Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans.

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.

Lipoprotein (a): When to Measure and How to Treat?

PURPOSE OF REVIEW: The purpose of this article is to review current evidence for lipoprotein (a) (Lp(a)) as a risk factor for multiple cardiovascular (CV) disease phenotypes, provide a rationale for Lp(a) lowering to reduce CV risk, identify therapies that lower Lp(a) levels that are available clinically and under investigation, and discuss future directions. RECENT FINDINGS: Mendelian randomization and epidemiological studies have shown that elevated Lp(a) is an independent and causal risk factor for atherosclerosis and major CV events. Lp(a) is also associated with non-atherosclerotic endpoints such as venous thromboembolism and calcific aortic valve disease. It contributes to residual CV risk in patients receiving standard-of-care LDL-lowering therapy. Plasma Lp(a) levels present a skewed distribution towards higher values and vary widely between individuals and according to ethnic background due to genetic variants in the LPA gene, but remain relatively constant throughout a person's life. Thus, elevated Lp(a) (≥50 mg/dL) is a prevalent condition affecting >20% of the population but is still underdiagnosed. Treatment guidelines have begun to advocate measurement of Lp(a) to identify patients with very high levels that have a family history of premature CVD or elevated Lp(a). Lipoprotein apheresis (LA) efficiently lowers Lp(a) and was recently associated with a reduction of incident CV events. Statins have neutral or detrimental effects on Lp(a), while PCSK9 inhibitors significantly reduce its level by up to 30%. Specific lowering of Lp(a) with antisense oligonucleotides (ASO) shows good safety and strong efficacy with up to 90% reductions. The ongoing CV outcomes study Lp(a)HORIZON will provide a first answer as to whether selective Lp(a) lowering with ASO reduces the risk of major CV events. Given the recently established association between Lp(a) level and CV risk, guidelines now recommend Lp(a) measurement in specific clinical conditions. Accordingly, Lp(a) is a current target for drug development to reduce CV risk in patients with elevated levels, and lowering Lp(a) with ASO represents a promising avenue.

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

A Feasibility Study on the Use of the Method of Loci for Improving Episodic Memory Performance in Schizophrenia and Non-clinical Subjects.

We investigated the feasibility of a short intervention using the Method of Loci (MoL), a well-known visuospatial mnemonic, to improve episodic memory recall performance in schizophrenia. The MoL training protocol comprised encoding and recall of two lists of items (words and images), a training session and practice with MoL. Then, participants had the opportunity to put into practice the newly learned MoL and were instructed to encode and recall two new lists of items using. This approach was first validated with healthy individuals (N = 71). Subsequently, five individuals with schizophrenia completed the protocol. Improvement in healthy individuals was observed for the word list (Wilcoxon effect size r = 0.15). No significant memory improvement was denoted in the schizophrenia group, possibly due to participants' difficulties using the method efficiently and due to fatigue. The MoL seems to require episodic memory, working memory monitoring and executive functions, making it suboptimal for a population with impairments in all those domains. Future research should examine the use of other strategies, better suited for individuals with cognitive impairments like those found in schizophrenia.

ApoA-I mimetic does not improve left ventricular diastolic dysfunction in rabbits without aortic valve stenosis.

BACKGROUND: We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS. METHODS: Rabbits were exposed to three different protocols to develop LVDD. First, rabbits were exposed to 0.5% cholesterol-rich diet for an average of 17 weeks. Second, rabbits were subjected to surgical ascending aortic constriction (AAC), to mimic the effect of fixed reduced aortic valve area, and studied after 10 weeks. The third model combined both cholesterol-enriched diet (for 12 weeks) and surgical AAC. The control group consisted of age-matched rabbits under normal diet. After development of LVDD, rabbits were randomized to receive infusions of saline or apoA-I mimetic (25 mg/kg) 3 times per week for 4 weeks. Detailed cardiac structure and function measurements were assessed at baseline and weekly during treatment period. Histological and molecular analyses were performed on LV samples. RESULTS: In the three models, echocardiographic results showed development of LVDD over time, with preserved LV systolic and aortic valve functions versus controls. ApoA-I mimetic infusions did not significantly improve echocardiographic parameters nor molecular markers of cardiac inflammation, oxidative stress and fibrosis. CONCLUSION: ApoA-I mimetic therapy did not directly improve LVDD. These results indicate that previously observed changes of LVDD were caused by AVS improvement induced by this treatment.

