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author:("Lai, shanghan")
1.  Effect of GSTM1-Polymorphism on Disease Progression and Oxidative Stress in HIV Infection: Modulation by HIV/HCV Co-Infection and Alcohol Consumption 
Objective
To examine the effects of GSTM1 null-allele polymorphism on oxidative stress and disease progression in HIV infected and HIV/hepatitis C (HCV) co-infected adults.
Methods
HIV-infected and HIV/HCV co-infected participants aged 40–60 years old with CD4 cell count >350 cells/ µl, were recruited. GSTM1 genotype was determined by quantitative PCR. Oxidative stress (mitochondrial 8-oxo-2’-deoxyguanosine [8-oxo-dG], malondialdehyde [MDA], oxidized glutathione and Complexes I and IV), apoptosis and HIV disease (CD4 count and viral load) markers were measured. Gene copies were not quantified, thus the Hardy-Weinberg formula was not applicable.
Results
Of the 129 HIV-infected participants, 58 were HIV/HCV co-infected. GSTM1 occurred in 66% (62/94) in those of African descent, and 33% (11/33) of the Caucasians. Those with GSTM1 coding for the functional antioxidant enzyme Glutathione S-transferase (GST), had higher CD4 cell count (β=3.48, p=0.034), lower HIV viral load (β=−0.536, p=0.018), and lower mitochondrial 8-oxo-dG (β=−0.28, p=0.03). ART reduced oxidative stress in the participants with the GSTM1 coding for the functional antioxidant enzyme. HIV/HCV co-infected participants with the GSTM1 coding for the functional antioxidant enzyme also had lower HIV viral load, lower 8-oxo-dG and lower rate of apoptosis, but also higher oxidized glutathione. Alcohol consumption was associated with lower HIV viral load but higher oxidized glutathione in those with the GSTM1 genotype coding for the functional antioxidant enzyme.
Conclusion
The GSTM1 genotype coding for the functional antioxidant enzyme is associated with lower HIV disease severity, and with lower oxidative stress, compared to GSTM1 null-allele polymorphism. HCV co-infection and alcohol use may be associated with increased oxidative stress even in the presence of the GSTM1 coding for the functional antioxidant enzyme. The null-gene, on the contrary, appears to have a detrimental effect on immune function, viral load control, and antioxidant status, suggesting a potential benefit from antioxidants in HIV infected patients with the defective gene.
doi:10.4172/2155-6113.1000237
PMCID: PMC3887471  PMID: 24416632
GSTM-1 polymorphism; HIV disease progression; Oxidative stress; HIV/HCV co-infection; Alcohol consumption
2.  Vitamin D deficiency is associated with development of subclinical coronary artery disease in HIV-infected African American cocaine users with low Framingham-defined cardiovascular risk 
Chronic cocaine use may lead to premature atherosclerosis, but the prevalence of and risk factors for coronary artery disease (CAD) in asymptomatic cocaine users have not been reported. The objective of this study was to examine whether vitamin D deficiency is associated with the development of CAD in human immunodeficiency virus (HIV)-infected African American cocaine users with low CAD risk.
Methods
In this prospective follow-up study, we investigated 169 HIV-infected African American cocaine users with low Framingham risk at baseline. The main outcome measures were incidence of subclinical CAD and development of subclinical CAD.
Results
Fifty of the 169 African Americans had evidence of subclinical disease on the initial cardiac computed tomography. A second cardiac computed tomography was performed on the 119 African Americans without disease on the first scan. The total sum of person-years of follow-up was 289.6. Subclinical CAD was detected in 11 of these, yielding an overall incidence of 3.80/100 person-years (95% confidence interval 1.90–6.80). Among the factors investigated, only vitamin D deficiency was independently associated with development of subclinical CAD. The study did not find significant associations between CD4 count, HIV viral load, or antiretroviral treatment use and the incidence of subclinical CAD. This study appears to suggest that there is a threshold level of vitamin D (10 ng/mL) above which the effect of vitamin D on subclinical CAD is diminished.
Conclusion
The incidence of subclinical CAD in HIV-infected African American cocaine users with low CAD risk is high, especially in those with vitamin D deficiency. Well designed randomized clinical trials are warranted to confirm the role of vitamin D deficiency in the development of CAD in HIV-infected African American cocaine users with low CAD risk.
doi:10.2147/VHRM.S50537
PMCID: PMC3833705  PMID: 24265555
vitamin D deficiency; subclinical coronary artery disease; cocaine use; prospective follow-up study; African Americans
3.  Vitamin D deficiency is associated with coronary artery calcification in cardiovascularly asymptomatic African Americans with HIV infection 
Objective
Patients with HIV infection are at increased risk for coronary artery disease (CAD), and growing evidence suggests a possible link between vitamin D deficiency and clinical/subclinical CAD. However, the relationship between vitamin D deficiency and coronary artery calcification (CAC), a sensitive marker for subclinical CAD, in those with HIV infection is not well investigated.
