Medicine and Health Sciences Commons^™

In Translation V.1:No.2 (2010:Fall), Matthew J. Cook

UCHC Articles - Research

Momentum Continues: Newly Formed CICATS IRB The newly established CICATS Institutional ReviewBoard (IRB), chaired by Julian Ford, PhD, is officially operational. Applications are currently being accepted for review of CICATS research studies and trials. The first convened meeting was held on November 18, 2010.

Research Navigation There are two new members of CICATS available to you in your research investigator corner — the Regulatory Analyst and the Investigator Advocate.

The Gateway Stacey Anderson, Operations Manager The Gateway serves as the primary point of contact for researchers seeking assistance, referral, services and resources. This “nerve center” promotes collaborative clinical and translational …

Middle Cerebral Artery Occlusion Model In Rodents: Methods And Potential Pitfalls, Fudong Liu, Louise D. Mccullough

UCHC Articles - Research

A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of …

Egf Receptor Kinase Activity Is Required For Gap Junction Closure And For Part Of The Decrease In Ovarian Follicle Cgmp In Response To Luteinizing Hormone, Rachael P. Norris, Marina Freudzon, Viacheslav O. Nikolaev, Laurinda A. Jaffe

UCHC Articles - Research

The meiotic cell cycle in mouse oocytes is arrested in prophase, and then restarted when luteinizing hormone (LH) acts on the surrounding granulosa cells. The granulosa cells keep meiosis arrested by providing a source of cGMP that diffuses into the oocyte through gap junctions, and LH restarts the cell cycle by closing the junctions and by decreasing granulosa cell cGMP, thus lowering oocyte cGMP. Epidermal growth factor receptor (EGFR) activation is an essential step in triggering LH-induced meiotic resumption, but its relationship to the cGMP decrease in the follicle is incompletely understood, and its possible function in causing gap junction …

Mhc Class I And Tcr Avidity Control The Cd8 T Cell Response To Il-15/Il-15rα Complex, Thomas A. Stoklasek, Sara L. Colpitts, Henry M. Smilowitz, Leo Lefrançois

UCHC Articles - Research

IL-15 operates via a unique mechanism termed transpresentation. In this system, IL-15 produced by one cell type is bound to IL-15Rα expressed by the same cell and is presented to apposing cells expressing the IL-15Rβ/γC complex. We have shown that administering soluble IL-15Rα complexed with IL-15 can greatly enhance IL-15 activity. We now show that the naive CD8 T cell response to exogenous IL-15/IL-15Rα complex is MHC class I dependent. In the absence of β2 microglobulin, naive CD8 T cells scarcely proliferated in response to IL-15/IL-15Rα complex, whereas memory cells proliferated, although to a lesser extent, compared with levels in …

Erlotinib Added To Carboplatin And Paclitaxel As First-Line Treatment Of Ovarian Cancer: A Phase Ii Study Based On Surgical Reassessment, Carolyn D. Runowicz

UCHC Articles - Research

Background

The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC).

Methods

Patients with stage III-IV OFPC initiated treatment within 12 weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175 mg/m²) and carboplatin (AUC 6) every 3 weeks for up to 6 cycles, plus oral erlotinib 150 mg daily. The primary objective was to determine whether the pCR rate at reassessment …

The Decade Of The Dendritic Nmda Spike, Srdjan D. Antic, Wen-Liang Zho, Anna R. Moore, Shaina M. Shor, Katerina D. Ikonomu

UCHC Articles - Research

In the field of cortical cellular physiology, much effort has been invested in understanding thick apical drites of pyramidal neurons and the regenerative sodium and calcium spikes that take place in the apical trunk. Here we focus on thin dendrites of pyramidal cells (basal, oblique, and tuft dendrites), and we discuss one relatively novel form of an electrical signal (“NMDA spike”) that is specific for these branches. Basal, oblique, and apical tuft dendrites receive a high density of glutamatergic synaptic contacts. Synchronous activation of 10–50 neighboring glutamatergic synapses triggers a local dendritic regenerative potential, NMDA spike/plateau, which is characterized by …

Exposure To Potentially Traumatic Events In Early Childhood: Differential Links To Emergent Psychopathology, Margaret J. Briggs-Gowan, Julian D. Ford, Kimberly J. Mccarthy

UCHC Articles - Research

Objective To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. Method Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family violence and non-interpersonal events) and recent stressful life events were assessed with the Preschool Age Psychiatric Assessment (PAPA) and Child Life Events Scale. Child psychiatric symptoms and disorders were assessed with parent-reports in the PAPA, a comprehensive, developmentally sensitive interview. Sociodemographic risk, parental anxiety and depressive symptoms (Center for Epidemiologic …

Serum Fibrosis Markers Are Associated With Liver Disease Progression In Non-Responder Patients With Chronic Hepatitis C, Herbert L. Bonkovsky

UCHC Articles - Research

Abstract

OBJECTIVES

The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC)

DESIGN/SETTING

462 prior non-responders to peginterferon and ribavirin enrolled in the randomized phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), n-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1, and YKL-40.

