of a risk score based on smoking, diabetes, employment grade, and continuous levels of blood pressure, cholesterol concentration, and body mass index (BMI), men in the highest 5% had a 15 year shorter life expectancy from age 50 (20.2 v 35.4 years). Conclusion Despite substantial changes in these risk factors over time, baseline differences in risk factors were associated with 10 to 15 year shorter life expectancy from age 50.

Prognostic Value of Coronary Revascularisation Related Myocardial Injury: A Cardiac Magnetic Resonance Imaging Study

Abstract: Aims: Myocardial revascularisation improves outcomes in patients with coronary artery disease. However, these procedures may themselves cause irreversible myocardial injury. The prognostic value of procedural myocardial injury is uncertain. Methods and results: We quantified procedural myocardial necrosis using delayed enhancement cardiovascular magnetic resonance imaging (DE-CMR) in 152 consecutive patients before and shortly after percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The primary endpoint was defined as death, non-fatal myocardial infarction, sustained ventricular arrhythmia, unstable angina or heart failure requiring hospitalisation. During a median follow-up of 2.9 years, 27 patients (18%) reached the primary endpoint. 49 patients (32%) had evidence of new procedure-related myocardial hyperenhancement with a median mass of 5.0 g (interquartile range 2.7–9.8). After adjustment for age and sex, these patients had a 3.1-fold (95% confidence interval 1.4 to 6.8; p = 0.004) higher risk of adverse outcome than patients without new hyperenhancement. Cardiac troponin levels and quantitative measures of left ventricular function after procedure did not show any significant independent association with the primary endpoint and they did not alter the independent association of new hyperenhancement. Conclusions: Myocardial injury during PCI or CABG, identified by DE-CMR, adversely affects clinical outcome. This suggests the benefits from revascularisation could partially be offset by new myocardial injury caused by the intervention itself.

Smoking, drinking and incident tuberculosis in rural India: population-based case–control study

Abstract: BACKGROUND To investigate the extent to which smoking and/or drinking can increase the incidence of pulmonary tuberculosis (TB), a population-based case-control study was conducted in rural south India. METHODS A total of 1839 males and 870 females treated in 2000-03 by state TB clinics were interviewed at home in 2004-05 about their education, smoking and drinking habits before disease onset. As controls, 2134 men and 2119 women without TB were randomly chosen from case villages and interviewed. Incidence rate ratios (RRs) are from logistic regression, adjusted for age and education. RESULTS No women smoked or drank. The main analyses are of men aged 35-64 years, 949 cases treated for new pulmonary TB and 1963 controls. In the study, 81.5% of the cases and 55.2% of the controls had ever smoked, yielding a standardized ever- vs never-smoker TB incidence RR of 2.7 [95% confidence interval (CI) 2.2-3.3, P < 0.00001). Among control ever-smokers 96% still smoked, 71% used only bidis (mean 17 per day) and 28% used only cigarettes (mean 7 per day). After additional adjustment for alcohol, this RR was 2.2 (95% CI 1.7-2.7, P < 0.00001), but even among those who had never drunk alcohol the standardized ever- vs never-smoker RR was 2.6 (95% CI 2.0-3.6, P < 0.00001). The corresponding RRs for ever- vs never-drinking were somewhat less extreme: 2.2 (95% CI 1.8-2.6, P < 0.00001) without adjustment for smoking, 1.5 (95% CI 1.2-1.9, P = 0.00004) with adjustment for smoking and 2.1 (95% CI 1.4-3.0, 2P = 0.0001) among those who had never smoked. Among control ever-drinkers, 96% still drank and 99% used only spirits (mean 0.3 l/week). CONCLUSIONS This study of reliably confirmed disease (by the criteria of state TB clinics) demonstrates an increased incidence of pulmonary TB among those who smoke and among those who drink. The effects of smoking after adjustment for drinking were more definite than those of drinking after adjustment for smoking.

Body mass index and mortality from lung cancer in smokers and nonsmokers: a nationally representative prospective study of 220,000 men in China.

