Digital Commons Network^™

Deletion Of Gsk-3beta In Mice Leads To Hypertrophic Cardiomyopathy Secondary To Cardiomyoblast Hyperproliferation., Risto Kerkela, Lisa Kockeritz, Katrina Macaulay, Jibin Zhou, Bradley W. Doble, Cara Beahm, Sarah Greytak, Kathleen Woulfe, Chinmay M. Trivedi, James R. Woodgett, Jonathan A. Epstein, Thomas Force, Gordon S. Huggins

Center for Translational Medicine Faculty Papers

Based on extensive preclinical data, glycogen synthase kinase-3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b(-/-) embryoid bodies. While GSK-3alpha-deficient mice …

Heme Induces Endothelial Tissue Factor Expression: Potential Role In Hemostatic Activation In Patients With Hemolytic Anemia, Yamaja Setty, Suhita G. Betal, Jie Zhang, Marie J. Stuart

Department of Pediatrics Faculty Papers

Objectives: We explored the possibility that heme, an inflammatory mediator and a product of intravascular hemolysis in patients with hemolytic anemia including sickle cell disease, could modulate hemostasis by an effect on endothelial tissue factor (TF) expression.

Methods: Levels of TF mRNA, protein and procoagulant activity were measured in heme-treated endothelial cells. Results: Heme induces TF expression on the surface of both macrovascular and microvascular endothelial cells in a concentration-dependent manner, with 12-fold to 50-fold induction being noted (enzyme-linked immunosorbent assay) between 1 and 100 μm heme (P < 0.05). Complementary flow cytometry studies showed that the heme-mediated endothelial TF expression was quantitatively similar to that of tumor necrosis factor-alpha (TNF-α). Heme also upregulated the expression of TF mRNA (8-fold to 26-fold), protein (20-fold to 39-fold) and procoagulant activity (5-fold to 13-fold) in endothelial cells in a time-dependent manner. The time-course of heme-mediated TF antigen expression paralleled the induction of procoagulant activity, with antibody blocking studies demonstrating specificity for TF protein. Interleukin (IL)-1α, and TNF-α are not involved in mediating the heme effect, as antibodies against these cytokines and IL-1-receptor antagonist failed to block heme-induced TF expression. Inhibition of heme-induced TF mRNA expression by sulfasalazine and curcumin suggested that the transcription factor nuclear factor kappaB is involved in mediating heme-induced TF expression in endothelial cells.

Conclusions: Our results demonstrate that heme induces TF expression by directly activating …

Predicting Length Of Treatment For Neonatal Abstinence Syndrome In Methadone-Exposed Neonates., Neil S. Seligman, Nicole Salva, Edward J. Hayes, Kevin C. Dysart, Edward C. Pequignot, Jason K. Baxter

Department of Obstetrics and Gynecology Faculty Papers

OBJECTIVE: The objective of the study was to identify maternal variables predicting length of treatment for neonatal abstinence syndrome (NAS).

STUDY DESIGN: This was a retrospective cohort study of infants treated for NAS during 2000-2006 whose mothers were on methadone maintenance at delivery. Mixed-effects linear regression was used to examine the interaction of maternal and neonatal variables with length of treatment.

RESULTS: Of 204 neonates born to methadone exposed mothers, the average dose at delivery was 127 mg daily (25-340 mg) with median length of treatment 32 days (1-122 days). Trimester of initial exposure (P = .33), methadone dose at …

Phosphatidylserine-Positive Erythrocytes Bind To Immobilized And Soluble Thrombospondin-1 Via Its Heparin-Binding Domain, Suhita G. Betal, Yamaja Setty