Methods
CAC was quantified using a Siemens Cardiac 64 scanner, and vitamin D levels and the presence of traditional and novel risk factors for CAD were obtained in 846 HIV-infected African American (AA) participants aged 25 years or older in Baltimore, MD, USA without symptoms or clinical evidence of CAD.
Results
The prevalence of vitamin D deficiency (25-hydroxy vitamin D <10 ng/mL) was 18.7%. CAC was present in 238 (28.1%) of the 846 participants. Logistic regression analysis revealed that the following factors were independently associated with CAC: age (adjusted odds ratio [OR]: 1.11; 95% confidence interval [CI]: 1.08–1.14); male sex (adjusted OR: 1.71; 95% CI: 1.18–2.49); family history of CAD (adjusted OR: 1.53; 95% CI: 1.05–2.23); total cholesterol (adjusted OR: 1.006; 95% CI: 1.002–1.010); high-density lipoprotein cholesterol (adjusted OR: 0.989; 95% CI: 0.979–0.999); years of cocaine use (adjusted OR: 1.02; 95% CI: 1.001–1.04); duration of exposure to protease inhibitors (adjusted OR: 1.004; 95% CI: 1.001–1.007); and vitamin D deficiency (adjusted OR: 1.98; 95% CI: 1.31–3.00).
Conclusion
Both vitamin D deficiency and CAC are prevalent in AAs with HIV infection. In order to reduce the risk for CAD in HIV-infected AAs, vitamin D levels should be closely monitored. These data also suggest that clinical trials should be conducted to examine whether vitamin D supplementations reduce the risk of CAD in this AA population.
doi:10.2147/VHRM.S48388
PMCID: PMC3758221  PMID: 24009422
African Americans; HIV infection; antiretroviral therapy; coronary artery calcification; vitamin D deficiency
4.  Vitamin D Deficiency Is Associated with Significant Coronary Stenoses in Asymptomatic African American Chronic Cocaine Users 
International Journal of Cardiology  2011;158(2):211-216.
Background
Chronic cocaine use may lead to premature atherosclerosis, however, the prevalence of and risk factors for coronary artery disease in asymptomatic cocaine users have not been reported.
Methods
Between August 2007 and June 2010, 385 African American chronic cocaine users aged 25 to 54 years were consecutively enrolled in a study to investigate the prevalence of CT angiographically- defined significant (≥50%) coronary stenosis and related risk factors. Sociodemographic, drug-use behavior, medical history and medication data were obtained by interview and confirmed by medical chart review. Clinical examinations were performed as well as extensive laboratory tests including those for fasting lipid profiles, HIV, high sensitivity C-reactive protein, and vitamin D. Contrast-enhanced coronary CT angiography was performed.
Results
Significant coronary stenosis was detected in 52 of 385 participants (13.5%). The prevalences were 12% and 30% in those with low risk and with middle-high risk Framingham score, respectively. In those with low risk scores, the prevalences of significant stenosis were 10% and 18% in those without and with vitamin D deficiency, defined as serum 25-(OH) vitamin D < 10 ng/mL (p=0.08). Multiple logistic regression analysis revealed that vitamin D deficiency (adjusted OR=2.18, 95% CI: 1.07–4.43) is independently associated with the presence of significant coronary stenosis after controlling for traditional risk factors.
Conclusions
The study indicates that the prevalence of significant coronary stenoses is high in asymptomatic young and middle-aged African American chronic cocaine users. These findings emphasize the importance of aggressive reduction of risk factors, including vitamin D deficiency in this population.
doi:10.1016/j.ijcard.2011.01.032
PMCID: PMC3118853  PMID: 21295360
Chronic cocaine use; Significant coronary stenosis; Vitamin D deficiency; CT coronary angiography
5.  Vitamin D Deficiency Is Associated With Silent Coronary Artery Disease in Cardiovascularly Asymptomatic African Americans With HIV Infection 
Human immunodeficiency virus (HIV)–infected African Americans (AAs) may have a higher risk of cardiovascular complications. Our study suggests that vitamin D deficiency Is independently associated with silent coronary artery disease (CAD) in HIV-infected AAs without symptoms/clinical evidence of CAD. Further longitudinal studies are needed.
Background. Growing evidence suggests that vitamin D deficiency Is associated with clinical coronary artery disease (CAD). The relationship between vitamin D deficiency and subclinical CAD in HIV-infected individuals is not well-characterized.
Methods. Computed tomographic (CT) coronary angiography was performed using contrast-enhanced 64-slice multidetector CT imaging, and vitamin D levels and the presence of traditional and novel risk factor for CAD were obtained in 674 HIV-infected African American (AA) participants aged 25–54 years in Baltimore, MD, without symptoms/clinical evidence of CAD.