Smartwatches are more distracting than mobile phones while driving: Results from an experimental study.

The use of smartwatches raises a number of questions about their potential for distraction in situations where sustained attention is paramount, like driving a motor vehicle. Our research examines distraction caused by smartwatch use in comparison to mobile phone use while driving. It also studies the difference in distractions caused by inbound text messages versus inbound voice messages, and outbound replies through text messages versus outbound voice replies. A within-subject experiment was conducted in a driving simulator where 31 participants received and answered text messages under four conditions: they received notifications (1) on a mobile phone, (2) on a smartwatch, and (3) on a speaker, and then responded orally to these messages. They also (4) received messages in a "texting" condition where they had to reply through text to the notifications. Eye tracking gaze distribution results show that participants were more distracted in the smartwatch condition than in the mobile phone condition, they were less distracted in the speaker condition than in the phone condition, and they were more distracted in the texting condition than in any of the others. The participants' driving performance remained the same in all conditions except in the texting condition, wherein it became worse. Eye tracking and pupillometry results suggest that participants' mental workload might be lower in the texting condition than in the other three conditions, although this result might be caused by a higher number of glances at the device in that condition. This study contributes to a better understanding of the distraction potential of smartwatches as well as identifying vocal assistants as the least distracting way of communicating while driving a vehicle. Industry leaders could become a key factor in informing the public of the smartwatch's potential for distraction.

Efficacy of psychological interventions targeting cognitive biases in schizophrenia: A systematic review and meta-analysis.

Cognitive biases, which are tendencies to systematically process, select and remember certain information (e.g., jumping to conclusions), are exacerbated in schizophrenia and associated with delusions. Here we review and quantitatively assess psychological interventions targeting cognitive biases (e.g., metacognitive training, reasoning training, Maudsley review training programme) to evaluate their efficacy in improving cognitive biases, positive symptoms, and insight. Overall, thirty-two studies, including 15 distinct interventions and 2738 participants, were identified through a comprehensive keyword database search. Meta-analytic effect sizes were calculated and heterogeneity, publication bias, and subgroup analyses (study bias, active/passive intervention) were conducted. We observed significant small to moderate beneficial effects of cognitive interventions on cognitive biases (Hedges' g = 0.27; 95% CI = [0.13-0.41]; z = 3.77; p < .001), positive symptoms (Hedges' g = 0.30; 95% CI = [0.13-0.48]; z = 3.44, p < .005), and insight (Hedges' g = 0.35; 95% CI = [0.15-0.56]; z = 3.37,p < .005). Interestingly, studies with high risk of bias or passive control condition did not differ significantly from those with low risk or active control condition, respectively. Thus, cognitive biases are malleable via psychological interventions, which also exert, either directly or indirectly through reduced cognitive biases, beneficial effects on positive symptoms and insight.

Investigational drugs in development for hypertriglyceridemia: a coming-of-age story.

Introduction: Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering.Areas covered: We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed.Expert opinion: We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being 'optimally' treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.

Social Values and Determinants of Cultural Fit in Quebec: The Roles of Ancestry, Linguistic Group, and Mental Health Status.

