Identification and Evaluation of Blood-Based Biomarkers for Abdominal Aortic Aneurysm.

INTRODUCTION: Blood-based biomarkers for abdominal aortic aneurysm (AAA) have been studied individually; however, we considered a panel of proteins to investigate AAA prognosis and its potential to improve predictive accuracy. MATERIALS AND METHODS: Using a prospectively recruited cohort of patients with/without AAA (n = 452), we conducted a prognostic study to develop a model that accurately predicts AAA outcomes using clinical features and circulating biomarker levels. Serum concentrations of 9 biomarkers were measured at baseline, and the cohort was followed for 2 years. The primary outcome was major adverse aortic event (MAAE; composite of rapid AAA expansion [>0.5 cm/6 months or >1 cm/12 months], AAA intervention, or AAA rupture). Using 10-fold cross-validation, we trained a random forest model to predict 2 year MAAE using (1) clinical characteristics, (2) biomarkers, and (3) clinical characteristics and biomarkers. RESULTS: Two-year MAAE occurred in 114 (25%) patients. Two proteins were significantly elevated in patients with AAA compared with those without AAA (angiopoietin-2 and aggrecan), composing the protein panel. For predicting 2 year MAAE, our random forest model achieved area under the receiver operating characteristic curve (AUROC) 0.74 using clinical features alone, and the addition of the 2-protein panel improved performance to AUROC 0.86. CONCLUSIONS: Using a combination of clinical/biomarker data, we developed a model that accurately predicts 2 year MAAE.

A machine learning algorithm for peripheral artery disease prognosis using biomarker data.

Peripheral artery disease (PAD) biomarkers have been studied in isolation; however, an algorithm that considers a protein panel to inform PAD prognosis may improve predictive accuracy. Biomarker-based prediction models were developed and evaluated using a model development (n = 270) and prospective validation cohort (n = 277). Plasma concentrations of 37 proteins were measured at baseline and the patients were followed for 2 years. The primary outcome was 2-year major adverse limb event (MALE; composite of vascular intervention or major amputation). Of the 37 proteins tested, 6 were differentially expressed in patients with vs. without PAD (ADAMTS13, ICAM-1, ANGPTL3, Alpha 1-microglobulin, GDF15, and endostatin). Using 10-fold cross-validation, we developed a random forest machine learning model that accurately predicts 2-year MALE in a prospective validation cohort of PAD patients using a 6-protein panel (AUROC 0.84). This algorithm can support PAD risk stratification, informing clinical decisions on further vascular evaluation and management.

Current Biomarkers for Carotid Artery Stenosis: A Comprehensive Review of the Literature.

Carotid artery stenosis (CAS), an atherosclerotic disease of the carotid artery, is one of the leading causes of transient ischemic attacks (TIA) and cerebrovascular attacks (CVA). The atherogenic process of CAS affects a wide range of physiological processes, such as inflammation, endothelial cell function, smooth muscle cell migration and many more. The current gold-standard test for CAS is Doppler ultrasound; however, there is yet to be determined a strong, clinically validated biomarker in the blood that can diagnose patients with CAS and/or predict adverse outcomes in such patients. In this comprehensive literature review, we evaluated all of the current research on plasma and serum proteins that are current contenders for biomarkers for CAS. In this literature review, 36 proteins found as potential biomarkers for CAS were categorized in to the following nine categories based on protein function: (1) Inflammation and Immunity, (2) Lipid Metabolism, (3) Haemostasis, (4) Cardiovascular Markers, (5) Markers of Kidney Function, (6) Bone Health, (7) Cellular Structure, (8) Growth Factors, and (9) Hormones. This literature review is the most up-to-date and current comprehensive review of research on biomarkers of CAS, and the only review that demonstrated the several pathways that contribute to the initiation and progression of the disease. With this review, future studies can determine if any new markers, or a panel of the proteins explored in this study, may be contenders as diagnostic or prognostic markers for CAS.

Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences.

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient-provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes.

Sex-specific roles of cellular inflammation and cardiometabolism in obesity-associated depressive symptomatology.

