Chemical identification and quantification of volatile organic compounds emitted by sewage sludge.

The recycling of organic waste products (e.g. sewage sludge, SS) is currently being promoted as a substitute for mineral fertilizers for agricultural lands. The spreading of SS allows the recycling of the nutrients and organic matter it contains. SS contains various pollutants such as volatile organic compounds (VOCs) that adversely affect the ecosystem and human health through ozone production and serve as critical precursors of atmospheric secondary organic aerosols. There are very few studies quantifying the gaseous compounds emitted from SS, and those studies primarily address their odorant properties for identifying suitable odour abatement techniques. There is an urgent need for more comprehensive quantitative information on VOCs emitted from SS as aerosol precursors. In this context, an experimental study was performed on SS samples taken from a wastewater treatment plant located in France. Undigested SS (UDSS), digested SS (DSS) and SS with 30% and 60% dryness were collected from different stages of treatment sequence and analyzed using atmospheric simulation chambers coupled to proton-transfer-reaction quadrupole ion-guide time-of-flight mass spectrometer. Our study revealed that SS samples emitted a large spectrum of VOCs. 380 compounds were detected, quantified and classified into different chemical groups. The VOC emissions increased with the increase in the dryness of the sample; the highest being in SS 60%, followed by SS 30%, UDSS and DSS. OVOCs were dominant in SS 60%. The statistical analysis showed that the anaerobic digestion and the dewatering to 60% of dryness decreased the emissions of sulphuric compounds. Aromatic compounds and indoles (e.g. skatole) were emitted significantly from the UDSS. Some of these VOCs can serve as precursor gases for atmospheric aerosol formation. The experimental dataset obtained in this study provides an accurate inventory reference for the VOC emissions from SS samples and shows the impacts of the treatment on emission characteristics of VOCs.

On the benefits of using multivariate analysis in mass spectrometric studies of combustion-generated aerosols.

The intricate chemistry of the carbonaceous particle surface layer (which drives their reactivity, environmental and health impacts) results in complex mass spectra. In this respect, detailed molecular-level analysis of combustion emissions may be challenging even with high-resolution mass spectrometry. Building on a recently proposed comprehensive methodology (encompassing all stages from sampling to data reduction), we propose herein a comparative analysis of soot particles produced by three different sources: a miniCAST standard generator, a laboratory diffusion flame and a single cylinder internal combustion engine. The surface composition is probed by either laser or secondary ion mass spectrometry. Two examples of multivariate analysis, Principal component analysis and hierarchical clustering analysis proved their efficiency in both identifying general trends and evidencing subtle differences that otherwise would remain unnoticed in the plethora of data generated during mass spectrometric analyses. Chemical information extracted from these multivariate statistical procedures contributes to a better understanding of fundamental combustion processes and also opens to practical applications such as the tracing of engine emissions.

Glycerol metabolism alteration in adipocytes from n3-PUFA-depleted rats, an animal model for metabolic syndrome.

Aquaglyceroporin 7 (AQP7) is a glycerol transporter expressed in adipocytes. Its expression has been shown to be modulated in obesity. Metabolic syndrome is characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension. An animal model displaying several features of metabolic syndrome was used to study the AQP7 expression at both mRNA and protein level and glycerol flux in adipocytes. Second generation n3-PUFA depleted female rats is a good animal model for metabolic syndrome as it displays characteristic features such as liver steatosis, visceral obesity, and insulin resistance. Our data show a reduced expression of AQP7 at the protein level in adipose tissue from n3-PUFA-depleted rats, without any changes at the mRNA levels. [U-(14)C]-Glycerol uptake was not modified in adipocytes from n3-PUFA-depleted animals.

Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization.

UNLABELLED: Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) levelabove 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). CONCLUSION: The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.

Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition.

BACKGROUND: There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism. RESULTS: n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPAR gamma), and an increased beta-oxidation (CPT1, PPAR alpha and PGC1 alpha) without modification of fatty acid esterification (DGAT2, GPAT1), secretion (MTTP) or intracellular transport (L-FABP). Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice. CONCLUSION: n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between beta-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.