Many quantitative cross-cultural research studies assume that cultural groups consist of anyone born and raised in the same country. Applying these criteria to the formation of study samples may produce cohorts that share a country but are heterogeneous in relevant domains of culture. For example, in Canada, Franco- and Anglo-Canadians are generally assumed to represent different linguistic groups but the same cultural group. However, speaking a different first language also can mean exposure to different media, information, and conventions, which are known to shape certain cultural domains, such as social values. Other factors may also produce cultural heterogeneity. For example, ancestral origins and recency of familial migration may influence endorsed social values after exposure to diverse cultures or norms. Mental health status or psychiatric conditions may also influence subscription of social values due to different lifestyle demands. Understanding the nuanced contributions of diverse backgrounds to cultural membership and fit (i.e., the degree to which an individual behaves like other cultural members) is useful when performing quantitative cross-cultural studies to minimize alternative explanations for statistical outcomes. This study used Cultural Consensus Analysis (CCA) to assess the cultural fit of social values for 222 Canadians, who had participated in cross-cultural neuropsychological experiments. CCA is an anthropological statistical method for evaluating cultural agreement of a sample. Participants were systematically evaluated by linguistic groups (French and English), migratory generation (1st-3rd+), and mental health status (healthy and patient). Group and individual variances were statistically interrogated. Results demonstrated that Franco- and Anglo-Canadians represent different cultural groups cohabitating in Quebec. Social values dividing Franco- and Anglo-Canadians were also identified. Second and third generation Canadians held more heterogeneous social values than Canadians, whose families had migrated earlier. Second generation Canadians with psychiatric disorders showed notably reduced cultural fit with other Canadians, which supports other literature reporting difficulties experienced by second generation migrants. However, third and later generations of Canadians with psychiatric disorders held a greater range of social values compared to healthy Canadians but still were good fits for Canadian culture. This study concluded that linguistic group and migratory generation partially determines cultural group for the social values domain while mental health status does not, contrary to theories proposed by previous literature.

The Prevalence of Negative Symptoms Across the Stages of the Psychosis Continuum.

BACKGROUND: Patients in every stage of the psychosis continuum can present with negative symptoms. While no treatment is currently available to address these symptoms, a more refined characterization of their course over the lifetime could help in elaborating interventions. Previous reports have separately investigated the prevalence of negative symptoms within each stage of the psychosis continuum. Our aim in this review is to compare those prevalences across stages, thereby disclosing the course of negative symptoms. METHODS: We searched several databases for studies reporting prevalences of negative symptoms in each one of our predetermined stages of the psychosis continuum: clinical or ultra-high risk (UHR), first-episode of psychosis (FEP), and younger and older patients who have experienced multiple episodes of psychosis (MEP). We combined results using the definitions of negative symptoms detailed in the Brief Negative Symptom Scale, a recently developed tool. For each negative symptom, we averaged and weighted by the combined sample size the prevalences of each negative symptom at each stage. RESULTS: We selected 47 studies totaling 1872 UHR, 2947 FEP, 5039 younger MEP, and 669 older MEP patients. For each negative symptom, the prevalences showed a comparable course. Each negative symptom decreased from the UHR to FEP stages and then increased from the FEP to MEP stages. CONCLUSIONS: Certain psychological, environmental, and treatment-related factors may influence the cumulative impact of negative symptoms, presenting the possibility for early intervention to improve the long-term course.

Cognitive capacity similarly predicts insight into symptoms in first- and multiple-episode psychosis.

BACKGROUND: Lack of insight is a frequent characteristic of psychotic disorders, both in patients who recently experienced a first episode of psychosis (FEP) and those who experience recurrent multiple episodes (MEP). Insight is a multifaceted construct: its clinical form notably includes the unawareness of being ill, of symptoms, and of the need for treatment. Cognitive capacity is among the key determinants of insight into symptoms, but less is known about whether stage of illness (FEP vs. MEP) moderates this association. METHODS: Our aim is to evaluate the association between cognitive capacity and symptom unawareness using structural equation modeling and moderated multiple regression. A total of 193 FEP and MEP patients were assessed using the CogState battery and the Scale to Assess Unawareness of Mental Disorder. RESULTS: Analyses suggest that cognitive capacity accounts for a relatively small proportion of the total variation in symptom unawareness (6.4%). There was no evidence to suggest a moderating effect of stage of illness on this association. CONCLUSIONS: The effect of general cognitive capacity on symptom unawareness is relatively small, and this basic relation was unrelated to stage of illness. It is possible that stage of illness could moderate this association only for certain facets of insight not assessed in this study (e.g., unawareness of the need for treatment).

