This report describes the public health impact of Alzheimer's disease, including incidence and prevalence, mortality rates, costs of care, and the overall impact on caregivers and society. It also examines in detail the financial impact of Alzheimer's on families, including annual costs to families and the difficult decisions families must often make to pay those costs. An estimated 5.4 million Americans have Alzheimer's disease. By mid-century, the number of people living with Alzheimer's disease in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's disease every 66 seconds. By 2050, one new case of Alzheimer's is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2013, official death certificates recorded 84,767 deaths from Alzheimer's disease, making it the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥ 65 years. Between 2000 and 2013, deaths resulting from stroke, heart disease, and prostate cancer decreased 23%, 14%, and 11%, respectively, whereas deaths from Alzheimer's disease increased 71%. The actual number of deaths to which Alzheimer's disease contributes is likely much larger than the number of deaths from Alzheimer's disease recorded on death certificates. In 2016, an estimated 700,000 Americans age ≥ 65 years will die with Alzheimer's disease, and many of them will die because of the complications caused by Alzheimer's disease. In 2015, more than 15 million family members and other unpaid caregivers provided an estimated 18.1 billion hours of care to people with Alzheimer's and other dementias, a contribution valued at more than $221 billion. Average per-person Medicare payments for services to beneficiaries age ≥ 65 years with Alzheimer's disease and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2016 for health care, long-term care and hospice services for people age ≥ 65 years with dementia are estimated to be $236 billion. The costs of Alzheimer's care may place a substantial financial burden on families, who often have to take money out of their retirement savings, cut back on buying food, and reduce their own trips to the doctor. In addition, many family members incorrectly believe that Medicare pays for nursing home care and other types of long-term care. Such findings highlight the need for solutions to prevent dementia-related costs from jeopardizing the health and financial security of the families of people with Alzheimer's and other dementias.

We have examined the discrete species of simian virus 40 (SV40) RNA present very early in infection of monkey cells with wild-type virus, with mutant tsA58 virus, and with the corresponding DNAs to distinguish between two classes of models for control of late transcription: (i) positive control mediated by large-T antigen and (ii) negative control mediated by a repressor protein associated with viral DNA in the virion. Total cytoplasmic or nuclear polyadenylated RNAs from infected cells were denatured with glyoxal, separated by electrophoresis on agarose gels, and transferred to diazobenzyloxymethyl paper. The positions of specific early and late RNA species were determined with region-specific SV40 DNA probes. The technique can detect individual RNAs present at the level of less than one copy per cell. After 9.5 h at 37 degrees C, appreciable amounts of two early RNAs (2.6 kilobases [kb] and 2.9 kb) were present in the cytoplasm of cells infected with wild-type virus or DNA, along with much smaller amounts of two late RNAs, 1.6 kb (16S) and 2.5 kb (19S). The amounts of the late RNAs were reduced, but they were still synthesized in the presence of cytosine arabinoside, an inhibitor of DNA synthesis. In comparable infections with tsA58 virus or DNA at nonpermissive temperature (41 degrees C), substantial amounts of the two early RNAs were again present, but the two late RNAs could not be detected. However, small amounts of the late RNAs were found when infections with tsA58 virus or DNA were prolonged to 30 h at 41 degrees C. These results are not consistent with negative control of late transcription through the action of a repressor and, taken together with other data, suggest that T antigen has an active role in late RNA synthesis. Specific early and late viral RNAs were also detected in the nuclear poly(A)(+) fractions and were similar in size to the RNA species found in the cytoplasmic polyadenylated fractions. The late nuclear RNAs (1.8 and 2.9 kb) were significantly larger than the late cytoplasmic species, possibly because they are precursors. The 2.6- and 2.9-kb early RNAs found in the cytoplasm are probably the messengers for large-T and small-t antigens, respectively.

Differential DNA methylation is important for the epigenetic regulation of gene expression. Allele-specific methylation of the inactive X chromosome has been demonstrated at promoter CpG islands, but the overall pattern of methylation on the active X(Xa) and inactive X (Xi) chromosomes is unknown. We performed allele-specific analysis of more than 1000 informative loci along the human X chromosome. The Xa displays more than two times as much allele-specific methylation as Xi. This methylation is concentrated at gene bodies, affecting multiple neighboring CpGs. Before X inactivation, all of these Xa gene body-methylated sites are biallelically methylated. Thus, a bipartite methylation-demethylation program results in Xa-specific hypomethylation at gene promoters and hypermethylation at gene bodies. These results suggest a relationship between global methylation and expression potentiality.

