Medicine and Health Sciences Commons^™

Dementia Risk Reduction: Why Haven't The Pharmacological Risk Reduction Trials Worked? An In-Depth Exploration Of Seven Established Risk Factors, Ruth Peters, John Breitner, Sarah James, Gregory A. Jicha, Pierre-Francois Meyer, Marcus Richards, A. David Smith, Hussein N. Yassine, Erin L. Abner, Atticus H. Hainsworth, Patrick G. Kehoe, Nigel Beckett, Christopher Weber, Craig Anderson, Kaarin J. Anstey, Hiroko H. Dodge

Neurology Faculty Publications

Identifying the leading health and lifestyle factors for the risk of incident dementia and Alzheimer's disease has yet to translate to risk reduction. To understand why, we examined the discrepancies between observational and clinical trial evidence for seven modifiable risk factors: type 2 diabetes, dyslipidemia, hypertension, estrogens, inflammation, omega-3 fatty acids, and hyperhomocysteinemia. Sample heterogeneity and paucity of intervention details (dose, timing, formulation) were common themes. Epidemiological evidence is more mature for some interventions (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) than others. Trial data are promising for anti-hypertensives and B vitamin supplementation. Taken together, these risk factors highlight a future need …

The Role Of Decorin And Biglycan Signaling In Tumorigenesis, Valentina Diehl, Lisa Sophie Huber, Jonel Trebicka, Malgorzata Wygrecka, Renato V. Iozzo, Liliana Schaefer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer …

Β2 Integrin Cd11d/Cd18: From Expression To An Emerging Role In Staged Leukocyte Migration, Eoin N. Blythe, Lynne C. Weaver, Arthur Brown, Gregory A. Dekaban

Paediatrics Publications

CD11d/CD18 is the most recently discovered and least understood β2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration – two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under …

Proteinase 3 Contributes To Endothelial Dysfunction In An Experimental Model Of Sepsis, Eric K. Patterson, Carolina Gillio-Meina, Claudio M. Martin, Douglas D. Fraser, Logan R. Van Nynatten, Marat Slessarev, Gediminas Cepinskas

Paediatrics Publications

In sepsis-induced inflammation, polymorphonuclear neutrophils (PMNs) contribute to vascular dysfunction. The serine proteases proteinase 3 (PR3) and human leukocyte elastase (HLE) are abundant in PMNs and are released upon degranulation. While HLE’s role in inflammation-induced endothelial dysfunction is well studied, PR3’s role is largely uninvestigated. We hypothesized that PR3, similarly to HLE, contributes to vascular barrier dysfunction in sepsis. Plasma PR3 and HLE concentrations and their leukocyte mRNA levels were measured by ELISA and qPCR, respectively, in sepsis patients and controls. Exogenous PR3 or HLE was applied to human umbilical vein endothelial cells (HUVECs) and HUVEC dysfunction was assessed by …

Allografts For Skin Closure During In Utero Spina Bifida Repair In A Sheep Model, Lovepreet K Mann, Jong Hak Won, Rajan Patel, Eric P Bergh, Jeannine Garnett, Meenakshi B Bhattacharjee, Ponnada A Narayana, Ranu Jain, Stephen A Fletcher, Dejian Lai, Ramesha Papanna

Student and Faculty Publications

OBJECTIVES: Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function.

METHODS: In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). …

Aberrantly Low Stat3 And Stat5 Responses Are Associated With Poor Outcome And An Inflammatory Gene Expression Signature In Pediatric Acute Myeloid Leukemia., P Narayanan, T-K Man, R B Gerbing, R Ries, A M Stevens, Y-C Wang, X Long, A S. Gamis, T Cooper, S Meshinchi, T A Alonzo, M S Redell

Manuscripts, Articles, Book Chapters and Other Papers

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low …

Dark Side Of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, And Immune Modulation, Boopathi Ettickan, Chellappagounder Thangavel

