query: Taxation of sugar-sweetened beverages reduced the incidence rate of type II diabetes in India.

title: Averting Obesity and Type 2 Diabetes in India through Sugar-Sweetened Beverage Taxation: An Economic-Epidemiologic Modeling Study

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BACKGROUND Taxing sugar-sweetened beverages (SSBs) has been proposed in high-income countries to reduce obesity and type 2 diabetes. We sought to estimate the potential health effects of such a fiscal strategy in the middle-income country of India, where there is heterogeneity in SSB consumption, patterns of substitution between SSBs and other beverages after tax increases, and vast differences in chronic disease risk within the population.
 METHODS AND FINDINGS Using consumption and price variations data from a nationally representative survey of 100,855 Indian households, we first calculated how changes in SSB price alter per capita consumption of SSBs and substitution with other beverages. We then incorporated SSB sales trends, body mass index (BMI), and diabetes incidence data stratified by age, sex, income, and urban/rural residence into a validated microsimulation of caloric consumption, glycemic load, overweight/obesity prevalence, and type 2 diabetes incidence among Indian subpopulations facing a 20% SSB excise tax. The 20% SSB tax was anticipated to reduce overweight and obesity prevalence by 3.0% (95% CI 1.6%-5.9%) and type 2 diabetes incidence by 1.6% (95% CI 1.2%-1.9%) among various Indian subpopulations over the period 2014-2023, if SSB consumption continued to increase linearly in accordance with secular trends. However, acceleration in SSB consumption trends consistent with industry marketing models would be expected to increase the impact efficacy of taxation, averting 4.2% of prevalent overweight/obesity (95% CI 2.5-10.0%) and 2.5% (95% CI 1.0-2.8%) of incident type 2 diabetes from 2014-2023. Given current consumption and BMI distributions, our results suggest the largest relative effect would be expected among young rural men, refuting our a priori hypothesis that urban populations would be isolated beneficiaries of SSB taxation. Key limitations of this estimation approach include the assumption that consumer expenditure behavior from prior years, captured in price elasticities, will reflect future behavior among consumers, and potential underreporting of consumption in dietary recall data used to inform our calculations.
 CONCLUSION Sustained SSB taxation at a high tax rate could mitigate rising obesity and type 2 diabetes in India among both urban and rural subpopulations.

title: Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women.

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CONTEXT Sugar-sweetened beverages like soft drinks and fruit punches contain large amounts of readily absorbable sugars and may contribute to weight gain and an increased risk of type 2 diabetes, but these relationships have been minimally addressed in adults.
 OBJECTIVE To examine the association between consumption of sugar-sweetened beverages and weight change and risk of type 2 diabetes in women.
 DESIGN, SETTING, AND PARTICIPANTS Prospective cohort analyses conducted from 1991 to 1999 among women in the Nurses' Health Study II. The diabetes analysis included 91,249 women free of diabetes and other major chronic diseases at baseline in 1991. The weight change analysis included 51,603 women for whom complete dietary information and body weight were ascertained in 1991, 1995, and 1999. We identified 741 incident cases of confirmed type 2 diabetes during 716,300 person-years of follow-up.
 MAIN OUTCOME MEASURES Weight gain and incidence of type 2 diabetes.
 RESULTS Those with stable consumption patterns had no difference in weight gain, but weight gain over a 4-year period was highest among women who increased their sugar-sweetened soft drink consumption from 1 or fewer drinks per week to 1 or more drinks per day (multivariate-adjusted means, 4.69 kg for 1991 to 1995 and 4.20 kg for 1995 to 1999) and was smallest among women who decreased their intake (1.34 and 0.15 kg for the 2 periods, respectively) after adjusting for lifestyle and dietary confounders. Increased consumption of fruit punch was also associated with greater weight gain compared with decreased consumption. After adjustment for potential confounders, women consuming 1 or more sugar-sweetened soft drinks per day had a relative risk [RR] of type 2 diabetes of 1.83 (95% confidence interval [CI], 1.42-2.36; P<.001 for trend) compared with those who consumed less than 1 of these beverages per month. Similarly, consumption of fruit punch was associated with increased diabetes risk (RR for > or =1 drink per day compared with <1 drink per month, 2.00; 95% CI, 1.33-3.03; P =.001).
 CONCLUSION Higher consumption of sugar-sweetened beverages is associated with a greater magnitude of weight gain and an increased risk for development of type 2 diabetes in women, possibly by providing excessive calories and large amounts of rapidly absorbable sugars.

title: Trends in sugar-sweetened beverage consumption among youth and adults in the United States: 1999-2010.

