Musculoskeletal Diseases Commons^™

Advancing Small Molecule Therapies For Myotonic Dystrophy Type 1, Sawyer M. Hicks

Electronic Theses & Dissertations (2024 - present)

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by the expression of expanded CUG (CUG^exp) repeat RNA from the myotonic dystrophy protein kinase (DMPK) gene. This CUG^exp repeat RNA’s gain-of-function mechanism leads to the sequestration of muscleblind-like (MBNL) proteins, resulting in widespread alternative splicing dysregulation across tissues. Despite significant research, there are currently no approved therapeutics targeting the underlying causes of DM1. This dissertation explores the development and optimization of a novel class of small molecules, Modified Polycyclic Compounds (MPCs), designed to address splicing dysregulation in DM1. MPCs were designed from previously published …

Healthcare Disparities Among Hypermobile Spectrum Disorder And Hypermobile Ehlers-Danlos Syndrome Patients, Brooke A. Martinez

Honors Undergraduate Theses

Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common subtype of rare connective tissue disorder called Ehlers-Danlos Syndrome (EDS). Hypermobile Spectrum Disorder (HSD) is a connective tissue disorder that presents itself similarly to hEDS. Both disorders primarily affect individuals assigned to females at birth (AFAB), and symptoms range from joint instability, musculoskeletal pain, dizziness, fatigue, depression, and anxiety. Due to many factors like lack of education or attitudes among medical professionals (MPs), receiving a diagnosis of either of these conditions can be a challenging and grueling journey for patients. An online survey was conducted and distributed over social media platforms to …

Factors Leading To Osteoporosis In Turner Syndrome, Daniella O. Aleshinloye

Honors Undergraduate Theses

Turner Syndrome (TS) is a chromosomal disorder from conception characterized by the partial or complete absence of the second X chromosome in females. Chromosomal abnormalities, both numerical and structural, contribute to a significantly higher prevalence of fractures (30.5-32.2%) compared to non-TS postmenopausal women (14.9%). This highlights the intrinsic bone abnormalities associated with TS and increased fracture risk. Peripheral quantitative computed tomography (pQCT) is commonly used to assess bone mineral density (BMD). However, its accuracy in individuals with TS is limited due to the partial volume effect, highlighting the need for further clinical research to understand bone density changes compared to …

Ergonomics Of Various Modalities For Ear Surgery, Matthew E Lin, Sheng Zhou, Seiji Kakeheta, Tsukasa Ito, Seiji B Shibata

Faculty, Staff and Student Publications

OBJECTIVE: Evaluate ergonomic differences of various modalities for performing middle ear surgery.

STUDY DESIGN: Observational study.

SETTING: Two academic tertiary care centers.

METHODS: Attending physicians and residents performing middle ear surgery were photographed intraoperatively. Intraoperative photographs were analyzed using the validated Rapid Upper Limb Assessment (RULA) tool to measure musculoskeletal disease (MSD) risk. Descriptive statistics and significance testing were used to characterize and compare ergonomic differences between surgical modalities. Multivariable ordinal regression was performed to assess factors associated with increased MSD risk, as determined by the final RULA score.

RESULTS: Most of our 110 intraoperative photos featured attendings (82.7%) performing …

A Suspected Case Of Levetiracetam Induced Rhabdomyolysis, Luke Merrill Ms, Layne Hohn Ms, Marlee Jones Ms, Sydney Gibson Ms, Ty Moody Md, Anthony Breemo Md

Aesculapius Journal (Health Sciences & Medicine)

Background: Levetiracetam is a broad-spectrum antiseizure drug which works to terminate convulsions and is used in the treatment of certain types of seizures. It is commonly used to treat epilepsy in adults, and has proven an effective treatment for adults with focal seizures. This drug is normally well tolerated, but commonly reported adverse effects include fatigue, somnolence, and dizziness. A few less common effects have been noted as well, including behavioral disturbances, thrombocytopenia, and—in very few cases—rhabdomyolysis.

Case Report: Our case reports a 55-year-old male who presented to a rural emergency department for active convulsing and unresponsiveness. Initial …

Amondys 45 (Casimersen), A Novel Antisense Phosphorodiamidate Morpholino Oligomer: Clinical Considerations For Treatment In Duchenne Muscular Dystrophy, Megan E. Vasterling, Rebecca J. Maitski, Brice A. Davis, Julie E. Barnes, Rucha A. Kelkar, Rachel J. Klapper, Hirni Patel, Shahab Ahmadzadeh, Sahar Shekoohi, Alan D. Kaye, Giustino Varrassi

School of Medicine Faculty Publications

AMONDYS 45 (casimersen) is an antisense oligonucleotide therapy used to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by a mutation in the DMD gene. Symptoms include progressive muscle weakness, respiratory and cardiac complications, and premature death. Casimersen targets a specific mutation in the DMD gene that results in the absence of dystrophin protein, a key structural component of muscle fibers. While there is currently no cure for DMD, exon-skipping therapy works by restoring the reading frame of the mutated gene, allowing the production of a partially functional dystrophin protein. Clinical trials of casimersen have shown promising results …

