LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3beta-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3beta-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.

OBJECTIVE

To determine the prevalence of people with diabetes who meet hemoglobin A1c (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010.

METHODS

Data were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988-1994, 1999-2002, 2003-2006, and 2007-2010. Participants were 4,926 adults aged ≥ 20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination (n = 1,558 for valid LDL levels). Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins.

RESULTS

In 2007-2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs. These levels of control were significant improvements from 1988 to 1994 (all P < 0.05). Statin use significantly increased between 1988-1994 (4.2%) and 2007-2010 (51.4%, P < 0.01). Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals (P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals (P < 0.02). Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals (P < 0.01). Younger individuals were less likely to meet A1C and LDL goals.

CONCLUSIONS

Despite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups. Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality.

BACKGROUND

Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that depends partially on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown.

RESULTS

Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (n=1957; mean age, 40+/-9 years; 49% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (called the PAT ratio) as the natural logarithm of the ratio of postdeflation to baseline pulse amplitude in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of the PAT ratio to cardiovascular risk factors was strongest in the 90- to 120-second postdeflation interval (overall model R(2)=0.159). In stepwise multivariable linear regression models, male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering treatment were inversely related to PAT ratio, whereas increasing age was positively related to PAT ratio (all P<0.01).

CONCLUSIONS

Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further investigations to define the clinical utility and predictive value of digital pulse amplitude.

BACKGROUND

The intercellular adhesion molecule ICAM-1 mediates adhesion and transmigration of leucocytes to the vascular endothelial wall, a step proposed to be critical in the initiation and progression of atherosclerosis. Whether concentrations of soluble ICAM-1 (sICAM-1) are raised in apparently healthy individuals who later suffer acute myocardial infarction is unknown.

METHODS

We obtained baseline plasma samples from a prospective cohort of 14,916 healthy men enrolled in the Physicians' Health Study. With a nested case-control design, we measured sICAM-1 concentrations for 474 participants who developed a first myocardial infarction, and 474 controls (participants who remained healthy throughout the 9-year follow-up). Cases were matched to controls according to age and smoking status at the time of myocardial infarction.

RESULTS

We found a significant association between increasing concentration of sICAM-1 and risk of future myocardial infarction (p = 0.003), especially among participants with baseline sICAM-1 concentrations in the highest quartile >> 260 ng/mL; relative risk 1.6 [95% Cl 1.1-2.4], p = 0.02). This association was present overall as well as among non-smokers, and persisted after control for lipid and non-lipid risk factors. In multivariate analyses, the risk of future myocardial infarction was 80% higher for participants with baseline sICAM-1 concentrations in the highest quartile (relative risk 1.8 [1.1-2.8], p = 0.02). Similar risk estimates were seen among non-smokers. We found slight but significant correlations between sICAM-1 and fibrinogen, high-density-lipoprotein cholesterol, homocysteine, triglycerides, tissue-type plasminogen-activator antigen, and C-relative protein, but adjustment for these altered the risk little. The risk of myocardial infarction associated with raised concentrations of sICAM-1 seemed to increase with length of follow-up.

CONCLUSIONS

Our data support the hypothesis that cellular mediators of inflammation have a role in atherogenesis and provide a clinical basis to consider antiadhesion therapies as a novel means of cardiovascular disease prevention.

The transmembrane proteins of the tetraspanin superfamily are implicated in a diverse range of biological phenomena, including cell motility, metastasis, cell proliferation and differentiation. The tetraspanins are associated with adhesion receptors of the integrin family and regulate integrin-dependent cell migration. In cells attached to the extracellular matrix, the integrin-tetraspanin adhesion complexes are clustered into a distinct type of adhesion structure at the cell periphery. Various tetraspanins are associated with phosphatidylinositol 4-kinase and protein kinase C isoforms, and they may facilitate assembly of signalling complexes by tethering these enzymes to integrin heterodimers. At the plasma membrane, integrin-tetraspanin signalling complexes are partitioned into specific microdomains proximal to cholesterol-rich lipid rafts. A substantial fraction of tetraspanins colocalise with integrins in various intracellular vesicular compartments. It is proposed that tetraspanins can influence cell migration by one of the following mechanisms: (1) modulation of integrin signalling; (2) compartmentalisation of integrins on the cell surface; or (3) direction of intracellular trafficking and recycling of integrins.