Results. The prevalence of vitamin D deficiency (25-hydroxy vitamin D <10 ng/mL) was 20.0% (95% confidence interval [CI], 16.9–23.1). Significant (≥50%) coronary stenosis was present in 64 (9.5%) of 674 participants. Multiple logistic regression analysis revealed that male gender (adjusted odds ratio [OR], 2.19; 95% CI, 1.17–4.10), diastolic BP ≥85 mmHg (adjusted OR: 1.94, 95% CI: 1.02 –3.68), low-density lipoprotein cholesterol ≥100 mg/dL (adjusted OR, 1.95; 95% CI, 1.13–3.36), cocaine use for ≥15 years (adjusted OR, 1.77; 95% CI, 1.01–3.10), use of antiretroviral therapies for ≥6 months (adjusted OR, 2.26; 95% CI, 1.17–4.36), year of enrollment after 2005 (adjusted ORs for 2006–2007, 2008–2009, and 2010 were 0.32 [95% CI, 0.13–0.76], 0.26 [95% CI, 0.12–0.56], and 0.32 (95% CI, 0.15–0.65], respectively), and vitamin D deficiency (adjusted OR, 2.28; 95% CI, 1.23–4.21) were independently associated with significant coronary stenosis.
Conclusions. Both vitamin D deficiency and silent CAD are prevalent in HIV-infected AAs. In addition to management of traditional CAD risk factors and substance abuse, vitamin D deficiency should be evaluated in HIV-infected AAs. These data support the conduct of a prospective trial of vitamin D in this high-risk patient population.
doi:10.1093/cid/cis306
PMCID: PMC3404715  PMID: 22423137
7.  Newborn thyroxine levels and childhood ADHD 
Clinical biochemistry  2002;35(2):131-136.
Objectives
Normal brain development is highly dependent on adequate levels of iodine and thyroid hormone. It has been suggested that Attention Deficit Hyperactivity Disorder (ADHD) is the consequence of prenatal thyroidal endocrine disruption. The hypothesis was examined using neonatal thyroxine levels as a bio-marker of prenatal thyroid status and comparing it to subsequent development of ADHD.
Design and methods
In a matched case-control study, cases were defined as children diagnosed with ADHD, while children born in the same hospital and tested on the same day served as matched controls. Conditional logistic regression analysis with unequal numbers of controls was performed.
Results
The neonatal thyroxine levels were within normal limits for each of the children who were subsequently diagnosed as having ADHD, and their distribution was no different from that of their controls.
Conclusions
Children diagnosed with ADHD do not demonstrate prenatal thyroidal dysfunction as reflected in the newborn thyroxine levels, therefore neonatal thyroxine levels are not a bio-marker for the subsequent development of ADHD.
PMCID: PMC3635835  PMID: 11983348
Neonatal thyroxine (T4); Thyroid hormone; Attention deficit hyperactivity disorder; ADHD; Thyroid dysfunction
8.  Cholesterol Is Associated with the Presence of a Lipid Core in Carotid Plaque of Asymptomatic, Young-to-Middle-Aged African Americans with and without HIV Infection and Cocaine Use Residing in Inner-City Baltimore, Md., USA 
Background
Stroke remains a leading cause of death in the United States. While stroke-related mortality in the USA has declined over the past decades, stroke death rates are still higher for blacks than for whites, even at younger ages. The purpose of this study was to estimate the frequency of a lipid core and explore risk factors for its presence in asymptomatic, young-to-middle-aged urban African American adults recruited from inner-city Baltimore, Md., USA.
Methods
Between August 28, 2003, and May 26, 2005, 198 African American participants aged 30-44 years from inner-city Baltimore, Md., were enrolled in an observational study of subclinical atherosclerosis related to HIV and cocaine use. In addition to clinical examinations and laboratory tests, B-mode ultrasound for intima-media thickness of the internal carotid arteries was performed. Among these 198, 52 were selected from the top 30th percentile of maximum carotid intima-media thickness by ultrasound, and high-resolution black blood MRI images were acquired through their carotid plaque before and after the intravenous administration of gadodiamide. Of these 52, 37 with maximum segmental thickness by MRI >1.0 mm were included in this study. Lumen and outer wall contours were defined using semiautomated analysis software. The frequency of a lipid core in carotid plaque was estimated and risk factors for lipid core presence were explored using logistic regression analysis.