Abstract: The mean baseline BMI was 21.7 kg/m 2 , and 2,145 lung cancer deaths were recorded during 15 years of follow-up. The prevalence of smoking was strongly inversely associated with BMI, but no apparent relationship was seen between amount smoked (or other measures of smoking intensity) and BMI among smokers. Overall there was a strong inverse association between BMI and lung cancer mortality (p < 0.0001 for trend) after excluding the first 3 years of follow-up. This association appeared to be confined mainly to current smokers, with no apparent relationship in nonsmokers (p < 0.001 for difference between slopes). Among current smokers, the inverse association appeared to be log-linear, with each 5 kg/m 2 lower BMI associated with a 35% (95% confidence interval: 24–46%; p < 0.0001) higher lung cancer mortality, and it persisted after excluding those who had reported poor health status or history of any disease or respiratory symptoms at baseline. In this relatively lean Chinese male population, low BMI was strongly associated with increased risk of lung cancer only among current smokers. ' 2009 UICC Lung cancer is among the commonest types of cancer throughout China, causing some 400,000 deaths annually. During the last few decades the disease rate has risen steadily, especially among males, as a consequence of the recent large increase in cigarette consumption. 1,2 Despite the rise in smoking-related diseases, the emerging tobacco hazard in China remains at an early stage due to the delayed effect of increase in cigarette consumption, with only about 12% of male adult deaths being attributed to smoking during the 1990s, a proportion similar to that in the USA during the early 1950s. 3 Currently about two-thirds of men aged 15 or over in China smoke, compared to fewer than 5% of women. 3,4 Although there is little variation in the smoking prevalence between different regions of China, the absolute lung cancer rate varies considerably, with the nonsmoker lung cancer rate in some parts of China being about 10 times greater than that among US nonsmokers. 3 This suggests that factors other than smoking contribute significantly to disease risk in the population. 3,5,6 Several observational studies have examined the relationship between lung cancer and body mass index (BMI), an indirect but useful measure of body fatness. 7‐23 Most of these studies have shown BMI to be inversely associated with the risk of lung cancer, with particularly high excess risk among very lean people (BMI < 18.5 kg/m 2 ). Questions remain, however, about the nature of the association, particularly the relevance to it of smoking. Some studies have attributed the inverse association of BMI and lung cancer risk entirely to incomplete control of confounding by smoking and/or of reverse causality due to pre-existing dis

The prevalence of chronic diseases and major disease risk factors at different ages among 150,000 men and women living in Mexico City: cross-sectional analyses of a prospective study.

Abstract: While most of the global burden from chronic diseases, and especially vascular diseases, is now borne by low and middle-income countries, few large-scale epidemiological studies of chronic diseases in such countries have been performed. From 1998–2004, 52 584 men and 106 962 women aged ≥35 years were visited in their homes in Mexico City. Self reported diagnoses of chronic diseases and major disease risk factors were ascertained and physical measurements taken. Age- and sex-specific prevalences and means were analysed. After about age 50 years, diabetes was extremely common – for example, 23.8% of men and 26.9% of women aged 65–74 reported a diagnosis. By comparison, ischaemic heart disease was reported by 4.8% of men and 3.0% of women aged 65–74, a history of stroke by 2.8% and 2.3%, respectively, and a history of cancer by 1.3% and 2.1%. Cancer history was generally more common among women than men – the excess being largest in middle-age, due to breast and cervical cancer. At older ages, the gap narrowed because of an increasing prevalence of prostate cancer. 51% of men and 25% of women aged 35–54 smoked cigarettes, while 29% of men and 41% of women aged 35–54 were obese (i.e. BMI ≥30 kg/m2). The prevalence of treated hypertension or measured blood pressure ≥140/90 mmHg increased about 50% more steeply with age among women than men, to 66% of women and 58% of men aged 65–74. Physical inactivity was highly prevalent but daily alcohol drinking was relatively uncommon. Diabetes, obesity and tobacco smoking are highly prevalent among adults living in Mexico City. Long-term follow-up of this and other cohorts will establish the relevance of such factors to the major causes of death and disability in Mexico.

The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99.