Case Report And Literature Review Of An Atypical Polymyalgia Rheumatica And Its Management, Saad Bilal Ahmed, Saara Ahmad, Hanmei Pan

Department of Biological & Biomedical Sciences

Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of the elderly population that increases in incidence as age advances. It is characterised by the sudden or sub-acute onset of symptoms affecting the shoulder and pelvic girdles, often accompanied by constitutional symptoms. Due to the lack of consensual diagnostic criteria and specific laboratory or radiological investigations for PMR, its diagnosis can be very challenging, particularly because it can be mimicked or masked by other geriatric syndromes. PMR responds well to glucocorticoid treatment, but if left untreated, can lead to morbidity and poor quality of life. We present the case of an …

Prevalence And Clinical Characteristics Of Temporomandibular Disorders In Adults: An Epidemiological Study In The Mediterranean Region Of Türkiye, Esra Yavuz, Selmi Yardimci, Humeyra Tercanli

Journal of Dentistry Indonesia

The prevalence and clinical characteristics of temporomandibular disorders (TMD) in the Mediterranean region of Türkiye have not yet been thoroughly investigated. Objective: This study aimed to determine the prevalence and severity of TMD in a sample of the population in this region and to characterize the clinical findings related to TMD. Methods: Four hundred and one participants were included in this study. “Presence of TMD” in the participants was evaluated using the Fonseca Anamnestic Index. Through clinical examination, the findings in the participants were classified as limited mouth opening, deviation, temporomandibular joint (TMJ) sounds, TMJ pain, and muscle …

Usp1 Expression Driven By Ews::Fli1 Dually Promotes Ewing Sarcoma Cell Survival By Mitigating The Replication Stress Response And Stabilizing Survivin, Halle Mallard

Theses & Dissertations

Ewing sarcoma (EWS) is a malignant pediatric bone cancer. EWS express a fusion oncogene resulting from the reciprocal translocation of EWSR1 an ETS transcription factor. In most EWS tumors, this occurs with FLI1, creating the EWS::FLI1 fusion oncogene which encodes an aberrant transcription factor. Independent of its transcriptional activity, EWS::FLI1 deregulates other cellular processes driving oncogenesis. For cases with a single, localized tumor, roughly 80% of patients remain event-free after five years. Disease dissemination is a problem – about 25% of patients have metastatic disease at diagnosis. Long-term survival for these patients is less than 40%. Presently, no second line …

Incidence Of Rapidly Progressive Osteoarthritis Following Intra-Articular Hip Corticosteroid Injection: A Systematic Review And Meta-Analysis, Franco M. Sabatini, Anna Cohen-Rosenblum, Travis B. Eason, Charles P. Hannon, Samuel D. Mounce, Chad A. Krueger, F Winston Gwathmey, Stephen T. Duncan, David C. Landy

School of Medicine Faculty Publications

BACKGROUND: The American Academy of Orthopedic Surgery recommends intra-articular corticosteroid injections (CSIs) for managing hip osteoarthritis (OA) based on short-term, prospective studies. Recent retrospective studies have raised concerns that CSIs may lead to rapidly progressive OA (RPOA). We sought to systematically review the literature of CSIs for hip OA to estimate the incidence of RPOA. METHODS: MEDLINE, Embase, and Cochrane Library were searched to identify original research of hip OA patients receiving CSIs. Overall, 27 articles involving 5831 patients published from 1988 to 2022 were included. Study design, patient characteristics, CSI details, follow-up, and cases of RPOA were recorded. Studies …

Is There Room For Individual Patient-Specified Preferences In The Patient-Reported Outcome Measurement Revolution?, Leif I. Solberg, Jeanette Y. Ziegenfuss, Rachael L. Rivard, Christine K. Norton, Robin R. Whitebird, Glyn Elwyn, Mark Swiontkowski

Journal of Patient-Centered Research and Reviews

Purpose: The study aim was to test the feasibility of collecting qualitative patient-preferred outcomes or goals and the degree of their attainment as an addition to a standardized process for collecting quantitative composite patient-reported outcome measures (PROMs) from patients undergoing knee joint replacement..

