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1.  Adiponectin and inducible ischemia in patients with stable coronary heart disease: data from the Heart and Soul study 
Atherosclerosis  2008;205(1):233-238.
Objective
Elevated concentrations of adiponectin are associated with a favorable metabolic profile but also with adverse cardiovascular outcomes. This apparent discrepancy has raised questions about whether adiponectin is associated with an increased or decreased risk of coronary heart disease (CHD). We sought to determine whether higher adiponectin levels are associated with exercise-induced ischemia in patients with stable CHD.
Methods and results
We measured total serum adiponectin concentrations and evaluated exercise-induced ischemia by stress echocardiography in a cross-sectional study of 899 outpatients with documented stable CHD. Of these, 217 (24%) had inducible ischemia. Although adiponectin levels correlated negatively with diabetes prevalence, body mass index, serum insulin, fasting glucose, low-density lipoprotein cholesterol, and triglycerides and positively with high-density lipoprotein cholesterol (all P< 0.005), elevated adiponectin concentrations were also associated with a greater risk of inducible ischemia. Each standard deviation (0.08 μg/mL) increase in log adiponectin was associated with a 35% greater odds of inducible ischemia (unadjusted odds ratio 1.35; 95% confidence interval 1.15–1.57; P=0.0002). Although attenuated, this association remained present after multivariable adjustment for traditional cardiovascular risk factors and other measures of cardiac function (adjusted odds ratio 1.21; 95% confidence interval 1.02–1.43; P=0.03).
Conclusions
Elevated concentrations of adiponectin are independently associated with inducible ischemia in patients with stable CHD. These findings raise the possibility that the presence of chronic inducible ischemia may alter the cardio-protective effects afforded by adiponectin secretion in the healthy population.
doi:10.1016/j.atherosclerosis.2008.11.014
PMCID: PMC2779844  PMID: 19111833
Adiponectin; Coronary heart disease (CHD); Ischemia; Adipokine; Reverse epidemiology
2.  Windows to the soul: vision science as a tool for studying biological mechanisms of information processing deficits in schizophrenia 
Cognitive and information processing deficits are core features and important sources of disability in schizophrenia. Our understanding of the neural substrates of these deficits remains incomplete, in large part because the complexity of impairments in schizophrenia makes the identification of specific deficits very challenging. Vision science presents unique opportunities in this regard: many years of basic research have led to detailed characterization of relationships between structure and function in the early visual system and have produced sophisticated methods to quantify visual perception and characterize its neural substrates. We present a selective review of research that illustrates the opportunities for discovery provided by visual studies in schizophrenia. We highlight work that has been particularly effective in applying vision science methods to identify specific neural abnormalities underlying information processing deficits in schizophrenia. In addition, we describe studies that have utilized psychophysical experimental designs that mitigate generalized deficit confounds, thereby revealing specific visual impairments in schizophrenia. These studies contribute to accumulating evidence that early visual cortex is a useful experimental system for the study of local cortical circuit abnormalities in schizophrenia. The high degree of similarity across neocortical areas of neuronal subtypes and their patterns of connectivity suggests that insights obtained from the study of early visual cortex may be applicable to other brain regions. We conclude with a discussion of future studies that combine vision science and neuroimaging methods. These studies have the potential to address pressing questions in schizophrenia, including the dissociation of local circuit deficits vs. impairments in feedback modulation by cognitive processes such as spatial attention and working memory, and the relative contributions of glutamatergic and GABAergic deficits.
doi:10.3389/fpsyg.2013.00681
PMCID: PMC3813897  PMID: 24198792
schizophrenia; visual system; fMRI; psychophysics; magnetic resonance spectroscopy
3.  Association of a Serotonin Transporter Polymorphism (5-HTTLPR) With Depression, Perceived Stress, and Norepinephrine in Patients With Coronary Disease: The Heart and Soul Study 
The American journal of psychiatry  2007;164(9):1379-1384.
Objective
The short allele of a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with stressful life events to predict depression in otherwise healthy individuals. Whether the short allele increases risk for depression associated with the stress of a chronic illness has not been established.
Method
In a cross-sectional genetic association study, the authors examined the association of 5-HTTLPR with current depression (measured by the Computerized Diagnostic Interview Schedule), perceived stress (measured by the Perceived Stress Scale), and 24-hour urinary norepinephrine excretion in 557 outpatients with chronic coronary disease.
Results
Among individuals carrying an s allele, 25% (97 of 383) had current depression, compared with 17% (29 of 174) of l/l homozygotes. The unadjusted odds ratio was 1.6, with a 95% confidence interval (CI) of 1.0–2.6; the age- and gender-adjusted odds ratio was also 1.6 (95% CI= 1.0–2.5). Participants carrying an s allele had a higher mean score for perceived stress than l/l homozygotes (5.4 versus 4.7) and a higher rate of moderate or high perceived stress (adjusted odds ratio=1.6, 95% CI=1.1–2.3). Mean 24-hour norepinephrine excretion was higher in s allele carriers (55.6 versus 50.2 μg/day), who were more likely to have norepinephrine values in the highest quartile (adjusted odds ratio=1.7, 95% CI=1.0–3.0).