Comparing cognitive clusters across first- and multiple-episode of psychosis.

Cognitive impairments in psychotic disorders (PD) present heterogeneously across patients. Between 2 and 5 clusters have been identified in previous studies with first-episode (FEP) and multiple-episodes of psychosis (MEP) patients suggesting different profiles of impairment. Past findings suggest there are differences between FEP and MEP patients regarding severity and number of affected cognitive domains. Heterogeneity of cognitive deficits in PD has perhaps hindered our understanding of their course. The present study compared non-affective FEP and MEP patients to assess whether illness chronicity could influence cognitive impairment profiles. We analyzed cognitive data, collected with the Cogstate Schizophrenia Battery, of FEP and MEP patients using cluster analysis. We compared clustering methods to obtain a more robust solution. For FEP patients, data were collected at their entry to a specialized clinic; the MEP group consisted of in- and outpatients. Results suggested cognitive heterogeneity was similar in FEP and MEP samples, although in different proportions. Three clusters were identified as the most stable solution and comprised groups of patients with either 1- no cognitive impairment (over-representation of FEP), 2- generalized deficits (over-representation of MEP), or 3- intermediate impairments. These findings encourage early interventions adapted to the profile of impairment.

Lipids, Apolipoproteins, and Inflammatory Biomarkers of Cardiovascular Risk: What Have We Learned?

Cardiovascular diseases (CVD) are the first cause of death in the world. CVD risk is influenced by multiple factors, some nonmodifiable such as age, sex, and genetic background, and others modifiable. Great progress has been made over the last decades in the identification of biomarkers of incident or recurrent CV risk and surrogate endpoints of CV outcomes. We present the current state of knowledge for CV biomarkers in plasma including lipids, apolipoproteins, inflammation-related, and emerging omics-based biomarkers. Clinically validated surrogate endpoints for CV outcomes include plasma low-density lipoprotein-cholesterol reduction, and plasma triglyceride reduction is a likely relevant surrogate endpoint. High-density lipoprotein-cholesterol is not a validated surrogate endpoint, but is a useful biomarker of CV risk. CV risk biomarkers of interest include apolipoprotein B and non-HDL-cholesterol, lipoprotein (a), C-reactive protein, and recently, genetic and protein-based risk scores and gut microbiota-derived trimethylamine oxide levels.

ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein).

BACKGROUND: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. METHODS: Adcy9-inactivated ( Adcy9Gt/Gt) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9Gt/Gt and CETPtg Adcy9WT), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. RESULTS: Adcy9Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9Gt/Gt mice compared to WT animals ( P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9Gt/Gt mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9Gt/Gt ( P<0.01 for all). Aortic endothelium from Adcy9Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P<0.05). Adcy9Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P<0.01 for both). Feed efficiency was increased in Adcy9Gt/Gt compared to WT mice ( P<0.01), which was accompanied by prolonged cardiac RR interval ( P<0.05) and improved nocturnal heart rate variability ( P=0.0572). Adcy9 inactivation-induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9Gt/Gt mice ( P>0.05 versus CETPtg Adcy9WT). CONCLUSIONS: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.

Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys.

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preß-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment.

The probability of object-scene co-occurrence influences object identification processes.