Rapid reduction of liver steatosis in omega3-depleted rats injected with a novel lipid emulsion.

The bolus intravenous administration of a novel medium-chain triglyceride: fish oil emulsion (MCT:FO) to normal subjects was recently found to increase within 60 min the amount of long-chain polyunsaturated omega3 fatty acids ( omega3) in platelet and leukocyte phospholipids and, hence, was proposed as a tool to prevent such pathological events as cardiac arrhythmia in selected patients who have to undergo urgent anesthesia and/or surgery. This study investigates whether other cells located outside the vascular bed may also benefit from this procedure for replenishing phospholipids with omega3. For such a purpose, the MCT:FO emulsion (1.0 ml) was injected into normal or omega3-depleted rats examined, one hour later, for the content and fatty acid pattern of liver triglycerides and phospholipids. Control experiments included the administration of saline or a medium-chain triglyceride:olive oil emulsion. The results reveal that the bolus intravenous injection of MCT:FO to the omega3-depleted rats resulted in the enrichment of liver phospholipids in omega3 and a marked reduction in hepatic steatosis. In conclusion, it is proposed that such a procedure may indeed allow a rapid supply of omega3 not only to circulating and vascular endothelial cells but also to extravascular cells, with a resulting correction of the biochemical and biophysical defects linked to a deficiency in these fatty acids.

Vitamin E transfer from lipid emulsions to plasma lipoproteins: mediation by multiple mechanisms.

The present study determined alpha-tocopherol mass transfer from an alpha-tocopherol-rich emulsion to LDL and HDL, and assessed the potential of different mechanisms to modulate alpha-tocopherol transfers. Emulsion particles rich in alpha-tocopherol were incubated in vitro with physiological concentrations of LDL or HDL. The influence of plasma proteins was assessed by adding human lipoprotein poor plasma (LPP) fraction with intact vs heat inactivated PLTP, or with a specific cholesteryl ester transfer protein (CETP) inhibitor, or by adding purified PLTP or pig LPP which lacks CETP activity. After 4 h incubation in absence of LPP, alpha-tocopherol content was increased by ~80% in LDL and ~160% in HDL. Addition of LPP markedly enhanced alpha-tocopherol transfer leading to 350-400% enrichment in LDL or HDL at 4 h. Higher (~10 fold) enrichment was achieved after 20 h incubation with LPP. Facilitation of alpha-tocopherol transfer was (i) more than 50% higher with human vs pig LPP (despite similar PLTP phospholipid transfer activity), (ii) reduced by specific CETP activity inhibition, (iii) not fully suppressed by heat inactivation, and (iv) not restored by purified PLTP. In conclusion, alpha-tocopherol content in LDL and HDL can be markedly raised by rapid transfer from an alpha-tocopherol-rich emulsion. Our results indicate that alpha-tocopherol mass transfer between emulsion particles and lipoproteins is mediated by more than one single mechanism and that this transfer may be facilitated not only by PLTP but likely also by other plasma proteins such as CETP.

Fragmentation branching ratios of highly excited hydrocarbon molecules CnH and their cations CnH+ (n

We have measured fragmentation branching ratios of neutral C(n)H and C(n)H(+) cations produced in high velocity (4.5 a.u) collisions between incident C(n)H(+) cations and helium atoms. Electron capture gives rise to excited neutral species C(n)H and electronic excitation to excited cations C(n)H(+). Thanks to a dedicated setup, based on coincident detection of all fragments, the dissociations of the neutral and cationic parents were recorded separately and in a complete way. For the fragmentation of C(n)H, the H-loss channel is found to be dominant, as already observed by other authors. By contrast, the H-loss and C-loss channels equally dominate the two-fragment break up of C(n)H(+) species. For these cations, we provide the first fragmentation data (n>2). Results are also discussed in the context of astrochemistry.

Glucose intolerance associated to insulin resistance and increased insulin secretion in rats depleted in long-chain omega3 fatty acids.

