Elevated Serum Cholesterol Levels Research Articles

30,000 Fewer Heart Attacks and Strokes in North Carolina: A Challenge to Prioritize Prevention

Heart disease and stroke are leading causes of death in North Carolina and are also important contributors to poor health and excess health care expenditures. The risk factors for heart disease, stroke, and other forms of cardiovascular disease are well known, and include smoking, high blood pressure, elevated serum cholesterol levels, diabetes mellitus, and obesity. These risk factors persist as a result of suboptimal assessment, treatment, and control; adverse trends in health behaviors; and environmental and societal conditions negatively affecting the pursuit of optimal cardiovascular health. If North Carolina is to do its share in making it possible for the national Million Hearts initiative to meet its goals, then 30,000 heart attacks and strokes need to be prevented in the state over the next 5 years. Both the Million Hearts initiative and North Carolina's Justus-Warren Heart Disease and Stroke Prevention Task Force Plan include specific recommendations aimed at the primary and secondary prevention of heart disease and stroke. Million Hearts focuses on the ABCS: aspirin use when appropriate, blood pressure control, cholesterol control, and smoking cessation or abstention. The task force plan also addresses physical inactivity, poor nutrition, and the control of obesity and diabetes. The commentaries published in this issue of the NCMJ address the challenge of cardiovascular disease prevention among children and adults across the state and highlight efforts to enhance prevention via public policies and legislation, community coalitions, and quality improvement in the clinical arena.

Management of dyslipidemia in CKD, dialysis and renal transplant recipient

Abstract Dyslipidemia is a well-established metabolic disorder in patients with chronic kidney diseases (CKD), on dialysis and renal transplant recipient. The elevated serum cholesterol levels have a definite role in the development and progression of atherosclerosis and the correlation between elevated serum LDL cholesterol as a risk factor for development of CHD has been firmly established. The HMG-CoA reductase inhibitors (statins) are the current drugs of choice for the treatment of hypercholesterolemia. The treatment with statins effectively lower total and LDL-cholesterol levels, moderately decreases triglycerides (TGs) levels, and have a little effect in increasing HDL-cholesterol levels. The statins therapy reduces the morbidity and mortality associated with CHD in patients with normal renal function. However, the beneficial effect of statin therapy on CVD morbidity and mortality in patients with CKD and advanced ESRD are controversial. Statin therapy reduces CVD mortality in patient with early CKD (not yet requiring dialysis) and their use is recommended for patients with early CKD. However, the recent results from the AURORA and SHARP studies have revealed statins treatment provide no CV mortality benefit in patient with advanced CKD or on long-term dialysis. This may be because athermatous coronary artery disease account for a small proportion of the CVD observed in patients with ESRD and/or on dialysis. In addition, advanced CKD result in structural and functional abnormalities of HDL, impaired cholesterol and chylomicron metabolism which leads to accelerated atherosclerosis and CVD in such patients. Collectively, these abnormalities are largely independent of cholesterol biosynthesis, and consequently are not corrected by statin therapy. Therefore lipid lowering therapy in patient with ESRD should be individualized. Atorvastatin and Rosuvastatin are most potent agents among the available statins in cholesterol lowering but are the most expensive. Simvastatin (20 mg/day) should be considered the drug of choice for most patients with chronic kidney disease because it is less expensive. Pravastatin and fluvastatin are the most suitable agents for transplant patients to achieve target cholesterol levels because of the reduced risk of drug interactions.

White spotting variant mouse as an experimental model for ovarian aging and menopausal biology.

Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell-containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies. Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography. The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. The reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in newborn mice and premature depletion of follicles in young mice, although mutant females have a normal life span after cessation of ovarian function. The Wv female mice exhibit consistent physiological changes that resemble common features of postmenopausal women. These alterations include follicle depletion, morphological aging of the ovary, altered serum levels of cholesterol, gonadotropins and steroid hormones, decreased bone density, and reduced cardiac function. These changes were not observed in male mice, either age-matched male Wv/Wv or wildtype mice, and are improbably caused by global loss of c-kit function. The Wv mouse may be a genetic, intact-ovary model that mimics closely the phenotypes of human menopause to be used for further studies to understand the mechanisms of menopausal biology.

