Publications by authors named "Stephen J Peterson"

74 Publications

Can charcoal improve outcomes in COVID-19 infections?

Med Hypotheses 2020 Nov 10;144:110176. Epub 2020 Aug 10.

Joan C. Edwards School of Medicine, Marshall University, United States. Electronic address:

COVID-19 infection causes considerable morbidity and mortality, especially to those who are aged, have impaired renal function and are obese. We propose to examine the potential utility of oral activated charcoal with the hypothesis that such treatment would lower absorption of microbiome derived toxins and ameliorate systemic oxidant stress and inflammation.
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http://dx.doi.org/10.1016/j.mehy.2020.110176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416710PMC
November 2020

The pivotal role of heme Oxygenase-1 in reversing the pathophysiology and systemic complications of NAFLD.

Arch Biochem Biophys 2021 01 26;697:108679. Epub 2020 Nov 26.

Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, 11215, USA. Electronic address:

The pathogenesis and molecular pathways involved in non-alcoholic fatty liver disease (NAFLD) are reviewed, as well as what is known about mitochondrial dysfunction that leads to heart disease and the progression to steatohepatitis and hepatic fibrosis. We focused our discussion on the role of the antioxidant gene heme oxygenase-1 (HO-1) and its nuclear coactivator, peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α) in the regulation of mitochondrial biogenesis and function and potential therapeutic benefit for cardiac disease, NAFLD as well as the pharmacological effect they have on the chronic inflammatory state of obesity. The result is increased mitochondrial function and the conversion of white adipocyte tissue to beige adipose tissue ("browning of white adipose tissue") that leads to an improvement in signaling pathways and overall liver function. Improved mitochondrial biogenesis and function is essential to preventing the progression of hepatic steatosis to NASH and cirrhosis as well as preventing cardiovascular complications.
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http://dx.doi.org/10.1016/j.abb.2020.108679DOI Listing
January 2021

OX-HDL: A Starring Role in Cardiorenal Syndrome and the Effects of Heme Oxygenase-1 Intervention.

Diagnostics (Basel) 2020 Nov 20;10(11). Epub 2020 Nov 20.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.

In this review, we will evaluate how high-density lipoprotein (HDL) and the reverse cholesterol transport (RCT) pathway are critical for proper cardiovascular-renal physiology. We will begin by reviewing the basic concepts of HDL cholesterol synthesis and pathway regulation, followed by cardiorenal syndrome (CRS) pathophysiology. After explaining how the HDL and RCT pathways become dysfunctional through oxidative processes, we will elaborate on the potential role of HDL dysfunction in CRS. We will then present findings on how HDL function and the inducible antioxidant gene heme oxygenase-1 (HO-1) are interconnected and how induction of HO-1 is protective against HDL dysfunction and important for the proper functioning of the cardiovascular-renal system. This will substantiate the proposal of HO-1 as a novel therapeutic target to prevent HDL dysfunction and, consequently, cardiovascular disease, renal dysfunction, and the onset of CRS.
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http://dx.doi.org/10.3390/diagnostics10110976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699797PMC
November 2020

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance.

Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group ( = 6) (2) HF diet; group ( = 6) (3) HF diet treated with PSO (40 mL/kg food) ( = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome.

Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure ( < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-, p-IRB tyr, and pAMPK, thereby decreasing insulin resistance.

Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.
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http://dx.doi.org/10.3390/ijms21155469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432301PMC
July 2020

Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm.

Antioxidants (Basel) 2020 Jul 18;9(7). Epub 2020 Jul 18.

Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are a number of medications that have been tried with some showing early clinical promise. This illness disproportionately affects patients with obesity, a chronic inflammatory disease with a baseline excess of cytokines. The majority of the medications used in the treatment of COVID-19 are metabolized by cytochrome P450 (CYP) enzymes, primarily CYP2D6. This is further complicated by genetic polymorphisms of CYP2D6, HO-1, ACE, and ACE-2. There is a potential role for HO-1 upregulation to treat/prevent cytokine storm. Current therapy must focus on antivirals and heme oxygenase upregulation. Vaccine development will be the only magic bullet.
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http://dx.doi.org/10.3390/antiox9070636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402116PMC
July 2020

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections.

Antioxidants (Basel) 2020 Jun 19;9(6). Epub 2020 Jun 19.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel "proof of concept" studies in the context of COVID-19.
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http://dx.doi.org/10.3390/antiox9060540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346191PMC
June 2020

Cold-Pressed Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice.