Abstract: The 1997 acute lymphoblastic leukaemia (ALL) trial (ALL97) was a randomised comparison of prednisolone versus dexamethasone and of 6-mercaptopurine versus 6-thioguanine During the first 2 years of the trial, review of survival data showed the preceding trial, UKALL XI, was no better than its predecessor and that survival for childhood ALL in the UK had not improved in the fashion witnessed by other cooperative treatment groups The therapy template was therefore altered to an American Children's Cancer Group (CCG) style regimen, including stratification by age, white cell count and early response to therapy by assessment of the bone marrow This phase of the trial was designated ALL97/99 Comparison of the two phases showed that the event-free survival (EFS) for both ALL97 and ALL97/99 was better than previous UKALL trials, as was overall survival (OS) for ALL97/99 Both EFS and OS were significantly better in ALL97/99 than in ALL97 (at five years, 800% vs 740%, P = 0002; and 880% vs 835%, P = 0005, respectively) Isolated central nervous system (CNS) relapse for patients in ALL97/99 was half that in ALL97 (30% vs 49%), P = 003) and the overall CNS relapse rate was halved in ALL97/99 (44% vs 96%, P < 000005) There were no significant differences for non-CNS relapse, induction deaths or deaths in remission between the two phases of the trial

Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion

Abstract: WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p=0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p=0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p=0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p=0.02 and p=0.01 respectively). The major allele (A) of rs765250, located in intron1,demonstrated the strongestevidencefor associationwithSBP,effect size3.14 mmHg(95%CI:1.23–4.9), DBP1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n=14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p=7610 23 ,c ombined with BRIGHT data-set p=2610 24 , n=17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p,10 27 ). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (.10 mmHg reduction) and risk for hypertension (OR,0.60). Our data indicates that multiple rare and commonWNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

Tobacco: The growing epidemic in China

Abstract: Summary China, with 20% of the world's population, produces and consumes about 30% of the world's cigarettes, and already suffers about a million deaths a year from tobacco. This is more than in any other country, and the hazards are expected to increase substantially during the next few decades, over and above the effects of demographic changes, as a delayed effect of the large increase in cigarette use between the 1950s and 1990s and of a further sharp increase in cigarette consumption since 1999. In developed countries cigarette smoking became popular during the first half of the twentieth century, but the main increase in tobacco deaths was not seen until several decades later, during the second half of the century. In the US, mean cigarette consumption per adult in 1910, 1930 and 1950 was 1, 4 and 10 a day, respectively, after which it remained fairly constant for a few decades. As a delayed result of this increase in cigarette smoking, the proportion of all US deaths at ages 35–69 attributed to tobacco rose over the next few decades from ‘‘only'' about 12% in 1950 to 33% in 1990. In Chinese men, the pattern of increase in cigarette smoking that had been seen between 1910 and 1950 in the US was repeated 40years later between 1952 and 1992. In most parts of China women now smoke far less than men. Mean cigarette consumption per Chinese man in 1952, 1972 and 1992 was 1, 4 and 10 per day, respectively, after which it leveled off for a few years, then continued to rise. Nationwide retrospective and prospective studies in China indicate that by 1990 tobacco already caused about 12% of all male deaths at ages 35–69, and by 2030 it will probably cause about one third of them, unless there is widespread cessation among those who already smoke. Although the overall hazard per cigarette smoker may be about the same in China as elsewhere, the chief diseases by which tobacco caused death in the 1990s were very different in China, with about half of the tobacco deaths involving emphysema rather than cardiovascular disease. The patterns of tobacco death also differed between one region and another, and may change substantially over time as a result of changes in diet and other factors. Large prospective epidemiological studies are now in place to monitor the evolution of the growing tobacco epidemic in China and elsewhere over the next few decades.