Conclusions
Among patients with chronic illness, carriers of the s allele of 5-HTTLPR are more vulnerable to depression, perceived stress, and high norepinephrine secretion. These factors may contribute to worse cardiovascular outcomes in these patients.
doi:10.1176/appi.ajp.2007.06101617
PMCID: PMC2771565  PMID: 17728423
4.  Depression and Cardiac Function in Patients With Stable Coronary Heart Disease: Findings From the Heart and Soul Study 
Psychosomatic medicine  2008;70(4):444-449.
Objective
To determine whether depression is associated with worse cardiac disease severity in patients with stable coronary heart disease (CHD). There is considerable evidence that depression is a risk factor for adverse cardiovascular events in patients with CHD. However, a frequent criticism of this literature is that the association between depression and adverse cardiovascular outcomes may be confounded by worse baseline cardiac disease severity in depressed patients.
Method
In a sample of 1020 outpatients with stable CHD, we examined the association between major depression (assessed using the Computerized National Institute of Mental Health Diagnostic Interview Schedule) with measures of cardiac disease severity, including systolic dysfunction, diastolic dysfunction, exercise-induced ischemia, and cardiac wall motion abnormalities. Cross-sectional univariate and multivariate models controlling for demographic and clinical variables were computed.
Results
Of the 1020 participants, 224 (22%) had current (past month) major depression. After adjustment for age, major depression was not associated with systolic dysfunction, diastolic dysfunction, inducible ischemia, or cardiac wall motion abnormalities. Similarly, multivariate models revealed no significant relationship between major depression and cardiac disease severity.
Conclusions
Overall, we found little evidence that depression is associated with worse cardiac disease severity. This suggests that greater baseline cardiac disease severity is unlikely to be responsible for the increased risk of CHD events in depressed patients.
doi:10.1097/PSY.0b013e31816c3c5c
PMCID: PMC2675877  PMID: 18434493
depression; cardiac function; coronary heart disease
5.  Depressive Symptoms and Perceived Doctor-Patient Communication in the Heart and Soul Study 
BACKGROUND
Doctor-patient communication is an important marker of health-care quality. Little is known about the extent to which medical comorbidities, disease severity and depressive symptoms influence perceptions of doctor-patient communication in patients with chronic disease.
METHODS
In a cross-sectional study of 703 outpatients with chronic coronary disease, we evaluated the extent to which patient reports of doctor-patient communication were influenced by medical comorbidities, disease severity and depressive symptoms. We assessed patient reports of doctor-patient communication using the Explanations of Condition and Responsiveness to Patient Preferences subscales from the “Interpersonal Processes of Care” instrument. Poor doctor-patient communication was defined as a score of <4 (range 1 to 5) on either subscale. All patients completed the nine-item Patient Health Questionnaire (PHQ) for measurement of depressive symptoms and underwent an extensive evaluation of medical comorbidities and cardiac function.
RESULTS
In univariate analyses, the following patient characteristics were associated with poor reported doctor-patient communication on one or both subscales: female sex, white or Asian race and depressive symptoms. After adjusting for demographic factors, medical comorbidities and disease severity, each standard deviation (5.4-point) increase in depressive symptom score was associated with a 50% greater odds of poor reported explanations of condition (OR 1.5, 95% CI, 1.2–1.8; p < 0.001) and a 30% greater odds of poor reported responsiveness to patient preferences (OR 1.3, 95% CI, 1.1–1.5; p = 0.01). In contrast, objective measures of disease severity (left ventricular ejection fraction, exercise capacity, inducible ischemia) and medical comorbidities (hypertension, diabetes, myocardial infarction) were not associated with reports of doctor-patient communication.
CONCLUSIONS
In outpatients with chronic coronary heart disease, depressive symptoms are associated with perceived deficits in doctor-patient communication, while medical comorbidities and disease severity are not. These findings suggest that patient reports of doctor-patient communication may partly reflect the psychological state of the patient.
doi:10.1007/s11606-009-0937-5
PMCID: PMC2669866  PMID: 19274477
doctor-patient communication; depression; chronic disease
6.  Understanding Brain, Mind and Soul: Contributions from Neurology and Neurosurgery 
Mens Sana Monographs  2011;9(1):129-149.
Treatment of diseases of the brain by drugs or surgery necessitates an understanding of its structure and functions. The philosophical neurosurgeon soon encounters difficulties when localising the abstract concepts of mind and soul within the tangible 1300-gram organ containing 100 billion neurones. Hippocrates had focused attention on the brain as the seat of the mind. The tabula rasa postulated by Aristotle cannot be localised to a particular part of the brain with the confidence that we can localise spoken speech to Broca’s area or the movement of limbs to the contralateral motor cortex. Galen’s localisation of imagination, reasoning, judgement and memory in the cerebral ventricles collapsed once it was evident that the functional units–neurones–lay in the parenchyma of the brain. Experiences gained from accidental injuries (Phineas Gage) or temporal lobe resection (William Beecher Scoville); studies on how we see and hear and more recent data from functional magnetic resonance studies have made us aware of the extensive network of neurones in the cerebral hemispheres that subserve the functions of the mind. The soul or atman, credited with the ability to enliven the body, was located by ancient anatomists and philosophers in the lungs or heart, in the pineal gland (Descartes), and generally in the brain. When the deeper parts of the brain came within the reach of neurosurgeons, the brainstem proved exceptionally delicate and vulnerable. The concept of brain death after irreversible damage to it has made all of us aware of ‘the cocktail of brain soup and spark’ in the brainstem so necessary for life. If there be a soul in each of us, surely, it is enshrined here.
doi:10.4103/0973-1229.77431
PMCID: PMC3115284  PMID: 21694966
Brain; Brainstem; Mind; Soul; Neurology; Neurosurgery; Philosophy
7.  Interleukin 6 and Atrial Fibrillation in Patients with Coronary Artery Disease: Data from the Heart and Soul Study 
American heart journal  2007;155(2):303-309.