Antioxidants (Basel) 2020 Jun 4;9(6). Epub 2020 Jun 4.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.
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http://dx.doi.org/10.3390/antiox9060489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346210PMC
June 2020

The Effects of Heme Oxygenase Upregulation on Obesity and the Metabolic Syndrome.

Antioxid Redox Signal 2020 05 22;32(14):1061-1070. Epub 2020 Jan 22.

New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York.

Obesity is a chronic condition that is characterized by inflammation and oxidative stress with consequent cardiovascular complications of hypertension, dyslipidemia, and vascular dysfunction. Obesity-induced metabolic syndrome remains an epidemic of global proportions. Gene targeting of the endothelium with a retrovirus using an endothelium-specific promoter vascular endothelium cadherin (VECAD)-HO-1 offers a potential long-term solution to adiposity by targeting the endothelium. This has resulted in improvements of both vascular function and adiposity attenuation. Heme oxygenase plays an ever-increasing role in the understanding of human biology in the complex conditions of obesity and the metabolic syndrome. The heme oxygenase 1 (HO-1) system creates biliverdin/bilirubin, which functions as an antioxidant, and carbon monoxide, which has antiapoptotic properties. Upregulation of HO-1 has been shown to improve adiposity as well as vascular function in both animal and human studies.
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http://dx.doi.org/10.1089/ars.2019.7954DOI Listing
May 2020

Cardioprotective Heme Oxygenase 1-PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice.

Obesity (Silver Spring) 2019 10 9;27(10):1560-1561. Epub 2019 Sep 9.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.

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http://dx.doi.org/10.1002/oby.22629DOI Listing
October 2019

Positive Effects of Heme Oxygenase Upregulation on Adiposity and Vascular Dysfunction: Gene Targeting vs. Pharmacologic Therapy.

Int J Mol Sci 2019 May 22;20(10). Epub 2019 May 22.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice.

Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control.

Results: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP.

Conclusion: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the "crosstalk" between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.
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http://dx.doi.org/10.3390/ijms20102514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566770PMC
May 2019

The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy.

Int J Mol Sci 2019 May 16;20(10). Epub 2019 May 16.

Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 49100, Israel.

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR.

Methods: Cardiomyopathy was induced in obese diabetic () mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy.

Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1.

Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.
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http://dx.doi.org/10.3390/ijms20102427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566501PMC
May 2019

Racial Disparities with Esophageal Cancer Mortality at a High-Volume University Affiliated Center: An All ACCESS Invitation.

J Natl Med Assoc 2020 Oct 7;112(5):478-483. Epub 2019 May 7.

Department of Medicine, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USA; Weill Cornell Medical College, New York, NY, USA.

Background: Esophageal cancer (EC) has a dismal prognosis with 5-year survival < 19%. Black patients with EC have higher mortality than white patients, but the cause of this disparity is unclear. We sought to investigate the impact of race upon overall mortality (OM) among EC patients at our institution.

Methods: We performed a single-center retrospective review of all patients diagnosed with EC between January 2010 through December 2016 with follow-up through October 2017. We compared the difference among categorical variables and mortality using Fisher's exact test. Odds ratios (OR) and hazard regression (HR) were constructed to analyze treatment options by race. The Kaplan-Meier method was used to plot OM curves by race. We also used a logistic regression analysis to construct a predictive model for mortality based on histology and race.

Results: We identified 77 patients (62% male) diagnosed with EC. There was no difference in treatments offered based on race. After adjusting for age, histology and stage, we found mortality was significantly higher in blacks when compared to whites (HR 14.07, 95% CI [2.33-129.70] p < 0.008). Our predictive model revealed that blacks had a higher probability of mortality at all stages of EC.

Conclusions: We found race to be an independent risk factor for OM in EC patients. This likely reflects differences in healthcare utilization or access, as evidenced by higher prevalence of Stage IV EC in black patients. Continued investigation is needed to address this disparity locally and nationally.
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http://dx.doi.org/10.1016/j.jnma.2019.04.005DOI Listing
October 2020

Oxidized HDL, Adipokines, and Endothelial Dysfunction: A Potential Biomarker Profile for Cardiovascular Risk in Women with Obesity.

Obesity (Silver Spring) 2019 01;27(1):87-93

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York, USA.

Objective: High BMI predicts adverse cardiovascular outcomes and positively correlates with increased levels of adipokines. The relationship among BMI, IL-6, TNFα, adiponectin, and oxidized high-density lipoprotein (Ox-HDL) with circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) has not been well studied. Elevated CEC levels have been described in both humans and mice with obesity and diabetes. Ox-HDL has been shown to be a potent driver of adipogenesis in vivo and in vitro. In this study, elevated BMI was examined in 2 groups of women studied in Brooklyn, New York, and Huntington, West Virginia, respectively.

