Medicine and Health Sciences Commons^™

Cytokine Storms, Evolution And Covid-19, Joe Alcock, Alix Masters

Department of Medicine Faculty Papers

Since the identification of severe illness caused by the novel coronavirus SARS-CoV-2, the role of the host immune system in causing disease has attracted widespread attention, along with intense interest in medical interventions that target the host immune response. A wide variety of agents have been proposed to treat a cytokine storm in coronavirus disease 2019 (COVID-19), but so far, only one class of medications, corticosteroids, has proved useful. In recent decades, experimental therapies for cytokine storms have been tried and mostly failed to help patients with severe sepsis and other infections. We summarize this history in order to frame …

A Foldable Nonpenetrating Keratoprosthesis: Medium To Long-Term Clinical Results In Patients With Corneal Blindness Due To Noninflammatory Anterior Cornea Disease., Jose M Vargas, Eric Shiuey

Department of Medicine Faculty Papers

PURPOSE: To report the medium to long-term safety and performance outcomes of the KeraKlear nonpenetrating artificial cornea (KeraKlear) as the primary procedure in patients with corneal blindness due to noninflammatory anterior cornea disease.

METHODS: Fifteen patients with corneal blindness (preoperative visual acuity [VA] of ≥20/200) due to a non-inflammatory anterior corneal condition were included in this prospective, single-center study. Preoperative diagnoses included corneal scars, keratoconus, and corneal dystrophies. Diseased corneas were implanted with the KeraKlear (KeraMed Inc., Irvine, California, USA) by a single surgeon (JMV) using a femtosecond laser to create all incisions. Participants were followed up with for as …

Etiology And Surgical Management Of Cervical Spinal Epidural Abscess (Sea):: A Systematic Review., Justin Iorio, Yusef Mosley, Md, Srinivas Prasad, Joshua Pelta-Heller, Jack Jallo, Soroush Shahrokh, James Harrop

Department of Medicine Faculty Papers

Study Design: Systematic analysis and review.

Objective: Evaluation of the presentation, etiology, management strategies (including both surgical and nonsurgical options), and neurological functional outcomes in patients with cervical spinal epidural abscess (SEA).

Methods: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria were used to create a framework based on which articles pertaining to cervical SEA were chosen for review following a search of the Ovid and PubMed databases using the search terms "epidural abscess" and "cervical." Included studies needed to have at least 4 patients aged 18 years or older, and to have been published within the …

Effect Of Oral Iron Repletion On Exercise Capacity In Patients With Heart Failure With Reduced Ejection Fraction And Iron Deficiency: The Ironout Hf Randomized Clinical Trial., Gregory D Lewis, Rajeev Malhotra, Adrian F Hernandez, Steven E Mcnulty, Andrew Smith, G Michael Felker, W H Wilson Tang, Shane J Larue, Margaret M Redfield, Marc J Semigran, Michael M Givertz, Peter Van Buren, David J Whellan, Kevin J Anstrom, Monica R Shah, Patrice Desvigne-Nickens, Javed Butler, Eugene Braunwald

Department of Medicine Faculty Papers

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown.

Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency.

Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (

Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. …

Utilization Of Hiv-1 Envelope V3 To Identify X4- And R5-Specific Tat And Ltr Sequence Signatures., Gregory C Antell, Will Dampier, Benjamas Aiamkitsumrit, Michael R Nonnemacher, Jeffrey M Jacobson, Vanessa Pirrone, Wen Zhong, Katherine Kercher, Shendra Passic, Jean W Williams, Gregory Schwartz, Uri Hershberg, Fred C Krebs, Brian Wigdahl

Department of Medicine Faculty Papers

BACKGROUND: HIV-1 entry is a receptor-mediated process directed by the interaction of the viral envelope with the host cell CD4 molecule and one of two co-receptors, CCR5 or CXCR4. The amino acid sequence of the third variable (V3) loop of the HIV-1 envelope is highly predictive of co-receptor utilization preference during entry, and machine learning predictive algorithms have been developed to characterize sequences as CCR5-utilizing (R5) or CXCR4-utilizing (X4). It was hypothesized that while the V3 loop is predominantly responsible for determining co-receptor binding, additional components of the HIV-1 genome may contribute to overall viral tropism and display sequence signatures …