The mysterious steps in carcinogenesis

Abstract: The mutational changes needed to create a cancer cell have been itemised in great detail (Hahn and Weinberg, 2002) These mutations are commonly assumed to accumulate over the course of years as a consequence of spontaneous replication errors or, in special cases, the misrepair of DNA lesions introduced by carcinogens such as tobacco smoke or sunlight Yet, there are numerous discrepancies between the mutagenicity of chemicals and their danger to humans (Clemmesen and Hjalgrim, 1977; Jansen et al, 1980; Ames et al, 1987), and the time course of carcinogenesis is deeply mysterious Indeed, we still do not know the proximate causes of most cancers even though these are what we want to learn how to avoid The classical method for creating cancers, in rabbits (Friedewald and Rous, 1944) in mice (Berenblum and Shubik, 1947) and perhaps in humans (Pott, 1775), by applying coal tar to the skin, involves a sequence of steps, called initiation and promotion (Friedewald and Rous, 1944), which bear no obvious relation to what is now known about the molecular biology of cancer For example, a mouse can be ‘initiated' by feeding it once with 1 mg of the coal tar derivative 9,10-dimethyl-1,2-benzanthracene (Boutwell, 1964) This single treatment with a mutagen apparently causes cells to undergo a permanent change so that, for the rest of the mouse's life, its skin has become susceptible to the production of papillomas and carcinomas on exposure to the non-mutagenic irritants in croton oil Surprisingly, a similar sequence has been seen using cells in vitro, where brief exposure to X-rays or methylcholanthrene apparently produces a permanent change in every cell so that, many generations later, its descendants occasionally undergo ‘spontaneous' transformation into cancer cells (Kennedy et al, 1980, 1984) Why does there have to be a long interval between a cell's exposure to a mutagen and the expression of the resulting mutations, and why do only a minority of the cell's descendants express these mutations? It would have been tempting to postulate that the various methods for producing cancer in the cells of animals are not good models of human carcinogenesis, were it not for the fact that humans and animals show the same strange relationship between dose of carcinogen and time of appearance of their cancers For example, although the incidence of lung cancer in smokers appears to be directly proportional to the number of cigarettes smoked per day (Zaridze and Peto, 1986), it is proportional to roughly the sixth power of the duration of smoking Similarly, when rats are continuously exposed to dietary carcinogens, their incidence of cancer rises as the first or second power of the dose rate but as a much higher power of time (Druckrey, 1967; Peto et al, 1997) If the carcinogen had simply to mutate a set of N genes to create cancer, the frequency of cancer should rise as the Nth power of the dose, and time would not be a major factor These numerous experiments suggest, therefore, that mutagenic carcinogens cause just one or two events and that these (similar to the initial event in in vitro carcinogenesis) are then followed by steps that accumulate solely with the passage of time, driven perhaps by cell division Thus, the rabbit whose ears have been painted with coal tar tends to develop its skin cancers where, months later, samples of its skin were excised and therefore had to be replaced by extra division in the surrounding epithelium (Linell, 1947) To take two well-documented examples of carcinogenesis in humans, a chimney sweep did not get scrotal cancer until after puberty when he had grown too large to climb chimneys (Pott, 1775); and smokers keep their raised rate of lung cancer for many years after they have stopped smoking (Halpern et al, 1993) To recapitulate, there are examples where the sequence changes found in cancer cells are the type known to be produced by the initiating carcinogen (Brash et al, 1991; Hsu et al, 1991; Hainaut and Pfeifer, 2001), but the study of cancer in humans and animals, overall, has produced a very confused picture The techniques of modern molecular biology have documented the many defects of cancer cells, so there is by now a fairly clear understanding of the basis for the dangerous properties of cancer cells However, the picture that emerges from the classical studies of the epidemiology of human cancers and of experimental carcinogenesis in animals is hard to reconcile with what has been learnt about mutagenesis in simple systems such as the bacteria Initiation seems to be far too efficient to be simply mutagenesis of certain oncogenes and suppressor genes, and the subsequent time-dependent steps are even more obscure In recent years, it has become plain that the management of biological information involves several unexpected mechanisms that limit the consequences when nucleic acids and proteins are damaged Interactions between cells can protect against their individual defects (Rubin, 2006) and, on a larger scale, the expansion of abnormal clones can be inhibited by their normal neighbours (Chao et al, 2008) Within each individual cell, there is a large set of ‘heat-shock proteins' (HSPs) that manages the folding and operation of the products of gene expression, and one of the actions of these HSPs is to sequester or remove the abnormal proteins produced as the result of mutation or chance misfolding After exposure to harsh environmental conditions such as a sudden rise in temperature, the pattern of synthesis of the various HSPs is altered, and the inactivation of one of the many HSP genes has been shown to result in the expression of previously hidden mutations, suggesting that one function of HSPs is to allow complex evolutionary steps to occur under conditions of stress even when the changes entail a combination of several individually disadvantageous steps (Rutherford and Lindquist, 1998) Keeping those mutations masked may contribute to tumorigenesis, because inactivation of one of the HSP genes has been found to lower the frequency of skin cancer in mice exposed to initiation by dimethylbenzanthracene and promotion by phorbol esters (Dai et al, 2007) The prime mystery in carcinogenesis remains the very first step, because it is hard to imagine how the numerous genetic changes found in cancer cells could have been produced in any cell as the result of a single exposure to a DNA-damaging agent, or why months or years should have to elapse before the effect of these changes is observed Past speculations about the process of carcinogenesis (as opposed to the characteristics of the end product) have had little popularity and negligible impact Indeed, the early suggestions that cancer cells owe their properties to mutation (Tyzzer, 1916) and that carcinogens interact with DNA (Boyland, 1952) were, in their time, violently attacked (Miller and Miller, 1952; Rous, 1959) Now, perhaps with all these recent discoveries of additional mechanisms that protect cells from damage, it may soon be possible to produce a plausible model for what is going on during carcinogenesis At least one new idea seems to be needed, and the main purpose of this article is to alert readers to new developments that could at last start to clarify what is going on during carcinogenesis