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BACKGROUND Reducing sugar-sweetened beverage (SSB) consumption is a recommended strategy to promote optimal health.
 OBJECTIVE The objective was to describe trends in SSB consumption among youth and adults in the United States.
 DESIGN We analyzed energy intake from SSBs among 22,367 youth aged 2-19 y and 29,133 adults aged ≥20 y who participated in a 24-h dietary recall as part of NHANES, a nationally representative sample of the US population with a cross-sectional design, between 1999 and 2010. SSBs included soda, fruit drinks, sports and energy drinks, sweetened coffee and tea, and other sweetened beverages. Patterns of SSB consumption, including location of consumption and meal occasion associated with consumption, were also examined.
 RESULTS In 2009-2010, youth consumed a mean (±SE) of 155 ± 7 kcal/d from SSBs, and adults consumed an age-adjusted mean (±SE) of 151 ± 5 kcal/d from SSBs--a decrease from 1999 to 2000 of 68 kcal/d and 45 kcal/d, respectively (P-trend < 0.001 for each). In 2009-2010, SSBs contributed 8.0% ± 0.4% and 6.9% ± 0.2% of daily energy intake among youth and adults, respectively, which reflected a decrease compared with 1999-2000 (P-trend < 0.001 for both). Decreases in SSB consumption, both in the home and away from home and also with both meals and snacks, occurred over the 12-y study duration (P-trend < 0.01 for each).
 CONCLUSION A decrease in SSB consumption among youth and adults in the United States was observed between 1999 and 2010.

title: Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis.

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BACKGROUND The relation between sugar-sweetened beverages (SSBs) and body weight remains controversial.
 OBJECTIVE We conducted a systematic review and meta-analysis to summarize the evidence in children and adults.
 DESIGN We searched PubMed, EMBASE, and Cochrane databases through March 2013 for prospective cohort studies and randomized controlled trials (RCTs) that evaluated the SSB-weight relation. Separate meta-analyses were conducted in children and adults and for cohorts and RCTs by using random- and fixed-effects models.
 RESULTS Thirty-two original articles were included in our meta-analyses: 20 in children (15 cohort studies, n = 25,745; 5 trials, n = 2772) and 12 in adults (7 cohort studies, n = 174,252; 5 trials, n = 292). In cohort studies, one daily serving increment of SSBs was associated with a 0.06 (95% CI: 0.02, 0.10) and 0.05 (95% CI: 0.03, 0.07)-unit increase in BMI in children and 0.22 kg (95% CI: 0.09, 0.34 kg) and 0.12 kg (95% CI: 0.10, 0.14 kg) weight gain in adults over 1 y in random- and fixed-effects models, respectively. RCTs in children showed reductions in BMI gain when SSBs were reduced [random and fixed effects: -0.17 (95% CI: -0.39, 0.05) and -0.12 (95% CI: -0.22, -0.2)], whereas RCTs in adults showed increases in body weight when SSBs were added (random and fixed effects: 0.85 kg; 95% CI: 0.50, 1.20 kg). Sensitivity analyses of RCTs in children showed more pronounced benefits in preventing weight gain in SSB substitution trials (compared with school-based educational programs) and among overweight children (compared with normal-weight children).
 CONCLUSION Our systematic review and meta-analysis of prospective cohort studies and RCTs provides evidence that SSB consumption promotes weight gain in children and adults.

title: Detection of sweet and umami taste in the absence of taste receptor T1r3.

text: The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.

title: The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type II diabetes mellitus

text: Abstract Evidence obtained in the 1990's strongly supports the notion that glycaemic control is important not only in Type I (insulin-dependent), but also in Type II (non-insulin-dependent) diabetes mellitus. Although measurement of HbA1c is the standard for assessing the effect of glucose control in the occurrence and prevention of diabetic sequelae, more recent evidence indicates that other glucose parameters are also important. Postchallenge and postprandial hyperglycaemic peaks seem to be prospective determinants of vascular damage in early Type II diabetes. Currently, there is no overall accepted standard approach for the pharmacological management of Type II diabetes. The United Kingdom Prospective Diabetes Study has shown that reaching a near-normal glycaemic target is critically important and the pharmacotherapy of this progressive disease is difficult. Loss of endogenous insulin secretion has been substantiated to cause the progression of Type II diabetes in the United Kingdom Prospective Diabetes Study. Early insulinization, however, was not advantageous over other forms of therapy. The advent of polypharmacy in recent years has greatly strengthened the treatment of this disease. This synergy has been extended of late with the development of early-phase insulin secretion agents. Two such agents, nateglinide and repaglinide, can be used to reduce mealtime glucose excursions and HbA1c as monotherapy, and in combination with metformin; their antidiabetic potential is similar to the combination treatment with glibenclamide and metformin. Additional substantiation of their long-term effect on improving life expectancy and reducing diabetic complications in Type II diabetic patients is now required.

title: Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1.

text: Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express alpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from alpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.

title: Peroxisome proliferator-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease.