Results
Of the 37 participants in this study, 12 (32.4%) were women. The mean age was 38.7 ± 4.9 years. A lipid core was present in 9 (17%) of the plaques. Seventy percent of the study participants had a history of cigarette smoking. The mean total cholesterol level was 176.1 ± 37.3 mg/dl, the mean systolic blood pressure was 113.1 ± 13.3 mm Hg, and the mean diastolic blood pressure was 78.9 ± 9.5 mm Hg. There were 5 participants with hypertension (13.5%). Twelve (32%) participants had a history of chronic cocaine use, and 23 (62%) were HIV positive. Among the factors investigated, including age, sex, blood pressure, cigarette smoking, C-reactive protein, fasting glucose, triglycerides, serum total cholesterol, coronary calcium, cocaine use, and HIV infection, only total cholesterol was significantly associated with the presence of a lipid core.
Conclusions
This study revealed an unexpectedly high rate of the presence of lipid core in carotid plaque and highlights the importance of cholesterol lowering to prevent cerebrovascular disease in this population. Further population-based studies are warranted to confirm these results.
doi:10.1159/000334661
PMCID: PMC3355645  PMID: 22327293
Carotid artery; Cholesterol; Lipid core; Risk factors; Stroke
9.  Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved 
ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery–induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is “energy starved” as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.
doi:10.1172/JCI57426
PMCID: PMC3248286  PMID: 22201686
10.  Failure in Short-term Prediction of Ventricular Tachycardia and Ventricular Fibrillation from Continuous ECG in Intensive Care Unit Patients 
Journal of electrocardiology  2010;43(5):400-407.
Background
Patients in the intensive care unit (ICU) setting are prone to malignant ventricular arrhythmias. We sought to test whether electrocardiographic markers of autonomic tone, ventricular irritability, and repolarization lability could be used in short-term prediction of ventricular arrhythmias in this patient population.
Methods
We studied 38 patients with sustained (> 30 seconds) monomorphic ventricular tachycardia (MVT), polymorphic ventricular tachycardia (PVT), or ventricular fibrillation (VF) while monitored in the ICU and 30 patients without arrhythmia in the ICU who served as controls. All patients had at least 12 hours of continuously recorded multi-lead ECG prior to arrhythmic event. Mean heart rate and measures of heart rate variability (HRV), QT variability (QTV), and ventricular ectopy were quantified in 1-hour epochs for the 12 hours pre-arrhythmic event and in 5-minute epochs for the last hour pre-event (and using a random termination time point in controls).
Results
A modest downward trend in QT variability and rise in heart rate were observed hours before PVT and VF events, although no significant changes heralded MVT, and no changes in any parameter predicted imminent ventricular arrhythmia of any type. There were no significant differences in ECG parameters between arrhythmia patients and controls.
Conclusions
In ICU patients, sustained ventricular arrhythmias are not preceded by change in electrocardiographic measures of autonomic tone, repolarization variability, and ventricular ectopy. Short-term arrhythmia prediction may be difficult or impossible in this patient population based on electrocardiographic measures alone.
doi:10.1016/j.jelectrocard.2010.02.005
PMCID: PMC2914842  PMID: 20378124
ventricular tachycardia; ventricular fibrillation; arrhythmia prediction; heart rate variability; QT variability
11.  Randomized Controlled Clinical Trial of Zinc Supplementation to Prevent Immunological Failure in HIV-Positive Adults1,2 
Background
Adequate zinc is critical for immune function; however, zinc deficiency occurs in >50% of HIV-infected adults. We examined the safety and efficacy of long-term zinc supplementation on HIV disease progression.
Methods
A prospective randomized controlled clinical trial was conducted with 231 HIV+ adults with low plasma zinc levels (<0.75 μg/ml), randomly assigned into zinc (12 mg of elemental zinc for women and 15 mg for men) or placebo, for 18 months. The primary endpoint was immunological failure. HIV-viral load and CD4+ cell count were determined every 6 months. Questionnaires, pill-counts, plasma zinc and C-reactive protein (hsCRP) were used to monitor adherence with study supplements and ART. Intent-to-treat analysis utilized multiple-event analysis, treating CD4+ cell count <200 cells/mm3 as recurrent immunological failure event. Cox proportional-hazard models and the general-linear model were used to analyze morbidity and mortality data.
Results
Zinc supplementation for 18 months reduced four-fold the likelihood of immunological failure, controlling for age, gender, lack of food, baseline CD4+ cell count, viral load, and antiretroviral therapy (RR=0.24[95%CI:0.10,0.56],p<0.002). Viral load indicated poor control with ART but was not affected by zinc supplementation. Zinc supplementation also reduced the rate of diarrhea by more than half (OR=0.4[95%CI:0.183-0.981],p=0.019) compared to placebo. There was no significant difference in mortality between the two groups.
Conclusion
This study demonstrated that long-term (18-month) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time. This evidence supports the use of zinc supplementation as an adjunct therapy in HIV+ adult cohorts with poor viral control.