The low density lipoprotein (LDL) receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma LDL, thereby providing cholesterol to cells. Mutations disrupting the function of this receptor produce autosomal dominant familial hypercholesterolemia (FH). Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. To date, 71 mutations in the LDL receptor gene have been characterized at a molecular level. In this report, we describe 79 additional mutations and review the insights that all 150 mutations have provided into the structure/function relationship of the receptor protein and the clinical manifestations of FH.

BACKGROUND

The United States spends considerably more money on health care than the United Kingdom, but whether that translates to better health outcomes is unknown.

OBJECTIVE

To assess the relative heath status of older individuals in England and the United States, especially how their health status varies by important indicators of socioeconomic position.

METHODS

We analyzed representative samples of residents aged 55 to 64 years from both countries using 2002 data from the US Health and Retirement Survey (n = 4386) and the English Longitudinal Study of Aging (n = 3681), which were designed to have directly comparable measures of health, income, and education. This analysis is supplemented by samples of those aged 40 to 70 years from the 1999-2002 waves of National Health and Nutrition Examination Survey (n = 2097) and the 2003 wave of the Health Survey for England (n = 5526). These surveys contain extensive and comparable biological disease markers on respondents, which are used to determine whether differential propensities to report illness can explain these health differences. To ensure that health differences are not solely due to health issues in the black or Latino populations in the United States, the analysis is limited to non-Hispanic whites in both countries.

METHODS

Self-reported prevalence rates of several chronic diseases related to diabetes and heart disease, adjusted for age and health behavior risk factors, were compared between the 2 countries and across education and income classes within each country.

RESULTS

The US population in late middle age is less healthy than the equivalent British population for diabetes, hypertension, heart disease, myocardial infarction, stroke, lung disease, and cancer. Within each country, there exists a pronounced negative socioeconomic status (SES) gradient with self-reported disease so that health disparities are largest at the bottom of the education or income variants of the SES hierarchy. This conclusion is generally robust to control for a standard set of behavioral risk factors, including smoking, overweight, obesity, and alcohol drinking, which explain very little of these health differences. These differences between countries or across SES groups within each country are not due to biases in self-reported disease because biological markers of disease exhibit exactly the same patterns. To illustrate, among those aged 55 to 64 years, diabetes prevalence is twice as high in the United States and only one fifth of this difference can be explained by a common set of risk factors. Similarly, among middle-aged adults, mean levels of C-reactive protein are 20% higher in the United States compared with England and mean high-density lipoprotein cholesterol levels are 14% lower. These differences are not solely driven by the bottom of the SES distribution. In many diseases, the top of the SES distribution is less healthy in the United States as well.

CONCLUSIONS

Based on self-reported illnesses and biological markers of disease, US residents are much less healthy than their English counterparts and these differences exist at all points of the SES distribution.

Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in the formation of lesions of atherosclerosis. This localized accumulation of leukocytes is a multistep process in which the endothelium remains intact and may regulate leukocyte recruitment by expressing specific adhesion molecules. To examine the relationship of adhesion molecule expression to initiation factors and the sites of lesion formation, we analyzed the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) en face on the aortic endothelium of control mice and homozygous apolipoprotein E-deficient (ApoE -/-) mice that develop complex lesions of atherosclerosis similar to those in humans. In control mice, VCAM-1 staining was weak and limited to sites of altered blood flow. In contrast, in the ApoE -/- mice, VCAM-1 appeared to be localized over the surface of groups of endothelial cells in lesion-prone sites. Expression of VCAM-1 preceded lesion formation, and increased expression above control levels appeared to be correlated with the extent of exposure to plasma cholesterol. Although ICAM-1 was the most prominent adhesion molecule in lesion-prone sites, its expression appeared to be independent of plasma cholesterol levels and was upregulated in both ApoE -/- and control mice. At lesion-prone sites associated with altered blood flow, ICAM-1 was located over the surface of each endothelial cell and on microvilli, whereas VCAM-1 was confined to the cell periphery in non-lesion-prone sites. PECAM-1 was localized at the cell periphery throughout the aorta, and its expression did not appear to be regulated. Thus, the levels, localization, and characteristics of expression of VCAM-1, ICAM-1, and PECAM-1 appear to be differentially regulated. Upregulation of VCAM-1 and ICAM-1 is associated with sites of lesion formation.