Methods: Twenty-six females with obesity and five lean controls without overt cardiovascular disease were enrolled, 13 from Huntington and 13 from Brooklyn. Cytokine levels, EPCs, and CECs were determined.

Results: Females with obesity had elevated levels of leptin, IL-6, and Ox-HDL, increased CEC levels, and decreased EPC and adiponectin levels (all P < 0.01). The Ox-HDL levels were higher in women from Brooklyn versus Huntington (P < 0.01), possibly from higher TNFα levels in Brooklyn or higher adiponectin levels in Huntington. Seventy-five percent of the variance in Ox-HDL levels could be predicted in this population (P < 0.01).

Conclusions: This study reveals a unique inflammatory biomarker profile in females with obesity.
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http://dx.doi.org/10.1002/oby.22354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309990PMC
January 2019

Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice.

J Nutr Metab 2017 14;2017:4964571. Epub 2017 Sep 14.

Department of Medicine, Weill Cornell Medicine/NYP Brooklyn Methodist Hospital, Brooklyn, NY 11215, USA.

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin-a transmembrane protein facilitating egress of cellular iron. Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages. Heme-heme oxygenase (HO) is a stress response system which reduces oxidative stress. We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in hepatic tissues from lean and obese mice. Obese mice exhibited hyperglycemia ( < 0.05); increased levels of proinflammatory cytokines (MCP-1, IL-6, < 0.05); oxidative stress ( < 0.05); and increased hepatic hepcidin levels ( < 0.05). Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice ( < 0.05). However, this effect is accompanied by a significant decline in ferritin expression. Additionally, there are reduced insulin receptor phosphorylation and attenuation of metabolic regulators pAMPK, pAKT, and pLKB1. Cobalt protoporphyrin- (CoPP-) induced HO-1 upregulation in obese mice reversed these alterations ( < 0.05), while attenuating hepatic hepcidin levels. These effects of CoPP were prevented in obese mice concurrently exposed to an inhibitor of HO (SnMP) ( < 0.05). Our results highlight a modulatory effect of HO on iron homeostasis mediated through the suppression of hepatic hepcidin.
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http://dx.doi.org/10.1155/2017/4964571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618758PMC
September 2017

The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA.

Horm Mol Biol Clin Investig 2017 Sep 1;31(2). Epub 2017 Sep 1.

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Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.3 ± 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 ± 0.3 vs. 1.4 ± 0.2-fold change, p < 0.03). Among lean subjects, NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.0 ± 0.4, p < 0.05). NOV and AHI were positively correlated (ρ = 0.49, p = 0.033). IL-6 and adiponectin differences in obese vs. lean and OSA vs. no OSA were consistent with an inflammatory phenotype in obese subjects and OSA subjects. NOV is a novel biomarker of the presence and severity of OSA and a potential marker of future cardiovascular and metabolic disease in OSA patients.
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http://dx.doi.org/10.1515/hmbci-2017-0029DOI Listing
September 2017

Milestones: a rapid assessment method for the Clinical Competency Committee.

Arch Med Sci 2017 Feb 29;13(1):201-209. Epub 2016 Nov 29.

Department of Medicine, Division of Cardiology, New York Medical College at Westchester Medical Center, Valhalla, New York, USA.

Introduction: Educational milestones are now used to assess the developmental progress of all U.S. graduate medical residents during training. Twice annually, each program's Clinical Competency Committee (CCC) makes these determinations and reports its findings to the Accreditation Council for Graduate Medical Education (ACGME). The ideal way to conduct the CCC is not known. After finding that deliberations reliant upon the new milestones were time intensive, our internal medicine residency program tested an approach designed to produce rapid but accurate assessments.

Material And Methods: For this study, we modified our usual CCC process to include pre-meeting faculty ratings of resident milestones progress with in-meeting reconciliation of their ratings. Data were considered largely via standard report and presented in a pre-arranged pattern. Participants were surveyed regarding their perceptions of data management strategies and use of milestones. Reliability of competence assessments was estimated by comparing pre-/post-intervention class rank lists produced by individual committee members with a class rank list produced by the collective CCC after full deliberation.

Results: Use of the study CCC approach reduced committee deliberation time from 25 min to 9 min per resident ( < 0.001). Committee members believed milestones improved their ability to identify and assess expected elements of competency development ( = 0.026). Individual committee member assessments of trainee progress agreed well with collective CCC assessments.

