Influence of apolipoprotein E polymorphism on serum lipids and lipoprotein changes from childhood to adulthood: the Bogalusa Heart Study

The influence of apolipoprotein (apo) E polymorphism on serum lipoproteins from childhood to adulthood was examined in 1520 individuals, aged 5-14 years at baseline, followed over a 16-year period. At both times, the e2 allele associated with lower LDL cholesterol (P < 0.001) and higher HDL cholesterol (P < 0.05-0.01), the e4 allele with higher LDL cholesterol (P < 0.001). The e2 allele lowered the adulthood LDL cholesterol level to a greater extent than the childhood level (P < 0.05). With respect to tracking, at the lowest quartile of LDL cholesterol distribution, the persistence in ranks over time was higher in the apoE2 group with E2/3 and E2/2 phenotypes compared with the apoE3 group with E3/3 phenotype and the apoE4 group with E3/4 and E4/4 phenotypes (P = 0.001). Longitudinal increases in the ponderal index (weight/height3) lowered the adulthood HDL cholesterol to a larger extent in e2 carriers (P = 0.017). The interindividual variability in LDL cholesterol due to childhood and adulthood ponderal index was 1.8- to 2.3-fold greater in the apoE2 group versus the apoE3 group. Likewise, cigarette smoking, alcohol use and oral contraceptive use in adulthood explained greater variability in triglycerides (5.3-fold), VLDL cholesterol (7.8-fold) and HDL cholesterol (2.9-fold) in the apoE2 group versus the apoE3 group. Thus, the apoE locus influences not only the levels and tracking of certain lipoproteins from childhood to adulthood but also modulates the association between lifestyle-related factors and lipoproteins.     

Increased secretion of gelatinases A and B from the aortas of cholesterol fed rabbits: relationship to lesion severity

Basement membrane degrading metalloproteinases (gelatinases) have been implicated in the regulation of vascular smooth muscle cell migration and proliferation in culture and during neointima formation in vivo. We compared the expression and activation of gelatinases A and B in explants derived from the arch, mid and distal portions of thoracic aortas of normal rabbits and those given a 1% cholesterol-containing diet for 8 weeks. Neointimal/medial ratio was less than 0.01 in normal rabbits but was significantly increased by cholesterol feeding in the arch (1.08±0.26), mid (0.75±0.28) and distal (0.32±0.12) portions of the aorta (mean±S.E.M., n=6), and to a significantly (P<0.05) greater extent in the arch and mid than distal portions. Secretion of gelatinase B measured by densitometric scanning of zymograms was undetectable from normal aortas, but was significantly increased by cholesterol feeding in the arch (0.16±0.06), mid (0.26±0.08) and distal (0.11±0.05) portions (optical density units, n=6, each P<0.05 versus normal diet). The increase in gelatinase B expression was localised by in situ hybridisation to neointimal vascular smooth muscle cells, macrophages and endothelial cells. Secretion of pro-gelatinase A was detected from normal aortas; it was increased by cholesterol feeding from the arch (4.0 versus 2.8, P<0.05) and mid (3.6 versus 2.8, P<0.05) but not distal portions of the aorta (1.8 versus 1.2, n.s.). Similar results were obtained for active gelatinase A secretion from the arch (0.50 versus 0.28, P<0.05) and mid (0.47 versus 0.23, P<0.05) but not distal portions (0.19 versus 0.20, n.s.). Increases in pro- and active gelatinase A secretion therefore paralleled the severity of atheroma formation. The results imply that increased basement membrane turnover mediated by gelatinases occurs during cholesterol induced atherosclerosis formation.     

Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients

Baseline cholesterol metabolism was hypothesized to regulate responses of cholesterol synthesis and absorption, and serum cholesterol lowering to hypolipidaemic treatment. Thus, serum cholesterol and non-cholesterol sterols were measured before and during long-term simvastatin treatment (inhibition of cholesterol synthesis) and subsequent combination of statin with plant stanol ester margarine (inhibition of cholesterol absorption) consumption in subjects with low (n=15) and high (n=15) absorption of cholesterol, defined by respective low and high baseline ratios of serum cholestanol to cholesterol. Cholesterol synthesis (defined by precursors of cholesterol) was markedly reduced by the long-term statin treatment in both groups, but more extensively in the low than high absorption group (P<0.05), yet the respective serum cholesterol reductions were similar. From among the absorption markers, sitosterol and cholestanol ratios were correspondingly increased more in the low than in the high absorption group. Plant stanol ester margarine consumption, combined with chronic statin treatment, further lowered the serum cholesterol level (P<0.001) only in the high absorption group. The sum of cholesterol absorption markers was reduced more (P<0.05) in the high than in the low absorption group, while the non-significant serum cholesterol reduction of the low absorption group was associated with relatively high increase of cholesterol synthesis. Thus, stanol ester margarine combined with chronic simvastatin treatment reduces cholesterol absorption and serum cholesterol more consistently in subjects with high than low baseline absorption of cholesterol. The profile of baseline cholesterol metabolism determines the changes in synthesis and absorption of cholesterol to hypolipidaemic treatments, but affects less differently serum cholesterol level.     

Elevated plasma activator inhibitor 1 is not related to insulin resistance and to gene polymorphism in healthy centenarians

Previous studies demonstrated a relationship between the degree of insulin resistance and plasma plasminogen activator inhibitor type-1 (PAI-1) levels. We aim at investigating the relationship between the degree of insulin resistance and plasma PAI-1 levels in aged subjects (n=83) and in healthy centenarians (n=42). In all subjects the degree of insulin resistance was assessed by HOMA method. Our data demonstrated that healthy centenarians have higher plasma PAI-1 levels (73.1±13.9 vs 23.7±14.7 ng/ml, P<0.001) and lower degree of insulin resistance (1.4±0.5 vs 3.3±1.3, P<0.001) than aged subjects. In aged subjects plasma PAI-1 levels correlated with the degree of insulin resistance (r=0.61, P<0.001), fasting plasma triglycerides (r=0.74, P<0.001) and age (r=0.33, P<0.001). All such associations were lost in centenarians. Plasma PAI-1 Ag levels were also similar in aged subjects and centenarians even after categorization for PAI gene polymorphism. In multivariate analysis, a model made by age, sex, body mass index, fasting plasma triglycerides, HOMA and PAI-1 gene explained 65 and 50% of plasma PAI-1 level variations in aged subjects and centenarians, respectively. Nevertheless, HOMA (P<0.001) was significantly and independently associated with plasma PAI-1 levels only in aged subjects. In conclusion, our data demonstrates that in healthy centenarians, plasma PAI-1 were not associated with the degree of insulin resistance as in aged subjects. Frequency of PAI-1 genotype does not provide an explanation for such differences between aged subjects and centenarians.     

Normal angiogram after myocardial infarction in young patients:: A prospective clinical-angiographic and long-term follow-up study

This is an observational study in which we compared the clinical characteristics and the long-term course of young patients having acute myocardial infarction and angiographically normal coronary arteries and young patients showing significant coronary artery disease. In 87 patients aged ≤40 years who suffered an acute myocardial infarction, enrolled in a prospective study over a period of 6.5 years, coronary anatomy was determined by angiography within a month of admission. The risk factors, clinical data, ventricular function and the long-term outcome were compared between patients with normal angiograms (Group 1, n=12) and patients with coronary artery disease (Group 2, n=75). Patients in Group 1 had a lower number of risk factors associated with them (17% vs. 64% with >1 risk factor, P<0.005), were younger (32±5 vs. 36±4, P<0.01), lighter smokers (25% vs. 55% for ≥2 packs per day, P<0.05), had less frequent hypertension (0 vs. 25%, P<0.05), hypercholesterolemia (17% vs. 52%, P=0.02) and had a lower mean total cholesterol level (201±42 vs. 245±60 mg/100 ml, P<0.05) than patients in Group 2. They also had a more common onset of their infarction during heavy physical exertion (67% vs. 17%, P<0.001). A history of previous myocardial infarction, infarct location, global left ventricular function and regional wall motion were similar in both groups. After a mean follow-up period of 41±23 months, no patient died or had a second myocardial infarction in Group 1, and 4 patients had died in Group 2. The appearance of angina, less frequent in Group 1 than Group 2, tended to correlate with the extension of the coronary artery disease. We concluded that young patients with myocardial infarction have good prognosis irrespective of the coronary anatomy, although patients with normal coronary angiograms had less risk factors and less frequent new ischaemic events.     