OBJECTIVE

Our goal was to estimate the prevalence of diabetes mellitus in youth <20 years of age in 2001 in the United States, according to age, gender, race/ethnicity, and diabetes type.

METHODS

The SEARCH for Diabetes in Youth Study is a 6-center observational study conducting population-based ascertainment of physician-diagnosed diabetes in youth. Census-based denominators for 4 geographically based centers and enrollment data for 2 health plan-based centers were used to calculate prevalence. Age-, gender-, and racial/ethnic group-specific prevalence rates were multiplied by US population counts to estimate the total number of US youth with diabetes.

RESULTS

We identified 6379 US youth with diabetes in 2001, in a population of approximately 3.5 million. Crude prevalence was estimated as 1.82 cases per 1000 youth, being much lower for youth 0 to 9 years of age (0.79 cases per 1000 youth) than for those 10 to 19 years of age (2.80 cases per 1000 youth). Non-Hispanic white youth had the highest prevalence (1.06 cases per 1000 youth) in the younger group. Among 10- to 19-year-old youth, black youth (3.22 cases per 1000 youth) and non-Hispanic white youth (3.18 cases per 1000 youth) had the highest rates, followed by American Indian youth (2.28 cases per 1000 youth), Hispanic youth (2.18 cases per 1000 youth), and Asian/Pacific Islander youth (1.34 cases per 1000 youth). Among younger children, type 1 diabetes accounted for>> or = 80% of diabetes; among older youth, the proportion of type 2 diabetes ranged from 6% (0.19 cases per 1000 youth for non-Hispanic white youth) to 76% (1.74 cases per 1000 youth for American Indian youth). We estimated that 154,369 youth had physician-diagnosed diabetes in 2001 in the United States.

CONCLUSIONS

The overall prevalence estimate for diabetes in children and adolescents was approximately 0.18%. Type 2 diabetes was found in all racial/ethnic groups but generally was less common than type 1, except in American Indian youth.

Recalcitrance to saccharification is a major limitation for conversion of lignocellulosic biomass to ethanol. In stems of transgenic alfalfa lines independently downregulated in each of six lignin biosynthetic enzymes, recalcitrance to both acid pretreatment and enzymatic digestion is directly proportional to lignin content. Some transgenics yield nearly twice as much sugar from cell walls as wild-type plants. Lignin modification could bypass the need for acid pretreatment and thereby facilitate bioprocess consolidation.

Until recently, the brain was studied almost exclusively by neuroscientists and the immune system by immunologists, fuelling the notion that these systems represented two isolated entities. However, as more data suggest an important role of the immune system in regulating the progression of brain aging and neurodegenerative disease, it has become clear that the crosstalk between these systems can no longer be ignored and a new interdisciplinary approach is necessary. A central question that emerges is whether immune and inflammatory pathways become hyperactivated with age and promote degeneration or whether insufficient immune responses, which fail to cope with age-related stress, may contribute to disease. We try to explore here the consequences of gain versus loss of function with an emphasis on microglia as sensors and effectors of immune function in the brain, and we discuss the potential role of the peripheral environment in neurodegenerative diseases.

The peak concentration and rate of clearance of neurotransmitter from the synaptic cleft are important determinants of synaptic function, yet the neurotransmitter concentration time course is unknown at synapses in the brain. The time course of free glutamate in the cleft was estimated by kinetic analysis of the displacement of a rapidly dissociating competitive antagonist from N-methyl-D-aspartate (NMDA) receptors during synaptic transmission. Glutamate peaked at 1.1 millimolar and decayed with a time constant of 1.2 milliseconds at cultured hippocampal synapses. This time course implies that transmitter saturates postsynaptic NMDA receptors. However, glutamate dissociates much more rapidly from alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Thus, the time course of free glutamate predicts that dissociation contributes to the decay of the AMPA receptor-mediated postsynaptic current.