An intragastric D-glucose tolerance test was performed, after overnight starvation, in female rats depleted in long-chain polyunsaturated omega3 fatty acids (omega3D rats) and control rats of same age and gender. The plasma D-glucose and insulin concentrations, insulinogenic index, and HOMA for insulin resistance were all higher, after overnight starvation, in omega3D rats than in control animals. Over the 120-minute period following the intragastric administration of D-glucose, the area under the curve for the same four variables was also higher in omega3D rats than in control animals. In addition to visceral obesity, liver steatosis, hypertension, and cardiac hypertrophy, the omega3D rats thus display further features of the metabolic syndrome, namely glucose intolerance and insulin resistance, despite hyperinsulinemia.

Changes in plasma LDL and HDL composition in patients undergoing cardiac surgery.

Changes of lipoprotein composition have been mainly reported in conditions of sepsis. This study characterized compositional changes in LDL and HDL during the acute phase response following cardiac surgery with cardiopulmonary bypass. Twenty-one patients undergoing cardiac surgery were included in this study. Blood samples were drawn before operation and on day 2 post-surgery. In parallel to plasma lipids and antioxidant status, lipoproteins were analyzed for lipid, apolipoprotein (apo), hydroperoxide and alpha-tocopherol content. Beyond decreases in lipid concentrations and antioxidant defenses, cardiac surgery induced substantial modifications in plasma lipoproteins. ApoB decrease in LDL fraction (-46%; P < 0.0001) reflected a marked reduction in the circulating particle number. LDL cholesteryl ester content relative to apoB concentration remained unchanged post-surgery while triglyceride (+113%; P < 0.001), free cholesterol (+22%; P < 0.05) and phospholipid (+23%; P < 0.025) were raised relative to apoB indicating increased particle size. In HDL, an abrupt rise of apoSAA (P < 0.05) was observed together with a decrease of apoA1 (-22%; P < 0.005). Cholesteryl ester content in HDL fraction decreased in parallel to apoA1 concentration while triglycerides, free cholesterol and phospholipids increased relative to apoA1. In contrast to unchanged alpha-tocopherol content, hydroperoxide content was increased in LDL and HDL. By comparison to sepsis, cardiac surgery induces a comparable reduction in circulating LDL but a more limited decrease in HDL particles. Furthermore, in contrast, cardiac surgery induces an increase in polar and non-polar lipids, as well as of particle size in both LDL and HDL.

Accelerated clearance of plasma triglycerides and free fatty acids in omega3-depleted rats.

The present study aims mainly at exploring the effects of a severe depletion in polyunsaturated long-chain omega3 fatty acids upon the fate of circulating lipids. The plasma concentration and fatty acid pattern of triglycerides, diglycerides, free fatty acids, and phospholipids were measured in omega3-depleted and control rats injected intravenously one hour before sacrifice with either saline, a control medium-chain triglyceride:olive oil emulsion or a medium-chain triglyceride:fish oil emulsion recently found to rapidly increase the phospholipid content of C20:5omega3 and C22:6omega3 in different cell types. The estimated fractional removal rate of the injected triglycerides and the clearance of free fatty acids from circulation were both higher in omega3-depleted rats than in control animals. The injection of the lipid emulsions apparently inhibited intracellular lipolysis, this being least pronounced in omega3-depleted rats. The increased clearance of circulating triglycerides and unesterified fatty acids in omega3-depleted rats may favor the cellular accumulation of lipids. In turn, such an accumulation and the lesser regulatory inhibition of tissular lipolysis may match the increased clearance of circulating unesterified fatty acids and, hence, account for the lack of any significant difference in plasma unesterified fatty acid concentration between these and control animals.

Rapid effects of the intravenous injection of a medium-chain triglyceride: fish oil emulsion on the triglyceride fatty acid pattern of soleus muscle from omega3 fatty acid-depleted rats.