Conclusions: Modification of the clinical competency process to include pre-meeting competence ratings with in-meeting reconciliation of these ratings led to shorter deliberation times, improved evaluator satisfaction and resulted in reliable milestone assessments.
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http://dx.doi.org/10.5114/aoms.2016.64045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206368PMC
February 2017

The role of 20-HETE in cardiovascular diseases and its risk factors.

Prostaglandins Other Lipid Mediat 2016 09 7;125:108-17. Epub 2016 Jun 7.

Cardiac Research Laboratory, Felsenstein Medical Research Center, Petah Tikva and Sackler School of Medicine, Tel Aviv University, Israel. Electronic address:

Arachidonic acid (AA) is metabolized in mammals by enzymes of the CYP4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) which plays an important role in the regulation of renal function, vascular tone and arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor, the up-regulation of which contributes to inflammation, oxidative stress, endothelial dysfunction and an increase in peripheral vascular resistance in models of obesity, diabetes, ischemia/reperfusion, and vascular oxidative stress. Recent studies have established a role for 20-HETE in normal and pathological angiogenic conditions. We discuss in this review the synthesis of 20-HETE and how it and various autacoids, especially the renin-angiotensin system, interact to promote hypertension, vasoconstriction, and vascular dysfunction. In addition, we examine the molecular mechanisms through which 20-HETE induces these actions and the clinical implication of inhibiting 20-HETE production and activity.
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http://dx.doi.org/10.1016/j.prostaglandins.2016.05.007DOI Listing
September 2016

Oxidized HDL is a potent inducer of adipogenesis and causes activation of the Ang-II and 20-HETE systems in human obese females.

Prostaglandins Other Lipid Mediat 2016 03 11;123:68-77. Epub 2016 May 11.

Department of Pharmacology, New York Medical College, Valhalla, NY 10595 USA; Department of Medicine, New York Medical College, Valhalla, NY 10595 USA; Marshall University, Joan C. Edwards School of Medicine, Huntington, WV 25701 USA.

Background: Oxidized-HDL (OX-HDL) has been reported to increase coronary events in obese patients; however, OX-HDL has not been studied in subjects with the metabolic syndrome. A high body mass index (BMI) correlates positively with higher levels of metabolic syndrome biomarkers including vasoconstrictors and adipokines. We hypothesize that a subject with a high BMI would present with higher levels of OX-HDL, 20-HETE and Angiotensin II (Ang II) with a reciprocal reduction in serum adiponectin.

Methods: Female subjects with a BMI of 17-25 and a BMI of 30-40, without overt cardiovascular disease, were enrolled in the study. All patients had a history and physical exam documenting the absence of signs and symptoms of cardiovascular disease. Appropriate screening was done and documented. Blood pressure was taken at two discrete points. The BP data are presented as the average. Changes in the relationship between BMI, OX-HDL, 20-HETE, Ang II, TNFα, isoprostane and adiponectin were examined. In addition, the effects of OX-HDL, 20-HETE and Ang II on adipogenesis were examined in human MSC derived adipocytes.

Results: Subjects with a high BMI>30 displayed an increase in OX-HDL and isoprostane (P<0.05) compared to those with the lower BMI<25 which was associated with an increase in Ang II and 20-HETE (p<0.05). Serum TNFα levels increased in subjects with a high BMI, compared to subjects with the lower BMI (p<0.05). In contrast, adiponectin levels were increased in subjects with a low BMI compared to obese subjects (p<0.05). In MSC derived adipocytes OX-HDL increased adipogenesis 6 fold at a concentration of 50ng compared to untreated adipocytes. Adipocytes treated with Ang II and 20-HETE also displayed increased adipogenesis (p<0.05), which was attenuated by endogenous increases of the anti-oxidant heme oxygenase-1. Our study demonstrates that OX-HDL presents a unique inflammatory biomarker profile in obese females with the metabolic syndrome at risk for developing cardiovascular disease.

Conclusions: Females with increased BMI (30-40) exhibit a marked increase in OX-HDL and isoprostane levels, which was associated with an increase in 20-HETE, TNF α and Ang II and decreased levels of adiponectin when compared to a group with a low BMI. OX-HDL had a more powerful adipogenic effect when compared to 20-HETE and Ang II. Our study demonstrates that OX-HDL presents a unique inflammatory biomarker profile in obese females with the metabolic syndrome at risk for developing cardiovascular disease. This represents a novel mechanism by which females with a high BMI and controlled blood pressure remain "at risk" for the development of the metabolic syndrome as a result of increased adipogenesis by OX-HDL and activation of the 20-HETE and Ang II systems.
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http://dx.doi.org/10.1016/j.prostaglandins.2016.04.004DOI Listing
March 2016

Racing Against the Clock: Internal Medicine Residents' Time Spent On Electronic Health Records.