In recent years, human and wildlife monitoring studies have identified perfluoroalkyl acids (PFAA) worldwide. This has led to efforts to better understand the hazards that may be inherent in these compounds, as well as the global distribution of the PFAAs. Much attention has focused on understanding the toxicology of the two most widely known PFAAs, perfluorooctanoic acid, and perfluorooctane sulfate. More recently, research was extended to other PFAAs. There has been substantial progress in understanding additional aspects of the toxicology of these compounds, particularly related to the developmental toxicity, immunotoxicity, hepatotoxicity, and the potential modes of action. This review provides an overview of the recent advances in the toxicology and mode of action for PFAAs, and of the monitoring data now available for the environment, wildlife, and humans. Several avenues of research are proposed that would further our understanding of this class of compounds.

BACKGROUND

Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk.

METHODS

NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry.

RESULTS

Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p<0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma.

CONCLUSIONS

The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

Neuroendocrine tumors (NETs) arise in most organs of the body and share many common pathologic features. However, a variety of different organ-specific systems have been developed for nomenclature, grading, and staging of NETs, causing much confusion. This review examines issues in the pathologic assessment of NETs that are common among primaries of different sites. The various systems of nomenclature are compared along with new proposal for grading and staging NETs. Although differences persist, there are many common themes, such as the distinction of well-differentiated (low and intermediate-grade) from poorly differentiated (high-grade) NETs and the significance of proliferative rate in prognostic assessment. A recently published minimum pathology data set is presented to help standardize the information in pathology reports. Although an ultimate goal of standardizing the pathologic classification of all NETs, irrespective of primary site, remains elusive, an understanding of the common themes among the different current systems will permit easier translation of information relevant to prognosis and treatment.

The relative proportion of additive and non-additive variation for complex traits is important in evolutionary biology, medicine, and agriculture. We address a long-standing controversy and paradox about the contribution of non-additive genetic variation, namely that knowledge about biological pathways and gene networks imply that epistasis is important. Yet empirical data across a range of traits and species imply that most genetic variance is additive. We evaluate the evidence from empirical studies of genetic variance components and find that additive variance typically accounts for over half, and often close to 100%, of the total genetic variance. We present new theoretical results, based upon the distribution of allele frequencies under neutral and other population genetic models, that show why this is the case even if there are non-additive effects at the level of gene action. We conclude that interactions at the level of genes are not likely to generate much interaction at the level of variance.

Osteopontin (OPN) is a highly phosphorylated sialoprotein that is a prominent component of the mineralized extracellular matrices of bones and teeth. OPN is characterized by the presence of a polyaspartic acid sequence and sites of Ser/Thr phosphorylation that mediate hydroxyapatite binding, and a highly conserved RGD motif that mediates cell attachment/signaling. Expression of OPN in a variety of tissues indicates a multiplicity of functions that involve one or more of these conserved motifs. While the lack of a clear phenotype in OPN "knockout" mice has not established a definitive role for OPN in any tissue, recent studies have provided some novel and intriguing insights into the versatility of this enigmatic protein in diverse biological events, including developmental processes, wound healing, immunological responses, tumorigenesis, bone resorption, and calcification. The ability of OPN to stimulate cell activity through multiple receptors linked to several interactive signaling pathways can account for much of the functional diversity. In this review, we discuss the structural features of OPN that relate to its function in the formation, remodeling, and maintenance of bones and teeth.

OBJECTIVE

Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain.

METHODS

Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets.

RESULTS

Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients.

CONCLUSIONS

Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Much qualitative research is interview based, and this paper provides an outline of qualitative interview techniques and their application in medical settings. It explains the rationale for these techniques and shows how they can be used to research kinds of questions that are different from those dealt with by quantitative methods. Different types of qualitative interviews are described, and the way in which they differ from clinical consultations is emphasised. Practical guidance for conducting such interviews is given.

"Executive function" is an umbrella term for functions such as planning, working memory, impulse control, inhibition and mental flexibility, as well as for the initiation and monitoring of action. The primacy of executive dysfunction in autism is a topic of much debate, as are recent attempts to examine subtypes of executive function within autism and other neurodevelopmental disorders that are considered to implicate frontal lobe function. This article will review cognitive behavioural studies of planning, mental flexibility and inhibition in autism. It is concluded that more detailed research is needed to fractionate the executive system in autism by assessing a wide range of executive functions as well as their neuroanatomical correlates in the same individuals across the lifespan.