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BACKGROUND Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism. Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of the peroxisome proliferator-activated receptor ligand bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period.
 METHODS AND RESULTS The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). The patients received either 400 mg bezafibrate retard (156 patients) or placebo (147 patients) once a day. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. During follow-up, development of new-onset diabetes was recorded in 146 patients: in 80 (54.4%) from the placebo group and 66 (42.3%) from the bezafibrate group (P=0.04). The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo: 4.6+/-2.3 versus 3.8+/-2.6 years (P=0.004). Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development (hazard ratio, 0.70; 95% CI, 0.49 to 0.99). Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level (hazard ratio, 1.22; 95% CI 1.0 to 1.51) and body mass index (hazard ratio, 1.10; 95% CI, 1.05 to 1.16).
 CONCLUSIONS Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination of bezafibrate with other recommended drugs for secondary prevention (statins and ACE inhibitors) would be as efficacious as suggested by our results remains to be determined.

title: Metabolic syndrome as a risk factor for diabetes.

text: The metabolic syndrome was initially described as an insulin-resistance syndrome characterized by the clustering of metabolic traits such as high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, abdominal obesity and different degrees of impaired glucose regulation. Although different definitions have been developed by various consensus groups, epidemiological studies demonstrate that they all associate the metabolic syndrome with a similar cardiometabolic risk, which is high for diabetes (ranging between three- and 20-fold), depending on the number of components and the inclusion of impaired fasting glucose, impaired glucose tolerance or both. The latter appear to indicate the failure of the beta cell to produce enough insulin to compensate for the increased demand due to insulin resistance. There is a hyperbolic relationship between insulin production and insulin sensitivity, which can be calculated by the disposition index. When this is altered there is a higher risk of developing Type 2 diabetes. There have been no clinical trials in subjects selected by the diagnosis of metabolic syndrome, but structured lifestyle changes have been tested in people with impaired fasting glucose/impaired glucose tolerance and have been able to reduce incident Type 2 diabetes by almost 50%, as long as a weight loss of at least 5% is achieved. Oral antidiabetic and anti-obesity drugs have also been successful to a lesser degree. Some fibrates have reduced or delayed incident diabetes. Extended-release niacin has a neutral effect and statins are controversial. ACE inhibitors and ARBs are the antihypertensive agents least associated with incident diabetes.

title: Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System

text: Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future. Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years. While antihypertensive agents such as diuretics or β-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral in most studies. Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the β cells. Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3–6 years, compared with a thiazide diuretic, β-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or β1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis. These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14–34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes.

title: Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies

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OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes.
 DESIGN Prospective longitudinal cohort study.
 SETTING Health professionals in the United States.
 PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies.
 MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires.
 RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts).
 CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.

title: A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening.

text: Cervix and Breast cancers are the most common cancers among women worldwide and extract a large toll in developing countries. In May 1998, supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started a cluster-randomized, controlled, screening-trial for cervix and breast cancer using trained primary health workers to provide health-education, visual-inspection of cervix (with 4% acetic acid-VIA) and clinical breast examination (CBE) in the screening arm, and only health education in the control arm. Four rounds of screening at 2-year intervals will be followed by 8 years of monitoring for incidence and mortality from cervix and breast cancers. The methodology and interim results after three rounds of screening are presented here. Good randomization was achieved between the screening (n = 75360) and control arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition; Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completion rate; Improving case fatality ratios. The ever-screened and never-screened participants in the screening arm show significant differences with reference to the variables religion, language, age, education, occupation, income and health-seeking behavior for gynecological and breast-related complaints. During the same period, in the control arm we see excellent participation rate for health education; Low attrition and a good number of symptomatic referrals for both cervix and breast.