J Grad Med Educ 2016 Feb;8(1):39-44

Background: Since the late 1980s, resident physicians have spent increasing amounts of time on electronic health record (EHR) data entry and retrieval. Objective longitudinal data measuring time spent on the EHR are lacking.

Objective: We sought to quantify the time actually spent using the EHR by all first-year internal medicine residents in a single program (N = 41).

Methods: Active EHR usage data were collected from the audit logs for May, July, and October 2014 and January 2015. Per recommendations from our EHR vendor (Cerner Corporation), active EHR usage time was defined as more than 15 keystrokes, or 3 mouse clicks, or 1700 "mouse miles" per minute. Active EHR usage time was tallied for each patient chart viewed each day and termed an electronic patient record encounter (EPRE).

Results: In 4 months, 41 interns accumulated 18,322 hours of active EHR usage in more than 33,733 EPREs. Each intern spent on average 112 hours per month on 206 EPREs. Interns spent more time in July compared to January (41 minutes versus 30 minutes per EPRE, P < .001). Time spent on the EHR in January echoed that of the previous May (30 minutes versus 29 minutes, P = .40).

Conclusions: First-year residents spent a significant amount of time actively using the EHR, achieving maximal proficiency on or before January of the academic year. Decreased time spent on the EHR may reflect greater familiarity with the EHR, growing EHR efficiencies, or other factors.
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http://dx.doi.org/10.4300/JGME-D-15-00240.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763387PMC
February 2016

Mobile physician reporting of clinically significant events-a novel way to improve handoff communication and supervision of resident on call activities.

J Patient Saf 2014 Dec;10(4):211-7

From the *Department of Medicine, and †Department of Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, New York.

Objectives: Reporting of clinically significant events represents an important mechanism by which patient safety problems may be identified and corrected. However, time pressure and cumbersome report entry procedures have discouraged the full participation of physicians. To improve the process, our internal medicine training program developed an easy-to-use mobile platform that combines the reporting process with patient sign-out.

Methods: Between August 25, 2011, and January 25, 2012, our trainees entered clinically significant events into i-touch/i-phone/i-pad based devices functioning in wireless-synchrony with our desktop application. Events were collected into daily reports that were sent from the handoff system to program leaders and attending physicians to plan for rounds and to correct safety problems.

Results: Using the mobile module, residents entered 31 reportable events per month versus the 12 events per month that were reported via desktop during a previous 6-month study period.

Conclusions: Advances in information technology now permit clinically significant events that take place during "off hours" to be identified and reported (via handoff) to next providers and to supervisors via collated reports. This information permits hospital leaders to correct safety issues quickly and effectively, while attending physicians are able to use information gleaned from the reports to optimize rounding plans and to provide additional oversight of trainee on call patient management decisions.
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http://dx.doi.org/10.1097/PTS.0b013e31829952ffDOI Listing
December 2014

Electronic Capture of Written Handoff Information: What Are the Next Steps?

Am J Ther 2016 May-Jun;23(3):e785-91

Department of Medicine, New York Medical College, Valhalla, NY.

Communication lapses during patient care transitions are reported to be frequent and may result in patient harm. The primary objective of our study was to assess the completeness, accuracy, and usefulness of our electronic handoff system to guide future software changes and educational interventions. We randomly selected and reviewed 707 of 2840 available handoff records generated on the medicine service of an academic medical center between August 1, 2012 and December 31, 2012. We used both quantitative and qualitative analytical techniques to characterize sign-outs in the following dimensions: completeness, usefulness and accuracy of information content, handoff task category, logic, internal consistency and appropriateness of assigned tasks, and composition and complexity of assigned tasks. The degree of completeness of information varied considerably across domains. Completeness was highest for entry of assigned tasks (99.9%), nearly as high for hospital course/presenting illness (95%), and relatively high (87%-98%) for entry of provider name and contact information, principal diagnosis, allergies, current clinical condition, mental status, and code status. Eighty-eight percent written handoffs described clinical condition and hospital course and whether there were tasks to complete. In 58% of suitable records, all problems listed in the electronic health record (EHR) were also present in the history of present illness. The accuracy of entered information also displayed wide variation. Only 80% of cardiovascular medications matched the contemporaneous EHR pharmacy record. Birth dates and allergies were identical in the handoff system and EHR in 95% and 86% of respective records. Of assigned tasks, 8% contained at least 1 unnecessary component or illogical/internally inconsistent element. Use of a handoff system, which organizes information entry through a standard template, promotes completeness of written handoff information. Inaccuracies in handoff data are associated with manual entry and should be discouraged. Programs should be encouraged to develop robust interfaces between the EHR and handoff platforms to promote entry of complete and accurate data and to enhance provider workflow.
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http://dx.doi.org/10.1097/MJT.0000000000000052DOI Listing
February 2017

Improving resident morning sign-out by use of daily events reports.