Background
Previous studies suggest that markers of inflammation are elevated in patients with atrial fibrillation (AF). However, because inflammation has been implicated in contributing to risk of both AF and coronary artery disease (CAD), which are often present in the same populations, it is important to control for confounding by the presence of CAD. We therefore examined several biomarkers of inflammation and ultimately genotyped IL-6 polymorphisms in AF patients in a cohort of subjects with known CAD.
Methods
We performed a cross-sectional analysis of 971 participants in the Heart and Soul Study, 46 of whom had AF. IL-6, CRP, tumor necrosis factor-α, CD-40 ligand, monocyte chemoattractant protein-1, and fibrinogen levels were measured.
Results
In both unadjusted and adjusted analyses, IL-06 was the only biomarker significantly associated with AF (median IL-6 3.76 pg/ml and 2.52 pg/ml in those with and without AF, respectively, p=0.0005; adjusted odds ratio [OR] 1.77 p=0.032). The IL-6 –174CC genotype was significantly associated with the presence of AF in the adjusted analysis (OR 2.34, p=0.04) and with higher IL-6 levels (p=0.002).
Conclusions
In this cohort of subjects with CAD, AF was significantly associated with elevated IL-6 levels and the IL-6 –174CC genotype. No associations were found with other biomarkers, including CRP. This suggests that IL-6 is a uniquely important mediator in the pathophysiology of AF.
doi:10.1016/j.ahj.2007.09.006
PMCID: PMC2247366  PMID: 18215601
8.  Association of Anemia With Diastolic Dysfunction Among Patients With Coronary Artery Disease in the Heart and Soul Study 
We performed a cross-sectional study to evaluate the association of anemia with diastolic dysfunction and left ventricular hypertrophy (LVH) in outpatients who had coronary artery disease. Logistic regression was used to examine the association of blood hemoglobin (Hb) concentrations with diastolic dysfunction and LVH in 822 participants in the Heart and Soul Study who had normal sinus rhythm and preserved systolic function (left ventricular ejection fraction ≥50%). Using transthoracic echocardiography, diastolic dysfunction was defined as diastolically dominant pulmonary vein flow, and LVH was defined as left ventricular mass index >90 g/m2. Anemia (Hb <13 g/dl) was present in 24% of participants (197 of 822). The prevalence of diastolic dysfunction ranged from 8% in participants who did not have anemia (Hb ≥13 g/dl) to 13% in those who had moderate anemia (Hb 11 to 13 g/dl) to 24% in those who had severe anemia (Hb < 11 g/dl, p = 0.004 for trend). After multivariable adjustment, moderate anemia (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.1 to 3.6) and severe anemia (OR 6.6, 95% CI 1.9 to 24.9) remained strongly associated with diastolic dysfunction. In contrast, moderate anemia (OR 1.4, 95% CI 1.0 to 2.1) and severe anemia (OR 1.6, 95% CI 0.6 to 4.6) were not significantly associated with LVH. We found anemia to be strongly associated with diastolic dysfunction but not with LVH in this community-based sample of outpatients who had established coronary disease.
doi:10.1016/j.amjcard.2004.09.029
PMCID: PMC2776659  PMID: 15670540
9.  mHealth: A Strategic Field without a Solid Scientific Soul. A Systematic Review of Pain-Related Apps 
PLoS ONE  2014;9(7):e101312.
Background
Mobile health (mHealth) has undergone exponential growth in recent years. Patients and healthcare professionals are increasingly using health-related applications, at the same time as concerns about ethical issues, bias, conflicts of interest and privacy are emerging. The general aim of this paper is to provide an overview of the current state of development of mHealth.
Methods and Findings
To exemplify the issues, we made a systematic review of the pain-related apps available in scientific databases (Medline, Web of Science, Gale, Psycinfo, etc.) and the main application shops (App Store, Blackberry App World, Google Play, Nokia Store and Windows Phone Store). Only applications (designed for both patients and clinicians) focused on pain education, assessment and treatment were included. Of the 47 papers published on 34 apps in scientific databases, none were available in the app shops. A total of 283 pain-related apps were found in the five shops searched, but no articles have been published on these apps. The main limitation of this review is that we did not look at all stores in all countries.
Conclusions
There is a huge gap between the scientific and commercial faces of mHealth. Specific efforts are needed to facilitate knowledge translation and regulate commercial health-related apps.
doi:10.1371/journal.pone.0101312
PMCID: PMC4085095  PMID: 24999983
10.  A Community of Curious Souls: An Analysis of Commenting Behavior on TED Talks Videos 
PLoS ONE  2014;9(4):e93609.