Exploring the question‐behaviour effect: Randomized controlled trial of motivational and question‐behaviour interventions

Measuring intentions and other cognitions to perform a behaviour can promote performance of that behaviour (the question-behaviour effect, QBE). It has been suggested that this effect may be amplified for individuals motivated to perform the behaviour. The present research tested the efficacy of combining a motivational intervention (providing personal risk information) with measuring intentions and other cognitions in a fully crossed 2 × 2 design with an objective measure of behaviour in an at-risk population using a randomized controlled trial (RCT). Participants with elevated serum cholesterol levels were randomized to one of four conditions: a combined group receiving both a motivational intervention (personalized cardiovascular disease risk information) and a QBE manipulation (completing a questionnaire about diet), one group receiving a motivational intervention, one group receiving a QBE intervention, or one group receiving neither. All participants subsequently had the opportunity to obtain a personalized health plan linked to reducing personal risk for coronary heart disease. Neither the motivational nor the QBE manipulations alone significantly increased rates of obtaining the health plan. However, the interaction between conditions was significant. Decomposition of the interaction indicated that the combined condition (motivational plus QBE manipulation) produced significantly higher rates of obtaining the health plan (96.2%) compared to the other three groups combined (80.3%). The findings provide insights into the mechanism underlying the QBE and suggest the importance of motivation to perform the behaviour in observing the effect. What is already known on this subject? Research has indicated that merely asking questions about a behaviour may be sufficient to produce changes in that or related behaviours (referred to as the question-behaviour effect; QBE). Previous studies have suggested that the QBE may be moderated by the individual's motivation to change the behaviour, i.e., the QBE will only produce increases in the behaviour among those with strong motivation to perform the behaviour. However, no study has directly tested this prediction by manipulating motivation and examining impacts on the QBE. What does this study add? The present study tested the individual and combined effects of a motivational and a QBE intervention in a fully crossed design using a randomized controlled trial (RCT) and showed that: a combined intervention significantly increased behaviour. effect partially mediated by cognitions.

Pancreatitis in the setting of the metabolic syndrome

There is paucity of literature on the relation of obesity with recurrent and chronic pancreatitis. We recorded the clinical details and the outcome of five patients with recurrent pancreatitis who had components of the metabolic syndrome. Their age ranged from 8 to 20 years. All five patients had acanthosis nigricans. Body mass index (BMI) could not be evaluated as these patients lost weight following episodes of pancreatitis. Three patients had two or more first-degree relatives who had diabetes mellitus. Only one patient had severe necrotizing pancreatitis. Coexisting liver disease was seen in two patients. Elevated serum cholesterol levels and moderately elevated serum triglycerides along with elevated serum amylase levels observed in these patients suggest possibility of a different mechanism from that of hypertriglyceridemia-related pancreatitis. Evaluation of pancreatic steatosis should be considered in patients with pancreatitis in the setting of metabolic syndrome.

Anticonvulsant Effect of Pitavastatin in Mice Induced by Pentylenetetrazole

Problem statement: The 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality by their lipid-lowering actions. It has been suggested that statins appear to have therapeutic benefits in diseases that are unrelated to elevated serum cholesterol levels. The aim of this study was to evaluation the effect of intraperitoneally injection of different doses of pitavastatin on PTZ-induced seizure threshold in mice. Approach: Mice were divided into 9 groups randomly: the first group received saline normal (ip) (control group); the second group received Carboxymethylcellulose (CMC) 0.5% (ip) (vehicle group) and the next groups received respectively different doses of pitavastatin (1, 5, 10, 20, 40, 80 and 100 mg kg daily-1) for 4 days (ip) before determination of seizure threshold induced by PTZ. Results: Results showed that PTZ-induced seizure threshold in control mice was 35.48±1.39 mg kg-1. Intraperitoneal injection of pitavastatin showed significant (p<0.05) increase of PTZ-induced seizure threshold in a dose dependently manner. Conclusion: According to our results, pitavastatin has anticonvulsant effects on mice. Nevertheless, new studies must be carried out in order to determine the beneficial effects of statins in treatment of epilepsy.