Summary
This study demonstrated that long-term (18-month) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time. This evidence supports the use of zinc supplementation as an adjunct therapy in HIV+ adult cohorts with poor viral control.
doi:10.1086/652864
PMCID: PMC2874106  PMID: 20455705
zinc supplementation; immunological failure; diarrhea; HIV disease progression
12.  Alcohol Use Accelerates HIV Disease Progression 
Abstract
The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV+ adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4+ cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23–6.85, p = 0.015) more likely to present a decline of CD4 to ≤200 cells/μl, independent of baseline CD4+ cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to ≤200 cells/mm3 (HR = 7.76: 95% CI: 1.2–49.2, p = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4+ cell decline (HR = 3.57: 95% CI: 1.24–10.31, p = 0.018). Frequent alcohol intake was associated with higher viral load over time (β = 0.259, p = 0.038). This significance was maintained in those receiving ART (β = 0.384, p = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4+ cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART.
doi:10.1089/aid.2009.0211
PMCID: PMC2875959  PMID: 20455765
13.  Coronary Vessel Wall Evaluation by Magnetic Resonance Imaging in the Multi-Ethnic Study of Atherosclerosis: Determinants of Image Quality 
Objective
Coronary artery wall magnetic resonance imaging (MRI) has been developed to assess coronary lumen diameter and wall thickness. The purpose of this study was to evaluate the physiological parameters that affect the measures of coronary wall thickness using black-blood MRI pulse sequences.
Methods
Eighty-seven participants (38 men and 49 women) of the Multi-Ethnic Study of Atherosclerosis were enrolled in the coronary artery wall MRI study. Cine 4-chamber imaging was used to determine the coronary artery rest period. Free-breathing whole-heart magnetic resonance angiography with motion adaptor navigator was performed to localize the coronary arteries in 64 participants. Cross-sectional free-breathing black-blood images were acquired using electrocardiogram-gated, turbo spin echo sequence. Imaging parameters were as follows: repetition time = 2 R-R intervals, time to echo = 33 milliseconds, echo train length = 13, bandwidth = 305 Hz/pixel, matrix = 416 × 416, field of view = 420 × 420 mm, and slice thickness = 4 to 5 mm.
Results
Imaging was completed in 215 (92%) of 234 coronary segments; 9 participants had incomplete scans. Mean age was 62.6 ± 8.4 years (range, 45–81 years). Mean body mass index was 29.2 ± 5.9 kg/m2. A higher proportion of images with quality of “good” was seen in the right coronary artery (40.5%) compared to the left main and left anterior descending coronary arteries (31.9% and 26.4%, respectively). There was a very good agreement between observers in the image quality scores (κ = 0.79, P < 0.001). Lower heart rate, male sex, and longer coronary rest period were associated with higher image quality score (P < 0.05). Signal-to-noise ratio was higher in participants with Agatston calcium score of more than 10 in the right coronary and left main arteries (48.5 vs 69.7, P = 0.001; and 53.4 vs 61.6, P = 0.032, respectively).
Conclusion
Improved depiction of the coronary artery wall with MRI is related to coronary rest period and atherosclerotic plaque burden as measured by calcium score and inversely related to heart rate. Because longer coronary artery rest periods are associated with improved image quality both for angiography with MRI and coronary artery wall imaging, heart rate–lowering methods in association with these techniques appear to be a logical application.
doi:10.1097/RCT.0b013e3181648606
PMCID: PMC3037090  PMID: 19188777
coronary; magnetic resonance imaging; image quality; MRI; cardiac
14.  Long-Term Combination Antiretroviral Therapy Is Associated with the Risk of Coronary Plaques in African Americans with HIV Infection 
AIDS Patient Care and STDs  2009;23(10):815-824.
Abstract
The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for gender, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for more than 18 months (adjusted odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users.
doi:10.1089/apc.2009.0048
PMCID: PMC2761979  PMID: 19803679
15.  Engraftment, Differentiation and Functional Benefits of Autologous Cardiosphere-Derived Cells in Porcine Ischemic Cardiomyopathy 
Circulation  2009;120(12):1075-1083.
Background
Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation.
Methods and Results
Mesenchymal stem cells, which resemble CDCs in size and thrombogenecity, have been associated with infarction following intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100U/mL heparin and 250μg/mL nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with post-infarct left ventricular dysfunction showed CDC doses ≥107 but <2.5×107 result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (~107 total) and 7 received placebo (vehicle alone). Cardiac MRI 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, p=0.01), while placebo did not (17.7% to 15.3%, p=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, dP/dt max and dP/dt min were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation.
Conclusions
Intracoronary delivery of CDCs in a pre-clinical model of post-infarct LV dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks’ follow-up motivates human studies in post-MI patients and in chronic ischemic cardiomyopathy.
doi:10.1161/CIRCULATIONAHA.108.816058
PMCID: PMC2848167  PMID: 19738142
Stem cells; myocardial infarction; heart failure
16.  Characterization of Radiofrequency Ablation Lesions With Gadolinium-Enhanced Cardiovascular Magnetic Resonance Imaging 
OBJECTIVES
This study was designed to evaluate the characteristics of gadolinium-enhanced imaging of radiofrequency ablations.