Drug cross-resistance and therapy-induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing

Abstract: P>Previous results with individualised tumour response testing (ITRT) in vitro in chronic lymphocytic leukaemia (CLL) have consistently shown good correlation with patient response and survival. We describe here an improved test and report its use with samples from the Leukaemia Research Fund CLL4 randomised clinical trial and previously treated patients. ITRT was performed by the tumour response to anti-neoplastic compounds (TRAC) assay, a modification of the differential staining cytotoxicity (DiSC) assay. Improvements included drying drugs into wells before assay and using the Octospot system to cytocentrifuge eight spots of cells onto one microscope slide. We successfully tested 765/782 (98%) cellular blood samples received within 48 h of phlebotomy. Cross-resistance (Pearson's r > 0 center dot 7) in untreated CLL was found between similar drugs. Mitoxantrone (r = 0 center dot 31), cyclophosphamide (r = 0 center dot 35) and pentostatin (r = 0 center dot 29) had low cross-resistance with fludarabine. Treatment resulted in increased resistance to chlorambucil, cyclophosphamide, doxorubicin, mitoxantrone, corticosteroids, cladribine and fludarabine (P < 0 center dot 01) but not to pentostatin. These results provide further rationale for standard drug combinations such as fludarabine-mitoxantrone and fludarabine-mitoxantrone-cyclophosphamide and suggest possible pentostatin salvage in fludarabine-resistant patients. ITRT results could assist both in determining the best treatment for individual patients and in the design and rationale of future clinical trials.

The mysterious steps in carcinogenesis: addendum.

Abstract: Sir, In the past 100 years, many explanations have been proposed for the process of carcinogenesis but none of them has proved to be totally persuasive. For this reason, we deliberately did not offer a modern synthesis in our review article (Brash and Cairns, 2009). However, in the last few years, thanks to certain experiments, a possible interpretation has emerged, which could be of practical importance. We now see that all cells (bacterial, yeast and mammalian cells) are more far-sighted than we had imagined. Confronted by stressful or damaging changes in their environment, populations of cells activate a programme that raises their mutation rate for several generations but temporarily masks the mutant phenotypes. This greatly increases the likelihood that some of them will be able to flourish in the new environment. Two important observations suggest that induction of this ‘stress response' might be the crucial initiating event in cancer. (1) When cells are exposed to chemical or physical initiators in vitro, every cell can be initiated so that it yields transformed descendants, which implies that initiation is the long-term activation of a programme rather than the production of mutations in certain genes (Kennedy et al, 1984). (2) Inactivation of one of the genes involved in the stress response protects mice against various experimental cancers (Dai et al, 2007). If the formation of most cancers is initiated by activation of a programme that depends on the interplay of several gene products, then defects in some of these products (although evolutionarily deleterious) might prevent most cancers; therefore, it may be useful to look for polymorphisms that protect against cancer rather than, as has become usual these days, concentrate solely on those that increase the risk. This could not easily be done with humans (whose lifetime risk of cancer is only about 50%), but could be done with mice. Even within inbred strains, mice are known to vary in susceptibility to skin cancer, and only a few generations of selective breeding can produce mice that are largely insusceptible (Boutwell, 1964). So the project would be to look for the genetic changes that accompany such selection and then, if found, study the frequency of changes in the equivalent human genes in relation to the risk of cancer, using the DNA samples that have already been collected for the many studies of genetic susceptibility.