BACKGROUND: Obesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. Therefore, we analyzed sex in associations between inflammation and metabolic syndrome (MetS) criteria on depressive symptomatology. Specifically, we examined whether sex positively moderates the relationship between depressive symptoms and inflammation among women, and whether MetS has parallel effects among men. METHODS: Depressive symptoms, MetS, and inflammation were assessed in 129 otherwise healthy adults. Depressive symptoms were assessed using Beck Depression Inventory (BDI-Ia). Monocyte inflammation regulation (BARIC) was quantified using flow cytometry measurement of TNF-α suppression by ß-agonist. Moderation effects of sex on associations between BARIC, MetS criteria, and BDI were estimated using two-way ANOVA and linear regression, adjusting for BMI, and by sex subgroup analyses. RESULTS: Obese individuals reported more depressive symptoms. Sex did not formally moderate this relationship, though BDI scores tended to differ by BMI among women, but not men, in subgroup analysis. Poorer inflammation control and higher MetS criteria were correlated with somatic depressive symptoms. Sex moderated associations between MetS criteria and somatic symptoms; among men, MetS criteria predicted somatic symptoms, not among women. Subgroup analysis further indicated that poorer inflammation control tended to be associated with higher somatic symptoms in women. CONCLUSIONS: These results indicate that obesity-related inflammation and MetS factors have sex-specific effects on depressive symptoms in a non-clinical population. Although pathophysiological mechanisms underlying sex differences remain to be elucidated, our findings suggest that distinct vulnerabilities to depressive symptoms exist between women and men, and highlight the need to consider sex as a key biological variable in obesity-depression relationships. Future clinical studies on comorbid obesity and depression should account for sex, which may optimize therapeutic strategies.

SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.

Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca(2+)- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca(2+) retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca(2+) and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca(2+)- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.

Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease.

Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate ßAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1ß, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes.

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.

BACKGROUND: Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. OBJECTIVES: This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. METHODS: Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor promoter. RESULTS: Compared with control subjects, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B167 expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions. CONCLUSIONS: Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and effective new therapy for nonischemic heart failure.

Benefit of physical fitness against inflammation in obesity: role of beta adrenergic receptors.

Evidence shows that both poor physical fitness and obesity are linked to low-grade inflammation and inflammatory diseases. However, their relative roles on inflammation and underlying mechanisms remain unclear. Given the inhibitory effect of catecholamines on inflammatory cytokine production, we speculated that compromised responsiveness of immune cells' beta adrenergic receptors (ß-ARs) to agonists may be associated with constitutively elevated levels of inflammatory cytokines. We examined circulating levels of inflammatory cytokines TNF, IL-1ß, IL-6 and ß-AR sensitivity of, 70 overweight or obese compared to 26 normal-weight, otherwise healthy individuals in order to investigate the associations among obesity, physical fitness, and low-grade inflammation and to examine the role of ß-ARs in these relationships. Cardiorespiratory fitness was determined by VO2peak (ml/kg/min) via a treadmill exercise. Beta-AR sensitivity was evaluated by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by isoproterenol. In all participants, BMI, which was initially a predictor of IL-1ß and IL-6 levels independent of demographic characteristics, no longer significantly predicted them after controlling for fitness levels. Among the overweight or obese participants, greater cardiorespiratory fitness was a strong predictor of lower levels of TNF and IL-1ß after controlling for the covariates. When ß-AR sensitivity was controlled for, however, fitness was no longer a significant predictor of those cytokines. Monocytic ß-AR sensitivity was negatively associated with inflammatory marker levels and diminished in obese individuals; however, when fitness was controlled for, the significant weight group differences in ß-AR sensitivity disappeared. Our findings indicate that better cardiorespiratory fitness protects against obesity-related low-grade inflammation and ß-AR desensitization. Given the significance of ß-AR function in pathogenesis of various diseases, clinical implications of its role in the fitness-inflammation association among the obese are profound.

Differential TNF production by monocyte subsets under physical stress: blunted mobilization of proinflammatory monocytes in prehypertensive individuals.