BACKGROUND
Gadolinium-enhanced magnetic resonance imaging (MRI) has been used successfully to evaluate tissue necrosis after myocardial infarction. In electrophysiology, radiofrequency energy is used to create a targeted myocardial necrosis for the treatment of various arrhythmias.
METHODS
Using a power-controlled, cooled-tip 7-F catheter system, radiofrequency lesions (10 to 40 W for 30 s) were created on the epicardium of the right ventricle in eight mongrel dogs. After injection of 0.225 mmol/kg gadolinium, T1-weighted fast gradient echo images were obtained during a follow-up of 10 h using an intrathoracic high-resolution coil. Radiofrequency ablations were analyzed on the MR images and compared with gross anatomy and histopathology.
RESULTS
Four distinct phases of signal enhancement were observed. After gadolinium injection, radiofrequency lesions were delineated clearly as contrast-free areas of low signal intensity (contrast-to-noise ratio [CNR] = −21.1 ± 19.8). Signal enhancement in the lesion periphery started 4.0 ± 1.8 min after injection and progressively extended toward the lesion center at a rate of 0.02 mm/min. Full delayed enhancement was observed after 98 ± 21 min (CNR = +17.8 ± 9.0). During the follow-up period, CNR started to decrease, but the lesions were detectable for as long as 10 h of follow-up. During the first three phases of enhancement, MRI correlated well with the pathological findings (r = 0.88, r = 0.88, and r = 0.86 [p < 0.001], respectively).
CONCLUSIONS
Radiofrequency ablation can be evaluated accurately by using gadolinium-enhanced MRI, which may allow the noninvasive assessment of procedural success. The dissimilar wash-in and wash-out kinetics compared with myocardial infarction suggest a different pathophysiological process with complete loss of microvasculature.
doi:10.1016/j.jacc.2005.07.070
PMCID: PMC2943962  PMID: 16412863
17.  Multiple imputation for missing cardiac magnetic resonance imaging data: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
The Canadian Journal of Cardiology  2009;25(7):e232-e235.
BACKGROUND:
Cardiac magnetic resonance imaging (MRI) is a non-invasive technique used to accurately and reproducibly measure biological parameters such as left ventricular mass. However, some subjects either refuse or are unable to complete testing, and the impact of excluding these missing data from predictive models is unknown.
METHODS:
Multiple imputation was applied to cardiac MRI data that were previously analyzed using a complete case approach. The model variables – 10 traditional cardiovascular risk factors and five sociodemographic variables – were used as a basis for imputation. Men and women were imputed separately. The primary focus was assessing the change in the cardiovascular predictors of left ventricular geometry and systolic function.
RESULTS:
Although 27% of participants were missing cardiac MRI data, multiple imputation returned results similar to those of a complete case analysis. These results were robust to the point of including additional variables in the imputation analysis above and beyond the model variables. The degree of variance explained by the models increased marginally but the statistical inference was altered for only two predictors out of 53 cardiovascular risk factors using multiple imputation.
DISCUSSION:
The results suggest that the cardiac MRI data in the Multi-Ethnic Study of Atherosclerosis (MESA) do not substantively change when missing data are handled using multiple imputation. Future analyses of cardiac MRI data may consider the complete case approach to be adequate despite the high rate of missing data in this population.
PMCID: PMC2723032  PMID: 19584978
Comparison of methods; Complete case; Magnetic resonance imaging; Multiple imputation
18.  Positive remodeling of the coronary arteries detected by MRI in an asymptomatic population: the Multi-Ethnic Study of Atherosclerosis (MESA) 
OBJECTIVES
The purpose of this study was to assess coronary arterial remodeling as a marker of subclinical atherosclerosis using coronary wall MRI in an asymptomatic population-based cohort.
BACKGROUND
In early atherosclerosis, compensatory enlargement of both the outer wall of the vessel as well as the lumen, termed compensatory enlargement or positive remodeling, occurs before luminal narrowing.
METHODS
179 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using black-blood coronary wall MRI. Coronary cross-sectional area (vessel size), lumen area, and mean wall thickness of the proximal coronary arteries were measured.
RESULTS
Men had a greater vessel size, lumen area, and mean wall thickness than women (38.3±11.3 versus 32.6±9.4 mm2, 6.7±3.2 versus 5.3±2.4 mm2, and 2.0±0.3 versus 1.9±0.3 mm, respectively, p<0.05). No significant coronary artery narrowing was present by magnetic resonance angiography. Overall, coronary vessel size increased 25.9 mm2 per millimeter increase in coronary wall thickness, while lumen area increased only slightly at 3.1 mm2 for every millimeter increase in wall thickness (difference in slopes, p<0.0001). Adjusting for age and gender, participants with Agatston score greater than zero were more likely to have wall thickness greater than 2.0 mm (odds ratio 2.0, 95% CI 1.01–3.84).