Dual blockade of the renin-angiotensin system: are two better than one?

Abstract: The beneficial effects of blood pressure-lowering treatments on the risks of major cardiovascular events are well established [1]. Interruption of the renin–angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) has been shown to be an effective strategy for lowering blood pressure. Randomized trials have shown that ACEi can lower blood pressure by an average of 5/2 mmHg and reduce the risks of cardiovascular events and cardiovascular mortality by ∼20% (and total mortality by 10%) [2–6]. ARBs produce similar reductions in blood pressure and vascular events (although fewer patients have received them in randomized trials) [7–9]. Further, RAS blockade has been reliably shown to reduce the risk of kidney disease progression [10–15]. A meta-analysis of ACEi and ARB monotherapy in diabetic nephropathy demonstrated reductions in end-stage renal disease (ESRD) of around one-quarter for both treatments [16]. Similarly, an individual patient data meta-analysis of ACEi in non-diabetic kidney disease showed a relative risk reduction of 31% (95% CI 5–49%). The major trials of ACEi or ARB monotherapy in various patient populations are summarized in Table 1. As shown in Table 1, among patients at a low risk of renal progression ESRD occurs rarely, and only after many years or even decades. This probably explains the lack of renal benefit reported in large general population trials and meta-analyses of such trials [17–19]. Furthermore, there is some evidence that even the relative benefit might depend on baseline risk, making it even less likely that any true benefit could be detected in existing trials [10]. Whether the observed benefits of RAS blockade are only mediatedbytheirbloodpressure-loweringeffectorwhether other effects also play a role remains controversial; there is some evidence that interruption of the RAS provides more benefit than would simply be expected by the degree of blood pressure reduction alone [5,7,20]. It has been suggested that incomplete blockade of the RAS with ACEi or ARB monotherapy can cause a phenomenon called ‘aldosterone escape’, in which the lack of negative feedback from end-products of the RAS causes a reactive increase in renin and consequent increases in angiotensin I and II concentrations which overwhelm the pharmacological blockade [21]. Dual blockade would therefore be attractive as ACEi and ARB inhibit the RAS at different steps. However, there is continuing uncertainty about the balance of benefits and harms of dual RAS blockade, both in terms of cardiovascular risk and progression of kidney disease. This question will be discussed here in the context of recent evidence from randomized controlled trials.

Relationship between HLA‐DP supertype and survival in childhood acute lymphoblastic leukaemia: evidence for selective loss of immunological control of residual disease?

Abstract: We recently reported that two of six HLA-DP supertypes (DP1-4, 6, 8) were associated with susceptibility (DP2) and resistance (DP1) to childhood acute lymphoblastic leukaemia (ALL). To determine whether DP supertypes are associated with childhood ALL prognosis, we compared treatment outcomes in a cohort (n = 798) of DPB1-typed ALL cases in the UK Medical Research Council UKALL XI trial. No differences in clinical characteristics and outcome between DPB1-typed and untyped (n = 1292) cases suggest no selection bias. Event-free survival (EFS) rates in patients with DP1 and DP3 supertypes were significantly worse than in patients with DP2, DP4, DP6 and DP8 [10-year EFS: 55%; 95% confidence interval (CI) = 49-61%; compared with 64% (61-68%), P = 0.006]. Ten-year EFS in DP1/DP3 heterozygous patients [30% (2-58%)] was significantly worse than in patients with DP1, DP3 or neither allele [56% (50-62%); P = 0.02]. Lack of evidence that DP1 or DP3 are associated with known prognostic factors leads us to suggest that these two supertypes exert an independent effect on prognosis. This may involve abrogation of DP1/3-restricted T-cell control of residual disease due to selective effects of chemotherapy. Further studies of HLA supertypes in relation to outcome in recent childhood ALL trials may resolve this question.