title: A new look at the heart in diabetes mellitus: from ailing to failing

text: This review discusses some of the mechanisms inherent in diabetes that predispose patients to increased cardiac morbidity and mortality. Single photon emission computerized tomography or photon emission tomography with radioactive labeled analogues of norepinephrine have shown that cardiac sympathetic dysfunction and incompetence are early and also late abnormalities in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus. Furthermore, myocardial blood flow assessment with photon emission tomography has shown that in patients without myocardial perfusion deficits, endothelial-dependent vasodilatation is severely reduced in relation to cardiac sympathetic dysfunction. In addition, signs of endothelial activation have also been found early in patients with Type I and Type II diabetes in whom vascular disease has not been clinically detected. This activation in conjunction with glycaemic control is important in determining macrovascular mortality. Cardiac sympathetic dysfunction is partially restored to normal with near normalisation of glycaemia. Interpretations. Recently unrecognized “subtle” changes predispose the heart to failure, after ischaemia-induced remodelling, and arteriosclerotic plaques to instability and rupture. These changes act in conjunction with effects, driven by hyperglycaemia and diabetes, on the endothelium of large blood vessels, e. g. on nitric oxide release or on protein kinase-C β activation. Meticulous glucose control early on and rapid recompensation of hyperglycaemia in patients with acute coronary syndrome are part of a successful intensive multifactorial approach to prevent the heart in diabetes converting from ailing to failing. [Diabetologia (2000) 43: 1455–1469]

title: Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.

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CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available.
 OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD.
 DESIGN Prospective cohort study.
 SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6.
 MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria.
 RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58).
 CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.

title: Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study.

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OBJECTIVE Hyperinsulinemia may promote mammary carcinogenesis. Insulin resistance has been linked to an increased risk of breast cancer and is also characteristic of type 2 diabetes. We prospectively evaluated the association between type 2 diabetes and invasive breast cancer incidence in the Nurses' Health Study.    RESEARCH DESIGN AND METHODS A total of 116,488 female nurses who were 30-55 years old and free of cancer in 1976 were followed through 1996 for the occurrence of type 2 diabetes and through 1998 for incident invasive breast cancer, verified by medical records and pathology reports.
 RESULTS During 2.3 million person-years of follow-up, we identified 6,220 women with type 2 diabetes and 5,189 incident cases of invasive breast cancer. Women with type 2 diabetes had a modestly elevated incidence of breast cancer (hazard ratio [HR] = 1.17; 95% CI 1.01-1.35) compared with women without diabetes, independent of age, obesity, family history of breast cancer, history of benign breast disease, reproductive factors, physical activity, and alcohol consumption. This association was apparent among postmenopausal women (1.16; 0.98-1.62) but not premenopausal women (0.83; 0.48-1.42). The association was predominant among women with estrogen receptor-positive breast cancer (1.22; 1.01-1.47).
 CONCLUSIONS Women with type 2 diabetes may have a slightly increased risk of breast cancer.

title: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.

text: Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of beta-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.

title: Long term pharmacotherapy for obesity and overweight: updated meta-analysis.

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OBJECTIVE To summarise the long term efficacy of anti-obesity drugs in reducing weight and improving health status.
 DESIGN Updated meta-analysis of randomised trials.
 DATA SOURCES Medline, Embase, the Cochrane controlled trials register, the Current Science meta-register of controlled trials, and reference lists of identified articles. All data sources were searched from December 2002 (end date of last search) to December 2006.    STUDIES REVIEWED Double blind randomised placebo controlled trials of approved anti-obesity drugs used in adults (age over 18) for one year or longer.
 RESULTS 30 trials of one to four years' duration met the inclusion criteria: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623), and four rimonabant (n=6365). Of these, 14 trials were new and 16 had previously been identified. Attrition rates averaged 30-40%. Compared with placebo, orlistat reduced weight by 2.9 kg (95% confidence interval 2.5 kg to 3.2 kg), sibutramine by 4.2 kg (3.6 kg to 4.7 kg), and rimonabant by 4.7 kg (4.1 kg to 5.3 kg). Patients receiving active drug treatment were significantly more likely to achieve 5% and 10% weight loss thresholds. Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein. Sibutramine improved [corrected] concentrations of high density lipoprotein cholesterol and triglycerides [corrected] Rimonabant improved concentrations of high density lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but increased the risk of mood disorders.
 CONCLUSIONS Orlistat, sibutramine, and rimonabant modestly reduce weight, have differing effects on cardiovascular risk profiles, and have specific adverse effects.

title: Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association.