Effect of Intraperitoneally Injection of Different Doses of Lovastatin on Pain and Inflammatory Response Induced by Formalin in Mice

Problem statement: The 3-Hydroxy-3-Methyl Glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have been unequivocally shown to reduce cardiovascular morbidity and mortality. T heir lipid-lowering actions are by reversible and compet itive inhibition of the enzyme HMG-CoA reductase, a precursor of cholesterol. It has been suggested tha t statins appear to have therapeutic benefits in di seases that are unrelated to elevated serum cholesterol levels, such as pain and inflammatory. The aim of this stu dy was to determination the effect of intraperitoneally in jection of different doses of lovastatin on pain an d inflammatory response induced by formalin in mice. Approach: Mice were divided into 9 groups randomly: the first group received saline normal (i p) (saline group); the second group received Carboxymethylcellulose (CMC) 0.5% (ip) (vehicle group) and the next groups received respectively different doses of lovastatin (1, 5, 10, 20, 40, 80 and 100 mg kg daily -1 ) for 4 days (ip) before formalin test. After intrapawly injection of formalin, the time of hind paw biting and licking time measured in 5 min interval for an hour. Results: Results showed that formalin induces biphasic pain response (the first phase: 0-5 min and the second phase 15-40 min after inject ion). Intraperitoneal injection of lovastatin showe d significant (p<0.05) decrease of pain responses in the first and the second phase in a dose dependentl y manner. Conclusion: According to our results, lovastatin has analgesic and anti-inflammatory effects on mice. Nevertheless, new studies must be carried out in order to determine the beneficial effects of st atins in treatment of pain and inflammatory.

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet

Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.

Antihyperlipidemic activity of Cassia auriculata flowers in triton WR 1339 induced hyperlipidemic rats

The flower extract of Cassia auriculata, herb has been used traditionally in India for medicinal purposes. The plant has been reported to treat hyperglycemia and associated hyperlipidemia. Hyperlipidemia and oxidative stress are known to accelerate coronary artery disease and progression of atherosclerotic lesions. The present work was undertaken to investigate the possible antihyperlipidemic and antioxidative effect of C. auriculata flower on hyperlipidemic rats. Hyperlipidemia was induced in rats by a single intravenous (iv) injection of Triton WR 1339 (300 mg/kg b.w.) and it showed sustained elevated levels of serum cholesterol and triglyceride. Ethanolic extract of C. auriculata flowers (Et-CAF) (150, 300, 450 mg/kg b.w./day) was administered to normal and hyperlipidemic rats for 14 days. Serum and liver tissue were analysed at three different time intervals for lipid profile, lipid peroxidation products, antioxidants enzymes and the activity were compared to the cholesterol-lowering drug, lovastatin (10 mg/kg/b.w.). Parameters were altered during hyperlipidemia and reverted back to near normal values after Et-CAF treatment or standard drug lovastatin. Lipid peroxidation decreased whereas the activities of superoxide dismutase, glutathione peroxidase and catalase increased in Et-CAF treated rats. Pronounced changes were observed at 450 mg/kg b.w. of Et-CAF for 2 weeks and it was comparable to the standard drug lovastatin. The current study provides a strong evidence that Et-CAF has a beneficial effect in treating hyperlipidemia and ROS without any side effects at the dosage and duration studied.

Elevated Serum Cholesterol Levels in Women with Premenstrual Dysphoric Disorder

To study the association of premenstrual serum total cholesterol level (TC) with premenstrual dysphoric disorder (PMDD). The premenstrual serum cholesterol levels of 34 patients with PMDD and 20 normal controls were measured, and the rates ofhypercholesterolemia in the 2 groups were compared. The mean of the premenstrual cholesterol level of the study group was 180.82 +/- 34.47 mg/dL, while that of the control group was 162.45 +/- 21.29 mg/dL (t = 2.152, df = 52, p = 0.036). The prevalence of premenstrual hypercholesterolemia (serum total cholesterol > 200 mg/dL) was 23.53% (8/34) in the PMDD group and zero in the normal control group (chi-square = 5.524, df = 1, p = 0.019). The results showed elevated premenstrual serum cholesterol in PMDD and implied a new direction of research to further explore the etiology of PMDD. It is suggested that the pathophysiology of premenstrual dysphoric disorder may be similar to that of anxiety disorders.