J Patient Saf 2015 Mar;11(1):36-41

From the Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York.

Objectives: The clinician arriving at the hospital in the morning may not yet be aware of key overnight clinical activity. To address this situation at our facility, we modified our handoff software to permit continuous updating of clinical information and the automatic relay of important overnight clinical updates to relevant providers each morning.

Methods: Cross-covering residents electronically entered safety concerns and clinical issues within the reporting module of the handoff software between 5 PM and 7 AM. This updated their handoff-information at shift change and permitted the generation of reports that were emailed to primary providers and reviewed before 7 AM prerounds. At 7:30 sign-out, if a resident was already aware of an issue being signed out, he/she indicated this so that sign-out could quickly proceed to the next patient. Study sign-out duration was recorded, and residents were surveyed regarding the new communication system.

Results: Morning sign-out duration decreased from 25.5 to 22.7 minutes (P = 0.0338). All respondents agreed strongly (12/14, 86%) or somewhat (2/14, 14%) that daily morning events reports prevented "loss of key information between shifts" and enhanced safety greatly (10/14, 71%) or moderately (4/14, 29%).All agreed either strongly (10/14, 71%) or somewhat (4/14, 29%) that the daily report improved the quality of handoff information and strongly (12/14, 86%) or somewhat (2/14, 14%) that the report was convenient.

Conclusions: The collection of key clinical handoff information and its automatic forwarding to incoming providers reduced the average duration of resident morning sign-out and significantly enhanced provider perceptions regarding patient safety and the quality of handoff information.
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http://dx.doi.org/10.1097/PTS.0b013e31829e4f56DOI Listing
March 2015

Association of corrected QT interval with long-term mortality in patients with syncope.

Arch Med Sci 2013 Dec 5;9(6):1049-54. Epub 2013 Dec 5.

Department of Medicine, Division of Internal Medicine, Westchester Medical Center/ New York Medical College, Valhalla, New York, USA.

Introduction: The electrocardiographic parameters QRS duration, QRS-T angle and QTc can predict mortality in patients with cardiovascular disease. The prgnostic value of these parameters in hospitalized patients with syncope needs investigation.

Material And Methods: We retrospectively studied 590 consecutive patients hospitalized with syncope. After excluding patients with baseline abnormal rhythm, QT- prolonging medications, and missing data, 459 patients were analyzed. Baseline demographic characteristics, co-morbidities, medication use, San Francisco Syncope Rule (SFSR) and Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) score and data on mortality were collected. The categorical variables and continuous variables of the 2 groups of patients with prolonged QTc and normal QTc interval were analyzed by Fischer's exact test and Mann-Whitney Test. A stepwise Cox regression model was used for time to death analysis.

Results: Of 459 patients, prolonged QTc interval was observed in 122 (27%). Mean follow-up was 41 months. Patients with prolonged QTc interval had higher prevalence of cardiovascular disease, OESIL score, high risk SFSR, hypertension, dyslipidemia, coronary artery disease, congestive heart failure, and increased mortality. Stepwise Cox regression analysis showed that significant independent prognostic factors for time to death were prolonged QTc interval (p = 0.005), age (p = 0.001), diabetes mellitus (p = 0.001) and history of malignancy (p = 0.006). QRS duration and QRS-T angle were not independent predictors of mortality.

Conclusions: A prolonged QTc interval is an independent predictor of long-term mortality in hospitalized patients with syncope.
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http://dx.doi.org/10.5114/aoms.2013.39383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902715PMC
December 2013

Operationalizing the internal medicine milestones-an early status report.

J Grad Med Educ 2013 Mar;5(1):130-7

Background: The internal medicine milestones were developed to advance outcomes-based residency training and will play an important role in the next accreditation system.

Innovation: As an element of our program's participation in the internal medicine educational innovations project, we implemented a milestones-based evaluation process in our general medicine and pulmonary-critical care rotations on July 1, 2010.

Measures: Outcomes assessed included survey-rated acceptability to participating faculty, residents, and clinical competency committee members.