Second generation rats depleted in long-chain polyunsaturated omega3 fatty acids display several features of the metabolic syndrome, including visceral obesity, liver steatosis, insulin resistance, hypertension, and cardiac hypertrophy. In the framework of an extensive study on such metabolic, hormonal and functional perturbations, the phospholipid fatty acid pattern and ex vivo metabolism of D-glucose were recently investigated in the soleus muscle of these omega3-depleted rats. The present study deals with the triglyceride fatty acid content and pattern of the soleus muscle in control animals and omega3-depleted rats. Some of the latter rats were injected intravenously 60-120 minutes before sacrifice with either an omega3 fatty acid-rich medium-chain triglyceride/fish oil emulsion (omega3-FO rats) or a control medium-chain triglyceride/olive oil emulsion (omega3-OO rats). The total fatty acid content of triglycerides was comparable in control and omega3-depleted rats and, in both cases, inversely related to their C20:4omega6 relative content. At variance with the situation found in control rats, no long-chain polyunsaturated omega3 fatty acid (C18:3omega3, C20:5omega3, C22:5omega3, C22:6omega3) was detected in the omega3-depleted rats. Unexpectedly, the triglyceride content in most long-chain polyunsaturated omega6 fatty acids (C18:2omega6, C20:3omega6, C20:4omega6 and C22:4omega6) had also decreased in the latter rats. Moreover, the activity of Delta9-desaturase was apparently increased in the omega3-depleted rats, as judged from the C16:1omega7/C16:0 and C18:1omega9/C18:0 ratios. The omega3-FO rats differed from omega3-OO rats by a lower contribution of C18:2omega6 metabolites (C18:3omega6, C20:3omega6, C20:4omega6 and C22:4omega6). These findings indicate that the prior injection of the medium-chain triglyceride/fish oil emulsion, known to increase the muscle phospholipid content in long-chain polyunsaturated omega3 fatty acids, may nevertheless accentuate the depletion in long-chain polyunsaturated omega6 fatty acids otherwise found in the triglycerides of omega3-depleted rats. Such a dual effect is reminiscent of that observed, under the same experimental conditions, for selected variables in D-glucose metabolism in the soleus muscle.

Adverse effects of conjugated alpha-linolenic acids (CLnA) on lipoprotein profile on experimental atherosclerosis in hamsters.

Conjugated linoleic acids (CLAs) such as rumenic acid (RA) have the potential to alter blood lipid profiles in animals and in humans. In contrast, physiological effects of conjugated α-linolenic acids (CLnAs), which concomitantly are omega-3 and conjugated fatty acids, are still unknown. The aim of this study was to evaluate the potential of CLnA to interfere in early steps of atherosclerosis by altering lipoprotein profiles and fatty streaks in the aortas. F1B hamsters were fed a control or one of the three hypercholesterolemic (HC) diets: HC-control, HC-RA (18:2 cis-9, trans-11) or HC-CLnA (CLnA: equimolar mixture of 18:3 cis-9, trans-11, cis-15 and cis-9, trans-13, cis-15) diet. In low-cholesterol control-fed hamsters, the proportion of high-density lipoprotein cholesterol (HDL-C) was around 45% while in HC-fed hamsters, HDL-C was around 10% and cholesterol was mostly (80%) carried by triglyceride-rich lipoproteins (TRL). Low-density lipoprotein (LDL) triglycerides (TGs) increased by approximately 60% in hamsters fed either HC-RA or HC-CLnA compared with HC-controls but not compared with the low-cholesterol control diet. HDL cholesterol decreased by 24% and 16% in hamsters fed HC-RA and HC-CLnA, respectively. Small dense LDL-cholesterol increased by approximately 60% in hamsters fed HC-RA and HC-CLnA compared with the HC-control group and by more than a 100% compared with hamsters on the control diet. The relative percentage of liver cholesteryl ester content increased by 88% in hamsters fed HC diets compared with the control diet. Significant differences in fatty streaks were observed between control and HC-diet-fed hamsters. However, no significant difference was observed among the HC-diet-fed hamsters. This study shows that animals fed any one of the HC diets developed an adverse lipoprotein profile compared with a normolipidic diet. Also, HC-RA or HC-CLnA diets altered lipoprotein profile compared with animals fed the HC-control diet but had no beneficial effects on atherosclerosis.