text: Angiotensin converting enzyme (ACE) inhibitors are now one of the most frequently used classes of antihypertensive drugs. Beyond their utility in the management of hypertension, their use has been extended to the long-term management of patients with congestive heart failure (CHF), as well as diabetic and nondiabetic nephropathies. Although ACE inhibitor therapy usually improves renal blood flow (RBF) and sodium excretion rates in CHF and reduces the rate of progressive renal injury in chronic renal disease, its use can also be associated with a syndrome of “functional renal insufficiency” and/or hyperkalemia. This form of acute renal failure (ARF) most commonly develops shortly after initiation of ACE inhibitor therapy but can be observed after months or years of therapy, even in the absence of prior ill effects. ARF is most likely to occur when renal perfusion pressure cannot be sustained because of substantial decreases in mean arterial pressure (MAP) or when glomerular filtration rate (GFR) is highly angiotensin II (Ang II) dependent. Conditions that predict an adverse hemodynamic effect of ACE inhibitors in patients with CHF are preexisting hypotension and low cardiac filling pressures. The GFR is especially dependent on Ang II during extracellular fluid (ECF) volume depletion, high-grade bilateral renal artery stenosis, or stenosis of a dominant or single kidney, as in a renal transplant recipient. Understanding the pathophysiological mechanisms and the common risk factors for ACE inhibitor–induced functional ARF is critical, because preventive strategies for ARF exist, and if effectively used, they may permit use of these compounds in a less restricted fashion.   Under normal physiological conditions, renal autoregulation adjusts renal vascular resistance, so that RBF and GFR remain constant over a wide range of MAPs.1 The intrinsic renal autoregulation mechanism is adjusted by Ang II and the sympathetic nervous system. When renal perfusion pressure falls (as in …

title: Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.

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CONTEXT Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes.
 OBJECTIVE To determine whether elevated plasma levels of biomarkers reflecting endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1]; and vascular cell adhesion molecule 1 [VCAM-1]) predict development of type 2 diabetes in initially nondiabetic women.
 DESIGN AND SETTING Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in 1976.
 PARTICIPANTS Of 121 700 women initially enrolled, 32 826 provided blood samples in 1989-1990; of those free of diabetes, cardiovascular disease, or cancer at baseline, 737 developed incident diabetes by 2000. Controls (n = 785) were selected according to matched age, fasting status, and race.
 MAIN OUTCOME MEASURE Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-1, and VCAM-1.
 RESULTS Baseline median levels of the biomarkers were significantly higher among cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs 247.0 ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values < or =.004]). Elevated E-selectin and ICAM-1 levels predicted incident diabetes in logistic regression models conditioned on matching criteria and adjusted for body mass index (BMI), family history of diabetes, smoking, diet score, alcohol intake, activity index, and postmenopausal hormone use. The adjusted relative risks for incident diabetes in the top quintile vs the bottom quintiles were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for ICAM-1 (95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment for waist circumference instead of BMI or further adjustment for baseline levels of C-reactive protein, fasting insulin, and hemoglobin A(1c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations.
 CONCLUSION Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.

title: Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates.

text:
CONTEXT Ghrelin is an orexigenic hormone that can increase body weight. Its circulating levels increase before meals and are suppressed after food ingestion. Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets.
 OBJECTIVE We sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins.
 DESIGN This was a randomized, within-subjects cross-over study.
 SETTING The study was conducted at a University Clinical Research Center.
 PARTICIPANTS There were 16 healthy human subjects included in the study.
 INTERVENTIONS Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided.
 MAIN OUTCOME MEASURES The magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined.
 RESULTS All beverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone.
 CONCLUSIONS These findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.


query: Ten percent (10%) of kidney cancers in the UK are attributable to excess weight.

title: Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults

text:
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers.
 METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects.
 FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI.
 INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups.
 FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.

title: Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study

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BACKGROUND Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.
 METHODS We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption).
 FINDINGS After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing).
 INTERPRETATION Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.
 FUNDING Cancer Research UK and the UK Medical Research Council.

title: Ten years' experience with alendronate for osteoporosis in postmenopausal women.

text:
BACKGROUND Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years.
 METHODS The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study.
 RESULTS Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit.
 CONCLUSIONS The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.

title: Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole

text: Objective:In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.Design and Measurement:C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg−1 body weight), alone or with APAP (30 mg kg−1 body weight) or THII (4.5 mg kg−1 body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined. Results:OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O2 uptake and H2O2 production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.Conclusions:We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.

title: Cancer survival increases in Europe, but international differences remain wide.