Department of Dermatology and Cutaneous Biology Faculty Papers

Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex …

Long-Term Treatment With Senolytic Drugs Dasatinib And Quercetin Ameliorates Age-Dependent Intervertebral Disc Degeneration In Mice, Emanuel J Novais, Victoria Tran, Shira N Johnston, Kayla R Darris, Alex J Roupas, Garrett A Sessions, Irving Shapiro, Brian O Diekman, Makarand V Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, …

Intravesical Cd74 And Cxcr4, Macrophage Migration Inhibitory Factor (Mif) Receptors, Mediate Bladder Pain, Shaojing Ye, Fei Ma, Dlovan F. D. Mahmood, Katherine L. Meyer-Siegler, Raymond E. Menard, David E. Hunt, Lin Leng, Richard Bucala, Pedro L. Vera

Physiology Faculty Publications

BACKGROUND: Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo.

METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary …

A Distinct Difference Between Air And Mucosal Temperatures In Human Respiratory Tract, Mehdi Khosravi, Ruei-Lung Lin, Ashish P. Maskey, Subodh Pandey, An-Hsuan Lin, Lu-Yuan Lee

Internal Medicine Faculty Publications

xtensive evidence indicates that several types of temperature-sensitive ion channels are abundantly expressed in the sensory nerves innervating airway mucosa. Indeed, airway temperature is known to play an important role in regulating respiratory functions. However, the actual airway mucosal temperature and its dynamic changes during the respiratory cycle have not been directly measured. In previous studies, airway tissue temperature was often estimated by indirect measurement of the peak exhaled breath temperature (PEBT). In view of the poor thermal conductivity of air, we believe that the airway tissue temperature cannot be accurately determined by the exhaled air temperature, and this study …

Role Of Interferon Gamma Release Assay In The Diagnosis And Management Of Mycobacterium Tuberculosis-Associated Uveitis: A Review, Samra Rahman, Muhammad Irfan, Rehman Siddiqui

Section of Pulmonary & Critical Care

Tuberculosis (TB)-associated uveitis is a common cause of infectious uveitis in the developing world. Diagnosis of TB uveitis remains a challenge. The role of interferon gamma release assays (IGRAs) is uncertain. Herein we summarise the available literature on the utility of IGRAs in the diagnosis and management of TB uveitis. We searched PubMed database from 1 August 2010 to 31 July 2020 using the following keywords alone and in combination: 'interferon-gamma release assay', 'QuantiFERON', 'T-SPOT.TB', 'TB uveitis', 'serpiginous like choroiditis', 'tuberculoma', 'TB vasculitis', 'TB panuveitis' and 'ocular tuberculosis'. Data from 58 relevant studies were collated. The review is focused on …

Upregulation Of Inflammatory Cytokines In Pulmonary Embolism Using Biochip-Array Profiling., Emily Bontekoe, Yevgeniy Brailovsky, Debra Hoppensteadt, Jack Bontekoe, Fakiha Siddiqui, Joshua Newman, Omer Iqbal, Trent Reed, Jawed Fareed, Amir Darki

Department of Medicine Faculty Papers

The complex pathophysiology of pulmonary embolism (PE) involves hemostatic activation, inflammatory processes, cellular dysfunction, and hemodynamic derangements. Due to the heterogeneity of this disease, risk stratification and diagnosis remains challenging. Biochip-array technology provides an integrated high throughput method for analyzing blood plasma samples for the simultaneous measurement of multiple biomarkers for potential risk stratification. Using biochip-array method, this study aimed to quantify the inflammatory biomarkers such as interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and epidermal growth factor (EGF) in 109 clinically …

Prolonged Activated Partial Thromboplastin Time Secondary To Factor Xii Deficiency In Two Surgical Patients, Bushra Moiz, Muhammed Wahhaab Sadiq, Muhammad Abdullah Javed, Baqir Hasan Jafry, Muhammad Anees

Section of Haematology/Oncology

Factor XII (FXII) plays a pivotal role in hemostasis, inflammation and complement system. Its deficiency is usually an incidental finding in an otherwise asymptomatic patient who is identified during his/her routine preoperative blood work. This study aimed in evaluating the clinical course of the surgical patients having FXII deficiency. Information regarding demographics, laboratory tests and management of patients was obtained through medical chart and in-house integrated laboratory management system whereas the medical literature was searched through PubMed®. During the study period, two patients were consulted for FXII deficiency prior to the various surgical procedures. Both patients had uneventful surgeries without …