Elevated blood pressure (BP) and infiltration of the vasculature by monocytes contribute to vascular pathology; but, monocyte migratory characteristics based on differing inflammatory potential under adrenergic activation remains unclear. We compared nonclassical (CD14(+)CD16(++); HLA-DR(+)), intermediate (CD14(++)CD16(+); HLA-DR(++)), and classical (CD14(++)CD16(-); HLA-DR(+/-)) monocyte trafficking and their LPS-stimulated TNF production in response to a physical stressor (20-min treadmill exercise at 65-70% VO(2peak)) in participants with high prehypertension (PHT), mild PHT or normal BP (NBP). To determine adrenergic receptor (AR) sensitivity, pre-exercise cells were also treated with isoproterenol (Iso). When cells were stimulated with LPS, the CD16 molecules were downregulated, and monocyte subsets were differentiated based on HLA-DR expression. Monocyte subpopulations (as % of total monocytes) and intracellular TNF production were evaluated by flow cytometry. TNF production in all subsets decreased post-exercise and with ex-vivo incubation with Iso, irrespective of BP (p<0.001), with nonclassical and intermediate monocytes being a major source of TNF production. Overall, % nonclassical monocytes increased, % intermediate did not change, whereas % classical decreased post-exercise (p<0.001). However, % increase in nonclassical monocytes under exercise-induced adrenergic activation was blunted in high PHT individuals (p<0.05), but not in individuals with mild PHT and NBP. These findings extend our previous reports by showing that the mobilization of proinflammatory monocytes under physical stress is attenuated with even mild BP elevation. This may be indicative of monocytic AR desensitization and/or greater adhesion of "proinflammatory" monocytes to the vascular endothelium in hypertension with potential clinical implications of vascular pathology.

Effect of eszopiclone on sleep, fatigue, and pain in patients with mucositis associated with hematologic malignancies.

PURPOSE: Patients with malignancy sometimes develop painful mucositis and require patient-controlled analgesia (PCA) to treat their pain. Pain disrupts sleep and there is some evidence that analgesic medications also disrupt sleep. This study examined whether treatment with the sedative hypnotic eszopiclone could improve self-reports of sleep, fatigue, and pain as well as decrease opioid self-administered via PCA. METHODS: Inpatients who developed mucositis severe enough to require PCA treatment were randomized double-blind to a 2-day trial on eszopiclone or placebo-administered at bedtime. Patients completed questionnaires which assessed sleep, pain, and fatigue. PCA medication was calculated in terms of morphine equivalents. Data were analyzed with unpaired t tests and repeated measures analysis of variance. RESULTS: Twenty-two patients were randomized to placebo and 23 to eszopiclone. Groups were comparable in age and treatment characteristics. Mean pain scores were lower in the eszopiclone group at all time points (morning p = 0.01, afternoon p = 0.04, evening p = 0.04). The eszopiclone group reported increased sleep time (p < 0.05), fewer nighttime awakenings (p < 0.001), better self-reported sleep quality (p = 0.01), and depth (p = 0.04). There were no significant differences between eszopiclone and placebo in terms of self-reports of fatigue or opioid usage. CONCLUSION: Sedative hypnotic agents improve sleep and analgesia even in the setting of considerable pain and discomfort.

Knowledge and attitudes of Pakistani medical students towards HIV-positive and/or AIDS patients.

As the incidence of HIV increases, one of the major steps in preventing a widespread epidemic is to make certain that medical students are prepared to recognize and treat HIV infections and their related conditions, and to counsel patients about avoiding risks that might lead to infections. This cross-sectional study assessed the knowledge level of 357 medical students and their attitudes about AIDS and HIV enrolled in a Medical College in Karachi, Pakistan. Only 6% of the students had complete knowledge on symptoms of HIV/AIDS and 7% of the students had complete knowledge on the modes of transmission of HIV. Statistical analysis of demographic factors affecting knowledge was done. Linear regression and Maentel-Haenszel tests showed that older and clinical students were more knowledgeable of symptoms and modes of transmission of HIV/AIDS. Ten attitudes were correlated with knowledge and none of these showed an association. These results on knowledge indicate that education about HIV/AIDS should be incorporated in the curriculum and interventions must be taken by public health professionals to avoid poor treatment outcomes.