Cell-Free Circulating Mitochondrial Dna Content And Risk Of Hepatocellular Carcinoma In Patients With Chronic Hbv Infection., Ling Li, Hie-Won Hann, Shaogui Wan, Richard Hann, Chun Wang, Yinzhi Lai, Xishan Ye, Alison Evans, Ronald E. Myers, Phd, Dsw, Zhong Ye, Bingshan Li, Jinliang Xing, Hushan Yang

Department of Medicine Faculty Papers

Recent studies have demonstrated a potential link between circulating cell-free mitochondrial DNA (mtDNA) content and cancers. However, there is no study evaluating the association between circulating mtDNA as a non-invasive marker of hepatocellular carcinoma (HCC) risk. We conducted a nested case-control study to determine circulating mtDNA content in serum samples from 116 HBV-related HCC cases and 232 frequency-matched cancer-free HBV controls, and evaluate the retrospective association between mtDNA content and HCC risk using logistic regression and their temporal relationship using a mixed effects model. HCC cases had significantly lower circulating mtDNA content than controls (1.06 versus 2.47, P = 1.7 …

Reduction Of Ctrp9, A Novel Anti-Platelet Adipokine, Contributes To Abnormal Platelet Activity In Diabetic Animals., Wenqing Wang, Wayne Bond Lau, Yajing Wang, Xin-Liang Ma, Rong Li

Department of Medicine Faculty Papers

Platelet hyper-reactivity is a crucial cause of accelerated atherosclerosis increasing risk of thrombotic vascular events in diabetic patients. The mechanisms leading to abnormal platelet activity during diabetes are complex and not fully defined. The current study attempted to clarify the role of CTRP9, a novel adiponectin paralog, in enhanced platelet activity and determined whether CTRP9 may inhibit platelet activity. Adult male C57BL/6 J mice were randomized to receive high-fat diet (HFD) or normal diet (ND). 8 weeks after HFD, animals were sacrificed, and both plasma CTRP9 and platelet aggregation were determined. HFD-fed animals increased weight gain significantly, and became hyperglycemic …

Chimeric Cells Of Maternal Origin Do Not Appear To Be Pathogenic In The Juvenile Idiopathic Inflammatory Myopathies Or Muscular Dystrophy., Carol M Artlett, Sihem Sassi-Gaha, Ronald C Ramos, Frederick W Miller, Lisa G Rider

Department of Medicine Faculty Papers

INTRODUCTION: Microchimeric cells have been studied for over a decade, with conflicting reports on their presence and role in autoimmune and other inflammatory diseases. To determine whether microchimeric cells were pathogenic or mediating tissue repair in inflammatory myopathies, we phenotyped and quantified microchimeric cells in juvenile idiopathic inflammatory myopathies (JIIM), muscular dystrophy (MD), and noninflammatory control muscle tissues.

METHOD: Fluorescence immunophenotyping for infiltrating cells with sequential fluorescence in situ hybridization was performed on muscle biopsies from ten patients with JIIM, nine with MD and ten controls.

RESULTS: Microchimeric cells were significantly increased in MD muscle (0.079 ± 0.024 microchimeric cells/mm(2) …

The Effect Of Aspirin On Bleeding And Transfusion In Contemporary Cardiac Surgery., Jordan E Goldhammer, Gregary D. Marhefka, Constantine Daskalakis, Mark W Berguson, John E Bowen, James Diehl, Jianzhong Sun

Department of Medicine Faculty Papers

OBJECTIVE: Despite evidence that preoperative aspirin improves outcomes in cardiac surgery, recommendations for aspirin use are inconsistent due to aspirin's anti-platelet effect and concern for bleeding. The purpose of this study was to investigate preoperative aspirin use and its effect on bleeding and transfusion in cardiac surgery.

