Medicine and Health Sciences Commons^™

Identification Of Experimentally Induced Colitis By In Vitro Nuclear Magnetic Resonance., R H Rolandelli, S H Saul, R G Settle, D O Jacobs, Raymond Singer, G L Wolf, J L Rombeau

Raymond L Singer MD

The present study determined whether in vitro nuclear magnetic resonance could be used to assess experimentally induced colitis in rats. Acute colitis was induced in 6 Sprague-Dawley rats by acetic acid enema, while 6 control animals received saline enemas. All animals were sacrificed 24 hours post-enema, and NMR relaxation times, T1 and T2, of colonic samples were determined on a 10 MHz spin analyzer (RADX, Houston, TX). Colonic water content was determined on the same samples by desiccation. Colitis animals showed significantly higher T1 and T2 relaxation times and tissue water content than controls. T1 and T2 times correlated significantly …

Innovative Techniques In Preventing And Salvaging Neurovascular Pedicle Flaps In Reconstructive Foot And Ankle Surgery., Thomas Zgonis, John Stapleton

John J Stapleton DPM, FACFAS

Pedicle flaps to cover soft tissue defects of the foot, ankle, and lower extremity are invaluable. However, venous congestion and flap necrosis, a common complication, poses greater morbidity to the patient as few remaining options for attempted limb salvage remain. The authors discuss how to prevent flap failure by allowing close observation and strict offloading of the pedicle flap through current external fixation designs. This article also discusses the role of medicinal leeches in reestablishing blood flow through the pedicle flap to prevent tissue necrosis. In addition, the use of hydrosurgery as an innovative technique offers the surgeon another option …

Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation Of The Mitochondrial Ca2+ Uniporter., Jin O-Uchi, Bong Sook Jhun, Shangcheng Xu, Stephen Hurst, Anna Raffaello, Xiaoyun Liu, Bing Yi, Huiliang Zhang, Polina Gross, Jyotsna Mishra, Alina Ainbinder, Sarah Kettlewell, Godfrey L Smith, Robert T Dirksen, Wang Wang, Rosario Rizzuto, Shey-Shing Sheu

Department of Medicine Faculty Papers

AIMS: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells.

RESULTS: α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine …

Mitochondrial Ion Channels/Transporters As Sensors And Regulators Of Cellular Redox Signaling., Jin O-Uchi, Shin-Young Ryu, Bong Sook Jhun, Stephen Hurst, Shey-Shing Sheu

Department of Medicine Faculty Papers

SIGNIFICANCE: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently.

RECENT ADVANCES: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca2+ uniporter pore, …

Breach Of Tolerance: Primary Biliary Cirrhosis., Lifeng Wang, Fu-Sheng Wang, Christopher Chang, M Eric Gershwin

Department of Medical Genetics Faculty Papers

In primary biliary cirrhosis (PBC), the breach of tolerance that leads to active disease involves a disruption in several layers of control, including central tolerance, peripheral anergy, a "liver tolerance effect," and the action of T regulatory cells and their related cytokines. Each of these control mechanisms plays a role in preventing an immune response against self, but all of them act in concert to generate effective protection against autoimmunity without compromising the ability of the host immune system to mount an effective response to pathogens. At the same time, genetic susceptibility, environmental factors, including infection agents and xenobiotics, play …

Overexpression Of The Astrocyte Glutamate Transporter Glt1 Exacerbates Phrenic Motor Neuron Degeneration, Diaphragm Compromise, And Forelimb Motor Dysfunction Following Cervical Contusion Spinal Cord Injury., Ke Li, Charles Nicaise, Daniel Sannie, Tamara J Hala, Elham Javed, Jessica L Parker, Rajarshi Putatunda, Kathleen A Regan, Valérie Suain, Jean-Pierre Brion, Fred Rhoderick, Megan C Wright, David J Poulsen, Angelo C Lepore

Farber Institute for Neuroscience Faculty Papers

A major portion of spinal cord injury (SCI) cases affect midcervical levels, the location of the phrenic motor neuron (PhMN) pool that innervates the diaphragm. While initial trauma is uncontrollable, a valuable opportunity exists in the hours to days following SCI for preventing PhMN loss and consequent respiratory dysfunction that occurs during secondary degeneration. One of the primary causes of secondary injury is excitotoxic cell death due to dysregulation of extracellular glutamate homeostasis. GLT1, mainly expressed by astrocytes, is responsible for the vast majority of functional uptake of extracellular glutamate in the CNS, particularly in spinal cord. We found that, …

Necrostatin-1 Analogues: Critical Issues On The Specificity, Activity And In Vivo Use In Experimental Disease Models., N Takahashi, L Duprez, S Grootjans, A Cauwels, W Nerinckx, J B Duhadaway, V Goossens, R Roelandt, F Van Hauwermeiren, C Libert, W Declercq, N Callewaert, G C Prendergast, A Degterev, J Yuan, P Vandenabeele

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × …

Quantifying The Cdk Inhibitor Vmy-1-103'S Activity And Tissue Levels In An In Vivo Tumor Model By Lc-Ms/Ms And By Mri., Paul Sirajuddin, Sudeep Das, Lymor Ringer, Olga C Rodriguez, Angiela Sivakumar, Yi-Chien Lee, Aykut Üren, Stanley T Fricke, Brian Rood, Alpay Ozcan, Sean S Wang, Sana Karam, Venkata Yenugonda, Patricia Salinas, Emanuel Petricoin, Michael Pishvaian, Michael P Lisanti, Yue Wang, Richard Schlegel, Bahram Moasser, Chris Albanese

Kimmel Cancer Center Faculty Papers

The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with …

Perspectives On: Sgp Symposium On Mitochondrial Physiology And Medicine: Mitochondria Take Center Stage., Shey-Shing Sheu, Robert T Dirksen, Edward N Pugh

Center for Translational Medicine Faculty Papers

No abstract provided.

Dyschronic, A Drosophila Homolog Of A Deaf-Blindness Gene, Regulates Circadian Output And Slowpoke Channels., James E C Jepson, Mohammad Shahidullah, Angelique Lamaze, Drew Peterson, Huihui Pan, Kyunghee Koh

Farber Institute for Neuroscience Faculty Papers

Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward-genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause …

Loss Of Αt-Catenin Alters The Hybrid Adhering Junctions In The Heart And Leads To Dilated Cardiomyopathy And Ventricular Arrhythmia Following Acute Ischemia., Jifen Li, Steven Goossens, Jolanda Van Hengel, Erhe Gao, Lan Cheng, Koen Tyberghein, Xiying Shang, Riet De Rycke, Frans Van Roy, Glenn L Radice

Center for Translational Medicine Faculty Papers

It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a 'hybrid adhering junction' or 'area composita'. The α-catenin family member αT-catenin, part of the N-cadherin-catenin adhesion complex in the heart, is the only α-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that αT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. …

Prefabrication Of A Secondary Tram Flap., Geoffrey G. Hallock Md

Department of Surgery

A secondary TRAM flap was prefabricated in a rat model using the rectus muscle. The right rectus muscle was elevated as an inferiorly pedicled muscle flap in one experimental group (n = 6) and as a superiorly pedicled muscle flap in a second group (n = 5) and then sandwiched between a silicone sheet and the abdominal skin. Two weeks later, the abdominal skin and attached rectus muscle were elevated over the silicone sheet as a secondary TRAM flap. The surviving skin paddle areas of these prefabricated TRAM flaps were compared with superiorly (n = 7) and inferiorly (n = …

The Rat Tram Flap: A Human Analogue?, Geoffrey G. Hallock Md

Department of Surgery

No abstract provided.