Lipid-lowering therapy with fluvastatin inhibits oxidative modification of low density lipoprotein and improves vascular endothelial function in hypercholesterolemic patients

This prospective randomized trial was designed to elucidate clinically the effect of fluvastatin on inhibiting oxidation of the low density lipoprotein (LDL) and improving the vascular endothelial function as well as its lipid-lowering effects, in comparison with pravastatin. Of 64 consecutive dyslipidemic patients, 40 patients, whose level of total cholesterol or LDL-cholesterol maintained the criteria of the hypercholesterolemia in spite of 12-week dietary therapy, were randomly assigned to receive either fluvastatin (n=20) or pravastatin (n=20). We assessed the titer of antibody against oxidized LDL (anti-Ox-LDL) as a biomarker for LDL-oxidation, and the forearm blood flow response during reactive hyperemia by venous occlusion plethysmography, which indicates the endothelium-dependent vasodilator capacity. After the 16-week lipid-lowering therapy, the anti-Ox-LDL titer significantly decreased in the fluvastatin group (P<0.01) but did not change in the pravastatin group. The percent increase in the forearm blood flow at the peak reactive hyperemia from the baseline value (%RH) significantly increased in the fluvastatin group (P<0.001) but did not change in the pravastatin group. The ratio of the %RH after the therapy over the baseline value negatively correlated with that of the anti-Ox-LDL titer (R=0.73, P<0.001) in all patients. Fluvastatin may serve as an ideal drug for reducing the risk of atherosclerosis, not only by its cholesterol-lowering effect but also by its unique effects of inhibiting LDL oxidation and improving the vascular endothelial function.     

Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction

Elevated plasminogen activator inhibitor type 1 (PAI-1) activity has been shown to correlate with plasma insulin, proinsulin-like molecules, serum triglycerides and insulin sensitivity in both non-insulin dependent diabetic (NIDDM) subjects and subjects with coronary heart disease. We examined the relative roles of these variables in determining PAI-1 activity in four groups of male caucasian subjects: non-diabetic subjects with (n=38) and without (n=38) previous myocardial infarction (MI) and NIDDM subjects with (n=26) and without (n=30) previous MI. Insulin and proinsulin-like molecules were measured using specific two-site immunometric assays and insulin sensitivity estimated using the Homeostasis Model Assessment (HOMA) model. Subjects were comparable in age and body mass index. In univariate analysis, there were significant correlations of PAI-1 activity with intact and des-31,32-proinsulin and serum triglycerides in non-diabetic subjects with (r=0.52, P=0.001; r=0.58, P<0.001; r=0.41, P=0.010) and without (r=0.31, P=0.056; r=0.46, P=0.006; r=0.41, P=0.011) MI, but not with plasma insulin or insulin sensitivity. In NIDDM subjects, PAI-1 activity correlated significantly with intact and des-31,32-proinsulin and serum triglyceride (r=0.47, P=0.015; r=0.58, P=0.002; r=0.44, P=0.026) only in subjects with MI. In multiple regression analysis, MI was the most important determinant of PAI-1 activity levels (r²=0.31, F=55.6, P<0.001). In conclusion, concentrations of proinsulin-like molecules and serum triglycerides appear to be stronger determinants of PAI-1 activity than plasma insulin or insulin sensitivity in both NIDDM subjects and non-diabetic subjects with and without MI. However, the relationship of MI with PAI-1 activity is independent of these variables.     

Apolipoprotein E polymorphism influences lipid phenotypes in Chinese families with familial combined hyperlipidemia.