Department of Pediatrics Faculty Papers

Phosphatidylserine (PS)-dependent erythrocyte adhesion to endothelium and sub-endothelial matrix components is mediated in part via thrombospondin (TSP). While TSP exhibits multiple cell-binding domains, the PS-binding site on TSP is unknown. Since a cell-binding domain for anionic heparin is located at the amino-terminus, we hypothesized that PS-positive red cells (PS+ve-RBCs) bind to this domain. We demonstrate that both heparin and its low-molecular-weight derivative enoxaparin (0.5-50u/ml) inhibited PS+ve-RBC adhesion to immobilized TSP in a concentration-dependent manner (21-77% inhibition, P<0.05). Pre-incubation of immobilized TSP with an antibody against the heparin-binding domain blocked PS+ve-RBC adhesion to TSP. Antibodies that recognize the collagen- and the carboxy-terminal CD47-binding domain on TSP had no effect on this process. While pre-incubation of PS+ve-RBCs with TSP-peptides from the heparin-binding domain containing the specific heparin-binding motif KKTRG inhibited PS+ve-erythrocyte adhesion to matrix TSP (P<0.001), these peptides in the immobilized form supported PS-mediated erythrocyte adhesion. A TSP-peptide lacking the binding-motif neither inhibited nor supported PS+ve-RBC adhesion. Additional experiments show that soluble-TSP also interacted with PS+ve-RBCs via its heparin-binding domain. Our results demonstrate that PS-positive erythrocytes bind to both immobilized and soluble TSP via its heparin-binding domain and that both heparin and enoxaparin, at clinically relevant concentrations, block this interaction. Other studies have shown that heparin inhibited P-selectin- and soluble-TSP-mediated sickle erythrocyte adhesion to endothelial cells. Our results taken together with the previously documented findings provide a rational basis for clinical use of heparin or its low-molecular-weight derivatives as therapeutic agents in treating vaso-occlusive pain in patients with sickle cell disease.

Jefferson Alumni Bulletin – Volume 57, Number 4, Fall 2008

The Bulletin (formerly the Jefferson Medical College Alumni Bulletin)

Jefferson Alumni Bulletin – Volume 57, Number 4, Fall 2008

Dean’s Column; Page 2

New Dean Announcement; Page 3

Findings: Researchers Show Antibody to Breast Cancer-Secreted Protein Blocks Metastasis, Chinese Food Good for Your Heart; Page 4

Medical Education Today; Page 6

Moving Forward with Interprofessional Education; Page 12

On Campus; Page 14

Class Notes; Page 22

In Memoriam; Page 22

Giving; Page 24

By the Numbers; Page 37

Dowload The Pdf Of The Full Issue

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Pennsylvania Hospice Network Participates In 2-Day Intensive Workshop On New Hospice Conditions Of Participation

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

July 10, 2008 Dhp Summer Seminar: The Jefferson School Of Health Policy And Population Health

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Value-Based Purchasing And The Cms 2008 Physician Quality Reporting Initiative (Pqri)

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Greater Philadelphia Schweitzer Fellowship Program: Fellow-Site Mentor Evaluation And Site Expansion, Nicole M. Cobb Maom

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Annual Fellows Day: The Changing Landscape Of Ambulatory Care Outcomes Research-June 30,2008

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The 16th Annual Paul Brucker Lecture: Patient-Centered Primary Care, Howard K. Rabinowitz Md

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Alcohol Use In Pregnancy: A Public Health Problem, Joshua H. Barash

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Navigating Toward A Quality Career, Valerie Pracilio

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Stretching The Boundaries Of Medical Education, Marina V. Zeltser Ba

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Jefferson Doctor Of Nursing Practice Degree, Mary Lou Manning Phd, Crnp, Jennifer Bellot Phd, Rn, Mhsa, Beth Ann Swan Phd, Crnp, Faan

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Birth Of A Center For Interprofessional Education, Molly A. Rose, Christine A. Arenson Md

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Jefferson School Of Health Policy And Population Health-Part One, David B. Nash Md, Mba, Caroline Golab Phd

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Cytoplasmic Tail Of The Rabies Virus G Protein Is An Essential Domain Controlling Death/Survival In Human Neuronal Cells, Christophe Prehaud, Mireille Lafage, Gene S. Tan, Françoise Mégret, Pauline Ménager, Matthias Schnell, Henri Buc, Monique Lafon

Department of Microbiology and Immunology Faculty Papers

Poster presentation.