Contextual information allows the human brain to make predictions about the identity of objects that might be seen and irregularities between an object and its background slow down perception and identification processes. Bar and colleagues modeled the mechanisms underlying this beneficial effect suggesting that the brain stocks information about the statistical regularities of object and scene co-occurrence. Their model suggests that these recurring regularities could be conceptualized along a continuum in which the probability of seeing an object within a given scene can be high (probable condition), moderate (improbable condition) or null (impossible condition). In the present experiment, we propose to disentangle the electrophysiological correlates of these context effects by directly comparing object-scene pairs found along this continuum. We recorded the event-related potentials of 30 healthy participants (18-34 years old) and analyzed their brain activity in three time windows associated with context effects. We observed anterior negativities between 250 and 500 ms after object onset for the improbable and impossible conditions (improbable more negative than impossible) compared to the probable condition as well as a parieto-occipital positivity (improbable more positive than impossible). The brain may use different processing pathways to identify objects depending on whether the probability of co-occurrence with the scene is moderate (rely more on top-down effects) or null (rely more on bottom-up influences). The posterior positivity could index error monitoring aimed to ensure that no false information is integrated into mental representations of the world.

Development of a new bioactivatable fluorescent probe for quantification of apolipoprotein A-I proteolytic degradation in vitro and in vivo.

BACKGROUND AND AIMS: The potential benefits of high-density lipoproteins (HDL) against atherosclerosis are attributed to its major protein component, apolipoprotein A-I (apoA-I). Most of the apoA-I in the vascular wall appears to be in its lipid-poor form. The latter, however, is subjected to degradation by proteases localized in atherosclerotic plaques, which, in turn, has been shown to negatively impact its atheroprotective functions. Here, we report the development and in vivo use of a bioactivatable near-infrared full-length apoA-I-Cy5.5 fluorescent probe for the assessment of apoA-I-degrading proteolytic activities. METHODS: Fluorescence quenching was obtained by saturation of Cy5.5 fluorophore molecules on apoA-I protein. ApoA-I cleavage led to near-infrared fluorescence enhancement. In vitro proteolysis of the apoA-I probe by a variety of proteases including serine, cysteine, and metalloproteases resulted in an up to 11-fold increase in fluorescence (n = 5, p ≤ 0.05). RESULTS: We detected activation of the probe in atherosclerotic mice aorta sections using in situ zymography and showed that broad-spectrum protease inhibitors protected the probe from degradation, resulting in decreased fluorescence (-54%, n = 6 per group, p ≤ 0.0001). In vivo, the injected probe showed stronger fluorescence emission in the aorta of human apoB transgenic Ldlr-/- atherosclerotic mice (ATX) as compared to wild-type mice. In vivo observations were confirmed by ex vivo aorta imaging quantification where a 10-fold increase in fluorescent signal in ATX mice (p ≤ 0.05 vs. control mice) was observed. CONCLUSIONS: The use of this probe in different applications may help to assess new molecular mechanisms of atherosclerosis and may improve current HDL-based therapies by enhancing apoA-I functionality.

Heightened Responses of the Parahippocampal and Retrosplenial Cortices during Contextualized Recognition of Congruent Objects.

Context sometimes helps make objects more recognizable. Previous studies using functional magnetic resonance imaging (fMRI) have examined regional neural activity when objects have strong or weak associations with their contexts. Such studies have demonstrated that activity in the parahippocampal cortex (PHC) generally corresponds with strong associations between objects and their spatial contexts while retrosplenial cortex (RSC) activity is linked with episodic memory. However these studies investigated objects viewed in associated contexts, but the direct influence of scene on the perception of visual objects has not been widely investigated. We hypothesized that the PHC and RSC may only be engaged for congruent contexts in which the object could typically be found but not for neutral contexts. While in an fMRI scanner, 15 participants rated the recognizability of 152 photographic images of objects, presented within congruent and incongruent contexts. Regions of interest were created to examine PHC and RSC activity using a hypothesis-driven approach. Exploratory analyses were also performed to identify other regional activity. In line with previous studies, PHC and RSC activity emerged when objects were viewed in congruent contexts. Activity in the RSC, inferior parietal lobe (IPL) and fusiform gyrus also emerged. These findings indicate that different brain regions are employed when objects are meaningfully contextualized.