Alteration of adipocyte metabolism in omega3 fatty acid-depleted rats.

Presently an insufficient supply of long-chain polyunsaturated omega3 fatty acid is prevalent in Western populations leading to potential metabolic consequences. Based on this fact, this study deals mainly with various aspects of lipid metabolism in second generation female omega3-depleted rats. The parametrial fat and body weights were higher in omega3-depleted than control animals. This coincided with liver steatosis but did not alter heart triglyceride/phospholipid ratio. The net uptake of [U-14C] palmitate by adipocytes was also higher in omega3-depleted rats than in control animals. The uptake of D-[U- 4C] glucose or [1,2 (-14)C] acetate by adipocytes was lower, however in omega3-depleted than control animals and was unaffected by insulin in the former as distinct from latter animals. Despite comparable basal lipolysis, the increase in glycerol output from adipocytes provoked by theophylline was higher in omega3-depleted than control rats. The fatty acid pattern of lipids in adipose tissue was characterized in the omega3-depleted rats by a much lower omega3 content, higher apparent Delta 9-saturase and elongase activities, lower efficiency for the conversion of C18:2omega6 to C20:4omega6 and higher efficiency for the conversion of C18:3omega3 to C20:5omega3. These features were compared to those prevailing in liver and plasma lipids. The present study thus extends knowledge on the alteration of lipid metabolism resulting from a deficiency in long-chain polyunsaturated omega3 fatty acids.

Acute in vivo administration of a fish oil-containing emulsion improves post-ischemic cardiac function in n-3-depleted rats.

A novel i.v. lipid preparation (MCT:FO) containing 80% medium chain-triacylglycerols and 20% fish oil was recently developed to rapidly replenish cell membrane phospholipids with omega 3 (n-3) polyunsaturated fatty acids (PUFA). In regard of this property, we investigated the effect of a single i.v. administration of MCT:FO on the recovery of cardiac function after ischemia in control and n-3-depleted rats. Results were compared with those obtained either with a control preparation, where FO was replaced by triolein (MCT:OO), or with saline. Saline (1 ml) or lipid preparation (also 1 ml) was injected as a bolus via the left saphenous vein. After 60 min the heart was removed and perfused for 20 min in normoxic conditions according to Langendorff. Thereafter, the heart was subjected to a 20 min zero-flow normothermic ischemia, followed by 40 min reperfusion. Cardiac mechanical and metabolic functions were monitored. In control rats, the previous administration of a lipid preparation (MCT:FO or MCT:OO) versus saline improved cardiac function during aerobic reperfusion post-ischemia. N-3-depleted rats showed decreased basal cardiac function and impaired recovery following ischemia. However, the bolus injection of MCT:FO opposed the deleterious effect of long-term n-3-deficiency and, in this respect, was superior to MCT:OO over the first 20 min of reperfusion. This novel approach to rapidly correct n-3 PUFA-deficiency might be clinically relevant and offer interesting perspectives in the management of acute ischemic accidents.

Pancreatic islet function in omega-3 fatty acid-depleted rats: alteration of calcium fluxes and calcium-dependent insulin release.