BACKGROUND

Carotid artery intima-media thickness (IMT) is associated with cardiovascular risk factors and is recognized as an important predictive measure of clinical coronary atherosclerosis events in middle-aged and elderly populations. However, information on the association of carotid IMT in young adults with different risk factors measured in childhood, adulthood, or as a cumulative burden of each of the risk factors measured serially from childhood to adulthood is limited.

OBJECTIVE

To examine the association between carotid IMT in young adults and traditional cardiovascular risk factors measured since childhood.

METHODS

A cohort study of 486 adults aged 25 to 37 years from a semirural black and white community in Bogalusa, La (71% white, 39% men), who had at least 3 measurements of traditional risk factors since childhood, conducted between September 1973 and December 1996.

METHODS

Association of carotid IMT with risk factors, including systolic blood pressure, lipoprotein levels, and body mass index.

RESULTS

Male vs female (0.757 mm vs 0.719 mm) and black vs white (0.760 mm vs 0.723 mm) participants had increased carotid IMT (P<.001 for both). In multivariable analyses, significant predictors for being in top vs lower 3 quartiles of carotid IMT in young adults were childhood measures of low-density lipoprotein cholesterol (LDL-C) level (odds ratio [OR], 1.42, corresponding to 1-SD change specific for age, race, and sex; 95% confidence interval [CI], 1.14-1.78) and body mass index (BMI; OR, 1.25; 95% CI, 1.01-1.54); adulthood measures of LDL-C level (OR, 1.46; 95% CI, 1.16-1.82), high-density lipoprotein cholesterol (HDL-C) level (OR, 0.67; 95% CI, 0.51-0.88), and systolic blood pressure (OR, 1.36; 95% CI, 1.08-1.72); and long-term cumulative burden of LDL-C (OR, 1.58; 95% CI, 1.24-2.01) and HDL-C (OR, 0.75; 95% CI, 0.58-0.97) levels measured serially from childhood to adulthood. An increasing trend in carotid IMT across quartiles of LDL-C level measured in childhood was observed, with a mean value of 0.761 mm (95% CI, 0.743-0.780 mm) for those at the top quartile vs 0.724 mm (95% CI, 0.715-0.734 mm) for those in the lower 3 quartiles (P<.001).

CONCLUSIONS

Childhood measures of LDL-C level and BMI predict carotid IMT in young adults. The prevention implications of these findings remains to be explored.

BACKGROUND

HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year.

RESULTS

We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45+/-8 years) and in 63 age- and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91+/-0.33 mm in HIV patients and 0.74+/-0.17 mm in control subjects (P=0.0001). Multivariable predictors of baseline IMT in HIV patients were age (P<0.001), LDL cholesterol (P<0.001), cigarette pack-years (P=0.005), Latino race (P=0.062), and hypertension (P=0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (P=0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074+/-0.13 mm, compared with -0.006+/-0.05 mm in 27 control subjects (P=0.002). Age (P<0.001), Latino race (P=0.02), and nadir CD4 count < or =200 (P=0.082) were multivariable predictors of IMT progression.

CONCLUSIONS

Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count < or =200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.

Rhodococcus sp. strain RHA1, a soil bacterium related to Mycobacterium tuberculosis, degrades an exceptionally broad range of organic compounds. Transcriptomic analysis of cholesterol-grown RHA1 revealed a catabolic pathway predicted to proceed via 4-androstene-3,17-dione and 3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (3,4-DHSA). Inactivation of each of the hsaC, supAB, and mce4 genes in RHA1 substantiated their roles in cholesterol catabolism. Moreover, the hsaC(-) mutant accumulated 3,4-DHSA, indicating that HsaC(RHA1), formerly annotated as a biphenyl-degrading dioxygenase, catalyzes the oxygenolytic cleavage of steroid ring A. Bioinformatic analyses revealed that 51 rhodococcal genes specifically expressed during growth on cholesterol, including all predicted to specify the catabolism of rings A and B, are conserved within an 82-gene cluster in M. tuberculosis H37Rv and Mycobacterium bovis bacillus Calmette-Guérin. M. bovis bacillus Calmette-Guérin grew on cholesterol, and hsaC and kshA were up-regulated under these conditions. Heterologously produced HsaC(H37Rv) and HsaD(H37Rv) transformed 3,4-DHSA and its ring-cleaved product, respectively, with apparent specificities approximately 40-fold higher than for the corresponding biphenyl metabolites. Overall, we annotated 28 RHA1 genes and proposed physiological roles for a similar number of mycobacterial genes. During survival of M. tuberculosis in the macrophage, these genes are specifically expressed, and many appear to be essential. We have delineated a complete suite of genes necessary for microbial steroid degradation, and pathogenic mycobacteria have been shown to catabolize cholesterol. The results suggest that cholesterol metabolism is central to M. tuberculosis's unusual ability to survive in macrophages and provide insights into potential targets for novel therapeutics.

Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the autosomal recessive disorder sitosterolemia. Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxysterol receptors liver X receptor (LXR) alpha and LXRbeta. Diets containing high cholesterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine. This increase was also observed using synthetic ligands of LXR and its heterodimeric partner, the retinoid X receptor. In situ hybridization analyses of tissues from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation. In addition, expression of the LXR target gene ABCA1, previously implicated in the control of cholesterol absorption, was also dramatically up-regulated in jejunal enterocytes upon exposure to LXR agonists. These changes in ABC transporter gene expression were not observed in mice lacking LXRs. Furthermore, in the rat hepatoma cell line FTO2B, LXR-dependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by LXRs. The addition of ABCG5 and ABCG8 to the growing list of LXR target genes further supports the notion that LXRs serve as sterol sensors to coordinately regulate sterol catabolism, storage, efflux, and elimination.

BACKGROUND

The beneficial effects of flavonoid consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence.

OBJECTIVE

We aimed to systematically review the effectiveness of different flavonoid subclasses and flavonoid-rich food sources on cardiovascular disease (CVD) and risk factors--ie, lipoproteins, blood pressure, and flow-mediated dilatation (FMD).

METHODS

Methods included a structured search strategy on MEDLINE, EMBASE, and Cochrane databases; formal inclusion or exclusion, data extraction, and validity assessment; and meta-analysis.

RESULTS

One hundred thirty-three trials were included. No randomized controlled trial studied effects on CVD morbidity or mortality. Significant heterogeneity confirmed differential effects between flavonoid subclasses and foods. Chocolate increased FMD after acute (3.99%; 95% CI: 2.86, 5.12; 6 studies) and chronic (1.45%; 0.62, 2.28; 2 studies) intake and reduced systolic (-5.88 mm Hg; -9.55, -2.21; 5 studies) and diastolic (-3.30 mm Hg; -5.77, -0.83; 4 studies) blood pressure. Soy protein isolate (but not other soy products or components) significantly reduced diastolic blood pressure (-1.99 mm Hg; -2.86, -1.12; 9 studies) and LDL cholesterol (-0.19 mmol/L; -0.24, -0.14; 39 studies). Acute black tea consumption increased systolic (5.69 mm Hg; 1.52, 9.86; 4 studies) and diastolic (2.56 mm Hg; 1.03, 4.10; 4 studies) blood pressure. Green tea reduced LDL (-0.23 mmol/L; -0.34, -0.12; 4 studies). For many of the other flavonoids, there was insufficient evidence to draw conclusions about efficacy.

CONCLUSIONS

To date, the effects of flavonoids from soy and cocoa have been the main focus of attention. Future studies should focus on other commonly consumed subclasses (eg, anthocyanins and flavanones), examine dose-response effects, and be of long enough duration to allow assessment of clinically relevant endpoints.

Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5'-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRalpha/RXR or LXRbeta/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.