The TED (Technology, Entertainment, Design) Talks website hosts video recordings of various experts, celebrities, academics, and others who discuss their topics of expertise. Funded by advertising and members but provided free online, TED Talks have been viewed over a billion times and are a science communication phenomenon. Although the organization has been derided for its populist slant and emphasis on entertainment value, no previous research has assessed audience reactions in order to determine the degree to which presenter characteristics and platform affect the reception of a video. This article addresses this issue via a content analysis of comments left on both the TED website and the YouTube platform (on which TED Talks videos are also posted). It was found that commenters were more likely to discuss the characteristics of a presenter on YouTube, whereas commenters tended to engage with the talk content on the TED website. In addition, people tended to be more emotional when the speaker was a woman (by leaving comments that were either positive or negative). The results can inform future efforts to popularize science amongst the public, as well as to provide insights for those looking to disseminate information via Internet videos.
doi:10.1371/journal.pone.0093609
PMCID: PMC3981706  PMID: 24718634
11.  The price of your soul: neural evidence for the non-utilitarian representation of sacred values 
Sacred values, such as those associated with religious or ethnic identity, underlie many important individual and group decisions in life, and individuals typically resist attempts to trade off their sacred values in exchange for material benefits. Deontological theory suggests that sacred values are processed based on rights and wrongs irrespective of outcomes, while utilitarian theory suggests that they are processed based on costs and benefits of potential outcomes, but which mode of processing an individual naturally uses is unknown. The study of decisions over sacred values is difficult because outcomes cannot typically be realized in a laboratory, and hence little is known about the neural representation and processing of sacred values. We used an experimental paradigm that used integrity as a proxy for sacredness and which paid real money to induce individuals to sell their personal values. Using functional magnetic resonance imaging (fMRI), we found that values that people refused to sell (sacred values) were associated with increased activity in the left temporoparietal junction and ventrolateral prefrontal cortex, regions previously associated with semantic rule retrieval. This suggests that sacred values affect behaviour through the retrieval and processing of deontic rules and not through a utilitarian evaluation of costs and benefits.
doi:10.1098/rstb.2011.0262
PMCID: PMC3260841  PMID: 22271790
functional magnetic resonance imaging; sacred values; utility; deontologic; rules
12.  A home for body and soul: Substance using women in recovery 
Background
We report on an in-depth qualitative study of 28 active and former substance addicted women of low or marginal income on the core components of a harm reduction-based addiction recovery program. These women volunteered to be interviewed about their perceptions of their therapeutic needs in their transition from substance addiction to recovery.
Method
Data were gathered about women’s experiences and essential needs in addiction recovery, what helped and what hindered their past efforts in recovery, and their views of what would constitute an effective woman-centred recovery program. The research was based upon the experience and knowledge of the women in interaction with their communities and with recovery programs. The study was informed by harm reduction practice principles that emphasize the importance of individual experience in knowledge construction, reduction of harm, low threshold access, and the development of a hierarchy of needs in regard to addiction recovery.
Results
Three core needs were identified by study participants: normalization and structure, biopsychosocial-spiritual safety, and social connection. What hindered recovery efforts as identified by participants was an inner urban location, prescriptive recovery, invidious treatment, lack of safety, distress-derived distraction, problem-focused treatment, coercive elements of mutual support groups, and social marginalization. What helped included connection in counselling and therapy, multidisciplinary service provision, spirituality focus, opportunities for learning and work, and a safe and flexible structure. Core components of an effective recovery program identified by women themselves stand in contrast to the views of service providers and policymakers, particularly in regard to the need for a rural location for residential programs, low threshold access, multidisciplinary service provision of conventional and complementary modalities and therapies for integrated healing, long-term multi-phase recovery, and variety and choice of programming.
Conclusion
A key barrier to the addiction recovery of women is the present framework of addiction treatment, as well as current drug laws, policies and service delivery systems. The expectation of women is that harm reduction-based recovery services will facilitate safe, supportive transitioning from the point of the decision to access services, through independent living with community integration.
doi:10.1186/1477-7517-10-39
PMCID: PMC3878194  PMID: 24359089
13.  “Souls of the ancestor that knock us out” and other tales. A qualitative study to identify demand-side factors influencing malaria case management in Cambodia 
Malaria Journal  2012;11:335.
Background
Appropriate case management of suspected malaria in Cambodia is critical given anti-malarial drug resistance in the region. Improving diagnosis and the use of recommended malarial treatments is a challenge in Cambodia where self-treatment and usage of drug cocktails is widespread, a notable difference from malaria treatment seeking in other countries. This qualitative study adds to the limited evidence base on Cambodian practices, aiming to understand the demand-side factors influencing treatment-seeking behaviour, including the types of home treatments, perceptions of cocktail medicines and reasons for diagnostic testing. The findings may help guide intervention design.
Methods
The study used in-depth interviews (IDIs) (N = 16) and focus group discussions (FGDs) (N = 12) with Cambodian adults from malaria-endemic areas who had experienced malaria fever in the previous two weeks. Data were analysed using NVivo software.
Results
Findings suggest that Cambodians initially treat suspected malaria at home with home remedies and traditional medicines. When seeking treatment outside the home, respondents frequently reported receiving a cocktail of medicines from trusted providers. Cocktails are perceived as less expensive and more effective than full-course, pre-packaged medicines. Barriers to diagnostic testing include a belief in the ability to self-diagnose based on symptoms, cost and reliance on providers to recommend a test. Factors that facilitate testing include recommendation by trusted providers and a belief that anti-malarial treatment for illnesses other than malaria can be harmful.