METHODS: This retrospective study involved consecutive patients (n=1571) who underwent CABG, valve, or combined CABG and valve surgery at a single center between March 2007 and July 2012. Of all patients, 728 met the inclusion criteria and were divided into two groups: those using (n=603) or not using (n=125) aspirin within 5 days …

Kallikrein Family Proteases Klk6 And Klk7 Are Potential Early Detection And Diagnostic Biomarkers For Serous And Papillary Serous Ovarian Cancer Subtypes., Ayala Tamir, Ushma Jag, Sreeja Sarojini, Craig Schindewolf, Takemi Tanaka, Rajendra Gharbaran, Hiren Patel, Anil Sood, Wei Hu, Ruzeen Patwa, Patrick Blake, Polina Chirina, Jin Oh Jeong, Heejin Lim, Andre Goy, Andrew Pecora, K Stephen Suh

Department of Medicine Faculty Papers

BACKGROUND: Early detection of ovarian cancer remains a challenge due to widespread metastases and a lack of biomarkers for early-stage disease. This study was conducted to identify relevant biomarkers for both laparoscopic and serum diagnostics in ovarian cancer.

METHODS: Bioinformatics analysis and expression screening in ovarian cancer cell lines were employed. Selected biomarkers were further validated in bio-specimens of diverse cancer types and ovarian cancer subtypes. For non-invasive detection, biomarker proteins were evaluated in serum samples from ovarian cancer patients.

RESULTS: Two kallikrein (KLK) serine protease family members (KLK6 and KLK7) were found to be significantly overexpressed relative to normal …

Blau Syndrome, The Prototypic Auto-Inflammatory Granulomatous Disease., Carine H Wouters, Anne Maes, Kevin P Foley, John Bertin, Carlos D Rose

Department of Medicine Faculty Papers

Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau …

Understanding The Power Of Perinatal Events And Metabolic Status In Childhood., Bonita Falkner, Julie Ingelfinger

Department of Medicine Faculty Papers

No abstract provided.

Adiponectin Inhibits Tumor Necrosis Factor-Α-Induced Vascular Inflammatory Response Via Caveolin-Mediated Ceramidase Recruitment And Activation., Yajing Wang, Xiaoliang Wang, Wayne Bond Lau, Yuexing Yuan, David Booth, Jing-Jing Li, Rosario Scalia, Kyle Preston, Erhe Gao, Walter Koch, Xin-Liang Ma

Department of Medicine Faculty Papers

RATIONALE: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.

OBJECTIVE: The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.

METHODS AND RESULTS: Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P87% of adiponectin-induced nCDase …

Xiaoqinglong Granules As Add-On Therapy For Asthma: Latent Class Analysis Of Symptom Predictors Of Response., Qinglin Zha, Seqi Lin, Chi Zhang, Christopher Chang, Hanrong Xue, Cheng Lu, Miao Jiang, Yan Liu, Zuke Xiao, Weiyou Liu, Yunfei Shang, Jianjian Chen, Minyong Wen, Aiping Lu

Department of Medicine Faculty Papers

Xiaoqinglong granules (XQLG) has been shown to be an effective therapy in asthma animal models. We reviewed the literature and conducted this study to assess the impact of XQLG as an add-on therapy to treatment with fluticasone/salmeterol (seretide) in adult patients with mild-to-moderate, persistent asthma. A total of 178 patients were randomly assigned to receive XQLG and seretide or seretide plus placebo for 90 days. Asthma control was assessed by asthma control test (ACT), symptoms scores, FEV(1), and PEF. Baseline patient-reported Chinese medicine (CM)-specific symptoms were analyzed to determine whether the symptoms may be possible indicators of treatment response by …

A Genome-Wide Methylation Study On Essential Hypertension In Young African American Males., Xiaoling Wang, Bonita Falkner, Haidong Zhu, Huidong Shi, Shaoyong Su, Xiaojing Xu, Ashok Kumar Sharma, Yanbin Dong, Frank Treiber, Bernard Gutin, Gregory Harshfield, Harold Snieder

Department of Medicine Faculty Papers

OBJECTIVE: There is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.