Results: Faculty and residents agreed that the milestones promoted a common understanding of what knowledge, skills, and attitudes should be displayed at particular points in residents' professional development and enhanced evaluators' ability to provide specific performance feedback. Most residents and faculty members agreed that the milestones promoted fairness and uniformity in the evaluation process. Clinical competency committee members agreed the milestones improved the quality of information available for deliberations and resulted in more uniform promotion standards. Faculty rated the use of too many milestones per form/tool at a mean of 7.3 (where 1 was minimally problematic, and 10 was maximally problematic) and the potential for evaluator fatigue (mean, 8.2) as the most significant challenges to the use of milestones. Eight of 12 faculty members would recommend milestones in other programs; 4 were uncertain.

Conclusions: Despite logistical challenges, educators and trainees found that milestones promoted a common understanding of what knowledge, skills and attitudes should be displayed at particular stages of training; permitted greater specificity in performance feedback; and enhanced uniformity and fairness in promotion decisions.
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http://dx.doi.org/10.4300/JGME-D-12-00130.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613298PMC
March 2013

Predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura.

Am J Med 2013 Nov 29;126(11):1016.e1-7. Epub 2013 Aug 29.

Department of Medicine, New York Medical College, Valhalla. Electronic address:

Background: Despite the widespread availability of plasmapheresis as a therapy, thrombotic thrombocytopenic purpura is associated with significant morbidity and mortality. There is a paucity of data on the predictors of poor clinical outcome in this population. Acute myocardial infarction is a recognized complication of thrombotic thrombocytopenic purpura. Little is known about the magnitude of this problem, its risk factors, and its influence on mortality in patients hospitalized with thrombotic thrombocytopenic purpura.

Methods: We used the 2001-2010 Nationwide Inpatient Sample database to identify patients aged ≥18 years with the diagnosis of thrombotic thrombocytopenic purpura (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 446.6) who also received therapeutic plasmapheresis (ICD-9-CM code 99.71) during the hospitalization. Patients with acute myocardial infarction were identified using the Healthcare Cost and Utilization Project Clinical Classification Software code 100. Stepwise logistic regression was used to determine independent predictors of in-hospital mortality and acute myocardial infarction in thrombotic thrombocytopenic purpura patients.

Results: Among the 4032 patients (mean age 47.5 years, 67.7% women, and 36.9% white) with thrombotic thrombocytopenic purpura who also underwent plasmapheresis, in-hospital mortality was 11.1%. Independent predictors of increased in-hospital mortality were older age (odds ratio [OR] 1.03; 95% confidence interval [CI], 1.02-1.04; P <.001), acute myocardial infarction (OR 1.89; 95% CI, 1.24-2.88; P = .003), acute renal failure (OR 2.75; 95% CI, 2.11-3.58; P <.001), congestive heart failure (OR 1.66; 95% CI, 1.17-2.34; P = .004), acute cerebrovascular disease (OR 2.68; 95% CI, 1.87-3.85; P <.001), cancer (OR 2.49; 95% CI, 1.83-3.40; P <.001), and sepsis (OR 2.59; 95% CI, 1.88-3.59; P <.001). Independent predictors of acute myocardial infarction were older age (OR 1.03; 95% CI, 1.02-1.04; P <.001), smoking (OR 1.60; 95% CI, 1.14-2.24; P = .007), known coronary artery disease (OR 2.59; 95% CI, 1.76-3.81; P <.001), and congestive heart failure (OR 2.40; 95% CI, 1.71-3.37; P <.001).

Conclusion: In this large national database, patients with thrombotic thrombocytopenic purpura had an in-hospital mortality rate of 11.1% and an acute myocardial infarction rate of 5.7%. Predictors of in-hospital mortality were older age, acute myocardial infarction, acute renal failure, congestive heart failure, acute cerebrovascular disease, cancer, and sepsis. Predictors of acute myocardial infarction were older age, smoking, known coronary artery disease, and congestive heart failure.
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http://dx.doi.org/10.1016/j.amjmed.2013.03.021DOI Listing
November 2013

Milestones: direct observation may be the key to accelerated training.

Am J Med 2013 Dec 26;126(12):1031-2. Epub 2013 Aug 26.

Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla.

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http://dx.doi.org/10.1016/j.amjmed.2013.05.004DOI Listing
December 2013

Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21.

Obesity (Silver Spring) 2014 Mar 2;22(3):705-12. Epub 2013 Dec 2.

Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA.

Objective: Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose, and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development.

Methods: Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content, and lipogenesis were assessed.

Results: CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels, and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, Fatty acid synthase (FAS) levels involving recruitment of FGF21, PPARα, and Glut 1. These beneficial effects were reversed by inhibition of HO activity.