Atypical Onset As Predictor Of Poor Outcome In Pediatric Systemic Lupus Erythematosus (Psle), A Taddio, E Rossetto, L Lepore, A C. Brescia, C Bracaglia, S Caminiti, E Cortis, D Rigante, A Stabile, M Montico, L Ronfani, C D. Rosé

Department of Pediatrics Faculty Papers

Poster Presentation.

Intravenous Inoculation Of Silver-Haired Bat Rabies Virus, But Not Of A Canine Strain, Elicits Lethal Encephalophathy In Mice By Fast Brain Invasion Via Neurosecretory Hypothalamic Fibers, Mirjam Ar Preuss, Marie-Luise Faber, Gene S. Tan, Bernhard Dietzschold, Matthias J. Schnell, Eberhard Weihe

Department of Microbiology and Immunology Faculty Papers

No abstract provided.

Presence Of Endometrial Adenocarcinoma In Situ In Complex Atypical Endometrial Hyperplasia Is Associated With Increased Incidence Of Endometrial Carcinoma In Subsequent Hysterectomy., Khush Mittal, Matjaz Sebenik, Cybil Irwin, Zhijije Yan, Dorota Popiolek, John Curtin, Juan Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The distinction of complex atypical endometrial hyperplasia from endometrial adenocarcinoma is often problematic. Foci of back-to-back arrangement of glands or foci of cribriform arrangement of glands smaller than 2.1 mm in diameter are considered insufficient for the diagnosis of endometrial adenocarcinoma by some authors, and sufficient to be diagnosed as endometrial adenocarcinoma by other authors. We refer to these foci as endometrial adenocarcinoma in situ. In this study, we evaluated findings in subsequent hysterectomy in complex atypical endometrial hyperplasia patients with and without adenocarcinoma in situ. Follow-up findings, including the presence or absence of endometrial adenocarcinoma in the hysterectomy specimen, …

Overexpression Of Matrix Metalloproteinase 9 In Tumor Epithelial Cells Correlates With Colorectal Cancer Metastasis., David S Zuzga, Ahmara Vivian Gibbons, Peng Li, Wilhelm Johannes Lubbe, Inna Chervoneva, Giovanni Mario Pitari

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Colorectal cancer mortality largely reflects metastasis, the spread of the disease to distant organs. Matrix metalloproteinase 9 (MMP-9) is a key regulator of metastasis and a target for anticancer strategies in colon cancer. Here, the overexpression of MMP-9 in pure tumor epithelial, but nor stromal, cell populations was associated with metastatic progression of colorectal cancer, as defined by reverse transcriptase-polymerase chain reaction (qRT-PCR) and confirmed by immunostaining. Thus, cancer cell MMP-9 represents a novel, selective prognostic and predictive factor that may be exploited for more effective disease stage stratification and therapeutic regimen selection in patients with colorectal cancer.

Decreased Expression Of Caveolin 1 In Patients With Systemic Sclerosis: Crucial Role In The Pathogenesis Of Tissue Fibrosis., Francesco Del Galdo, Federica Sotgia, Cecilia J. De Almeida, Jean-Francois Jasmin, Megan Musick, Michael P. Lisanti, Sergio A. Jimenez

Department of Medicine Faculty Papers

OBJECTIVE: Recent studies have implicated caveolin 1 in the regulation of transforming growth factor beta (TGFbeta) downstream signaling. Given the crucial role of TGFbeta in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro.