METHOD & RESULTS: We conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14-23 years and performed …

Biosynthetic Pathways And The Role Of The Mas Receptor In The Effects Of Angiotensin-(1-7) In Smooth Muscles., Marcio Augusto Fressatto De Godoy, Larissa Pernomian, Ana Maria De Oliveira, Satish Rattan

Department of Medicine Faculty Papers

Ang-(1-7) is produced via degradation of Ang II by the human angiotensin converting enzyme, also known as ACE2. In the cardiovascular system, Ang-(1-7) has been shown to produce effects that are opposite to those of Ang II. These include smooth muscle relaxation and cardioprotection. While the roles of Ang-(1-7) in other systems are currently topic of intense research, functional data suggest a relaxation action in gastrointestinal smooth muscles in a way that corroborates the results obtained from vascular tissues. However, more studies are necessary to determine a relevant role for Ang-(1-7) in the gastrointestinal system. The Ang-(1-7) actions are mediated …

The Use Of Infliximab In Older Inflammatory Bowel Disease Patients, Stephanie M. Moleski, Christina C. Lindenmeyer, Patricia L. Kozuch

Department of Medicine Faculty Papers

Limited data suggest anti-tumor necrosis factor (TNF) antibodies have equal efficacy but higher morbidity and mortality in older compared to younger inflammatory bowel disease (IBD) patients(1).

Proliferating Cell Nuclear Antigen Is Required For Loading Of The Smcx/Kmd5c Histone Demethylase Onto Chromatin., Zhihui Liang, Marc Diamond, Johanna A Smith, Matthias Schnell, René Daniel

Department of Medicine Faculty Papers

UNLABELLED: ABSTRACT:

BACKGROUND: Histone methylation is regulated by a large number of histone methyltransferases and demethylases. The recently discovered SMCX/KMD5C demethylase has been shown to remove methyl residues from lysine 4 of histone H3 (H3K4), and constitutes an important component of the regulatory element-1-silencing transcription factor (REST) protein complex. However, little is known about the cellular mechanisms that control SMCX activity and intracellular trafficking.

RESULTS: In this study, we found that small interfering RNA-mediated knockdown of proliferating cell nuclear antigen (PCNA) resulted in the reduction of the chromatin-bound SMCX fraction. We identified a PCNA-interaction protein motif (PIP box) in the …

The Interplay Between Nf-Kappab And E2f1 Coordinately Regulates Inflammation And Metabolism In Human Cardiac Cells., Xavier Palomer, David Álvarez-Guardia, Mercy M Davidson, Tung O Chan, Arthur M Feldman, Manuel Vázquez-Carrera

Department of Medicine Faculty Papers

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, …

Molecular Processes That Handle — And Mishandle — Dietary Lipids, Kevin Jon Williams

Department of Medicine Faculty Papers

Overconsumption of lipid-rich diets, in conjunction with physical inactivity, disables and kills staggering numbers of people worldwide. Recent advances in our molecular understanding of cholesterol and triglyceride transport from the small intestine to the rest of the body provide a detailed picture of the fed/fasted and active/sedentary states. Key surprises include the unexpected nature of many pivotal molecular mediators, as well as their dysregulation — but possible reversibility — in obesity, diabetes, inactivity, and related conditions. These mechanistic insights provide new opportunities to correct dyslipoproteinemia, accelerated atherosclerosis, insulin resistance, and other deadly sequelae of overnutrition and underexertion.

