Infectious and immunogenetic factors in bipolar disorder.

OBJECTIVE: Despite the evidence supporting the association between infection and bipolar disorder (BD), the genetic vulnerability that mediates its effects has yet to be clarified. A genetic origin for the immune imbalance observed in BD, possibly involved in the mechanisms of pathogen escape, has, however, been suggested in recent studies. METHOD: Here, we present a critical review based on a systematic literature search of articles published until December 2016 on the association between BD and infectious/immunogenetic factors. RESULTS: We provide evidence suggesting that infectious insults could act as triggers of maladaptive immune responses in BD and that immunogenetic vulnerability may amplify the effects of such environmental risk factors, increasing susceptibility to subsequent environmental encounters. Quality of evidence was generally impaired by scarce attempt of replication, small sample sizes and lack of high-quality environmental measures. CONCLUSION: Infection has emerged as a potential preventable cause of morbidity in BD, urging the need to better investigate components of the host-pathogen interaction in patients and at-risk subjects, and thus opening the way to novel therapeutic opportunities.

Insights into the effects of metal nanostructuring and oxidation on the work function and charge transfer of metal/graphene hybrids.

Graphene/metal heterojunctions are ubiquitous in graphene-based devices and, therefore, have attracted increasing interest of researchers. Indeed, the literature on the field reports apparently contradictory results about the effect of a metal on graphene doping. Here, we elucidate the effect of metal nanostructuring and oxidation on the metal work function (WF) and, consequently, on the charge transfer and doping of graphene/metal hybrids. We show that nanostructuring and oxidation of metals provide a valid support to frame WF and doping variation in metal/graphene hybrids. Chemical vapour-deposited monolayer graphene has been transferred onto a variety of metal surfaces, including d-metals, such as Ag, Au, and Cu, and sp-metals, such as Al and Ga, configured as thin films or nanoparticle (NP) ensembles of various average sizes. The metal-induced charge transfer and the doping of graphene have been investigated using Kelvin probe force microscopy (KPFM), and corroborated by Raman spectroscopy and plasmonic ellipsometric spectroscopy. We show that when the appropriate WF of the metal is considered, without any assumption, taking into account WF variations by nanostructure and/or oxidation, a linear relationship between the metal WF and the doping of graphene is found. Specifically, for all metals, nanostructuring lowers the metal WF. In addition, using gold as an example, a critical metal nanoparticle size is found at which the direction of charge transfer, and consequently graphene doping, is inverted.

Development of on-line FTIR spectroscopy for siloxane detection in biogas to enhance carbon contactor management.

Activated carbon filters are used to limit engine damage by siloxanes when biogas is utilised to provide electricity. However, carbon filter siloxane removal performance is poorly understood as until recently, it had not been possible to measure siloxanes on-line. In this study, on-line Fourier Transform Infrared (FTIR) spectroscopy was developed to measure siloxane concentration in real biogas both upstream (86.1-157.5mg m(-3)) and downstream (2.2-4.3mg m(-3)) of activated carbon filters. The FTIR provided reasonable precision upstream of the carbon vessel with a root mean square error of 10% using partial least squares analysis. However, positive interference from volatile organic carbons was observed in downstream gas measurements limiting precision at the outlet to an RMSE of 1.5mg m(-3) (47.8%). Importantly, a limit of detection of 3.2mg m(-3) was identified which is below the recommended siloxane limit and evidences the applicability of on-line FTIR for this application.

Elevated maternal C-reactive protein and autism in a national birth cohort.

Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.

Inducing humoral and cellular responses to multiple sporozoite and liver-stage malaria antigens using exogenous plasmid DNA.

A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4(+) and CD8(+) T cell compartments. Furthermore, hepatic CD8(+) lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8(+) granzyme B(+) T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

Autism spectrum disorders in IVF children: a national case-control study in Finland.