CONCLUSIONS
Coronary wall MRI detected positive arterial remodeling, in asymptomatic men and women with subclinical atherosclerosis.
doi:10.1016/j.jacc.2008.12.063
PMCID: PMC2793325  PMID: 19406347
subclinical atherosclerosis; magnetic resonance imaging; coronary artery disease; plaque
19.  HIV Infection and Abnormal Regional Ventricular Function 
Purpose
To examine the effect of HIV infection on regional left ventricular dysfunction in cardiovascularly asymptomatic individuals.
Methods
Nineteen HIV-negative and 27 HIV-positive cardiovascularly asymptomatic study participants in Baltimore, Maryland were selected and underwent tagged cardiac magnetic resonance imaging (MRI). Regional left ventricular myocardial mid-wall peak systolic circumferential strain (Ecc) and early diastolic strain rate (SRE) of the left ventricle were assessed with the use of the harmonic phase (HARP) analysis. The average Ecc and SRE measurements were compared between HIV-negative and HIV-positive individuals.
Results
Compared with the HIV-negatives, the HIV-positives had lower average Ecc and SRE measurements in 90% of the 16 standard left ventricular segments. Of the 14 segments with decreased Ecc strain, 3 were statistically significant and of 14 with decreased strain rate (SRE), 6 were statistically significant.
Conclusions
HIV infection may be associated with subclinical regional left ventricular systolic and diastolic dysfunction in individuals free of overt cardiovascular disease.
doi:10.1007/s10554-009-9493-7
PMCID: PMC2809797  PMID: 19763877
HIV infection; regional left ventricular dysfunction; tagging MRI; Myocardium strain; random-effects model
20.  MRI detects increased coronary wall thickness in asymptomatic individuals: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Purpose
To evaluate the use of coronary wall MRI as a measure of atherosclerotic disease burden in an asymptomatic population free of clinical cardiovascular disease.
Background
Coronary wall magnetic resonance imaging (MRI) is a noninvasive method for evaluation of arterial wall remodeling associated with atherosclerosis.
Materials and Methods
Asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) study were studied using black blood MRI. MRI assessed coronary wall thickness was compared to computed tomography calcium score, carotid intimal-medial thickness and risk factors for coronary artery disease.
Results
Eighty eight arterial segments were evaluated in 38 MESA participants (mean age, 61.3 ± 8.7 years). The maximum coronary wall thickness was greater for participants with 2 or more cardiovascular risk factors than for those with 1 or no risk factors (2.59 ± 0.33 mm versus 2.36 ± 0.30 mm, respectively, p=0.05.) For participants with zero calcium score, the mean and maximum coronary wall thickness for subjects with 2 or more risk factors for coronary artery disease were greater than the wall thickness for subjects with 1 or no risk factors (mean thickness: 1.95 ± 0.17 mm versus 1.7 ± 0.19 mm; maximum thickness: 2.67 ± 0.24 mm versus 2.32 ± 0.27 mm, respectively, p <0.05). Subjects with increased carotid intimal-medial thickness also had increased coronary artery wall thickness (p< 0.05).
Conclusions
Coronary artery wall MRI detects increased coronary wall thickness in asymptomatic individuals with subclinical markers of atherosclerotic disease and in individuals with zero calcium score.
doi:10.1002/jmri.21511
PMCID: PMC2577717  PMID: 18837001
coronary artery disease; atherosclerosis; MRI; plaque
21.  Toxic Effect of Methamphetamine on the Retina of CD1 Mice 
Current eye research  2009;34(9):785-790.
Purpose
To investigate whether systemic administration of methamphetamine (METH) induces retinal damage in CD1 mice.
Materials and Methods
Eighteen male CD1 mice were randomly assigned to three groups, six mice per group: Group 1 receiving a single dose of 40 mg/kg METH, Group 2 receiving four doses of 10 mg/kg METH, and Group 3 (control) receiving 40 mg/kg 0.9% NaCl solution. METH and NaCl were administered by intraperitoneal injection. Immunostaining of glial fibrillary acidic protein (GFAP), S-100 for astrocytes and Muller cells, CD11b for microglia, and tyrosine hydroxylase (TH) and TUNEL labeling for apoptotic cell death were performed on the retinal sections on day 1 and day 7 post-exposure.
Results
GFAP and S-100 immunoreactivity was observed in Group 1 mice. CD11b+ cells in Group 1 mice showed more intensely stained shorter and thicker cellular processes than Groups 2 and 3, indicating activated microglia in the mice exposed to large dose METH. No significant difference in TH level was seen among the three groups. TUNEL labeling did not reveal positive cells in the retinas of any of the 18 CD1 mice.