Pegylated Interferon 2a And 2b In Combination With Ribavirin For The Treatment Of Chronic Hepatitis C In Hiv Infected Patients., Ravinder Dhillon, Simona Rossi, Steven K Herrine

Department of Medicine Faculty Papers

Coinfection with hepatitis C virus (HCV) and HIV is an increasingly recognized clinical dilemma, particularly since the advent of highly active antiretroviral therapy. Several studies of this population have demonstrated both more rapid progression of liver disease and poorer overall prognosis compared to HCV monoinfected patients. Consensus guidelines, based primarily on the results of 4 major randomized trials, recommend treatment with peginterferon and ribavirin for 48 weeks in coinfected patients. However, this current standard of care is associated with lower response rates to therapy than those seen in monoinfected patients. Important predictors of response include HCV genotype, pretreatment HCV RNA …

Hiv-1 Tat And Aids-Associated Cancer: Targeting The Cellular Anti-Cancer Barrier?, Giuseppe Nunnari, Johanna A Smith, René Daniel

Department of Medicine Faculty Papers

The acquired immunodeficiency syndrome (AIDS) is accompanied by a significant increase in the incidence of neoplasms. Several causative agents have been proposed for this phenomenon. These include immunodeficiency and oncogenic DNA viruses and the HIV-1 protein Tat. Cancer in general is closely linked to genomic instability and DNA repair mechanisms. The latter maintains genomic stability and serves as a cellular anti-cancer barrier. Defects in DNA repair pathway are associated with carcinogenesis. This review focuses on newly discovered connections of the HIV-1 protein Tat, as well as cellular co-factors of Tat, to double-strand break DNA repair. We propose that the Tat-induced …

Up-Regulation Of Interferon-A/Apobec3g Signal Pathway Potently Inactivates Hiv-1 Infectivity In Resting Cd4-T Cells, Keyang Chen, Jialing Huang, Chune Zhang, Sophia Huang, Giuseppe Nunnari, Feng-Xiang Wang, Xiangrong Tong, Ling Gao, Kristi Nikisher, Hui Zhang

Department of Medicine Faculty Papers

Poster Presentation.

Multiple Metabolic Hits Converge On Cd36 As Novel Mediator Of Tubular Epithelial Apoptosis In Diabetic Nephropathy., Katalin Susztak, Emilio Ciccone, Peter Mccue, Kumar Sharma, Erwin P Böttinger

Department of Medicine Faculty Papers

BACKGROUND: Diabetic nephropathy (DNP) is a common complication of type 1 and type 2 diabetes mellitus and the most common cause of kidney failure. While DNP manifests with albuminuria and diabetic glomerulopathy, its progression correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis. However, mechanisms leading to TED in DNP remain poorly understood.

METHODS AND FINDINGS: We found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced …

Stent Placement Compared With Balloon Angioplasty For Obstructed Coronary Bypass Grafts. Saphenous Vein De Novo Trial Investigators., M P Savage, J S Douglas, D L Fischman, C J Pepine, S B King, J A Werner, S R Bailey, P A Overlie, S H Fenton, J A Brinker, M B Leon, S Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Treatment of stenosis in saphenous-vein grafts after coronary-artery bypass surgery is a difficult challenge. The purpose of this study was to compare the effects of stent placement with those of balloon angioplasty on clinical and angiographic outcomes in patients with obstructive disease of saphenous-vein grafts.

METHODS: A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later.

RESULTS: As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate …

A Randomized Comparison Of Coronary-Stent Placement And Balloon Angioplasty In The Treatment Of Coronary Artery Disease. Stent Restenosis Study Investigators., David L. Fischman, Martin B. Leon, Donald S. Baim, Richard A. Schatz, Michael P. Savage, Ian Penn, Katherine Detre, Lisa Veltri, Donald Ricci, Masakiyo Nobuyoshi, Michael Cleman, Richard Heuser, David Almond, Paul S. Teirstein, R. David Fish, Antonio Colombo, Jeffrey Brinker, Jeffrey Moses, Alex Shaknovich, John Hirshfeld, Stephen Bailey, Stephen Ellis, Randal Rake, Sheldon Goldberg

Department of Medicine Faculty Papers

BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes.

METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.

RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who …