STUDY QUESTION: Does IVF increase the risk of autism spectrum disorders (ASDs)? SUMMARY ANSWER: No association between IVF and ASDs or any of its subtypes was found in this sample. WHAT IS KNOWN ALREADY: Certain prenatal factors may increase the risk of ASDs. Studies on the association between IVF and ASDs have shown inconsistent results. IVF is known to increase the risk of perinatal problems but many of them are related to multiple pregnancies. STUDY DESIGN, SIZE, DURATION: This case-control study included 4164 autistic cases and 16 582 matched controls born in Finland in 1991-2005. The cases were diagnosed with ASDs by the year 2007. The maximum age at diagnosis was 16 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Four controls were matched to each case. For singletons the matching criteria were date of birth, place of birth, sex and residency in Finland. For twins the birth order within a twin pair was included as well. In the whole sample, there were 63 cases (1.51%) and 229 controls (1.38%) born after IVF. MAIN RESULTS AND THE ROLE OF CHANCE: No significant association was found between IVF and ASDs (adjusted odds ratio (OR): 0.9, 95% confidence interval (CI): 0.7-1.3) or its subtypes childhood autism (OR: 0.8, 95% CI: 0.4-1.5), Asperger's syndrome (OR: 0.9, 95% CI: 0.5-1.6) or other pervasive developmental disorder (OR: 1.0, 95% CI: 0.6-1.6). When only singletons were included, there was an association between IVF and Asperger's syndrome in an unadjusted analysis (OR: 2.0, 95% CI: 1.1-3.5) but this was not significant when adjusted for mother's socioeconomic status or parity. When the analyses were conducted separately for boys and girls, there was a significant association between IVF and Asperger's syndrome for boys in an unadjusted analysis (OR: 2.1, 95% CI: 1.2-3.7) but this was not significant in the final adjusted model. LIMITATIONS, REASONS FOR CAUTION: Information both on IVF and on ASDs was based on registers and it is possible that there is some misclassification. No information on different subtypes of IVF or other assisted reproduction techniques was available. Statistical power may have been insufficient. WIDER IMPLICATIONS OF THE FINDINGS: This study showed no increased risk of ASDs in children born after IVF but studies with larger sample sizes and information on different subtypes of IVF are needed to confirm the finding. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by Autism Speaks, NIMH 1K02-MH65422 and NIEHS 1R01ES019004. There are no competing interests.

Alterations in myocardial stiffness in elite athletes assessed by a new Doppler index.

BACKGROUND: In elite athletes left ventricular (LV) morphological changes are predicted to alter passive pressure/volume characteristics by reducing myocardial stiffness and increasing compliance. OBJECTIVE: To investigate the utility of a new Doppler tissue index based on the pressure volume relation ((E/Ea)/LVEDD), which provides a measure of myocardial stiffness, and to assess its usefulness in detecting cardiac adaptation in elite rowers. METHODS: Thirty-six international rowers who had trained intensively and a control group of 30 sedentary subjects, matched for age and sex, were enrolled in the study. LV septal and posterior wall thickness, mass, chamber size, transmitral Doppler peak early (E) and late (A) diastolic filling velocities and isovolumic relaxation times were measured. Early diastolic myocardial velocities (Ea) were averaged from four sites at the mitral annulus; diastolic stiffness was assessed with the use of three indices E, Ea and the LV end-diastolic diameter in diastole (LVEDD). The ratio, (E/Ea)/LVEDD, provides a new index of diastolic stiffness. Rowers were further divided into two groups based on the presence or absence of left ventricular hypertrophy (LVH) 12 mm. RESULTS: No significant difference in Ea was found between the two groups, but there was a difference in the stiffness index, which remained after adjustment for body surface area and heart rate (controls 1.48 (0.3) vs athletes 1.17 (0.34), p = 0.016). No difference in stiffness index was found between the groups with LVH 12 mm (1.11 (0.32) vs 1.17 (0.34), respectively, p = 0.68) CONCLUSIONS: Intense training reduces myocardial stiffness despite the development of LVH.