BACKGROUND: Apolipoprotein E (apoE) polymorphism is associated with changes in the lipoprotein profile of individuals with familial combined hyperlipidemia (FCHL), but its effects on the lipoprotein profiles of members of Chinese families with FCHL remain uncertain. METHODS AND RESULTS: 43 FCHL families (n=449) and 9 normolipidemic families (n=73) were recruited to assess the influence of apoE polymorphism on plasma lipids. The relative frequency of the epsilon4 allele in affected and unaffected FCHL relatives, spouses and normolipidemic members was 13.8%, 5.3%, 9.1% and 6.8%, respectively, with a significantly higher frequency in affected FCHL relatives, compared with unaffected FCHL relatives or normolipidemic members (p=0.0002 or p=0.029). In FCHL relatives, the apoE4 subset (E4/4 and E4/3) exhibited significantly higher levels of apoB, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) than did the apoE3 (E3/3) subset, especially in women (all p<0.05), and there was significant elevation of LDL-C concentrations in men only (p<0.05). In men, the apoE2 (E3/2) subset indicated a decreased level of apoB and increased apoA1 compared with those in the apoE3 subset (p<0.05). Conclusions: ApoE polymorphism appears to be associated with variance of the lipoprotein phenotype in Chinese families with FCHL.     

Duodenal epithelial transport in functional dyspepsia: Role of serotonin

AIM: To investigate functional duodenal abnormalities in functional dyspepsia (FD) and the role of serotonin (5-hydroxytryptamine, 5-HT) in mucosal ion transport and signalling. METHODS: Duodenal mucosal biopsies were obtained from 15 patients with FD and 18 healthy controls. Immunohistochemistry was used to study the number of 5-HT-containing cells and real-time polymerase chain reaction for expression of 5-HT receptors 1A, 1B, 2A, 2B, 3A, 3B, 3C, 3D, 3E, 4 and 7, as well as expression of the serotonin re-uptake transporter (SERT) gene SLC6A4 and tryptophan hydroxylase 1 (TPH1). Biopsies were mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current (SCC). RESULTS: Conductance was lower in FD [42.4 ± 4.7 mS/cm² (n = 15) vs 62.5 ± 4.5 mS/cm² (n = 18), P = 0.005]. 5-HT induced a dose dependent rise in SCC in both FD (n = 8) and controls (n = 9), the rise was lower in FD (P < 0.001). Mean number of 5-HT stained cells per high power field was the same [34.4 ± 8.4 in FD (n = 15) and 30.4 ± 3.7 in controls (n = 18), P = 0.647]. The following genes were highly expressed: 5-HT receptor HTR3E, HTR4, HTR7, SERT gene (SLC6A4) and TPH1. Differences in expression levels were observed for HTR3E (higher expression in FD, P = 0.008), HTR7 (lower expression in FD, P = 0.027), SLC6A4 (higher expression in FD, P = 0.033) and TPH1 (lower expression in FD, P = 0.031). CONCLUSION: Duodenal ion transport in response to exogenous 5-HT is abnormal in FD patients and associated with high expression of the HTR3E receptor and the serotonin transporter.     

Reduced platelet serotonin content and release in familial hypercholesterolaemia

Plasma and platelet serotonin (5-HT) concentrations, and resting and collagen-induced 5-HT release in platelet-rich plasma were studied in normal and familial hypercholesterolaemic (FH) subjects. Platelet 5-HT concentrations were significantly reduced (−37%, P<0.01) in FH patients whilst mean plasma concentrations, although increased, were not significantly different from those in normal subjects. Platelet 5-HT correlated negatively with plasma cholesterol when the data for normal subjects and FH patients were combined (r=−0.48, P=0.005). It also correlated negatively with low-density lipoprotein (LDL) (FH data, r=−0.59, P=0.03; normal and FH data, r=−0.49, P=0.004) but positively with high-density lipoprotein (HDL) (FH, r=0.79, P=0.001; normal and FH, r=0.37, P=0.03). Collagen (5–160 μg/ml) stimulated platelet 5-HT release occurred in a concentration-dependent manner. In FH patients stimulated 5-HT release was reduced (10 μg/ml collagen, −40%, P<0.05) and accompanied by increased collagen EC₅₀ values (P<0.02). Resting 5-HT release was increased substantially in FH patients but not significantly. Our data provide evidence for a relationship between circulating cholesterol and platelet serotonergic mechanisms. It is proposed that abnormalities relating to platelet-plasma 5-HT dynamics, perhaps due to enhanced platelet activity or decreased platelet uptake, may contribute to the cardiovascular complications in FH.     

Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels

Background: Oxidation processes play an important role in atherogenesis. Bilirubin IX is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). Methods: The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n=50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n=2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n=38) and control subjects (n=38). Results: The prevalence of IHD in GS subjects (aged 49.7±9.0 years) was 2% (0.05–10.7%, 95% confidence interval), compared to 12.1% in a general population (P<0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P<0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. Conclusions: In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity.     

Age-dependent slowing of enteric axonal transport in insulin-resistant mice

AIM:To investigate retrograde tracer transport by gastric enteric neurons in insulin resistant mice with low or high glycosylated hemoglobin(Hb).METHODS:Under anesthesia,the retrograde tracer fluorogold was superficially injected into the fundus or antrum using a microsyringe in KK Cg-Ay/J mice prior to onset of type 2 diabetes mellitus(T2DM;4 wk of age),at onset of T2DM(8 wk of age),and after 8,16,or 24 wk of untreated T2DM and in age-matched KK/HIJ mice.Six days later,mice were sacrificed by CO 2 narcosis followed by pneumothorax.Stomachs were removed and fixed.Sections from fundus,corpus and antrum were excised and mounted on a glass slide.Tracer-labeled neurons were viewed using a microscope and manually counted.Data were expressed as the number of neurons in short and long descending and ascending pathways and in local fundus and antrum pathways,and the number of neurons in all regions labeled after injection of tracer into either the fundus or the antrum.RESULTS:By 8 wk of age,body weights of KKAy mice(n=12,34±1 g) were heavier than KK mice(n=17,29±1 g;F(4,120)=4.414,P=0.002] and glycosylated Hb was higher [KK:(n=7),4.97%±0.04%;KKAy:(n=6),6.57%±0.47%;F(1,26)=24.748,P<0.001].The number of tracer labeled enteric neurons was similar in KK and KKAy mice of all ages in the short descending pathway [F(1,57)=2.374,P=0.129],long descending pathway [F(1,57)=0.922,P=0.341],local fundus pathway [F(1,53)=2.464,P=0.122],local antrum pathway [F(1,57)=0.728,P=0.397],and short ascending pathway [F(1,53)=2.940,P=0.092].In the long ascending pathway,fewer tracer-labeled neurons were present in KKAy as compared to KK mice [KK:(n=34),302±17;KKAy:(n=29),230±15;F(1,53)=8.136,P=0.006].The number of tracer-labeled neurons was decreased in all mice by 16 wk as compared to 8 wk of age in the short descending pathway [8 wk:(n=15),305±26;16 wk:(n=13),210±30;F(4,57)=9.336,P<0.001],local antrum pathway [8 wk:(n=15),349±20;16 wk:(n=13),220±33;F(4,57)=8.920,P<0.001],short ascending pathway [8 wk:(n=14),392±15;16 wk:(n     

Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit

Mononuclear cells, isolated from the blood of hyperlipidaemic patients, are hyper-reactive and possess an increased propensity to adhere to vascular endothelial cells. Hyperlipidaemia is also associated with a dysfunctional endothelium, to which mononuclear cells stick with greater avidity. In order to assess the importance of lipid peroxidation and free- adical generation in these processes, we have investigated the effects of probucol on mononuclear cell adhesion to vascular endothelial cells in vivo and in vitro in the cholesterol-fed rabbit. New Zealand White rabbits were fed either: (i) control chow (n = 15), (ii) 2% cholesterol (n = 11), or (iii) 2% choles erol with 1% probucol (n = 11). Mononuclear cell adherence to endothelium in the common carotid artery was assessed 5 weeks after the start of the experimental diet using the Hoechst 33342 staining technique. The 2% cholesterol diet caused a more than 6-fold increase in mean mononuclear cell adherence (P < 0.001). Concurrent probucol therapy abrogated the effects of cholesterol feeding, and in animals in this group, in vivo mononuclear cell adherence did not differ significantly from control animals. In vivo mononuclear cell adherence was directly related to serum cholesterol levels (r = 0.68, P < 0.0001) and inversely related to serum probucol concentrations (r = −0.63, P < 0.002). Concurrent probucol therapy also reduced the in vitro binding of mononuclear cells, isolated from hypercholesterolaemic animals, to endothelial cell monolayers (P < 0.01). These data suggest that the increased binding of mononuclear cells to vascular endothelium of cholesterol-fed rabbits may be a free radical mediated process that is inhibited by antioxidants.     