Studies in mice, hamsters, and rats demonstrate that repression of hepatic apoA-I expression by taurocholic acid in mice is not mediated by the farnesoid-X-receptor

It is claimed that apoA-I expression is repressed in mice by cholic acid (CA) and its taurine conjugate, taurocholic acid (TCA) via farnesoid X receptor (FXR) activation. We measured apoA-I expression in mice, hamsters, and rats treated with highly potent and selective synthetic FXR agonists or with TCA. All of the synthetic agonists bound to FXR with high affinity in a scintillation proximity assay. However, TCA did not compete with the radioligand up to the highest concentration used (100 μM). The C-site regulatory region of apoA-I, through which FXR has been reported to regulate its expression, is completely conserved across the species investigated. In both male and female human apoA-I-transgenic mice, we reproduced the previously reported strong inhibition of human apoA-I expression upon treatment with the typical supraphysiological dose of TCA used in such studies. However, in contrast to some previous reports, TCA did not repress murine apoA-I expression in the same mice. Also, more-potent and -selective FXR agonists did not affect human or murine apoA-I expression in this model. In LDL receptor-deficient mice and Golden Syrian hamsters, selective FXR agonists did not affect apoA-I expression, whereas in Wistar rats, some even increased apoA-I expression. In conclusion, selective FXR agonists do not repress apoA-I expression in rodents. Repression of human apoA-I expression by TCA in transgenic mice is probably mediated through FXR-independent mechanisms.

Clinical and pathological features of primary biliary cirrhotic patients with negative anti-mitochondria antibody

To explore the clinical and pathological features of primary biliary cirrhosis (PBC) patients with negative anti-mitochondria antibody (AMA). Two hundreds and eight PBC patients were enrolled. The clinical and histological data of the negative AMA cases were compared with the AMA/AMA-M2 positive cases. 30 out of the 208 cases (14.4%) were AMA negative patients in our study. The general status, biochemical tests and histological findings between the two groups had no significant difference (P > 0.05). The Gamma-globulin, IgG, IgM and IgA levels of AMA/AMA-M2 positive PBC patients were higher than that of the AMA negative cases (P < 0.05). The abnormal rate of cholesterol in AMA negative PBC patients was 65.4% as compared to 50.4% in AMA/AMA-M2 positive cases, no significant difference existed between (P > 0.05). Anti-nuclear antibody (ANA) was observed in 29 (96.7%) AMA negative PBC patients, including 14 (48.3%) with granular pattern, 8 (27.6%) with nuclear membrane pattern, 6 (20.7%) with kinetochore pattern and 1 (3.4%) with homogeneous pattern. AMA negative PBC patients had elevated serum ALP, GGT, IgM and cholesterol levels, and decreased serum AST, IgG and IgA levels as compared with that of autoimmune hepatitis patients (P < 0.05, respectively). In cholestatic patients with elevated IgM and cholesterol levels, ANA positive with non-homogeneous pattern, the diagnosis of PBC should be suspected, albeit AMA negative. The clinical, biochemical and histological features of the AMA negative PBC patients were similar to classic PBC patients, but quite different from autoimmune hepatitis.

Dietary Cholesterol and Its Effect on Tau Protein: A Study in Apolipoprotein E-Deficient and P301L Human Tau Mice

Apolipoprotein E (ApoE) is the major cholesterol transporter in the brain. There is epidemiological and experimental evidence for involvement of cholesterol metabolism in the development and progression of Alzheimer disease. A dietary effect on tau phosphorylation or aggregation, or a role of apoE in tau metabolism, has been studied experimentally, but the data are ambiguous. To elucidate the relationship between cholesterol and tau, we studied mice expressing P301L mutant human tau but not apoE (htau-ApoE) and P301L mice with wild-type ApoE (htau- ApoE); both genotypes develop neuron cytoskeletal changes similar to those found in Alzheimer disease. Mice were kept on a cholesterol-enriched diet or control diet for 15 weeks. The numbers of neurons with hyperphosphorylated and conformationally changed tau in the cerebral cortex were assessed by immunohistochemistry, and sterol levels were determined. Highly elevated dietary serum cholesterol levels enhanced ongoing tau pathology in htau-ApoE mice; this effect correlated with elevated brain cholesterol metabolite 27-hydroxycholesterol levels. Apolipoprotein E deficiency promoted significant increases of tau phosphorylation and conformational changes in mice on a control diet. In htau-ApoE mice on the high cholesterol regimen, brain oxysterol levels were less than in htau-ApoE mice, and the numbers of neurons with pathologically altered tau were similar to those in htau-ApoE mice on the high-cholesterol diet.

