Medical Genetics Commons^™

Enpp1 Variants In Patients With Gaci And Pxe Expand The Clinical And Genetic Heterogeneity Of Heritable Disorders Of Ectopic Calcification., Douglas Ralph, Yvonne Nitschke, Michael A Levine, Matthew Caffet, Tamara Wurst, Amir Hossein Saeidian, Leila Youssefian, Hassan Vahidnezhad, Sharon F Terry, Frank Rutsch, Jouni Uitto, Qiaoli Li

Department of Medicine Faculty Papers

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy …

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 …

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, …

A Role For The Histone Deacetylase Hdac4 In The Life-Cycle Of Hiv-1-Based Vectors., Johanna A Smith, Jennifer Yeung, Gary D Kao, René Daniel

Department of Medicine Faculty Papers

HIV-1 integration is mediated by the HIV-1 integrase protein, which joins 3'-ends of viral DNA to host cell DNA. To complete the integration process, HIV-1 DNA has to be joined to host cell DNA also at the 5'-ends. This process is called post-integration repair (PIR). Integration and PIR involve a number of cellular co-factors. These proteins exhibit different degrees of involvement in integration and/or PIR. Some are required for efficient integration or PIR. On the other hand, some reduce the efficiency of integration. Finally, some are involved in integration site selection. We have studied the role of the histone deacetylase …

Early Detection Of Response To Hydroxyurea Therapy In Patients With Sickle Cell Anemia., Samir K. Ballas, William F. Mccarthy, Nan Guo, Carlo Brugnara, Gail Kling, Robert L. Bauserman, Myron A. Waclawiw

Department of Medicine Faculty Papers

Red blood cells (RBC) and reticulocyte parameters were determined on peripheral blood from a subset of patients enrolled in the multicenter study of hydroxyuea (HU) in sickle cell anemia. Multiple blood samples were obtained every 2 weeks. Cellular indices were measured by flow cytometry. Generalized linear models were used to determine the relationship between the longitudinal trajectories of RBC and reticulocyte indices and HU usage. There was a significant relationship between HU usage and most of the RBC and reticulocyte indices. Hydroxyurea produced higher value trajectories than those generated by placebo usage for the hemoglobin (Hb) content of both the …

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 Protein Alter The Tight Junction Integrity And Function Of Retinal Pigment Epithelium: An In Vitro Study., Ling Bai, Zhenping Zhang, Hui Zhang, Xiumei Li, Qiurong Yu, Haotian Lin, Wenhui Yang

Department of Medicine Faculty Papers

BACKGROUND: How HIV-1 enter into the eyes remains obscure. We postulated that HIV-1 Tat protein can alter the expression of specific tight-junction proteins and disturb the blood retinal barrier, and contributes to HIV trafficking into the eyes. This study is to determine the effects of HIV-1 Tat proteins on the barrier function and tight-junction protein expression of retinal pigment epithelial cell (RPE). METHODS: A human RPE cell line (D407) cultured on microporous filter-supports was used. After treating with HIV-1 Tat protein, transepithelial electrical resistance (TER) of confluent RPE cells was measured by epithelial voltmeter. The permeability of the RPE cells …

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 …

High-Resolution Physical Map For Chromosome 16q12.1-Q13, The Blau Syndrome Locus., Xiaoju Wang, Helena Kuivaniemi, Gina Bonavita, Charlene J Williams, Gerard Tromp

Department of Medicine Faculty Papers

BACKGROUND: The Blau syndrome (MIM 186580), an autosomal dominant granulomatous disease, was previously mapped to chromosome 16p12-q21. However, inconsistent physical maps of the region and consequently an unknown order of microsatellite markers, hampered us from further refining the genetic locus for the Blau syndrome. To address this problem, we constructed our own high-resolution physical map for the Blau susceptibility region. RESULTS: We generated a high-resolution physical map that provides more than 90% coverage of a refined Blau susceptibility region. The map consists of four contigs of sequence tagged site-based bacterial artificial chromosomes with a total of 124 bacterial artificial chromosomes, …