Infection causes disturbances in lipid metabolism that may be mediated by cytokines. Therefore we studied plasma lipids, lipoproteins, triglyceride (TG) metabolism, and serum cytokines in three groups: patients with the acquired immunodeficiency syndrome (AIDS) without active secondary infection, patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls. Plasma TGs and FFA were increased in AIDS, while plasma cholesterol, high density lipoprotein (HDL) cholesterol, apolipoprotein-A-1 (Apo-A-1), low density lipoprotein (LDL) cholesterol, and Apo-B-100 levels were decreased. Increased TG levels in AIDS were primarily due to increases in very low density lipoprotein of normal composition; in addition, LDL and HDL were TG enriched. In HIV+, TGs and FFA were not increased, but total cholesterol, HDL cholesterol, Apo-A-1, and Apo-B-100 were significantly decreased. Interferon-alpha (IFN alpha) and C-reactive protein levels were increased in AIDS, but tumor necrosis factor and haptoglobin levels were not. There was a significant correlation between plasma TGs and IFN alpha levels (r = 0.477; P less than 0.01), but not between TGs and tumor necrosis factor, C-reactive protein, haptoglobin, or P-24 antigen. In addition, there was no relationship between circulating IFN alpha levels and plasma cholesterol, HDL cholesterol, Apo-A-1, LDL cholesterol, Apo-B-100, or FFA. TG clearance time and postheparin lipase were significantly decreased in AIDS and HIV+. There was a strong correlation between serum IFN alpha levels and TG clearance time in AIDS and HIV+ (r = 0.783; P less than 0.001). In summary, decreases in cholesterol and cholesterol containing lipoproteins (including HDL) in both AIDS and HIV+ precede the appearance of hypertriglyceridemia and are not related to IFN alpha or TG levels. Our data raise the possibility that with development of AIDS, subsequent increases in IFN alpha may contribute to increases in plasma TG levels in part by decreasing the clearance of TG.

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.

Peroxisome proliferator-activated receptors are expressed in many tissues, including adipocytes, hepatocytes, muscles and endothelial cells; however, the affinity depends on the isoform of PPAR, and different distribution and expression profiles, which ultimately lead to different clinical outcomes. Because they play an important role in lipid and glucose homeostasis, they are called lipid and insulin sensors. Their actions are limited to specific tissue types and thus, reveal a characteristic influence on target cells. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARβ/δ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels. Many natural and synthetic ligands influence the expression of these receptors. Synthetic ligands are widely used in the treatment of dyslipidemia (e.g. fibrates--PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones--PPARγ agonists). New generation drugs--PPARα/γ dual agonists--reveal hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action while the overexpression of PPARβ/δ prevents the development of obesity and reduces lipid accumulation in cardiac cells, even during a high-fat diet. Precise data on the expression and function of natural PPAR agonists on glucose and lipid metabolism are still missing, mostly because the same ligand influences several receptors and a number of reports have provided conflicting results. To date, we know that PPARs have the capability to accommodate and bind a variety of natural and synthetic lipophilic acids, such as essential fatty acids, eicosanoids, phytanic acid and palmitoylethanolamide. A current understanding of the effects of PPARs, their molecular mechanisms and the role of these receptors in nutrition and therapeutic treatment are delineated in this paper.

CD133 (prominin-1) was the first in a class of novel pentaspan membrane proteins to be identified in both humans and mice, and was originally classified as a marker of primitive haematopoietic and neural stem cells. Due to the highly restricted expression of CD133 family molecules on plasma membrane protrusions of epithelial and other cell types, in association with membrane cholesterol, a role in the organization of plasma membrane topology has also recently been assigned to this family. Studies have now confirmed the utility of CD133 as a marker of haematopoietic stem cells for human allogeneic transplantation. In addition, CD133 represents a marker of tumour-initiating cells in a number of human cancers, and therefore it may be possible to develop future therapies towards targeting cancer stem cells via this marker. The development of such therapies will be aided by a clearer understanding of the molecular mechanisms and signalling pathways that regulate the behaviour of CD133-expressing cells, and new data outlining the role of Wnt, Notch, and bone morphogenetic protein (BMP) signalling in CD133(+) cancer stem cell regulation are discussed within.

BACKGROUND

Progress of diabetes care is a subject of public health concern.

OBJECTIVE

To assess changes in quality of diabetes care in the United States by using standardized measures.

METHODS

National population-based, serial cross-sectional surveys.

METHODS

National Health and Nutrition Examination Survey (1988-1994 and 1999-2002) and the Behavioral Risk Factor Surveillance System (1995 and 2002).

METHODS

Survey participants 18 to 75 years of age who reported a diagnosis of diabetes.

METHODS

Glycemic control, blood pressure, low-density lipoprotein (LDL) cholesterol level, annual cholesterol level monitoring, and annual foot and dilated eye examination, as defined by the National Diabetes Quality Improvement Alliance measures.