Conclusions
Treatment-seeking behaviour for malaria in Cambodia is complex, driven by cultural norms, practicalities and episode-related factors. Effective malaria treatment programmes will benefit from interventions and communication materials that leverage these demand-side factors, promoting prompt visits to facilities for suspected malaria and challenging patients’ misconceptions about the effectiveness of cocktails. Given the importance of the patient-provider interaction and the pivotal role that providers play in ensuring the delivery of appropriate malaria care, future research and interventions should also focus on the supply side factors influencing provider behaviour.
doi:10.1186/1475-2875-11-335
PMCID: PMC3478967  PMID: 23039260
Treatment-seeking behaviour; Patient perceptions; Patient-provider interactions; Malaria diagnosis; Malaria treatment; Cocktail; ACT; Cambodia; Qualitative research
14.  Acute Myocardial Infarction in Patients With Versus Without Aortic Valve Sclerosis and Effect of Statin Therapy (from the Heart and Soul Study) 
The American journal of cardiology  2007;99(8):1128-1133.
Aortic sclerosis is associated with cardiovascular events in patients without coronary heart disease (CHD), but it is unclear whether this association exists in patients with established CHD or is independent of baseline cardiac disease severity. It is also unclear whether statins modify this association. In a prospective cohort study of 814 outpatients with established CHD and no evidence of aortic stenosis, the association of aortic sclerosis with subsequent cardiovascular events was examined using a multivariable Cox proportional hazards model. Of 814 participants, 324 (40%) had aortic sclerosis. During 4 years of follow-up, 10% with aortic sclerosis experienced a myocardial infarction (MI) compared with 5% of those without aortic sclerosis (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1 to 3.1, p = 0.02). This association was unchanged after adjustment for potential confounders and mediators (HR 2.4, 95% CI 1.3 to 4.8, p = 0.009). However, the association between aortic sclerosis and MI appeared to differ by statin use (p = 0.15 for interaction). Aortic sclerosis predicted subsequent MI in subjects not administered statins (adjusted HR 4.1, 95% CI 1.1 to 15.7, p = 0.04), but not in those administered statins (adjusted HR 1.7, 95% CI 0.8 to 3.9, p = 0.18). In conclusion, aortic sclerosis was present in 40% of patients with CHD and is independently associated with a 2.4-fold increased rate of subsequent MI. Statins may attenuate the increased risk of future MI in patients with aortic sclerosis.
doi:10.1016/j.amjcard.2006.11.057
PMCID: PMC2778470  PMID: 17437741
15.  Fetuin-A and kidney function in persons with coronary artery disease—data from the heart and soul study 
Background
Fetuin-A is a serum protein that inhibits ectopic vascular calcification and is present in lower concentrations in end-stage renal disease than in healthy controls. Whether fetuin-A concentrations are also lower in the setting of mild-to-moderate chronic kidney disease (CKD) is unknown.
Methods
We evaluated the associations of several parameters of kidney function including measured 24 h urinary creatinine clearance (CrCl), estimated glomerular filtration rate (GFR) by the Mayo Clinic quadratic GFR equation (qGFR), serum cystatin-C concentrations, and urinary albumin-to-creatinine ratio with serum fetuin-A concentrations in 970 outpatients with coronary artery disease. We used general linear models to determine the adjusted mean fetuin-A concentrations within each kidney function category.
Results
The mean age of the study sample was 67 years, 82% were male, 71% had hypertension and 26% had diabetes mellitus. In adjusted analysis, we observed no significant differences in mean fetuin-A concentrations across groups defined by CrCl, qGFR, or albumin-to-creatinine ratio groups. For example, adjusted mean fetuin-A concentrations were 0.66 g/l in participants with CrCl > 90, 60–90 and 45–60 ml/min/1.73 m2, and 0.65 g/l in participants with CrCl < 45 ml/min/1.73 m2. Higher serum cystatin-C (indicating worse kidney function) was associated with higher adjusted mean serum fetuin-A concentrations (lowest quartile 0.62 g/l, highest quartile 0.68 g/l; P for trend <0.001).
Conclusions
Among ambulatory patients with coronary artery disease, there is no evidence that mild-to-moderate CKD is associated with lower concentrations of serum fetuin-A compared with persons with normal renal function. The mechanisms explaining the association between CKD and vascular calcification remain elusive.
doi:10.1093/ndt/gfl204
PMCID: PMC2776687  PMID: 16644775
calcium; chronic kidney disease; fetuin-A; alpha-2-Heremans-Schmid-glycoprotein; vascular calcification; phosphorus
16.  Structural changes in the BH3 domain of SOUL protein upon interaction with the anti-apoptotic protein Bcl-xL 
Biochemical Journal  2011;438(Pt 2):291-301.