In this review, we describe the current state of knowledge about the biochemistry of mammalian peroxisomes, especially human peroxisomes. The identification and characterization of yeast mutants defective either in the biogenesis of peroxisomes or in one of its metabolic functions, notably fatty acid beta-oxidation, combined with the recognition of a group of genetic diseases in man, wherein these processes are also defective, have provided new insights in all aspects of peroxisomes. As a result of these and other studies, the indispensable role of peroxisomes in multiple metabolic pathways has been clarified, and many of the enzymes involved in these pathways have been characterized, purified, and cloned. One aspect of peroxisomes, which has remained ill defined, is the transport of metabolites across the peroxisomal membrane. Although it is clear that mammalian peroxisomes under in vivo conditions are closed structures, which require the active presence of metabolite transporter proteins, much remains to be learned about the permeability properties of mammalian peroxisomes and the role of the four half ATP-binding cassette (ABC) transporters therein.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in many tissues and are capable of differentiating into several different cell types. Exogenously administered MSCs migrate to damaged tissue sites, where they participate in tissue repair. Their communication with the inflammatory microenvironment is an essential part of this process. In recent years, much has been learned about the cellular and molecular mechanisms of the interaction between MSCs and various participants in inflammation. Depending on their type and intensity, inflammatory stimuli confer on MSCs the ability to suppress the immune response in some cases or to enhance it in others. Here we review the current findings on the immunoregulatory plasticity of MSCs in disease pathogenesis and therapy.

Stress-induced immunological reactions to exercise have stimulated much research into stress immunology and neuroimmunology. It is suggested that exercise can be employed as a model of temporary immunosuppression that occurs after severe physical stress. The exercise-stress model can be easily manipulated experimentally and allows for the study of interactions between the nervous, the endocrine, and the immune systems. This review focuses on mechanisms underlying exercise-induced immune changes such as neuroendocrinological factors including catecholamines, growth hormone, cortisol, beta-endorphin, and sex steroids. The contribution of a metabolic link between skeletal muscles and the lymphoid system is also reviewed. The mechanisms of exercise-associated muscle damage and the initiation of the inflammatory cytokine cascade are discussed. Given that exercise modulates the immune system in healthy individuals, considerations of the clinical ramifications of exercise in the prevention of diseases for which the immune system has a role is of importance. Accordingly, drawing on the experimental, clinical, and epidemiological literature, we address the interactions between exercise and infectious diseases as well as exercise and neoplasia within the context of both aging and nutrition.

Complex networks have been studied intensively for a decade, but research still focuses on the limited case of a single, non-interacting network. Modern systems are coupled together and therefore should be modelled as interdependent networks. A fundamental property of interdependent networks is that failure of nodes in one network may lead to failure of dependent nodes in other networks. This may happen recursively and can lead to a cascade of failures. In fact, a failure of a very small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. A dramatic real-world example of a cascade of failures ('concurrent malfunction') is the electrical blackout that affected much of Italy on 28 September 2003: the shutdown of power stations directly led to the failure of nodes in the Internet communication network, which in turn caused further breakdown of power stations. Here we develop a framework for understanding the robustness of interacting networks subject to such cascading failures. We present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure, which is opposite to how a single network behaves. Our findings highlight the need to consider interdependent network properties in designing robust networks.

OBJECTIVE

The phrase "time is brain" emphasizes that human nervous tissue is rapidly lost as stroke progresses and emergent evaluation and therapy are required. Recent advances in quantitative neurostereology and stroke neuroimaging permit calculation of just how much brain is lost per unit time in acute ischemic stroke.

METHODS

Systematic literature-review identified consensus estimates of number of neurons, synapses, and myelinated fibers in the human forebrain; volume of large vessel, supratentorial ischemic stroke; and interval from onset to completion of large vessel, supratentorial ischemic stroke.