The development of the adrenal gland zona glomerulosa in the rat. A morphological, immunohistochemical and biochemical study

We have studied the development of the adrenal gland in the rat comprising the ages ranging from 0 to 90 days after birth. The weight of the animals and that of the adrenal glands demonstrated a linear growth with time until 75 days, both in males and females. The area of the zona glomerulosa (ZG) increased in size from birth until ≈40 days of age. After that, growth had a much smaller slope (females, r=0.84, P<0.001; males, r=0.81, P<0.001). Aldosterone secretion had a marked increase until 20 days of age and thereafter demonstrated a tendency for a decrease (females, r=−0.19, P<0.02; males r=−0.26, P<0.001). Plasma renin activity followed a trend parallel to that of aldosterone. The steroid precursor 18-OH-deoxycorticosterone (18-OH-DOC) demonstrated a different course as it increased progressively with age especially in the females (females, r=0.57, P<0.001; males, r=0.40, P<0.001). The expression of the enzyme 3-β-hydroxysteroid dehydrogenase (3-β-HSD) was also studied by immunohistochemistry and it was shown to be very low at birth and starting to increase by 10 days of age. After 30/40 days of age the amount of this enzyme existing in the ZG was comparable with that of the outer zona fasciculata (ZF). We conclude that the development of the ZG in the rat has particularities that make it different from that of the rest of the cortex.     

Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

Background: Proteolytic imbalance might determine arterial remodeling and plaque destabilization in atherosclerotic vessels. The aim of this study was to examine differences in the patterns of metalloproteinases (MMPs) and MMP inhibitor (TIMP-1) expression in advanced human atheromas, both in relation to the plaque features and the vascular bed involved. Methods and results: Immunohistochemistry for MMP-1, -3, -9 and TIMP-1 as well as the collagen content were measured in vascular sections from patients undergoing peripheral revascularization (carotid n=11, femoral n=23) and aorto-coronary bypass surgery (mammary arteries n=20, as controls). Increased expression of all MMPs was detected in atherosclerotic as compared with control sections (P<0.01). Aneurismal plaques showed a significant increase of MMP-1 and-3 and a reduction in total collagen (P<0.05) in relation to occlusive lesions. Calcification areas in atherosclerotic plaques were consistently associated with increased TIMP-1 expression (P<0.01). Finally, MMP-9 expression was higher in occlusive lesions from carotid than femoral arteries (P<0.01). Conclusions: Aneurysm lesions expressed higher MMP-1 and-3 expression than occlusive plaques, and MMP-9 was mainly detected in carotid as compared with femoral arteries. TIMP-1 was associated with arterial calcification. These differences in the MMPs/TIMP-1 expression might determine the evolution of advanced atherosclerotic plaques and contribute to its vulnerability.     

The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study).

BACKGROUND: Statins and cholesterol absorption inhibitors lower the concentration of C-reactive protein (CRP). The genetic polymorphism of apolipoprotein (apo) E is a strong endogenous determinant of sterol homeostasis. We therefore examined the relationship of CRP to the apoE polymorphism. METHODS AND RESULTS: We studied 739 and 570 subjects with or without stable angiographic coronary artery disease (CAD), respectively. In carriers of apoE2, apoB was lower (P<0.001) than in apoE3/3 homozygotes; in individuals with apoE3/4 and apoE4/4, it was higher (P<0.001). Both in the presence and absence of CAD, CRP was higher in carriers of apoE2 (P=0.002) and apoE3/3 homozygotes (P=0.032) than in individuals with apoE3/4 or apoE4/4. Fibrinogen and white cell count were not related to the apoE genotype. CRP was associated with CAD. Compared to the lowest tertile, crude odds ratios were 1.87 (95% confidence interval (CI), 1.43-2.45, P<0.001) and 2.24 (95% CI, 1.71-2.94, P<0.001) in the second and third tertile. In carriers of apoE2, the use of tertiles defined in controls with apoE2 only diminished the odds ratios for CAD. In apoE3/4 heterozygotes or apoE4/4 homozygotes, the use of tertiles specific for this group only slightly increased the odds ratios. CONCLUSIONS:: The concentration of CRP, but not fibrinogen nor white blood cells is associated with the apoE polymorphism. The activity of the mevalonate pathway in the liver may be related to the metabolism of CRP. The predictive value of CRP for CAD may be modified by the apoE polymorphism.     