The SOUL protein is known to induce apoptosis by provoking the mitochondrial permeability transition, and a sequence homologous with the BH3 (Bcl-2 homology 3) domains has recently been identified in the protein, thus making it a potential new member of the BH3-only protein family. In the present study, we provide NMR, SPR (surface plasmon resonance) and crystallographic evidence that a peptide spanning residues 147–172 in SOUL interacts with the anti-apoptotic protein Bcl-xL. We have crystallized SOUL alone and the complex of its BH3 domain peptide with Bcl-xL, and solved their three-dimensional structures. The SOUL monomer is a single domain organized as a distorted β-barrel with eight anti-parallel strands and two α-helices. The BH3 domain extends across 15 residues at the end of the second helix and eight amino acids in the chain following it. There are important structural differences in the BH3 domain in the intact SOUL molecule and the same sequence bound to Bcl-xL.
doi:10.1042/BJ20110257
PMCID: PMC3174058  PMID: 21639858
apoptosis; Bcl-xL; Bcl-2 homology 3 domain (BH3 domain); crystal structure; NMR; SOUL; surface plasmon resonance; BH, Bcl-2 homology; HEBP, haem-binding protein; HSQC, heteronuclear single-quantum coherence; MPT, mitochondrial permeability transition; rmsd, root mean square deviation; RZPD, Deutsches Ressouroenzentrum für Genomforschung; SPR, surface plasmon resonance
17.  GALEN'S RECOGNITION OF THREE SOULS AND THEIR ORIGIN 
Ancient Science of Life  1986;6(2):69-76.
Galen's three souls incorporate previously existing ideas of soul. Soul is matter – cum – energy. As matter it is airlike, the finest by nature and as movement, like sound, the form of energy most subtle of its kind. Creator is depicted with Creation as the Cosmic egg and snake as Cosmic soul and the syllable Om, as the word incorporating creative energy. Om as humming sound is symbolized by Bees which produce such sound.
PMCID: PMC3331411  PMID: 22557550
18.  Lack of association of chromosome 9p21.3 genotype with cardiovascular structure and function in persons with stable coronary artery disease: The Heart and Soul Study 
Atherosclerosis  2008;205(2):492-496.
Objective
Recent large-scale genome-wide association studies have identified a novel susceptibility locus on chromosome 9p21.3 that contributes a significant attributable risk for myocardial infarction. The phenotypic significance of this locus in patients with established coronary artery disease is unknown. We sought to compare cardiovascular structure and function in carriers and non-carriers of the risk haplotype in a cross-sectional study.
Methods
We genotyped the rs1333049 single-nucleotide polymorphism in 593 Caucasian individuals with stable coronary artery disease recruited in the Heart and Soul study. All study subjects underwent resting and stress echocardiography. Linear and logistic regression models were used to examine the association between the rs1333049 polymorphism and echocardiographic parameters of cardiovascular structure and function.
Results
There was no association between rs1333049 genotype and echocardiographic phenotype (left ventricular hypertrophy, systolic dysfunction, diastolic dysfunction, inducible ischemia, exercise capacity, mitral annular calcification, and aortic plaque).
Conclusions
In a cross-sectional study of individuals with stable coronary artery disease, there was no association of chromosome 9p21.3 genotype with cardiovascular structure and function.
doi:10.1016/j.atherosclerosis.2008.12.026
PMCID: PMC2717182  PMID: 19171343
19.  Relationship of Urine Dopamine with Phosphorus Homeostasis in Humans: The Heart and Soul Study 
American journal of nephrology  2012;35(6):10.1159/000338483.
Background
Urine dopamine (DA) is produced in the proximal tubule and has been found to increase in response to dietary phosphorus intake, and to contribute to greater urinary phosphorus excretion in animal models. Whether urine DA is associated with phosphorus homeostasis in humans is uncertain.
Methods
This was a cross-sectional study of 884 outpatients. DA was measured from 24-hour urine collections. We examined cross-sectional associations between urine DA and serum phosphorus, 24-hour urine phosphorus (as an indicator of dietary phosphorus absorption), fractional excretion of phosphorus (FEphos), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). Models were adjusted for age, sex, race, eGFR, albuminuria, hypertension, heart failure, tobacco use, body mass index, and diuretic use.
Results
Mean age was 66.6 ± 11 years and mean eGFR was 71 ± 21.3 ml/min/1.73 m2. The mean urine DA was 193 ± 86 µg/day, mean serum phosphorus was 3.6 ± 0.6 mg/dl, mean daily urine phosphorus excretion was 671 ± 312 mg/day, and mean FEphos was 17 ± 9%. In adjusted models, each standard deviation higher DA was associated with 78.4 mg/day higher urine phosphorus and 0.9% lower FEphos (p < 0.05 for both). There was no statistically significant association between urine DA, serum phosphorus, FGF-23 or PTH in adjusted models.
Conclusions
Higher dietary phosphorus absorption is associated with higher urine DA in humans, consistent with animal models. However, higher urine DA is not associated with FGF-23 or PTH, suggesting that known mechanisms of renal tubular handling of phosphorus may not be involved in the renal dopamine-phosphorus regulatory pathway in humans.
doi:10.1159/000338483
PMCID: PMC3873852  PMID: 22572568
Urine dopamine; Phosphorus; Kidney; Proximal tubule
20.  Self-Efficacy as a Marker of Cardiac Function and Predictor of Heart Failure Hospitalization and Mortality in Patients With Stable Coronary Heart Disease: Findings From the Heart and Soul Study 
Objective
The authors sought to evaluate the association of self-efficacy with objective measures of cardiac function, subsequent hospitalization for heart failure (HF), and all-cause mortality.