Conclusion: Increased levels of HO-1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content, and fatty liver. The beneficial effect of HO-1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO-1 and HO activity are responsible for fatty liver.
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http://dx.doi.org/10.1002/oby.20559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830593PMC
March 2014

HO-1 induction improves the type-1 cardiorenal syndrome in mice with impaired angiotensin II-induced lymphocyte activation.

Hypertension 2013 Aug 10;62(2):310-6. Epub 2013 Jun 10.

Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701-3655, USA.

Type-1 cardiorenal syndrome, characterized by acute kidney dysfunction secondary to cardiac failure and renal arteriolar vasoconstriction, is mediated by the renin-angiotensin-aldosterone axis and sympathetic nervous system activation. Previous reports indicate that angiotensin II modulates immune function and causes recruitment and activation of T-lymphocytes. The goal of this study was to evaluate the effects of postischemic heart failure on renal morphology and circulation and the beneficial effects of heme oxygenase-1 (HO-1) induction in T-lymphocyte-suppressed severe combined immune deficiency (SCID) mice. Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with an HO-1 inducer, cobalt protoporphyrin, and with or without stannous mesoporphyrin, an inhibitor of HO activity. Heart and kidney function were studied 30 days after surgery. Fractional area change was reduced 30 days after surgery in both the C57 and SCID MI-groups as compared with their respective controls (P<0.01). Renal Pulsatility Index and renal injury were increased in C57 and SCID MI-groups compared with the sham group. HO-1 induction improved renal vasoconstriction as well as ameliorated renal injury in both the SCID and C57 MI-groups (P<0.01). However, improvement was more evident in SCID mice. In addition, our results showed that plasma creatinine, angiotensin II, and renin were significantly increased in the C57 and SCID MI-groups as compared with their respective controls. HO-1 induction decreased these parameters in both MI groups. Stannous mesoporphyrin reversed the beneficial effect of cobalt protoporphyrin in both mouse strains. The study demonstrates that T-lymphocyte suppression facilitated the HO-1-dependent improvement in the attenuation of type-1 cardiorenal syndrome.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771397PMC
August 2013

Increased heme-oxygenase 1 expression in mesenchymal stem cell-derived adipocytes decreases differentiation and lipid accumulation via upregulation of the canonical Wnt signaling cascade.

Stem Cell Res Ther 2013 Mar 12;4(2):28. Epub 2013 Mar 12.

Introduction: Heme oxygenase (HO), a major cytoprotective enzyme, attenuates oxidative stress and obesity. The canonical Wnt signaling cascade plays a pivotal role in the regulation of adipogenesis. The present study examined the interplay between HO-1and the Wnt canonical pathway in the modulation of adipogenesis in mesenchymal stem cell (MSC)-derived adipocytes.

Methods: To verify the role of HO-1 in generating small healthy adipocytes, cobalt protoporphyrin (CoPP), inducer of HO-1, was used during adipocyte differentiation. Lipid accumulation was measured by Oil red O staining and lipid droplet size was measured by BODIPY staining.

Results: During adipogenesis in vitro, differentiating pre-adipocytes display transient increases in the expression of genes involved in canonical Wnt signaling cascade. Increased levels of HO-1 expression and HO activity resulted in elevated levels of β-catenin, pGSK3β, Wnt10b, Pref-1, and shh along with increased levels of adiponectin (P < 0.05). In addition, induction of HO-1 resulted in a reduction in C/EBPα, PPARγ, Peg-1/Mest, aP2, CD36 expression and lipid accumulation (P < 0.05). Suppression of HO-1 gene by siRNA decreased Wnt10b, pGSK3β and β-catenin expression, and increased lipid accumulation. The canonical Wnt responsive genes, IL-8 and SFRP1, were upregulated by CoPP and their expression was decreased by the concurrent administration of tin mesoporphyrin (SnMP), an inhibitor of HO activity. Furthermore, knockdown of Wnt10b gene expression by using siRNA showed increased lipid accumulation, and this effect was not decreased by concurrent treatment with CoPP. Also our results show that blocking the Wnt 10b antagonist, Dickkopf 1 (Dkk-1), by siRNA decreased lipid accumulation and this effect was further enhanced by concurrent administration of CoPP.

Conclusions: This is the first study to demonstrate that HO-1 acts upstream of canonical Wnt signaling cascade and decreases lipogenesis and adipocyte differentiation suggesting that the HO-1 mediated increase in Wnt10b can modulate the adipocyte phenotype by regulating the transcriptional factors that play a role in adipogenesis. This is evidenced by a decrease in lipid accumulation and inflammatory cytokine levels, increased adiponectin levels and elevation of the expression of genes of the canonical Wnt signaling cascade.
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http://dx.doi.org/10.1186/scrt176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706794PMC
March 2013