Conclusions
A single large dose of METH induces an increase in short-term protein expression of GFAP and S-100 and in microglial activation. The results suggest that METH has a neurotoxic effect on CD1 mouse retina.
PMCID: PMC2765663  PMID: 19839872
22.  Long-term Combination Antiretroviral Therapy Is Associated with the Risk of Coronary Plaques in African Americans with HIV Infection 
AIDS patient care and STDs  2009;23(10):815-824.
The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for sex, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for >18 months (adjusted OR: 2.20, 95% CI:1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users.
doi:10.1089/apc.2009.0048
PMCID: PMC2761979  PMID: 19803679
HIV infection; Antiretroviral Therapy; Coronary Plaques; Cocaine Use; Coronary CT angiography; African Americans
23.  Early retinal vascular abnormalities in African-American cocaine users 
American journal of ophthalmology  2008;146(4):612-619.
Purpose
To evaluate early changes in the central retinal response in HIV positive patients without infectious retinitis using multifocal electroretinography (mfERG).
Design
The study was a case control study.
Methods
We evaluated three cohorts - HIV negative controls and two groups of HIV positive patients separated according to their nadir CD4 counts (≥100 and <100 for a minimum of 6 months). MfERG first (FOK) and second order (SOK) kernels were analyzed separately by areas of rings, quadrants and individual hexagons for each cohort.
Results
Of 103 hexagon locations of FOK results there were no significant differences in amplitudes of P1 and N1 across the groups (0.05
Conclusion
The results demonstrate widespread delay in latency in HIV positive patients, especially in those with prolonged low (below 100) CD4 nadir counts. These findings suggest early diffuse dysfunction of the inner retina resulted from severe HIV disease even in the era of HAART.
doi:10.1016/j.ajo.2008.05.037
PMCID: PMC2582056  PMID: 18662808
cocaine use; African American; HIV infection; retinal vascular changes
Objectives and design
The objective of this study was to explore whether increased levels of inflammatory cytokines are associated with the risk of clinically silent coronary artery disease.
Subjects
Three-hundred-fifty-six black adults aged 25–54 residing in inner city of Baltimore, Maryland, United States were included in this study.
Methods
Sociodemographics were assessed as were lipid profiles, IL-6, tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1), and high-sensitivity C-reactive protein (hs-CRP) levels. Computed tomography (CT) coronary angiography was performed.
Results
Coronary calcification was identified in 22.5% participants and 14% had significant (≥50%) coronary stenosis. Multiple logistic regression analyses suggested that IL-6 levels were independently associated with the presence of coronary calcification and significant coronary stenosis, while TNF-alpha, sICAM-1 and hs-CRP levels were not.
Conclusions
This study underscores a critical role for IL-6 in atherosclerosis and suggests that IL-6 may be a marker for significant coronary stenosis in cardiovascularly asymptomatic individuals.
doi:10.1007/s00011-008-8150-2
PMCID: PMC2737269  PMID: 19130178
interleukin-6 (IL-6); significant coronary stenosis; CT coronary angiography; marker for clinically silent CAD; black race
The Journal of infectious diseases  2005;192(10):1694-1700.
Background
Unsafe practices during illegal plasma donation in the late 1980s and early 1990s spread blood-borne infections in central China.
Methods
A cross-sectional survey of a random sample of 538 adult residents of 12 villages in rural Shanxi Province, where there had been an illegal commercial plasma-collection center, was conducted in 2003. Structured questionnaires were administered, and blood samples were tested for hepatitis C virus (HCV) antibodies.
Results
HCV seroprevalence rates were 8.2% in all subjects, 27.7% in former commercial plasma/blood donors, and 2.6% in nondonors. Selling blood or plasma was the strongest independent predictor of HCV seropositivity (odds ratio [OR], 14.4 [95% confidence interval {CI}, 7.1–31.6]). A history of blood transfusion was also independently associated with HCV seropositivity (OR, 8.3 [95% CI, 2.1–32.0]). Plasma donors had a higher risk of being HCV seropositive than did whole-blood donors (OR, 7.6 [95% CI, 2.9–20.9]), and female donors had a lower risk than did male donors (OR, 0.32 [95% CI, 0.12–0.80]). The strength of the association between selling blood and HCV seropositivity was weaker when plasma donors were excluded (OR, 8.0 vs. 14.4).
Conclusions
Unsafe practices during illegal plasma donation led to a high risk of HCV seropositivity for donors during the 1980s and 1990s. Failure to screen for HCV increased the risk of seropositivity for transfusion recipients during this same period. China has taken steps to halt illegal plasma collection and to improve blood-banking methods. However, there will be an ongoing challenge to care for patients with HCV infection, even as its incidence decreases.
doi:10.1086/497148
PMCID: PMC2730763  PMID: 16235166

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