Design
Observational cohort of ambulatory patients with stable CHD. The authors measured self-efficacy using a published, validated, 5-item summative scale, the Sullivan Self-Efficacy to Maintain Function Scale. The authors also performed a cardiac assessment, including an exercise treadmill test with stress echocardiography.
Main Outcome Measures
Hospitalizations for HF, as determined by blinded review of medical records, and all-cause mortality, with adjustment for demographics, medical history, medication use, depressive symptoms, and social support.
Results
Of the 1,024 predominately male, older CHD patients, 1013 (99%) were available for follow-up, 124 (12%) were hospitalized for HF, and 235 (23%) died during 4.3 years of follow-up. Mean cardiac self-efficacy score was 9.7 (SD 4.5, range 0–20), corresponding to responses between “not at all confident” and “somewhat confident” for ability to maintain function. Lower self-efficacy predicted subsequent HF hospitalization (OR per SD decrease = 1.4, p = 0006), and all-cause mortality (OR per SD decrease = 1.4, p < .0001). After adjustment, the association of cardiac self-efficacy with both HF hospitalization and mortality was explained by worse baseline cardiac function.
Conclusion
Among patients with CHD, self-efficacy was a reasonable proxy for predicting HF hospitalizations. The increased risk of HF associated with lower baseline self-efficacy was explained by worse cardiac function. These findings indicate that measuring cardiac self-efficacy provides a rapid and potentially useful assessment of cardiac function among outpatients with CHD.
doi:10.1037/a0013146
PMCID: PMC2764522  PMID: 19290708
self-efficacy; heart failure; epidemiology
21.  Optimizing Detection of Major Depression Among Patients with Coronary Artery Disease Using the Patient Health Questionnaire: Data from the Heart and Soul Study 
Journal of General Internal Medicine  2008;23(12):2014-2017.
BACKGROUND
Clinical guidelines recommend depression screening in patients with coronary artery disease (CAD), but how to accomplish this is unclear.
OBJECTIVE
We evaluated the test characteristics of the two-item Patient Health Questionnaire (PHQ-2), the nine-item Patient Health Questionnaire (PHQ-9), and a two-step screening approach (PHQ-2 then PHQ-9 if positive on PHQ-2), compared with the Computerized Diagnostic Interview Schedule (C-DIS) for major depression. We also evaluated a “PHQ diagnosis” of depression, requiring five of nine symptoms “more than half the days,” compared with the C-DIS.
DESIGN
Cross-sectional study of 1,024 outpatients with CAD.
MAIN RESULTS
Two hundred twenty-four patients (22%) had current major depression. Optimal cutpoints were ≥2 for the PHQ-2 (82% sensitive, 79% specific) and ≥6 for the PHQ-9 (83% sensitive, 76% specific). The two-step screening approach was less sensitive (75%), but more specific (84%), than the PHQ-2 or PHQ-9 alone. The “PHQ diagnosis” had low sensitivity (28%), but high specificity (96%).
CONCLUSIONS
Cutpoints of ≥2 on the PHQ-2 and ≥6 on the PHQ-9 had similar test characteristics. A two-step approach using the PHQ-2 followed by the PHQ-9 was no better than either instrument alone. A “PHQ diagnosis” of depression had high specificity, but poor sensitivity.
doi:10.1007/s11606-008-0802-y
PMCID: PMC2596499  PMID: 18815842
diagnostic accuracy; sensitivity; specificity; cardiovascular disease; depression; screening
22.  Red Blood Cell Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Socioeconomic Status in Patients with Established Coronary Artery Disease: Data from the Heart and Soul Study12 
The Journal of nutrition  2008;138(6):1135-1140.
Traditional cardiac risk factors only partially explain the biological mechanisms by which persons of lower socioeconomic status (SES) have higher cardiovascular risk. Dietary factors, resulting in lower circulating levels of (n-3) fatty acids, may also contribute to the increased risk of cardiovascular disease (CVD) in patients with low SES. We tested whether low SES is associated with RBC levels of (n-3) fatty acids in patients with coronary heart disease. We performed a cross-sectional analysis of 987 adults with stable coronary artery disease (CAD) recruited from San Francisco area outpatient clinics. Four SES measures (household income, education, occupation, and housing status) were assessed by self-report. RBC fatty acid levels of 2 (n-3) fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were measured in venous blood samples from fasting subjects. Participants with lower household income, education, occupation, and housing status had lower RBC levels of (n-3) fatty acids (P < 0.001 for all 4 measures). In multivariable models, household income, education, and occupation remained strongly associated with DHA and EPA levels after adjustment for demographic factors, BMI, physical activity, statin use, and kidney function (P < 0.001 for all 3 measures). Housing status was not associated with DHA or EPA after multivariable adjustment. Among patients with CAD, 3 indicators of low SES, household income, education, and occupation, were strongly associated with lower RBC levels of (n-3) fatty acids. Our results raise the possibility that (n-3) fatty acids may be an important mediating factor in the association between low SES and CVD.
PMCID: PMC2675885  PMID: 18492846
23.  Depression and Whole Blood Serotonin in Patients With Coronary Heart Disease From the Heart and Soul Study 
Psychosomatic medicine  2009;71(3):260-265.