Cardiac Cell Therapy: Insights Into The Mechanisms Of Tissue Repair, Hsuan Peng, Kazuhiro Shindo, Renée R. Donahue, Ahmed K. Abdel-Latif

Gill Heart & Vascular Institute Faculty Publications

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

Shear Stress Associated With Cardiopulmonary Bypass Induces Expression Of Inflammatory Cytokines And Necroptosis In Monocytes., Lan N. Tu, Lance Hsieh, Masaki Kajimoto, Kevin Charette, Nataliya Kibiryeva, Adriana Forero, Sarah Hampson, Jennifer A. Marshall, James O'Brien, Marta Scatena, Michael A. Portman, Ram Savan, Chris Benner, Alberto Aliseda, Muhammad Nuri, Douglas Bittel, Peter Pastuzsko, Vishal Nigam

Manuscripts, Articles, Book Chapters and Other Papers

Cardiopulmonary bypass (CPB) is required during most cardiac surgeries. CBP drives systemic inflammation and multiorgan dysfunction that is especially severe in neonatal patients. Limited understanding of molecular mechanisms underlying CPB-associated inflammation presents a significant barrier to improve clinical outcomes. To better understand these clinical issues, we performed mRNA sequencing on total circulating leukocytes from neonatal patients undergoing CPB. Our data identify myeloid cells, particularly monocytes, as the major cell type driving transcriptional responses to CPB. Furthermore, IL-8 and TNF-α were inflammatory cytokines robustly upregulated in leukocytes from both patients and piglets exposed to CPB. To delineate the molecular mechanism, we …

The Effect Of Age On Neurological Inflammation To Acute Sleep Fragmentation In Mice, Molly Taylor

Mahurin Honors College Capstone Experience/Thesis Projects

Obstructive sleep apnea is identified by recurring events of airway collapse during sleep, intermittent hypoxia, and perturbations in sleep continuity, known as sleep fragmentation. There is evidence to suggest that elderly patients are more at risk of developing obstructive sleep apnea. The purpose of this study was to assess whether age affects neurological inflammatory responses to acute sleep fragmentation. This assessment was made by subjecting young (4-5 months old) and old (10-11 months old) male C57BL/6j mice to automated sleep fragmentation, as well as having mice in both age categories as a control with no sleep fragmentation, for twenty-four hours. …

Study Design And Baseline Characteristics Of The Cardinal Trial: A Phase 3 Study Of Bardoxolone Methyl In Patients With Alport Syndrome., Glenn M. Chertow, Gerald B. Appel, Sharon Andreoli, Sripal Bangalore, Geoffrey A. Block, Arlene B. Chapman, Melanie P. Chin, Keisha L. Gibson, Angie Goldsberry, Kazumoto Iijima, Lesley A. Inker, Bertrand Knebelmann, Laura H. Mariani, Colin J. Meyer, Kandai Nozu, Megan O'Grady, Arnold L. Silva, Peter Stenvinkel, Roser Torra, Bradley A. Warady, Pablo E. Pergola

Manuscripts, Articles, Book Chapters and Other Papers

INTRODUCTION: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome.

METHODS: The CARDINAL phase 3 study is an international, …

A Structured Approach To Skin And Soft Tissue Infections (Sstis) In An Ambulatory Setting, Benjamin Silverberg

Faculty & Staff Scholarship

The skin is the largest, and arguably, the most vulnerable organ in the human body. Scratches and scrapes, bites and puncture wounds, impetigo and erysipelas—all these disruptions can lead to pain, swelling, and/or systemic symptoms. In this article, which is based on the Infectious Diseases Society of America’s 2014 guidelines and the World Society of Emergency Surgery and Surgical Infection Society of Europe’s 2018 consensus statement, a structured approach to skin and soft tissue infections (SSTIs) is reviewed, comparing treatment for suppurative and non-suppurative infections, and then discussing specific conditions commonly seen in Primary Care and Urgent Care facilities.