RESULTS

The typical final volume of large vessel, supratentorial ischemic stroke is 54 mL (varied in sensitivity analysis from 19 to 100 mL). The average duration of nonlacunar stroke evolution is 10 hours (range 6 to 18 hours), and the average number of neurons in the human forebrain is 22 billion. In patients experiencing a typical large vessel acute ischemic stroke, 120 million neurons, 830 billion synapses, and 714 km (447 miles) of myelinated fibers are lost each hour. In each minute, 1.9 million neurons, 14 billion synapses, and 12 km (7.5 miles) of myelinated fibers are destroyed. Compared with the normal rate of neuron loss in brain aging, the ischemic brain ages 3.6 years each hour without treatment. Altering single input variables in sensitivity analyses modestly affected the estimated point values but not order of magnitude.

CONCLUSIONS

Quantitative estimates of the pace of neural circuitry loss in human ischemic stroke emphasize the time urgency of stroke care. The typical patient loses 1.9 million neurons each minute in which stroke is untreated.

BACKGROUND

Prevalence of obesity in the United States has increased dramatically in recent decades, but the magnitude of change in cardiovascular disease (CVD) risk factors among the growing proportion of overweight and obese Americans remains unknown.

OBJECTIVE

To examine 40-year trends in CVD risk factors by body mass index (BMI) groups among US adults aged 20 to 74 years.

METHODS

Analysis of 5 cross-sectional, nationally representative surveys: National Health Examination Survey (1960-1962); National Health and Nutrition Examination Survey (NHANES) I (1971-1975), II (1976-1980), and III (1988-1994); and NHANES 1999-2000.

METHODS

Prevalence of high cholesterol level >> or =240 mg/dL >> or =6.2 mmol/L] regardless of treatment), high blood pressure >> or =140/90 mm Hg regardless of treatment), current smoking, and total diabetes (diagnosed and undiagnosed combined) according to BMI group (lean, <25; overweight, 25-29; and obese,>> or =30).

RESULTS

The prevalence of all risk factors except diabetes decreased over time across all BMI groups, with the greatest reductions observed among overweight and obese groups. Compared with obese persons in 1960-1962, obese persons in 1999-2000 had a 21-percentage-point lower prevalence of high cholesterol level (39% in 1960-1962 vs 18% in 1999-2000), an 18-percentage-point lower prevalence of high blood pressure (from 42% to 24%), and a 12-percentage-point lower smoking prevalence (from 32% to 20%). Survey x BMI group interaction terms indicated that compared with the first survey, the prevalence of high cholesterol in the fifth survey had fallen more in obese and overweight persons than in lean persons (P<.05). Survey x BMI changes in blood pressure and smoking were not statistically significant. Changes in risk factors were accompanied by increases in lipid-lowering and antihypertensive medication use, particularly among obese persons. Total diabetes prevalence was stable within BMI groups over time, as nonsignificant 1- to 2-percentage-point increases occurred between 1976-1980 and 1999-2000.

CONCLUSIONS

Except for diabetes, CVD risk factors have declined considerably over the past 40 years in all BMI groups. Although obese persons still have higher risk factor levels than lean persons, the levels of these risk factors are much lower than in previous decades.

We have isolated and characterized a cDNA for a novel Per-Arnt/AhR-Sim basic helix-loop-helix (bHLH-PAS) factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1alpha) and Drosophila trachealess (dTrh) gene product. The HIF1alpha-like factor (HLF) encoded by the isolated cDNA bound the hypoxia-response element (HRE) found in enhancers of genes for erythropoietin, vascular endothelial growth factor (VEGF), and various glycolytic enzymes, and activated transcription of a reporter gene harboring the HRE. Although transcription-activating properties of HLF were very similar to those reported for HIF1alpha, their expression patterns were quite different between the two factors; HLF mRNA was most abundantly expressed in lung, followed by heart, liver, and other various organs under normoxic conditions, whereas HIF1alpha mRNA was ubiquitously expressed at much lower levels. In lung development around parturition, HLF mRNA expression was markedly enhanced, whereas that of HIF1alpha mRNA remained apparently unchanged at a much lower level. Moreover, HLF mRNA expression was closely correlated with that of VEGF mRNA. Whole mount in situ hybridization experiments demonstrated that HLF mRNA was expressed in vascular endothelial cells at the middle stages (9.5 and 10.5 days postcoitus) of mouse embryo development, where HIF1alpha mRNA was almost undetectable. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung.

Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml(-1). This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.

BACKGROUND

Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease.

METHODS

We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS.

RESULTS

Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest).

CONCLUSIONS

Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.