Benefits of oat beta-glucan on respiratory infection following exercise stress: role of lung macrophages.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI). We have shown that consumption of the soluble oat fiber beta-glucan (ObetaG) can offset the increased risk for infection and decreased macrophage antiviral resistance following stressful exercise; however, the direct role of macrophages is unknown. This study examined the effect of macrophage depletion on the benefits of orally administered ObetaG on susceptibility to infection (morbidity, symptom severity, and mortality) following exercise stress. CL(2)MDP (Ex- H(2)O-CL(2)MDP, Ex-ObetaG-CL(2)MDP, Con-H(2)O-CL(2)MDP, Con-ObetaG-CL(2)MDP)-encapsulated liposomes were administered intranasally to deplete macrophages, and PBS (Ex-H(2)O-PBS, Ex-ObetaG-PBS, Con-H(2)O-PBS, Con-ObetaG-PBS)-encapsulated liposomes were given to macrophage-intact groups. Ex mice ran to volitional fatigue on a treadmill for 3 consecutive days, and ObetaG mice were fed a solution of 50% ObetaG in their drinking water for 10 consecutive days before infection. Fifteen minutes following the final bout of Ex or rest, mice were intranasally inoculated with 50 microl of a standardized dose of herpes simplex virus-1. Ex increased morbidity (P < 0.001) and symptom severity (P < 0.05) but not mortality (P = 0.09). The increase in morbidity and symptom severity was blocked by ObetaG consumption for 10 consecutive days before exercise and infection [morbidity (P < 0.001) and symptom severity (P < 0.05)]. Depletion of macrophages negated the beneficial effects of ObetaG on reducing susceptibility to infection following exercise stress, as evidenced by an increase in morbidity (P < 0.01) and symptom severity (P < 0.05). Results indicate that lung macrophages are at least partially responsible for mediating the beneficial effects of ObetaG on susceptibility to respiratory infection following exercise stress.

High-frequency subharmonic pulsed-wave Doppler and color flow imaging of microbubble contrast agents.

A recent study has shown the feasibility of subharmonic (SH) flow imaging at a transmit frequency of 20 MHz. This paper builds on these results by examining the performance of SH flow imaging as a function of transmit pressure. Further, we also investigate the feasibility of SH pulsed-wave Doppler (PWD) imaging. In vitro flow experiments were performed with a 1-mm-diameter wall-less vessel cryogel phantom using the ultrasound contrast agent Definity and an imaging frequency of 20 MHz. The phantom results show that there is an identifiable pressure range where accurate flow velocity and power estimates can be made with SH imaging at 10 MHz (SH10), above which velocity estimates are biased by radiation force effects and unstable bubble behavior, and below which velocity and power estimates are degraded by poor SNR. In vivo validation of SH PWD was performed in an arteriole of a rabbit ear, and blood velocity estimates compared well with fundamental (F20) mode PWD. The ability to suppress tissue signals using SH signals may enable the use of higher frame rates and improve sensitivity to microvascular flow or slow velocities near large vessel walls by reducing or eliminating the need for clutter filters.

Susceptibility to HSV-1 infection and exercise stress in female mice: role of estrogen.

Exhaustive exercise has been associated with an increased risk for upper respiratory tract infections in mice and humans. We have previously shown (Brown AS, Davis JM, Murphy AE, Carmichael MD, Ghaffer A, Mayer EP. Med Sci Sports Exerc 36: 1290-1295, 2004) that female mice are better protected from the lethal effects of herpes simplex virus type 1 (HSV-1) infection, both at rest and following exercise stress, but little is known about possible mechanisms. This study tested the effects of estrogen on HSV-1 infection and macrophage antiviral resistance following repeated exhaustive exercise. Female mice were assigned to either exercise (Ex) or control (C): intact female (I-C or I-Ex), ovariectomized female (O-C or O-Ex), or ovariectomized estrogen-supplemented female (E-C or E-Ex). Exercise consisted of treadmill running to volitional fatigue ( approximately 125 min) for 3 consecutive days. Intact female mice had a later time to death than O and E (P < 0.05) and fewer deaths than both O and E (P < 0.05). Exercise stress was associated with increased time to sickness (P < 0.05) and symptom severity at days 6 and 12-21 postinfection (P < 0.05) and decreased macrophage antiviral resistance (P < 0.001) in all groups. E had increased symptom severity at days 6 and 13-21 postinfection (P < 0.05). Results indicate that intact female mice are better protected from the lethal effects of HSV-1 infection and that exercise stress had a similar negative impact in all groups. This protective effect was lost in ovariectomized mice, but it was not reinstated by 17beta-estradiol replacement. This indicates that other ovarian factors, alone or in combination with estrogen, are responsible for the protective effects in females.

Value of transoesophageal echocardiography for diagnosis of intraoperative tumour embolization.

Malignant neoplasms such as renal cell carcinoma may invade the inferior vena cava leading to a risk of pulmonary tumour embolization during surgical excision. Although massive pulmonary tumour embolism occurs relatively rarely, it can have catastrophic consequences. We report the case of an acute intraoperative pulmonary tumour embolism during resection of a renal cell carcinoma. The use of transoesophageal echocardiography allowed the immediate diagnosis and appropriate management of the underlying cause of acute haemodynamic instability. The role of transoesophageal echocardiography in the diagnosis of pulmonary embolism is discussed.