Objective
To evaluate whether depression is associated with whole blood serotonin in outpatients with stable coronary heart disease (CHD). Depression is associated with incident CHD and with adverse cardiovascular outcomes. Dysregulation of peripheral serotonin, common to both depression and CHD, may contribute to this association.
Methods
We performed a cross-sectional study of 791 participants with stable CHD enrolled in the Heart and Soul Study and not taking antidepressant medication. We assessed major depression using the Computerized Diagnostic Interview Schedule (CDIS-IV) and measured whole blood serotonin (WBS) from fasting venous samples.
Results
Of the 791 participants, 114 (14%) had current (past month) major depression, 186 (24%) had past (but not current) major depression, and 491 (62%) had no history of depression. Age-adjusted mean WBS was higher in participants with current major depression (139 ± 6.5 ng/ml) than in those with past depression (120 ± 5.0 ng/ml) or no history of depression (119 ± 3.1 ng/ml) (p= .02). This association was unchanged after adjustment for demographic characteristics, medical comorbidities, medication use, and cardiac disease severity (p = .02). When serotonin was analyzed as a dichotomous variable, current depression was associated with a 70% greater odds of having WBS in the highest quartile (adjusted odds ratio = 1.71; 95% Confidence Interval = 1.03–2.83; p = .04).
Conclusions
In this sample of patients with stable CHD, current major depression was independently associated with higher mean WBS levels. Future studies should examine whether elevated WBS may contribute to adverse outcomes in patients with depression and CHD.
doi:10.1097/PSY.0b013e31819cc761
PMCID: PMC2734190  PMID: 19297311
depression; coronary heart disease; whole blood serotonin
24.  Self-Efficacy and Health Status in Patients With Coronary Heart Disease: Findings From the Heart and Soul Study 
Psychosomatic medicine  2007;69(4):306-312.
Objective
To examine the relationship between cardiac self-efficacy and health status, including symptom burden, physical limitation, quality of life, and overall health among outpatients with stable coronary heart disease (CHD). We hypothesized that lower self-efficacy would predict worse health status, independent of CHD severity and depression.
Methods
We performed a cross-sectional study of 1024 outpatients with CHD, who were recruited between 2000 and 2002 for the Heart and Soul Study. We administered a validated measure of cardiac self-efficacy, assessed cardiac function using exercise treadmill testing with stress echocardiography, and measured depressive symptoms using the Patient Health Questionnaire. Health status outcomes (symptom burden, physical limitation, and quality of life) were assessed using the Seattle Angina Questionnaire, and overall health was measured as fair or poor (versus good, very good, or excellent).
Results
After adjustment for CHD severity and depressive symptoms, each standard deviation (4.5-point) decrease in self-efficacy score was independently associated with greater symptom burden (adjusted odds ratio (OR) = 2.1, p = .001), greater physical limitation (OR = 1.8, p < .0001), worse quality of life (OR = 1.6, p < .0001), and worse overall health (OR = 1.9, p < .0001). Depressive symptoms and poor treadmill exercise capacity were also associated with poor health status, but left ventricular ejection fraction and ischemia were not.
Conclusions
Among patients with CHD, low cardiac self-efficacy is associated with poor health status, independent of CHD severity and depressive symptoms. Further study should examine if self-efficacy constitutes a useful target for cardiovascular disease management interventions.
doi:10.1097/PSY.0b013e3180514d57
PMCID: PMC2771191  PMID: 17510290
self-efficacy; health status; heart disease; epidemiology
25.  Association between Renal Insufficiency and Inducible Ischemia in Patients with Coronary Artery Disease: The Heart and Soul Study 
Chronic renal insufficiency (CRI) is a predictor of stroke, cardiovascular, and all-cause mortality, but the mechanisms responsible for these associations are unclear. Whether CRI was associated with severity of coronary artery disease (CAD) as measured by exercise stress echocardiography among outpatients with stable CAD was evaluated. This study is a cross-sectional analysis of the Heart and Soul study, a prospective cohort of patients with known CAD. Renal function was assessed by 24-h urine collection, and CRI was defined as measured creatinine clearance ≤60 ml/min. Exercise stress echocardiography was used to identify inducible ischemia, defined as any wall motion abnormality seen at stress but not at rest. Logistic regression was used to evaluate the association of CRI with exercise-induced ischemia after adjustment for cardiovascular risk factors. Participants with CRI composed 97 (23%) of the 431 participants and were characterized by older age, worse CAD, lower ejection fraction, greater left ventricular mass and higher C-reactive protein values. The prevalence of exercise-induced ischemia was also substantially greater in the participants with CRI (42% versus 23%; odds ratio [OR], 2.3; 95% confidence interval [CI], 1.4 to 3.8; P < 0.001). This association was minimally changed by adjustment for traditional cardiovascular risk factors and coronary disease history (OR, 2.0; 95% CI, 1.3 to 3.3; P < 0.01) and remained strong even after adjustment for C-reactive protein (OR, 2.3; 95% CI, 1.0 to 5.1; P < 0.04). CRI is strongly associated with exercise-induced ischemia in patients with CAD. The greater severity of atherosclerotic disease observed in patients with CRI may in part explain the association of CRI with increased cardiovascular risk among individuals with CAD.
PMCID: PMC2770344  PMID: 14638921

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