Methods: Patients of a large Midwestern medical group scheduled to have total replacement of their knee joint have been asked to complete a PROMs survey preoperatively and at 3 and 12 months after surgery since 2014. In March 2020, an open-ended question about their most important preferred outcome was added to the existing questionnaire. The responses for …

Cardiac Muscle-Restricted Partial Loss Of Nos1ap Expression Has Limited But Significant Impact On Electrocardiographic Features, Alexa Smith, Dallas Auer, Morgan Johnson, Ernesto Sanchez, Holly Ross, Christopher Ward, Aravinda Chakravarti, Ashish Kapoor

Faculty, Staff and Student Publications

Genome-wide association studies have identified sequence polymorphisms in a functional enhancer of the NOS1AP gene as the most common genetic regulator of QT interval and human cardiac NOS1AP gene expression in the general population. Functional studies based on in vitro overexpression in murine cardiomyocytes and ex vivo knockdown in zebrafish embryonic hearts, by us and others, have also demonstrated that NOS1AP expression levels can alter cellular electrophysiology. Here, to explore the role of NOS1AP in cardiac electrophysiology at an organismal level, we generated and characterized constitutive and heart muscle-restricted Nos1ap knockout mice to assess whether NOS1AP disruption alters the QT …

Ciprofloxacin-Induced Peripheral Neuropathy: A Case Report, Alexander Refaeian, Eric L. Vest, Michael Schmidt, Jorge D. Guerra, Mohd N. Refaei, Michael Refaeian, Ryan A. Floresca, Manouchehr Refaeian

HCA Healthcare Journal of Medicine

Introduction

Fluoroquinolones, a class of antibiotics, are commonly employed in the treatment of a wide array of bacterial infections. Recognized for their effectiveness against a broad spectrum of pathogens, fluoroquinolones have played a pivotal role in managing conditions like urinary tract infections and respiratory diseases. Nevertheless, their usage is not without contention due to their association with a variety of adverse effects, including tendon rupture and the less frequently reported issue of peripheral neuropathy.

Case Presentation

We present the case of a 42-year-old male who developed peripheral neuropathy several days after completing a 10-day course of ciprofloxacin for gastroenteritis. The …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Faculty, Staff and Student Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …

Garetosmab In Fibrodysplasia Ossificans Progressiva: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial, Maja Di Rocco, Eduardo Forleo-Neto, Robert J Pignolo, Richard Keen, Philippe Orcel, Thomas Funck-Brentano, Christian Roux, Sami Kolta, Annalisa Madeo, Judith S Bubbear, Jacek Tabarkiewicz, Małgorzata Szczepanek, Javier Bachiller-Corral, Angela M Cheung, Kathryn M Dahir, Esmée Botman, Pieter G Raijmakers, Mona Al Mukaddam, Lianne Tile, Cynthia Portal-Celhay, Neena Sarkar, Peijie Hou, Bret J Musser, Anita Boyapati, Kusha Mohammadi, Scott J Mellis, Andrew J Rankin, Aris N Economides, Dinko Gonzalez Trotter, Gary A Herman, Sarah J O'Meara, Richard Delgizzi, David M Weinreich, George D Yancopoulos, E Marelise W Eekhoff, Frederick S Kaplan

Faculty, Staff and Student Publications

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths …

Characterization Of Epithelial Growth Factor Transcripts Identified In Crotalus Atrox Venom, Ivan Lopez, Ying Jia

Research Symposium

Epithelial Growth Factor (EGF) is the primary source in regeneration and stimulation of essential fibroblasts cells commonly found in epithelium. Studies have shown that snake venom components are becoming a growing factor in treating illnesses such as cancer, muscular dystrophy, chronic pain, blood pressure, blood clotting, etc. EGF in human cells contains a promising quaternary structure that can bind to snake venom metalloproteinases, proposing a means of activating biochemical responses through protein-protein interactions to regulate unwanted cellular functions. This supports promising research in achieving a greater understanding of regulation along cellular pathways through ligands, increasing the likelihood of targeting unwanted …

Bad To The Bone. Not All Bone Tumors Are Cancer: Case Of Long Bone Osteomyelitis, Tat W. Yau, Bennet D. Franz, Hanadi A. Osman, Jessica C. Rivera, Ashaur Azhar

School of Medicine Faculty Publications

Long bone osteomyelitis could mimic bony tumor in clinical presentation and imaging studies. We present a case of a 47-year man who presented with leg pain, weight loss and night sweats that initially was thought to be related to osteosarcoma, later suffered a pathologic fracture from Staphylococcus aureus osteomyelitis. This case highlights the importance of source control of infection and careful clinical evaluation including radiographic and pathologic findings that can help physicians to differentiate between competing diagnoses.

Murine Models Of Graft Versus Host Disease (Gvhd): Focus On Ocular Gvhd, Philipp Steven, Victor L. Perez, Ajay Sharma

Pharmacy Faculty Articles and Research

Graft versus host disease (GVHD) remains a major and serious complication of allogeneic hematopoietic stem cell transplantation. Based on the time of onset, clinical phenotypes, progression kinetics, and pathophysiology, GVHD is stratified into acute, chronic, and overlapping types. The eyes are among the most commonly affected organs in GVHD. Mouse models have played an important role in understanding the several key elements of GVHD pathobiology. The current review discusses the immunology, pathology, and key phenotypic features of mouse models of systemic GVHD. Furthermore, a critical appraisal of mouse models of ocular GVHD (oGVHD) is provided. The disease mechanisms …

The Endosomal Escape Vehicle Platform Enhances Delivery Of Oligonucleotides In Preclinical Models Of Neuromuscular Disorders, Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian

Faculty, Staff and Student Publications

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of …