Cognitive dysfunction in older subjects with diabetes mellitus: impact on diabetes self-management and use of care services

Objective: To determine whether cognitive impairment is associated with changes in self-care behaviour and use of health and social services in older subjects with diabetes mellitus. Research design and methods: This was a community based, case-control study of subjects registered with general practices participating in the All Wales Research into Elderly (AWARE) Diabetes Study. The 396 patients aged 65 years or older with known diabetes mellitus were compared with 393 age- and sex-matched, non-diabetic controls. Adjusted odds ratio estimates of normal performance on Mini-Mental State Examination (MMSE) and Clock Drawing Test (numbers and hands) were determined. Information on self-care behaviours and use of services was obtained. Results: A total of 283 (71%) diabetic subjects scored 24 or more on MMSE, compared with 323 (88%) of controls (OR 0.54, P<0.0005). The mean (S.D.) scores were 24.5 (5.1) and 25.7 (4.3), respectively (difference between means 1.22; 95% CI 0.56, 1.88; P<0.001). Clock testing demonstrated that 257 (65%) and 286 (72%) diabetic subjects correctly placed the numbers and hands, respectively, compared with 299 (76%) and 329 (84%) of controls (OR 0.59, P<0.001 and P<0.52, P<0.0005, respectively). Both test scores declined with increasing age, earlier school leaving age and deteriorating visual acuity. Of other variables examined, only need for oral hypoglycaemic drugs or insulin, history of stroke, dementia or Parkinson's disease and symptoms of autonomic neuropathy significantly impaired one or more cognitive test scores. The odds ratios (95% CI) for normal cognitive test results in subjects with diabetes after adjusting for all significant variables was 0.74 (0.56, 0.97), P=0.029 for MMSE scores and 0.63 (0.44, 0.93), P=0.019, and 0.58 (0.38, 0.89), P=0.013, for the numbers and hands parts of the clock test, respectively. In comparison with diabetic subjects with no evidence of cognitive impairment, diabetic subjects with an MMSE score <23 were significantly less likely to be involved in diabetes self-care (P<0.001) and diabetes monitoring (P<0.001). A low MMSE score was also significantly associated with higher hospitalisation in the previous year (P=0.001), reduced ADL (activities of daily living) ability (P<0.001) and increased need for assistance in personal care (P=0.001). Conclusions: Elderly subjects with predominantly Type 2 diabetes mellitus display significant excess of cognitive dysfunction, associated with poorer ability in diabetes self-care and greater dependency. Routine screening of cognition in older subjects with diabetes is recommended.     

Changes in serum apolipoprotein and lipoprotein profile after alcohol withdrawal: effect of apolipoprotein E polymorphism