P02-71 - Serum cholesterol and treatment response in patients with depressive disorder

IntroductionThe previous studies reported that elevated serum cholesterol levels (≥ 200 mg/dl) were associated with poorer response to fluoxetine and nortiptyline treatment in patients with depression.AimsThe aim of this study was to examine the relationship between pretreatment serum cholesterol levels and clinical response to treatment with different antidepresants among inpatients with depressive disorder.MethodsOne hundred and four inpatients with depressive disorder who did not respond to previous treatment were enrolled in a six-week open study. New treatment (different antidepressant monotherapies, combinations or augmentations) was chosen according to clinical judgment. Serum cholesterol levels were obtained before starting new treatment. Cholesterol levels were classified as either elevated (≥ 200 mg/dl) or nonelevated. Clinical response was defined as ≥ 50% decrease in the Montgomery Åsberg Depression Rating Scale (MADRS) score at endpoint compared to baseline.ResultsForty-six patient (44%) were classified as having elevated cholesterol levels at baseline. Patients with elevated cholesterol levels did not significantly differ in gender ratio, baseline MADRS score, duration of current episode and number of previous episodes but were significantly older than patients with nonelevated cholesterol levels. After adjusting for age, gender, and Body Mass Index (BMI), we did not find significant differences in response rate and as well as in the pretreatment-posttreatment change in MADRS between patients with elevated cholesterol and patients with nonelevated levels.ConclusionWe did not demonstrate association between pretreatment cholesterol level and response to treatment in depressive disorder.Study was supported by the grant NS10368 IGA MZ CR.

The Therapeutic Role of Very Low-Density Lipoprotein Receptor Gene in Hyperlipidemia in Type 2 Diabetic Rats

Hyperlipidemia is a common feature of type 2 diabetes and is related to cardiovascular disease. The very low-density lipoprotein receptor (VLDLR) binds to and internalizes triglyceride-rich lipoproteins with high specificity. In this study, we evaluated the role of VLDLR in hyperlipidemia in type 2 diabetic rats. Type 2 diabetes was induced in male Wistar rats by injection of low-dose streptozotocin coupled with a high-fat diet. Recombinant adeno-associated viral (rAAV) vectors encoding the human VLDLR gene (rAAV·VLDLR) were intravenously administered to diabetic rats. Results showed that in vivo, total VLDLR mRNA and protein levels were significantly decreased in skeletal muscle (type I VLDLR mainly reduced) and adipose tissue (type II VLDLR mainly reduced) but not in heart in hypercholesterolemic, hypertriglyceridemic diabetic rats compared with normal rats. And in vitro, in 3T3-L1 adipocytes, insulin-induced (1.0 mmol/liter) insulin resistance significantly decreased VLDLR mRNA expression. In rats, rAAV·VLDLR delivery resulted in a reduction in serum cholesterol and triglyceride that lasted for the duration of the study (12 weeks). Fasting blood insulin was significantly lower in the rAAV·VLDLR group versus untreated diabetic rats although fasting blood glucose levels were not significantly different in both groups at the end of the study. rAAV·VLDLR-treated animals had significantly increased lipoprotein lipase activity and reduced aortic atherosclerosis. Taken together, our data suggest that type 2 diabetes and related insulin resistance manifest decreased VLDLR with elevated serum cholesterol and triglyceride levels, and overexpression of VLDLR through a single injection of rAAV·VLDLR reversed these effects and consequentially attenuated aorta atherosclerotic plaque progression.

鶏卵の健康・栄養機能の新展開

Japan is one of the top consumer countries in the world of chicken eggs at almost one egg per person per day. Chicken eggs contain eight essential amino acids in an ideal balance, giving an amino acid score that is as high as that for milk and beef (100) and the biological value that exceeds that of the latter foods (94). Furthermore, among animal-source foods, eggs are relatively rich in unsaturated fatty acids, fat-soluble vitamins and minerals such as phosphorus, calcium and iron. Despite these beneficial attributes, many consumers are worried about the relationship between chicken egg consumption and heart disease since chicken eggs are a high cholesterol food. Human studies in Japan reveal that consumption of egg yolk for 4 weeks did not result in an elevation of serum cholesterol level and there was no direct relationship between frequency of egg consumption and a risk of myocardial infarction in a 10-year follow-up study of 90,000 Japanese subjects. Rat studies provide evidence of the hypocholesterolemic action of egg yolk phospholipids and egg white proteins. Furthermore, feeding egg yolk phospholipids to rats with brain injuries and senescence-accelerated mice resulted in enhanced learning ability. These results indicate that chicken egg is an attractive food from the aspects of health promotion and nutritional function.

