Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device

Aims: Coronary computed tomography angiography (CCTA) is a first-line modality in the investigation of suspected coronary artery disease (CAD). Mapping of perivascular fat attenuation index (FAI) on routine CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which integrates standardized FAI mapping together with clinical risk factors and plaque metrics to provide individualized cardiovascular risk prediction. Methods and results: The study included 3912 consecutive patients undergoing CCTA as part of clinical care in the USA (n = 2040) and Europe (n = 1872). These cohorts were used to generate age-specific nomograms and percentile curves as reference maps for the standardized interpretation of FAI. The first output of CaRi-Heart® is the FAI-Score of each coronary artery, which provides a measure of coronary inflammation adjusted for technical, biological, and anatomical characteristics. FAI-Score is then incorporated into a risk prediction algorithm together with clinical risk factors and CCTA-derived coronary plaque metrics to generate the CaRi-Heart® Risk that predicts the likelihood of a fatal cardiac event at 8 years. CaRi-Heart® Risk was trained in the US population and its performance was validated externally in the European population. It improved risk discrimination over a clinical risk factor-based model [Δ(C-statistic) of 0.085, P = 0.01 in the US Cohort and 0.149, P < 0.001 in the European cohort] and had a consistent net clinical benefit on decision curve analysis above a baseline traditional risk factor-based model across the spectrum of cardiac risk. Conclusion: Mapping of perivascular FAI on CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which allows standardized measurement of coronary inflammation by calculating the FAI-Score of each coronary artery. The CaRi-Heart® device provides a reliable prediction of the patient's absolute risk for a fatal cardiac event by incorporating traditional cardiovascular risk factors along with comprehensive CCTA coronary plaque and perivascular adipose tissue phenotyping. This integration advances the prognostic utility of CCTA for individual patients and paves the way for its use as a dual diagnostic and prognostic tool among patients referred for CCTA

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Factors associated with dropout from treatment for eating disorders: a comprehensive literature review

<p>Abstract</p> <p>Background</p> <p>Dropout (DO) is common in the treatment of eating disorders (EDs), but the reasons for this phenomenon remain unclear. This study is an extensive review of the literature regarding DO predictors in EDs.</p> <p>Methods</p> <p>All papers in PubMed, PsycINFO and Cochrane Library (1980-2009) were considered. Methodological issues and detailed results were analysed for each paper. After selection according to inclusion criteria, 26 studies were reviewed.</p> <p>Results</p> <p>The dropout rates ranged from 20.2% to 51% (inpatient) and from 29% to 73% (outpatient). Predictors of dropout were inconsistent due to methodological flaws and limited sample sizes. There is no evidence that baseline ED clinical severity, psychiatric comorbidity or treatment issues affect dropout. The most consistent predictor is the binge-purging subtype of anorexia nervosa. Good evidence exists that two psychological traits (high maturity fear and impulsivity) and two personality dimensions (low self-directedness, low cooperativeness) are related to dropout.</p> <p>Conclusion</p> <p>Implications for clinical practice and areas for further research are discussed. Particularly, these results highlight the need for a shared definition of dropout in the treatment of eating disorders for both inpatient and outpatient settings. Moreover, the assessment of personality dimensions (impulse control, self-efficacy, maturity fear and others) as liability factors for dropout seems an important issue for creating specific strategies to reduce the dropout phenomenon in eating disorders.</p

Personal Goals, Well-Being and Deliberate Self-Harm

The present study sought to understand the perceived well-being value of future goals as a possible explanation for why persons who are suicidal remain attached to goals that are seen as unattainable. Deliberate self-harm patients (DSH; N = 24) were compared with matched hospital controls (N = 24) on a range of measures including current well-being and perceived future wellbeing in the context of imagined goal attainment. Despite the DSH group having substantially lower current levels of well-being, there was no difference between the groups when forecasting their future well-being in the context of imagined attainment. For DSH participants the thought of achieving an important future goal is seen as necessary and sufficient for attaining normal levels of future well-being, which may function to keep them attached to goals that areperceived as relatively unattainable

Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes

Human serum-derived hydroxy long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity

<p>Abstract</p> <p>Background</p> <p>Circulating levels of novel long-chain hydroxy fatty acids (called GTAs) were recently discovered in the serum of healthy subjects which were shown to be reduced in subjects with colorectal cancer (CRC), independent of tumor burden or disease stage. The levels of GTAs were subsequently observed to exhibit an inverse association with age in the general population. The current work investigates the biological activity of these fatty acids by evaluating the effects of enriched human serum extracts on cell growth and inflammation.</p> <p>Methods</p> <p>GTAs were extracted from commercially available bulk human serum and then chromatographically separated into enriched (GTA-positive) and depleted (GTA-negative) fractions. SW620, MCF7 and LPS stimulated RAW264.7 cells were treated with various concentrations of the GTA-positive and GTA-negative extracts, and the effects on cell growth and inflammation determined.</p> <p>Results</p> <p>Enriched fractions resulted in poly-ADP ribose polymerase (PARP) cleavage, suppression of NFκB, induction of IκBα, and reduction in NOS2 mRNA transcript levels. In RAW264.7 mouse macrophage cells, incubation with enriched fractions prior to treatment with LPS blocked the induction of several pro-inflammatory markers including nitric oxide, TNFα, IL-1β, NOS2 and COX2.</p> <p>Conclusions</p> <p>Our results show that human serum extracts enriched with endogenous long-chain hydroxy fatty acids possess anti-inflammatory and anti-proliferative activity. These findings support a hypothesis that the reduction of these metabolites with age may result in a compromised ability to defend against uncontrolled cell growth and inflammation, and could therefore represent a significant risk for the development of CRC.</p

Immunological Basis for the Gender Differences in Murine Paracoccidioides brasiliensis Infection

This study aimed to investigate the immunological mechanisms involved in the gender distinct incidence of paracoccidioidomycosis (pcm), an endemic systemic mycosis in Latin America, which is at least 10 times more frequent in men than in women. Then, we compared the immune response of male and female mice to Paracoccidioides brasiliensis infection, as well as the influence in the gender differences exerted by paracoccin, a P. brasiliensis component with carbohydrate recognition property. High production of Th1 cytokines and T-bet expression have been detected in the paracoccin stimulated cultures of spleen cells from infected female mice. In contrast, in similar experimental conditions, cells from infected males produced higher levels of the Th2 cytokines and expressed GATA-3. Macrophages from male and female mice when stimulated with paracoccin displayed similar phagocytic capability, while fungicidal activity was two times more efficiently performed by macrophages from female mice, a fact that was associated with 50% higher levels of nitric oxide production. In order to evaluate the role of sexual hormones in the observed gender distinction, we have utilized mice that have been submitted to gonadectomy followed by inverse hormonal reconstitution. Spleen cells derived from castrated males reconstituted with estradiol have produced higher levels of IFN-γ (1291±15 pg/mL) and lower levels of IL-10 (494±38 pg/mL), than normal male in response to paracoccin stimulus. In contrast, spleen cells from castrated female mice that had been treated with testosterone produced more IL-10 (1284±36 pg/mL) and less IFN-γ (587±14 pg/mL) than cells from normal female. In conclusion, our results reveal that the sexual hormones had a profound effect on the biology of immune cells, and estradiol favours protective responses to P. brasiliensis infection. In addition, fungal components, such as paracoccin, may provide additional support to the gender dimorphic immunity that marks P. brasiliensis infection

Recurrent, Robust and Scalable Patterns Underlie Human Approach and Avoidance

BACKGROUND. Approach and avoidance behavior provide a means for assessing the rewarding or aversive value of stimuli, and can be quantified by a keypress procedure whereby subjects work to increase (approach), decrease (avoid), or do nothing about time of exposure to a rewarding/aversive stimulus. To investigate whether approach/avoidance behavior might be governed by quantitative principles that meet engineering criteria for lawfulness and that encode known features of reward/aversion function, we evaluated whether keypress responses toward pictures with potential motivational value produced any regular patterns, such as a trade-off between approach and avoidance, or recurrent lawful patterns as observed with prospect theory. METHODOLOGY/PRINCIPAL FINDINGS. Three sets of experiments employed this task with beautiful face images, a standardized set of affective photographs, and pictures of food during controlled states of hunger and satiety. An iterative modeling approach to data identified multiple law-like patterns, based on variables grounded in the individual. These patterns were consistent across stimulus types, robust to noise, describable by a simple power law, and scalable between individuals and groups. Patterns included: (i) a preference trade-off counterbalancing approach and avoidance, (ii) a value function linking preference intensity to uncertainty about preference, and (iii) a saturation function linking preference intensity to its standard deviation, thereby setting limits to both. CONCLUSIONS/SIGNIFICANCE. These law-like patterns were compatible with critical features of prospect theory, the matching law, and alliesthesia. Furthermore, they appeared consistent with both mean-variance and expected utility approaches to the assessment of risk. Ordering of responses across categories of stimuli demonstrated three properties thought to be relevant for preference-based choice, suggesting these patterns might be grouped together as a relative preference theory. Since variables in these patterns have been associated with reward circuitry structure and function, they may provide a method for quantitative phenotyping of normative and pathological function (e.g., psychiatric illness).National Institute on Drug Abuse (14118, 026002, 026104, DABK39-03-0098, DABK39-03-C-0098); The MGH Phenotype Genotype Project in Addiction and Mood Disorder from the Office of National Drug Control Policy - Counterdrug Technology Assessment Center; MGH Department of Radiology; the National Center for Research Resources (P41RR14075); National Institute of Neurological Disorders and Stroke (34189, 05236