RESULTS

In the past decade, the proportion of persons with diabetes with poor glycemic control (hemoglobin A1c>> 9%) showed a nonstatistically significant decrease of 3.9% (95% CI, -10.4% to 2.5%), while the proportion of persons with fair or good lipid control (LDL cholesterol level < 3.4 mmol/L [<130 mg/dL]) had a statistically significant increase of 21.9% (CI, 12.4% to 31.3%). Mean LDL cholesterol level decreased by 0.5 mmol/L (18.8 mg/dL). Although mean hemoglobin A1c did not change, the proportion of persons with hemoglobin A(1c) of 6% to 8% increased from 34.2% to 47.0%. The blood pressure distribution did not change. Annual lipid testing, dilated eye examination, and foot examination increased by 8.3% (CI, 4.0% to 12.7%), 4.5% (CI, 0.5% to 8.5%), and 3.8% (CI, -0.1% to 7.7%), respectively. The proportion of persons reporting annual influenza vaccination and aspirin use improved by 6.8 percentage points (CI, 2.9 percentage points to 10.7 percentage points) and 13.1 percentage points (CI, 5.4 percentage points to 20.7 percentage points), respectively.

CONCLUSIONS

Data are self-reported, and the surveys do not have all National Diabetes Quality Improvement Alliance indicators.

CONCLUSIONS

Diabetes processes of care and intermediate outcomes have improved nationally in the past decade. But 2 in 5 persons with diabetes still have poor LDL cholesterol control, 1 in 3 persons still has poor blood pressure control, and 1 in 5 persons still has poor glycemic control.

OBJECTIVE

To examine risk factors for the prevalence of dry eye syndrome in a population-based cohort.

METHODS

The prevalence of dry eye was determined by history at the second examination (1993-1995) of the Beaver Dam Eye Study cohort (N = 3722).

RESULTS

The cohort was aged 48 to 91 years (mean +/- SD, 65 +/- 10 years) and 43% male. The overall prevalence of dry eye was 14.4%. Prevalence varied from 8.4% in subjects younger than 60 years to 19. 0% in those older than 80 years (P<.001 for test of trend). Age-adjusted prevalence in men was 11.4% compared with 16.7% in women (P<.001). After controlling for age and sex, the following factors were independently and significantly associated with dry eye in a logistic model: history of arthritis (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.56-2.33), smoking status (past, OR, 1.22; 95% CI, 0.97-1.52; current, OR, 1.82; 95% CI, 1.36-2.46), caffeine use (OR, 0.75; 95% CI, 0.61-0.91), history of thyroid disease (OR, 1.41; 95% CI, 1.09-1.84), history of gout (OR, 1.42; 95% CI, 1.02-1.96), total to high-density lipoprotein cholesterol ratio (OR, for 1 unit, 0.93; 95% CI, 0.88-0.99), diabetes (OR, 1.38; 95% CI, 1.03-1.86), and multivitamin use (past, OR, 1.35; 95% CI, 1. 01-1.81; current, OR, 1.41; 95% CI, 1.09-1.82). Nonsignificant variables included body mass; blood pressure; white blood cell count; hematocrit; history of osteoporosis, stroke, or cardiovascular disease; history of allergies; use of antihistamines, parasympathetics, antidepressants, diuretics, antiemetics, or other drying drugs; alcohol consumption; time spent outdoors; maculopathy; central cataract; and lens surgery.

CONCLUSIONS

The results suggest several factors, such as smoking, caffeine use, and multivitamin use, could be studied for preventive or therapeutic efficacy. Arch Ophthalmol. 2000;118:1264-1268

OBJECTIVE

This study sought to investigate whether prolongation of the heart rate-corrected QT (QTc) interval is a risk factor for sudden cardiac death in the general population.

BACKGROUND

In developed countries, sudden cardiac death is a major cause of cardiovascular mortality. Prolongation of the QTc interval has been associated with ventricular arrhythmias, but in most population-based studies no consistent association was found between QTc prolongation and total or cardiovascular mortality. Only very few of these studies specifically addressed sudden cardiac death.

METHODS

This study was conducted as part of the Rotterdam Study, a prospective population-based cohort study that comprises 3,105 men and 4,878 women aged 55 years and older. The QTc interval on the electrocardiogram was determined during the baseline visit (1990 to 1993) and the first follow-up examination (1993 to 1995). The association between a prolonged QTc interval and sudden cardiac death was estimated using Cox proportional hazards analysis.