BACKGROUND: Apolipoprotein (Apo) E genotype and alcohol consumption or withdrawal strongly affect lipoprotein (Lp) metabolism and, as with any genetic and environmental factors, they might interact. The aim of this study was to investigate this gene/environment interaction by analyzing the effect of the apoE genotype on the alcohol withdrawal-induced alterations in the serum Apo and Lp profile. METHODS: ApoE genotypes and concentrations of serum cholesterol, triglyceride, and Lps containing apoA-I, A-II, B, E, and C-III were determined in 84 male alcohol abusers before and after 3 weeks of abstinence. RESULTS: After withdrawal, concentrations of serum apoA-I, LpA-I, LpA-I/A-II, apoC-III, LpC-III-non-B, apoE, and LpE-non-B significantly decreased, whereas those of triglycerides and apoB increased; levels of cholesterol, LpC-III:B, and LpB:E were not affected. ANOVA shows that apoE polymorphism effects were quite similar before and after alcohol withdrawal on all serum Apos and Lps (the interaction term between withdrawal and apoE genotype was not significant). The only interaction term that was borderline significant (p < or = 0.10) concerned the apoB concentration. Before withdrawal, no association between apoB level and apoE polymorphism was observed, whereas after abstinence, a borderline significant (p < or = 0.10) gradient of concentration across the three groups of subjects (epsilon2 carriers < epsilon3/epsilon3 < epsilon4 carriers) was noticed. CONCLUSIONS: Alcohol abstinence causes major changes in the antiatherogenic Apos and Lps and may increase those known to be atherogenic. Heavy alcohol consumption seems to alter the effect of apoE polymorphism on apoB levels, and further investigations are needed to clarify the mechanisms involved in this phenomenon: a defect in sialylation of apoE, formation of acetaldehyde adducts on apoB, or both.     

Acceptance of living liver donation among medical students: A multicenter stratified study from Spain

AIM: To analyze the attitude of Spanish medical students toward living liver donation(LLD) and to establish which factors have an influence on this attitude.METHODS: Study type: A sociological, interdisciplinary, multicenter and observational study. Study population: Medical students enrolled in Spain(n = 34000) in the university academic year 2010-2011. Sample size: A sample of 9598 students stratified by geographical area and academic year. Instrument used to measure attitude: A validated questionnaire(PCID-DVH RIOS) was self-administered and completed anonymously. Data collection procedure: Randomly selected medical schools. The questionnaire was applied to each academic year at compulsory sessions. Statistical analysis: Student′s t test, χ2 test and logistic regression analysis.RESULTS: The completion rate was 95.7%(n = 9275). 89%(n = 8258) were in favor of related LLD, and 32%(n = 2937) supported unrelated LLD. The following variables were associated with having a more favorable attitude:(1) age(P = 0.008);(2) sex(P 0.001);(3) academic year(P 0.001);(4) geographical area(P = 0.013);(5) believing in the possibility of needing a transplant oneself in the future(P 0.001);(6) attitude toward deceased donation(P 0.001);(7) attitude toward living kidney donation(P 0.001);(8) acceptance of a donated liver segment from a family member if one were needed(P 0.001);(9) having discussed the subject with one's family(P 0.001) and friends(P 0.001);(10) a partner's opinion about the subject(P 0.001);(11) carrying out activities of an altruistic nature; and(12) fear of the possible mutilation of the body after donation(P 0.001).CONCLUSION: Spanish medical students have a favorable attitude toward LLD.     

Interaction between the APOC3 gene promoter polymorphisms, saturated fat intake and plasma lipoproteins

Objective: To test the hypothesis that APOC3 gene polymorphisms modulate the effect of saturated fat (SAT) intake on plasma lipoproteins and LDL size. Methods: We studied 336 randomly selected residents from Costa Rica. APOC3 polymorphisms were genotyped in the promoter region (T-455C, T-625del) and the C3238G 3′ untranslated region (UTR). Dietary intake was assessed by a validated food-frequency questionnaire (FFQ) and median saturated fat intake (11%) was used to define low and high exposure to saturated fat. Results: Allele frequencies were 0.49, 0.51 and 0.19 for the APOC3-455C, -625de1, and APOC3 3238G alleles, respectively. Significant gene–diet interactions were found for total (P<0.0004) and LDL cholesterol (P<0.01). In homozygotes for the APOC3-455T-625T alleles, saturated fat intake was associated with a 13% increase in total cholesterol (P<0.001) and a 20% increase in LDL cholesterol (P<0.001). In contrast, no association between plasma lipoproteins and saturated fat intake was found among carriers of the APOC3-455C-625del allele. The APOC3 3238G UTR allele did not modify the observed association. Conclusion: Compared to a diet high in saturated fat, a habitually low saturated fat diet is associated with a beneficial lipoprotein profile only among homozygotes of the APOC3 promoter 455T-625T polymorphism.