Considering the insufficient supply of long-chain polyunsaturated omega-3 fatty acids often prevailing in Western populations, this report deals mainly with alterations of Ca(2+) fluxes and Ca(2+)-dependent insulin secretory events in isolated pancreatic islets from omega-3-depleted rats. In terms of (45)Ca(2+) handling, the islets from omega-3-depleted rats, compared with those from normal animals, displayed an unaltered responsiveness to an increase in extracellular K(+) concentration, a lower inflow rate and lower fractional outflow rate of the divalent cation, and higher (45)Ca(2+)-labeled cellular pool(s) at isotopic equilibrium. The latter anomaly was corrected 120 min after intravenous injection of a novel medium-chain triglyceride-fish oil (MCT:FO) emulsion, distinct from a control omega-3-poor MCT-olive oil (MCT:OO) emulsion. At 8.3 mM D-glucose, insulin release was higher in islets from omega-3-depleted rats vs. control animals, coinciding with a higher cytosolic Ca(2+) concentration. The relative magnitude of the increase in insulin output attributable to a rise in D-glucose as well as extracellular Ca(2+) or K(+) concentration, to the absence vs. presence of verapamil and to the presence vs. absence of extracellular Ca(2+), theophylline, phorbol 12-myristate 13-acetate, or Ba(2+), was always more pronounced in islets from omega-3-depleted rats injected with the MCT:OO compared with the MCT:FO emulsion. A comparable situation prevailed when comparing islets from noninjected omega-3-depleted and normal rats. In light of these and previous findings, we propose that an impairment of Na(+),K(+)-ATPase activity plays a major, although not an exclusive, role in the perturbation of Ca(2+) fluxes and Ca(2+)-dependent secretory events in the islets from omega-3-depleted rats.

Intravenous lipid emulsions to deliver omega 3 fatty acids.

A rapid supply of n-3 polyunsaturated fatty acids (PUFA) may be indicated in some acute conditions because of the ability of n-3 PUFA to decrease inflammatory responses and cell sensitivity to various stimuli, and to improve endothelial dysfunction. To achieve these objectives, n-3 PUFA content needs to be quickly raised in cell membranes of key organs. Intravenous fish oil (FO) emulsions are available but their slow hydrolysis limits their infusion rate. Mixtures containing both FO triglycerides and medium chain triglycerides may overcome this problem. These new preparations are rapidly cleared from plasma and efficiently deliver n-3 PUFA to several tissues, largely via direct particle uptake. Recent data suggest that n-3 PUFA incorporation in phospholipids promptly modulates important cell functions. This review also focuses on a novel approach to rapidly supply n-3 PUFA to targeted organs which may offer interesting perspectives in the management of acute illnesses.

Beneficial effects of atorvastatin on sd LDL and LDL phenotype B in statin-naive patients and patients previously treated with simvastatin or pravastatin.

BACKGROUND: The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. METHODS: Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment. RESULTS: In addition to the expected LDL-C decrease (-34%; p<0.0001), a major reduction in sd LDL occurred after atorvastatin therapy (-38.2%; p<0.0001). Interestingly, sd LDL decreased as much in patients previously treated with other statins (-36%; p<0.002). A close correlation (r=0.89, p<0.001) was found between reduction of sd LDL and that of LDL-C, in patients with phenotype B. Although high-density lipoprotein-cholesterol (HDL-C) was not affected by atorvastatin treatment, plasma triglycerides decreased by 27.4% (p<0.0001). Only a weak correlation (r=0.35, p<0.01) was found between the reduction of plasma triglycerides and the decrease of sd LDL after atorvastatin treatment. CONCLUSION: These results show that the reduction of LDL-C by atorvastatin largely reflects a lowering of sd LDL. Our data also suggest that triglyceride lowering plays only a partial role in sd LDL reduction.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

Monoclonal antibodies against LDL progressively oxidized by myeloperoxidase react with ApoB-100 protein moiety and human atherosclerotic lesions.

Oxidized-LDL are involved in atherosclerosis pathogenesis, while the production of anti-ox-LDL monoclonal antibodies is critical for the development of diagnostic tools. This work reports the production of four monoclonal antibodies raised against human LDL, oxidized at different levels by the myeloperoxidase system. Characterization of these monoclonal antibodies showed that they do not cross-react with neither native LDL, VLDL nor hydrogen peroxide or Cu(2+)-oxidized LDL. Three of these antibodies recognize an epitope restricted to the protein moiety of mildly oxidized LDL, whereas the fourth antibody was partly dependent on the lipid presence of strongly oxidized LDL. All the antibodies were shown to react with human atherosclerotic lesions.