Role of lung macrophages on susceptibility to respiratory infection following short-term moderate exercise training.

Moderate exercise training is associated with a decreased risk for upper respiratory tract infection in human and animal studies, but the mechanisms have not been elucidated. Lung macrophages play an important role in resistance to respiratory infection, and moderate exercise can enhance macrophage antiviral resistance, but no studies have directly tested the role of lung macrophages in this response. This study tested the effect of lung macrophage depletion on susceptibility to infection following short-term moderate exercise training. Mice were assigned to one of four groups: exercise (Ex) and resting controls (Con) with and without clodronate encapsulated liposomes (CL(2)MDP-lip). Ex mice ran for 1 h on a treadmill for 6 days at 36 m/min, 8% grade. Fifteen minutes following exercise or rest on the last day of training, mice were intranasally inoculated with a standardized dose of herpes simplex virus type 1. Clodronate (Ex-CL(2)MDP-lip and Con-CL(2)MDP-lip) or PBS liposomes (Ex-PBS-lip and Con-PBS-lip) (100 microl) were intranasally administered following exercise or rest on the 4th day of training and again on the 4th day postinfection. Morbidity, mortality, and symptom severity were monitored for 21 days. Exercise decreased morbidity by 36%, mortality by 61%, and symptom severity score on days 5-7 (P < 0.05). Depletion of lung macrophages negated the beneficial effects of moderate exercise. This was indicated by no differences between Ex-CL(2)MDP-lip and Con-PBS-lip in morbidity (89 vs. 95%), mortality (79 vs. 95%), or symptom severity. Results indicate that lung macrophages play an important role in mediating the beneficial effects of moderate exercise on susceptibility to respiratory infection.

Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity.

Both moderate exercise and the soluble fiber beta-glucan can have beneficial effects on the initiation and growth of tumors, but the data are limited, and there is no information on their combined effects. This study tested the independent and combined effects of short-term moderate-exercise training and the soluble oat fiber beta-glucan (ObetaG) on the metatastic spread of injected tumor cells and macrophage antitumor cytotoxicity. Male C57BL/6 mice were assigned to one of four groups: exercise (Ex)-H2O, Ex-ObetaG, control (Con)-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 days before tumor administration and death. Exercise consisted of treadmill running (1 h/day) for 6 days. After rest or exercise on the last day of training, syngeneic B16 melanoma cells (2 x 10(5)) were administered via intravenous injection (n = 8-11 per group). Lungs were removed 14 days later, and tumor foci were counted. Additional mice (n = 8 per group) were killed, and peritoneal macrophages were assayed for cytotoxicity against the same mouse tumor cell line at various effector-to-target ratios. Both moderate exercise and ObetaG decreased lung tumor foci and increased macrophage cytotoxicity. However, there were no differences in lung tumor foci and macrophage cytotoxicity between Ex-ObetaG and either Ex-H2O or Con-ObetaG. These data suggest that, although not additive in their effects, both short-term moderate-exercise training and consumption of the soluble ObetaG can decrease the metatastic spread of injected B16 melanoma cells, and these effects may be mediated in part by an increase in macrophage cytotoxicity to B16 melanoma.

Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection.

Both moderate exercise and the soluble oat fiber beta-glucan can increase immune function and decrease risk of infection, but no information exists on their possible combined effects. This study tested the effects of moderate exercise and oat beta-glucan on respiratory infection, macrophage antiviral resistance, and natural killer (NK) cell cytotoxicity. Mice were assigned to four groups: exercise and water, exercise and oat beta-glucan, control water, or control oat beta-glucan. Oat beta-glucan was fed in the drinking water for 10 days before intranasal inoculation of herpes simplex virus type 1 (HSV-1) or euthanasia. Exercise consisted of treadmill running (1 h/day) for 6 days. Macrophage resistance to HSV-1 was increased with both exercise and oat beta-glucan, whereas NK cell cytotoxicity was only increased with exercise. Exercise was also associated with a 45 and 38% decrease in morbidity and mortality, respectively. Mortality was also decreased with oat beta-glucan, but this effect did not reach statistical significance. No additive effects of exercise and oat beta-glucan were found. These data confirm a positive effect of both moderate exercise and oat beta-glucan on immune function, but only moderate exercise was associated with a significant reduction in the risk of upper respiratory tract infection in this model.