Cytogenetics of Long-Term Survivors of ETV6-RUNX1 Fusion Positive Acute Lymphoblastic Leukemia

Abstract: This study describes the cytogenetics of 33 children with ETV6-RUNX1 positive acute lymphoblastic leukemia (ALL) who had been in continuous complete remission for a minimum of 8.8 years [median event-free survival (EFS) 10.9 years]. The results were compared with a published series of 16 fusion positive patients treated on the same childhood ALL trial, who had relapsed (median EFS, 2.3 years). Interphase fluorescence in situ hybridization (FISH) at diagnosis showed deletion of the second ETV6 signal from all fusion positive cells in 45% of the long-term survivors but in none of the relapsed patients, whereas patients with mixed populations with retained or lost second signals were more frequent among those who had relapsed (69%) than the long-term survivors (21%). Interphase populations with two fusion signals in 18% of the long-term survivors and 31% of relapsed patients were smaller in the long-term survivors (median, 4% of total cells) than in the relapsed patients (median, 84%). The additional copy of chromosome 21 in 30% of long-term survivors and in 69% of relapsed patients was a derived chromosome 21 in 20% and 55% of patients, respectively. Metaphase FISH for 26 long-term survivors and 15 relapsed patients revealed complex karyotypes in both groups. Variant translocations involved different chromosome arms between the long-term survivors and relapsed patients. It appears that the two groups have some distinguishing cytogenetic features at the time of diagnosis, which may provide pointers to relapse that are worthy of more detailed study.

Preventing premature mortality in chronic diseases for South Asians in the UK and beyond

Abstract: Whathaschangedinourunderstand-ing since ethnic disparities in coronary diseasemortalitywereinitiallyhighlighted?Wegivesomepast and future pointers in this field by citingexamples in the largest ethnic minority group inthe UK – people of SouthAsian origin.Biological differences are often first sought intrying to explain ethnic differences in diseasepatterns. The higher prevalence of diabetes inSouthAsians (predominately comprising peoplefrom India, Bangladesh, Pakistan and Sri Lanka)has been long known, and was thought to be themain driver behind the higher rates of coronaryheart disease mortality seen in this populationwhen compared to the majority indigenouspopulations in the developed societies to whichSouth Asians migrate to. Theories to explainthis have historically revolved around insulinresistance.

Changing strategies in the management of acute myocardial infarction in modern China

Abstract: Summary Ischaemic heart disease (IHD) is a common condition in China, accounting for more than 700,000 deaths each year mainly due to acute myocardial infarction (MI). Currently there is no nationally representative registry in China to provide data about the epidemiology, clinical management and prognosis of patients with MI. The present review has used information from a few large nationwide randomised trials and some small regional registries to assess the patterns of management of MI in China. As in many other countries, the management of acute MI in China has undergone a significant transformation during recent decades, due chiefly to an evidence-based approach to cardiovascular medicine. Antiplatelet therapy is now routinely given to almost all patients admitted with acute MI, using not only aspirin but increasingly combining it with clopidogrel. The overall use of reperfusion therapy is also consistent with that reported in Western populations, even though primary PCI is much less frequently used and the type of fibrinolytic agents commonly used may be less optimal in terms of the achieved patency rate of the infarct related artery. Anticoagulant therapy and ACE inhibitors are also used routinely in hospital, with about three-quarters of patients receiving such treatments consistently across different types of hospitals or regions. The use of beta-blocker therapy for acute MI in China has conventionally involved oral agents with little use of initial intravenous regimens, and this approach seems adequate for most patients with acute MI given the findings of the large COMMIT/CCS-2 trial in China. As a result of improved treatments, the hospital mortality for acute MI has declined significantly since the early 1990s. Despite a significant improvement in the general care of MI, there is still substantial under-, over- and inappropriate treatment of many patients in China. Further improvements, especially with respect to long-term management after MI, will rely not only on better implementation of the many established cost-effective treatments but also on improvements in the medical care system and more active engagement of the medical profession to improve risk factor management, such as smoking cessation.