text: The EUROCARE project analysed cancer survival data from 45 population-based cancer registries in 17 European countries, revealing wide international differences in cancer survival. We calculated 5-year relative survival for 1836287 patients diagnosed with one of 13 cancers during the period 1978-1989. The data, from 20 cancer registries in 13 countries, were grouped into four regions: Finland, Sweden, Iceland (Northern Europe); Denmark, England and Scotland (UK and Denmark); France, The Netherlands, Germany, Italy and Switzerland (Western Europe); Estonia and Poland (Eastern Europe), and broken down into four periods (1978-1980, 1981-1983, 1984-1986, 1987-1989). For each cancer, mean European and regional survival was estimated as the weighted mean of 5-year relative survival in each country. Survival increased with time for all tumours, particularly for cancers of testis (12% increase, i.e. from 79.9 to 91.9%), breast, large bowel, skin melanoma (approximately 9-10%), and lymphomas (approximately 7%). For most solid tumours, survival was highest in Northern Europe and lowest in Eastern Europe, and also low in the UK and Denmark. Regional variation was less marked for the lymphomas. Survival improved more in Western than Northern Europe, and the differences between these regions fell for bowel cancer (from 8.0% for those diagnosed in 1978-1980 to 2% for those diagnosed in 1987-1989), breast cancer (from 7.4% to 3.9%), skin melanoma (from 13.4% to 11.0%) and Hodgkin's disease (from 7.2 to 0.6%). For potentially curable malignancies such as Hodgkin's disease, large bowel, breast and testicular cancers, there were substantial increases in survival, suggesting an earlier diagnosis and more effective treatment. The persisting regional differences suggest there are corresponding differences in the availability of diagnostic and therapeutic facilities, and in the effectiveness of healthcare systems.

title: Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia.

text: Weight loss in cancer cachexia is attributable to decreased food intake and/or enhanced energy expenditure. We investigated the roles of the uncoupling proteins (UCPs) UCPI, -2, and -3 in a murine model of cachexia, the MAC16 adenocarcinoma. Weight fell to 24% below that of non-tumor-bearing controls (P < 0.01) 18 days after MAC16 inoculation, with significant reductions in fat-pad mass (-67%; P < 0.01) and muscle mass (-20%; P < 0.01). Food intake was 26-60% lower (P < 0.01) than in controls on days 17-18. Non-tumor-bearing mice, pair-fed to match MAC16-induced hypophagia, showed less weight loss (10% below controls, P < 0.01; 16% above MAC-16, P < 0.01) and smaller decreases in fat-pad mass (21% below controls, P < 0.01). Core temperature in MAC16 mice was significantly lower (-2.4 degrees C, P < 0.01) than in controls, and pair-feeding had no effect. MAC16 mice showed significantly higher UCP1 mRNA levels in brown adipose tissue (BAT) than in controls (+63%, P < 0.01), and pair-feeding had no effect. UCP2 and -3 expression in BAT did not differ significantly between groups. By contrast, UCP2 mRNA levels in skeletal muscle were comparably increased in both MAC16 and pair-fed groups (respectively, 183 and 163% above controls; both, P < 0.05), with no significant difference between these two groups. Similarly, UCP3 mRNA was significantly higher than controls in both MAC16 (+163%, P < 0.05) and pair-fed (+253%, P < 0.01) groups, with no significant difference between the two experimental groups. Overexpression of UCP1 in BAT in MAC16-bearing mice may be an adaptive response to hypothermia, which is apparently induced by tumor products; increased thermogenesis in BAT could increase total energy expenditure and, thus, contribute to tissue wasting. Increased UCP2 and -3 expression in muscle are both attributable to reduced food intake and may be involved in lipid utilization during lipolysis in MAC16-induced cachexia.

title: Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study

text:
BACKGROUND Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women.
 METHODS AND FINDINGS We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44-0.74) for total mortality, 0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54-1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths.
 CONCLUSIONS In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake-was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention. Please see later in the article for the Editors' Summary.

title: Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial.

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BACKGROUND Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up.
 METHODS Women aged 39-41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151.
 FINDINGS Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8-18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74-1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58-0·97) but not thereafter (RR 1·02, 0·80-1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93-1·04).
 INTERPRETATION Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40-49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis.
 FUNDING National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.

title: Predictors of mammographic density: insights gained from a novel regression analysis of a twin study.

text: Understanding which factors influence mammographically dense and nondense areas is important because percent mammographic density adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs ages 40 to 70 years. We used a novel regression modeling approach in which each twin's measure of dense and nondense area was regressed against one or both of the twin's and co-twin's covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin's covariates can be evaluated for consistency with causal and/or other models. By causal, we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual's weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures, which in absolute log cm(2)/kg was thrice stronger for nondense than dense area. After adjusting for weight, later age at menarche, and greater height were associated with greater dense and lesser nondense areas in a manner inconsistent with causality. The associations of dense and nondense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and percent mammographic density and possibly breast cancer risk.

title: Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries.

text:
OBJECTIVES To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures.
 DESIGN Multinational retrospective cohort study of cancer mortality.
 SETTING Cohorts of workers in the nuclear industry in 15 countries.
 PARTICIPANTS 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years.
 MAIN OUTCOME MEASUREMENTS Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities.
 RESULTS The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation.
 CONCLUSIONS These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

title: Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.