Sonovue improves endocardial border detection and variability in assessing wall motion score and ejection fraction during stress echocardiography.

BACKGROUND: Stress echocardiography is useful for assessing patients with coronary artery disease unable to undergo formal exercise testing. Considerable skill is required to avoid large intra- and inter-observer variability due to poor endocardial definition. Intravenous ultrasound contrast agents are now available which may improve this variability. AIM: To study intravenous Sonovue in assessing wall motion score and ejection fraction (EF) during stress echocardiography. METHODS: Thirty-eight patients undergoing arbutamine stress echocardiography for known or suspected coronary artery disease were studied. Echocardiographic analysis of wall motion score index, endocardial border detection (EBD) and EF was performed at rest and at peak stress before and after intravenous injection of Sonovue, by experienced and inexperienced observers. RESULTS: All three observers noted an improvement in endocardial border definition following Sonovue (p=<0.001). At baseline, there was a significant difference in wall motion score index between experienced and inexperienced observers at rest (p=0.01) and at peak stress (p=0.001). Following Sonovue administration this was no longer significant (p=0.07, p=0.114). Intra-observer variability of end diastolic, end systolic volumes (ESV) and EF improved following contrast (p<0.05) at rest and during stress. CONCLUSION: Sonovue significantly improved EBD and reduced intra-observer variability of EF at rest and during peak arbutamine infusion.

Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery.

AIMS: Vascular endothelial growth factor-A (VEGF-A) is an angiogenic and vasoprotective molecule whose expression is modulated by hypoxia and inflammatory mediators. Here we have tested the hypothesis that plasma levels of VEGF-A are influenced by pre-existing coronary artery disease and by changes in circulating interleukin-6 (IL-6). METHODS AND RESULTS: Plasma VEGF-A and IL-6 were measured prior to and at various time intervals following surgery in individuals with angiographically normal coronary arteries requiring cardiac valve replacement (N group) and in patients with coronary artery disease and stable angina undergoing coronary artery bypass grafting (CAD group). Baseline VEGF-A levels were not significantly different in CAD (22.3+/-2.6 pg x ml(-1)) compared to the N group (14.9+/-2.9 pg x ml(-1)). Following cardiac surgery there was a significant rise of VEGF-A in CAD (P<0.0005 vs baseline), but not in the N group, reaching a maximum (approximately 2 fold increase) after 24 h. Surgery caused a rapid increase of plasma IL-6 in both groups, but the rise was significantly larger in CAD patients (P<0.0005 vs N) where it preceded the increase in VEGF-A. Furthermore, in patients with CAD there was a significant correlation between the change in VEGF-A and the change in IL-6 (P<0.04). CONCLUSION: These findings demonstrate that in patients with coronary artery disease cardiothoracic surgery leads to an acute rise in VEGF-A. We suggest that this rise may result from an interaction between the pre-existing atheromatous process and a systemic increase of inflammatory mediators.

Prevalence of physical activity among South Carolina adults.

Participating in regular PA is associated with many health benefits. Overall, the prevalence of inactivity in South Carolina (33 percent) is among the highest in the Southeast and in the US as a nation. While few gender differences exist between the proportion of adults who report participation in sufficient PA (females 21 percent and males 23 percent), racial and age differences are apparent with ethnic minorities and older adults as the least active. The most popular PA among all adults is walking. Physicians can play a key role, through counseling, to help increase the prevalence of regular PA among those who are currently obtaining insufficient amounts of activity to derive optimal health benefits.

Effectiveness of the electronic medical record in cholesterol management in patients with coronary artery disease (Virtual Lipid Clinic).

This study demonstrates that the Virtual Lipid Clinic, an electronic medical record with computer-assisted cholesterol management, is associated with improved lipid management in patients with coronary artery disease. In comparison to traditional documentation methods with "pen and paper" charts, outpatient visits utilizing the electronic medical record were associated with a twofold increase in low-density lipoprotein (LDL) documentation, a threefold increase in achieving LDL goal, and a 30% increase in the use of lipid-lowering drugs.

Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia.

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.