RESULTS

During an average follow-up period of 6.7 years (standard deviation, 2.3 years) 125 patients died of sudden cardiac death. An abnormally prolonged QTc interval (>450 ms in men, >470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3).

CONCLUSIONS

Abnormal QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death.

Entry of monocytes into the vessel wall is an important event in atherogenesis. Previous studies from our laboratory suggest that oxidized arachidonic acid-containing phospholipids present in mildly oxidized low density lipoproteins (MM-LDL) can activate endothelial cells to bind monocytes. In this study, biologically active oxidized arachidonic acid-containing phospholipids were produced by autoxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) and analyzed by liquid chromatography and electrospray ionization mass spectrometry in conjuction with biochemical derivatization techniques. We have now determined the molecular structure of two of three molecules present in MM-LDL and Ox-PAPC that induce monocyte-endothelial interactions. These lipids were identified as 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (m/z 594.3) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (m/z 610.2). These two molecules were produced by unambiguous total synthesis and found to be identical by analytical techniques and bioactivity assays to those present in MM-LDL and Ox-PAPC. Evidence for the importance of all three oxidized phospholipids in vivo was suggested by their presence in fatty streak lesions from cholesterol-fed rabbits and by their immunoreactivity with natural antibodies present in ApoE null mice. Overall, these studies suggest that specific oxidized derivatives of arachidonic acid-containing phospholipids may be important initiators of atherogenesis.

BACKGROUND

Cardiovascular diseases and their associated risk factors remain the main cause of mortality in western societies. In order to assess the prevalence of cardiovascular risk factors (CVRFs) in the Caucasian population of Lausanne, Switzerland, we conducted a population-based study (Colaus Study). A secondary aim of the CoLaus study will be to determine new genetic determinants associated with CVRFs.

METHODS

Single-center, cross-sectional study including a random sample of 6,188 extensively phenotyped Caucasian subjects (3,251 women and 2,937 men) aged 35 to 75 years living in Lausanne, and genotyped using the 500 K Affymetrix chip technology.

RESULTS

Obesity (body mass index>> or = 30 kg/m2), smoking, hypertension (blood pressure>> or = 140/90 mmHg and/or treatment), dyslipidemia (high LDL-cholesterol and/or low HDL-cholesterol and/or high triglyceride levels) and diabetes (fasting plasma glucose>> or = 7 mmol/l and/or treatment) were present in 947 (15.7%), 1673 (27.0%), 2268 (36.7%), 2113 (34.2%) and 407 (6.6%) of the participants, respectively, and the prevalence was higher in men than in women. In both genders, the prevalence of obesity, hypertension and diabetes increased with age.

CONCLUSIONS

The prevalence of major CVRFs is high in the Lausanne population in particular in men. We anticipate that given its size, the depth of the phenotypic analysis and the availability of dense genome-wide genetic data, the CoLaus Study will be a unique resource to investigate not only the epidemiology of isolated, or aggregated CVRFs like the metabolic syndrome, but can also serve as a discovery set, as well as replication set, to identify novel genes associated with these conditions.

BACKGROUND

Whether lipoproteins are better markers than lipids and lipoproteins for coronary heart disease is widely debated. Our aim was to compare the apolipoproteins and cholesterol as indices for risk of acute myocardial infarction.

METHODS

We did a large, standardised case-control study of acute myocardial infarction in 12,461 cases and 14,637 age-matched (plus or minus 5 years) and sex-matched controls in 52 countries. Non-fasting blood samples were available from 9345 cases and 12,120 controls. Concentrations of plasma lipids, lipoproteins, and apolipoproteins were measured, and cholesterol and apolipoprotein ratios were calculated. Odds ratios (OR) and 95% CI, and population-attributable risks (PARs) were calculated for each measure overall and for each ethnic group by comparison of the top four quintiles with the lowest quintile.

RESULTS

The apolipoprotein B100 (ApoB)/apolipoprotein A1 (ApoA1) ratio had the highest PAR (54%) and the highest OR with each 1 SD difference (1.59, 95% CI 1.53-1.64). The PAR for ratio of LDL cholesterol/HDL cholesterol was 37%. PAR for total cholesterol/HDL cholesterol was 32%, which was substantially lower than that of the ApoB/ApoA1 ratio (p<0.0001). These results were consistent in all ethnic groups, men and women, and for all ages.

CONCLUSIONS

The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.