text:
BACKGROUND In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk of death from cardiac causes.
 METHODS Levels of C-reactive protein and fibrinogen at enrollment and the maximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patients included in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. The patients were followed for a mean of 37.0 months (range, 1.6 to 50.6).
 RESULTS During follow-up, 1.2 percent of the 173 patients with maximal blood troponin T levels of less than 0.06 microg per liter died of cardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 microg per liter and 15.4 percent of the 377 patients with levels of at least 0.60 microg per liter (P=0.007 and P=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patients with blood C-reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of 2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P=0.29 and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314 patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levels of 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004 and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of death from cardiac causes.
 CONCLUSIONS In unstable coronary artery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of death from cardiac causes. These markers are independent risk factors, and their effects are additive with respect to each other and other clinical indicators of risk.

title: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

text:
BACKGROUND For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years.
 METHODS In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633.
 FINDINGS Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%).
 INTERPRETATION For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.
 FUNDING Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

title: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: A 10-year cohort analysis

text: As more is learned about the development of cervical cancer, the value of annual Pap smear screening for all women is being questioned. This study was conducted to investigate whether women at higher risk for the development of cervical cancer could be identified by testing for the presence of human papillomavirus (HPV) in the cervical smear. These women could be followed annually, and the interval between screening Pap smears for women at lower risk could be increased. Study participants were women enrolled in the Kaiser Permanente healthcare plan in Portland, Oregon, who underwent annual Pap smear screening between April 1989, and November 1990. More than 20,000 women (20,810 of 23,702) had satisfactory cervical smears with sufficient samples for HPV testing, which was conducted using a polymerase chain reaction-based method with MYO9/11 primers. Most women (83.6%) had at least one follow-up smear during the study period; however, women with atypical squamous cells (ASC) or worse had more smears than women with normal results (mean, 4.4 vs. 3.3). Follow-up was conducted more or less annually for a total period of 122 months. HPV results were not used in deciding patient management. Ninety-six percent of the 20,810 baseline Pap smears were diagnosed as negative (N = 20,156). Thirteen percent of these patients tested positive for HPV. The baseline smears of 654 of the 20,810 women (3.1%) were classified as ASC or worse. Of these 654 smears, 417 (63.8%) were positive for HPV. One hundred seventy-eight women had a cytologic diagnosis of a low-grade squamous intraepithelial lesion or worse; of these, 143 (80.3%) tested positive for HPV. During the 10 years of follow-up, 171 patients developed cervical intraepithelial neoplasia (CIN) 3 or cervical cancer. The baseline smear was normal in 112 of these women and ASC or worse in 59 (34.5%). Only half (49.2%) of the 58 patients diagnosed within the first 45 months of follow-up had an abnormal baseline smear. During this first 45 months, 7.85% of the women whose initial Pap test was at least ASC were diagnosed with CIN 3 or cancer. The cumulative incidence at 10 years of follow-up was 10.2%. Sixty of the 171 women with CIN 3 or cervical cancer had a negative baseline HPV test. Of the 118 women who were diagnosed during the first 45 months of follow-up, 89 (79.4%) were HPV positive initially. The cumulative incidence of CIN 3 or cancer among the group with a positive baseline HPV test was 6.92% over 10 years but only 1.73% at 45 months. The risk of developing CIN 3 or cancer remained elevated throughout the study in those women with a positive baseline HPV test. The predictive ability of the baseline Pap smear diminished as the follow-up interval increased. Fifteen percent of the patients (N = 3216) had a positive Pap smear, a positive HPV test, or both at the initial examination. One hundred twenty-three (71.9%) were among the 171 women who developed CIN 3 or cancer. Eighty-six percent (102 of 123) of the patients who were diagnosed within the first 45 months were positive with at least one of the screening studies. The cumulative incidence over 45 months for women who had positive HPV testing and/or abnormal Pap smear results was 4.54%. Women with negative results in both screening tests had a cumulative risk of 0.16% for the same period. At 10 years the cumulative risk incidence for these two groups was 6.83% and 0.79%, respectively, yielding a negative predictive value of 99.1% for combined testing.

title: Mortality risk attributable to high and low ambient temperature: a multicountry observational study

text:
BACKGROUND Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures.
 METHODS We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature-mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5th temperature percentiles.
 FINDINGS We analysed 74,225,200 deaths in various periods between 1985 and 2012. In total, 7·71% (95% empirical CI 7·43-7·91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80-90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7·29%, 7·02-7·49) than by heat (0·42%, 0·39-0·44). Extreme cold and hot temperatures were responsible for 0·86% (0·84-0·87) of total mortality.
 INTERPRETATION Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios.
 FUNDING UK Medical Research Council.