The Mysterious Link between Cholesterol and Alzheimer?s Disease: Is the Blood-Brain Barrier a Suspect?

It is now well accepted that the deposition and aggregation of amyloid β (Aβ) peptides are hallmarks of Alzheimer’s disease (AD) [1]. These peptides are constitutively secreted by neurons but (for reasons that remain to be established) Aβ metabolism is altered in AD patients and leads slowly to the neurodegenerative process. With these considerations in mind, the identification of genetic, biochemical, environmental and dietary factors influencing Aβ peptide synthesis, clearance and degradation became a high priority for researchers working on AD. The enzyme responsible for Aβ peptide synthesis was soon identified as a β-secretase called β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [2]. The most important genetic risk factor for late-onset AD was identified as the APOe4 allele [ 3]. This gene encodes an apolipoprotein, a protein component of the low-density lipoprotein (LDL) particles involved in lipid transport throughout the body; this finding highlighted a probable relationship between AD and cholesterol metabolism. More recently, two other susceptibility loci linked to cholesterol metabolism have been identified in AD: CLU (coding for clusterin, another apolipoprotein) [4] and ABCA7 [5] (coding for the ATP-binding cassette sub-family A member 7 transporter involved in cholesterol homeostasis [6] ). This link between AD and cholesterol metabolism was reinforced by the observation that the sterol can modulate BACE1 activity and promote Aβ peptide biosynthesis [7]. Cholesterol was also identified as dietary risk factor in humans; since elevated serum cholesterol is a risk factor for developing AD and amount of Aβ peptide in the brain correlates with serum levels of LDL and total cholesterol [8,9]. Moreover, rabbits and mice on a cholesterol-enriched diet show elevated serum cholesterol levels, increased Aβ peptide deposition and cognitive impairment [10-14]. However, the reasons why serum cholesterol influences AD are difficult to determine, for two main reasons. Firstly, most of the accretion of cholesterol in the central nervous system (CNS) is due to de novo synthesis (reviewed in [15]). Secondly, the brain is isolated from the rest of body by the blood-brain barrier (BBB), a dynamic interface formed by brain capillary endothelial cells (BCECs) and sealed by complex tight junctions that restrict the paracellular pathway [16]. One of the BBB’s main roles is to supply the brain with essential nutrients and mediate the efflux of many waste products. To this end, BCECs express specific receptors or transporters in their luminal (plasma-side) and/ or abluminal (brain-side) membranes that force molecules to take the transcellular route.

Metabolic indices, energy and macronutrient intake according to weight status in a rural sample of 17-year-old adolescents

With adolescent health a priority on the WHO agenda, research into the diet, weight status and metabolic profile of adolescents is indicated. The present study aimed to assess the diet and metabolic parameters of a rural sample of adolescents. One hundred adolescents (17 years of age) were recruited from schools in Nea Madytos, Thessaloniki, Greece. Two previous-day food recalls were collected for each participant, and weight, height, waist circumference, serum lipids and fasting glucose levels were measured. The prevalence of underweight/overweight, central obesity, dyslipidemia and impaired fasting glucose (IFG) were calculated. Overweight was present in half the boys (51.2%) and one-fifth of the girls (21.3%). In the total sample 7.1% were underweight and another 7.1% were diagnosed with central obesity. Boys had an increased risk of abdominal obesity (OR:1.405, CI:0.7-2.8), IFG (OR:1.200, CI:0.3-4.9) and elevated triglycerides (OR:1.514, CI:1.0-2.4) and serum cholesterol levels (OR:1.806, CI:1.1-3.1). Central obesity increased the chances of IFG (OR:8.000, CI:1.6-39.1) and doubled the prevalence of dyslipidemia (OR:2.190, CI:0.5-9.1). Under-reporting of energy was found among overweight participants and was further verified by an inverse relationship between BMI and the ratio of energy intake to energy expenditure. Adolescents identified a dietary pattern high in fats in lieu of protein. Irrespectively of their weight status, teenagers consume a high fat diet; therefore, dietary counseling, as a means of preventive medicine, should be applied to all weight categories. In addition, the prevalence of obesity in a rural sample of adolescents appears to be higher compared with the whole of Greece.