METHODS: CAV1 expression in tissues was analyzed by …

The Dose-Response Of Nitrous Oxide In Postoperative Nausea In Patients Undergoing Gynecologic Laparoscopic Surgery: A Preliminary Study., Boris Mraovic, Tatjana Simurina, Zdenko Sonicki, Neven Skitarelic, Tong J. Gan

Department of Anesthesiology Faculty Papers

BACKGROUND: Whether nitrous oxide (N(2)O) increases the incidence of postoperative nausea and vomiting (PONV) after laparoscopic gynecologic surgery is still controversial, which may be due to the administration of different concentrations of inspired N(2)O. We investigated whether N(2)O results in a dose-response increase in PONV. METHODS: Patients undergoing gynecologic laparoscopic surgery were randomized to receive 30% oxygen with air (G0, n = 46), 50% N(2)O with oxygen (G50, n = 46), or 70% N(2)O with oxygen (G70, n = 45). A standardized general anesthetic was used with no PONV prophylaxis. Known risk factors for PONV were controlled. Metoclopramide was used …

An Approach To The Failed Ankle Arthrodesis, Steven M. Raikin, Venkat Rampuri

Department of Orthopaedic Surgery Faculty Papers

Ankle arthrodesis remains the gold standard of surgical treatment for advanced ankle joint arthritis. Failure can occur as a result of infection, nonunion or malunion, resulting in pain and poor function. This paper offers a systematic approach to preventing, and managing these problems should they occur. Revision arthrodesis performed with a detailed understanding of the appropriate alignment and mechanics of the ankle joint, combined with meticulous attention to understanding and reversing the cause of the failure can result in successful salvage and restoration of function.

Complete Resolution Of Gastric Amyloidosis After Autologous Stem Cell Transplantation., Dinu Cherian, Kristin Braun, Neal Flomenberg, Juan P. Palazzo, David Kastenberg

Division of Gastroenterology and Hepatology Faculty Papers

A 48-year-old female with multiple myeloma (MM) and amyloidosis presented with massive upper gastrointestinal (GI) bleeding one week after autologous stem cell transplantation (autologous-SCT). Esophagogastroduodenoscopy (EGD) demonstrated necrotic, purple, pigmented, friable lesions throughout the stomach (Figure 1a), along with a bleeding ulcer in the cardia (Figure 1b, Video 1) which was successfully treated with epinephrine (1:10,000) injections. Biopsies demonstrated nodular amyloid deposition (Figures 2) which was Congo red positive. The patient had no further hematemesis and was discharged home 4 days later. Ten months after autologous-SCT, EGD revealed a normal stomach (Figure 3, Video 2) with …

Domain-Oriented Reduction Of Rule-Based Network Models, Nikolay M. Borisov, Alexander S. Chistopolsky, James R. Faeder, Boris N. Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The coupling of membrane-bound receptors to transcriptional regulators and other effector functions is mediated by multi-domain proteins that form complex assemblies. The modularity of protein interactions lends itself to a rule-based description, in which species and reactions are generated by rules that encode the necessary context for an interaction to occur, but also can produce a combinatorial explosion in the number of chemical species that make up the signaling network. We have shown previously that exact network reduction can be achieved using hierarchical control relationships between sites/domains on proteins to dissect multi-domain proteins into sets of non-interacting sites, allowing the …

Freedom For The Bulgarian Nurses And A Palestinian Doctor., Lawrence Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

On July 24, 2007, the five Bulgarian nurses and the Palestinian, unjustly accused of infecting Libyan children with the AIDS virus, were freed by the Libyan government. They had spent a tumultuous seven years in prison, much of the time on death row, having been accused of injecting the children with tainted blood they had brought with them. This was not only preposterous but also an impossibility as the particular strain of the AIDS virus had been found in Libya, two years prior. [1]

Experimental Optic Neuritis Induced By A Demyelinating Strain Of Mouse Hepatitis Virus., Kenneth S. Shindler, Lawrence C. Kenyon, Mahasweta Dutt, Susan T. Hingley, Jayasri Das Sarma

Department of Neurology Faculty Papers

Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS). Pathological mechanisms and potential treatments for ON have been studied via experimental autoimmune MS models. However, evidence suggests that virus-induced inflammation is a likely etiology triggering MS and ON; experimental virus-induced ON models are therefore required. We demonstrate that MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting mixed inflammatory cell infiltration. In contrast, MHV-2, a nondemyelinating MHV strain, does not induce ON. Results reveal a reproducible virus-induced ON model important for the evaluation of …