Technology Evaluation: Pro-542, Progenics Pharmaceuticals Inc., Muhammad Mukhtar, Zahida Parveen, Roger J Pomerantz

Department of Medicine Faculty Papers

Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the …

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 …

Increased Abundance Of The Receptor-Type Protein-Tyrosine Phosphatase Lar Accounts For The Elevated Insulin Receptor Dephosphorylating Activity In Adipose Tissue Of Obese Human Subjects, Falyaz Ahmad, Robert V. Considine, Barry J. Goldstein

Department of Medicine Faculty Papers

Protein-tyrosine phosphatases (PTPases) have an essential role in the regulation of the steady-state phosphorylation of the insulin receptor and other proteins in the insulin signalling pathway. To examine whether increased PTPase activity is associated with adipose tissue insulin resistance in human obesity we measured PTPase enzyme activity towards the insulin receptor in homogenates of subcutaneous adipose tissue from a series of six lean and six nondiabetic, obese (body mass index > 30) subjects. The obese subjects had a mean 1.74-fold increase in PTPase activity (P < 0.0001) with a striking positive correlation by linear regression analysis between PTPase activity and body mass index among all of the samples (R = 0.918; P < 0.0001). The abundance of three candidate insulin receptor PTPases in adipose tissue was also estimated by immunoblot analysis. The most prominent increase was a 2.03-fold rise in the transmembrane PTPase LAR (P < 0.001). Of the three PTPase examined, only immunodepletion of LAR protein from the homogenates with neutralizing antibodies resulted in normalization of the PTPase activity towards the insulin receptor, demonstrating that the increase in LAR was responsible for the enhanced PTPase activity in the adipose tissue from obese subjects. These studies suggest that increased PTPase activity towards the insulin receptor is a pathogenetic factor in the insulin resistance of adipose tissue in human obesity and provide evidence for a potential role of the LAR PTPase in the regulation of insulin signalling in disease states.

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 …

Insulin Receptor And Epidermal Growth Factor Receptor Dephosphorylation By Three Major Rat Liver Protein-Tyrosine Phosphatases Expressed In A Recombinant Bacterial System, Naotake Hashimoto, Wei-Ren Zhang, Barry J. Goldstein

Department of Medicine Faculty Papers

Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of signal transduction mediated by reversible protein-tyrosine phosphorylation. In order to characterize individual rat hepatic PTPases that might have specificity for autophosphorylated receptor tyrosine kinases, we isolated cDNA segments encoding three PTPases (PTPase 1B, LAR and LRP) that are expressed in insulin-sensitive liver and skeletal muscle tissue, and evaluated their catalytic activity in vitro. The intrinsic PTPase activities of the full-length PTPase 1B protein and the cytoplasmic domains of LAR and LRP were studied by expression of recombinant cDNA constructs in the inducible bacterial vector pKK233-2 using extracts of …

Identification Of Persistent Defects In Insulin Receptor Structure And Function In Capillary Endothelial Cells From Diabetic Rats, Ching Fai Kwok, Barry J. Goldstein, Dirk Muller-Wieland, Tian-Shing Lee, C. Ronald Kahn, George L. King

Department of Medicine Faculty Papers

Insulin actions and receptors were studied in capillary endothelial cells cultured from diabetic BB rats and their nondiabetic colony mates. The endothelial cells from diabetic rats of 2 mo duration had persistent biological and biochemical defects in culture. Compared with normal rats, endothelial cells from diabetic rats grew 44% more slowly. Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6 +/- 0.7; diabetic: 2.6 +/- 0.4% per milligram protein, P < 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. Insulin stimulation of 2-deoxy-glucose uptake and alpha-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease in insulin-stimulated autophosphorylation (P < 0.05). ¹²⁵I-insulin cross-linking revealed an 140-kD alpha subunit of the insulin receptor similar to …