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Determinants of Osteonecrosis In Children with Acute Lymphoblastic Leukemia.

AbstractAbstract 1033Osteonecrosis is a debilitating corticosteroid-induced toxicity in patients treated for acute lymphoblastic leukemia (ALL). Our goal was to ascertain genetic and non-genetic risk factors for this complication. In St. Jude Total XV protocol for children with newly diagnosed ALL, we prospectively screened 365 patients with magnetic resonance imaging of hips and knees, irrespective of symptoms. We determined whether age, race, sex, ALL treatment arm, body mass index, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics and genome-wide germline genetic polymorphisms were associated with symptomatic (grade 2–4) osteonecrosis. Sixty-eight patients developed symptomatic osteonecrosis with a cumulative incidence of 17%. Age greater than 10 years (odds ratio 4.8; 95 % confidence interval [CI], 2.5–9.2; p = 0.00001) and treatment arm (standard/high risk vs. low risk) (odds ratio 2.5; 95% CI 1.2–4.9; p = 0.011) were associated with increased risk of osteonecrosis, and were included as covariates in all other analyses. Lower serum albumin (p = 0.04) and higher serum cholesterol levels (p = 0.02) were associated with symptomatic (grade 2–4) osteonecrosis. In addition, higher dexamethasone plasma exposure (area-under-the-curve) was associated with severe (grade 3–4) osteonecrosis (p = 0.0007). After adjusting for clinical features (age and treatment arm), we identified several single nucleotide polymorphisms (SNPs) associated with the risk of developing osteonecrosis. These include: ACP1 (rs12714403, p = 1.03 × 10-5; odds ratio 4.8; 95% CI 2.4–9.6), a gene involved in regulation of lipids and osteoblast differentiation; and SH3YL1 (rs4241316, p = 5.7 × 10-6; odds ratio 5.0; 95% CI 2.5–10.1). These SNPs were also associated with lower albumin and elevated serum cholesterol levels. In conclusion, older age, lower albumin levels, increased dexamethasone systemic exposure, and higher cholesterol levels were associated with osteonecrosis. Inherited genomic variation that predisposes to osteonecrosis may do so via pleiotropic effects on dexamethasone pharmacokinetics, serum cholesterol and serum albumin. Disclosures:Pui:EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria. Relling:St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

The First Case Report of the Treatment of Transplant Coronary Artery Disease With Dextran Sulfate Adsorption Lipid Apheresis

In patients who have undergone a heart transplant, the major cause of death is coronary artery disease (CAD). The etiology of cardiac-allograft vasculopathy is thought to be multifactorial, but due in large part to immune mechanisms that cause elevations in serum cholesterol levels. The dextran sulfate cellulose low-density lipoprotein (LDL) adsorption (DSA) apheresis procedure has been shown to reduce lipoprotein levels and markers of blood rheology to improve coronary perfusion to the transplanted heart. We report the first described case of the stabilization and reversal of progressive transplant CAD with DSA. We followed a 50-year-old male orthotopic heart transplant recipient with familial hyperlipidemia refractory to lipid lowering therapy with bi-weekly LDL-apheresis (DSA system) for 12 months. Quarterly pre- and post-apheresis blood investigations were obtained, as well as annual adenosine thallium (AT) studies. Creatinine kinase (CPK), creatinine, LDL, fibrinogen, and lipoprotein (a) were reduced by 70%, 26%, 23%, 47%, and 47%, respectively. AT before the initiation of apheresis revealed a small to medium sized, partially reversible perfusion defect in the anterolateral and inferoapical walls, with an ejection fraction (EF) of 49%, elevated left ventricular volume (171 mL), and an elevated pulmonary-to-myocardial (PMR) count ratio of 0.67 (normal <0.52). After 12 months of LDL apheresis with DSA, a repeat AT demonstrated no fixed or reversible perfusion abnormality, an EF of 51%, and the PMR had normalized (0.46). This is the first reported case demonstrating that in a heart transplant survivor with hyperlipidemia and progression of coronary artery disease, LDL apheresis with DSA therapy can lead to regression and is an effective treatment of post-transplant coronary disease.