title: Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review

text: To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage. MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation. Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9 %). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15 % of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg−1). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95 % confidence interval, 1.09–82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans. Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

title: Cross sectional stature and weight reference curves for the UK, 1990.

text: The current reference curves of stature and weight for the UK were first published in 1966 and have been used ever since despite increasing concern that they may not adequately describe the growth of present day British children. Using current data from seven sources new reference curves have been estimated from birth to 20 years for children in 1990. The great majority of the data are nationally representative. The analysis used Cole's LMS method and has produced efficient estimates of the conventional centiles and gives a good fit to the data. These curves differ from the currently used curves at key ages for both stature and weight. In view of the concerns expressed about the current curves and the differences between them and the new curves, it is proposed that the curves presented here should be adopted as the new UK reference curves.

title: Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.

text:
OBJECTIVE The aim of this study was to investigate whether diabetes and hypertension cause additive effects in the responses to various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained from streptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats (SHR).
 METHODS SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into a lateral tail vein at age 12 weeks. Eight weeks later the kidneys were isolated and perfused via the left renal artery with a physiological salt solution. Renal perfusion pressure was measured continuously. Concentration response curves were plotted for various vasoconstrictor and vasodilator agents.
 RESULTS Both the diabetic and the hypertensive state were associated with an increased wet kidney weight. The contractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) and angiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of the sensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those from normoglycaemic WKY rats. The maximal contractile responses both to PhE and to Ang II were enhanced in kidneys from SHR compared with those in kidneys from their normotensive controls, whereas simultaneously occurring diabetes impaired this sensitization. After precontraction with 3 x 10(-6) mol/l PhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside) vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups of animals.
 CONCLUSION In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, the isolated diabetic state did not influence the vasoconstriction caused by various agonists. However, the enhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetes mellitus. Endothelium-dependent and -independent vasorelaxation in this model was not affected neither by the hypertensive nor by the diabetic state.

title: Birth weight and mammographic density among postmenopausal women in Sweden.

text: Birth weight is a significant predictor of breast cancer risk in adult life and mammary gland mass could be an intermediate stage in this long process. We have studied the association of birth size measurements with mammographic density, a marker of mammary gland mass. For a population-based sample of 893 postmenopausal women without previous cancer in Sweden, we retrieved information on birth size from birth records and their most recent mammography. Film mammograms of the medio-lateral oblique view were digitized and the Cumulus software was used for computer-assisted semi-automated thresholding of mammographic density. Results were analyzed using generalized linear models controlling for possible confounders. Mean percent mammographic density increased when comparing the extreme categories of birth weight (from 15.6% to 18.6%) and head circumference (from 15.5% to 20.4%), and the corresponding linear trends were statistically significant (p values 0.02 and 0.007, respectively). The associations were particularly strong when the cutoff for high versus low mammographic density was set at the relatively high value of 50%. Compared to women weighing 3001-3500 grams at birth, women with birth weights >4000g were at almost 3-fold risk of developing high mammographic density (odds ratio: 2.9, 95% confidence interval 1.1 to 7.9). No association with mammographic density was evident with respect to birth length which, however, is known to be less accurately measured. These results indicate that adult breast density, a powerful predictor of breast cancer risk, has intrauterine roots, as reflected in birth size.

title: Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine.

text:
BACKGROUND Radiographic contrast agents can cause a reduction in renal function that may be due to reactive oxygen species. Whether the reduction can be prevented by the administration of antioxidants is unknown.
 METHODS We prospectively studied 83 patients with chronic renal insufficiency (mean [+/-SD] serum creatinine concentration, 2.4+/-1.3 mg per deciliter [216+/-116 micromol per liter]) who were undergoing computed tomography with a nonionic, low-osmolality contrast agent. Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline.
 RESULTS Ten of the 83 patients (12 percent) had an increase of at least 0.5 mg per deciliter (44 micromol per liter) in the serum creatinine concentration 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidence interval, 0.02 to 0.9). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 2.5+/-1.3 to 2.1+/-1.3 mg per deciliter (220+/-118 to 186+/-112 micromol per liter) 48 hours after the administration of the contrast medium, whereas in the control group, the mean serum creatinine concentration increased nonsignificantly (P=0.18), from 2.4+/-1.3 to 2.6+/-1.5 mg per deciliter (212+/-114 to 226+/-133 micromol per liter) (P<0.001 for the comparison between groups).
 CONCLUSIONS Prophylactic oral administration of the antioxidant acetylcysteine, along with hydration, prevents the reduction in renal function induced by contrast agents in patients with chronic renal insufficiency.

title: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.

text:
BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.
 METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points.
 RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051).
 CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.