OUTCOME MEASURES

All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 …

Conceptual And Methodological Issues Relevant To Cytokine And Inflammatory Marker Measurements In Clinical Research., Xin Zhoua, Maren S. Fragala, Janet E. Mcelhaney, George A. Kuchel

UCHC Articles - Research

PURPOSE OF REVIEW: To provide clinical investigators with an understanding of factors to consider when wishing to add cytokine and inflammatory marker measurements to their studies. RECENT FINDINGS: Inflammation involves complex and coordinated responses of the immune system to tissue damage. In the absence of tools to routinely assess inflammation within living tissues, measurements of humoral factors such as cytokines and other inflammatory mediators or markers can provide predictive clinical information and insights into disease mechanisms. Historically, enzyme-linked immunosorbent assays (ELISAs) became the gold standard, yet this approach of measuring a single protein in each sample limits the amount of …

A Detailed Mathematical Model Predicts Serial Engagement Of Ige-Fcεri Complexes Can Enhance Syk Activation In Mast Cells, Michael L. Blinov

UCHC Articles - Research

The term serial engagement was introduced to describe the ability of a single peptide, bound to a MHC molecule, to sequentially interact with TCRs within the contact region between a T cell and an APC. In addition to ligands on surfaces, soluble multivalent ligands can serially engage cell surface receptors with sites on the ligand, binding and dissociating from receptors many times before all ligand sites become free and the ligand leaves the surface. To evaluate the role of serial engagement in Syk activation, we use a detailed mathematical model of the initial signaling cascade that is triggered when FcepsilonRI …

The 6-Minute Walk Is Associated With Frailty And Predicts Mortality In Older Adults With Heart Failure, Alison Kleppinger, Amir Ahmad, Kristen M. Annis, W. David Hager, Anne M. Kenny

UCHC Articles - Research

Heart failure is the most rapidly increasing cardiovascular disease in the US and the primary discharge diagnosis for Medicare recipients. There are approximately 5.7 million people who have the diagnosis of HF in the US.¹ Heart failure constitutes the most common cause for re-hospitalization and has been identified by the Medicare Payment Advisory Commission as the highest cost to the healthcare system.^{2, 3} Hospitalizations of older patients can result in functional deterioration leading to dependency and disability.^{4, 5} Due to the unpredictable trajectory of heart failure exacerbations it is difficult to discern which patients are …

Effects Of Smoking Cessation On Body Composition In Postmenopausal Women, Alison Kleppinger, Mark D. Litt, Anne M. Kenny, Cheryl A. Oncken

UCHC Articles - Research

Abstract

Background

Smoking cessation is associated with weight gain, but the effects of smoking cessation on measures of body composition (BC) have not been adequately evaluated. The purpose of this study is to examine the effects of 16 months of cigarette abstinence on areas of BC measured by dual-energy x-ray absorptiometry (DXA).

Methods

One hundred fifty-two postmenopausal women participated in a smoking cessation study using the nicotine patch. Secondary analyses were conducted on data from 119 subjects (age 56±7 years, range 41–78 years) who had had DXA scans at baseline and 16 months later. Participants were classified either as quitters …

Crystal Structure Of The Gerbc Component Of A Bacillus Subtilis Spore Germinant Receptor, Yunfeng Li, Barbara Setlow, Peter Setlow, Bing Hao

UCHC Articles - Research

The nutrient germinant receptors (nGRs) of spores of Bacillus species are clusters of three proteins that play a critical role in triggering the germination of dormant spores in response to specific nutrient molecules. Here we report the crystal structure of the C protein of the GerB germinant receptor, so called GerBC, of Bacillus subtilis spores at 2.3 Å resolution. The GerBC protein adopts a previously uncharacterized type of protein fold consisting of three distinct domains, each of which is centered by a β sheet surrounded by multiple α helices. Secondary structure prediction and structure-based sequence alignment suggest that the GerBC …

Polymorphisms In The Macrophage Migration Inhibitory Factor Gene And Bone Loss In Postmenopausal Women, George A. Kuchel, Anne M. Kenny

UCHC Articles - Research

Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated …

Dental Hypotheses: Seeks To Publish Hypotheses From All Areas Of Dentistry, Edward F. Rossomando

UCHC Articles - Research

Starting a new open access journal in a rapid growing scientific panorama is a severe challenge. However, the first issue of dental hypotheses is now history and the even skeptics can appreciate that dental hypotheses is a success - it is a journal of high quality that provides an outlet for publication of articles that encourage readers to question dental paradigms. But dental hypotheses readers might have noticed that the majority of the articles published in the first issue of dental hypotheses concern clinical dentistry. However, dental hypotheses editors recognize that there are many other areas in dentistry that present …

In Translation, V.1:No.1 (2010:Summer), Matthew J. Cook

UCHC Articles - Research

Momentum is Strong. Thanks for taking time to learn about some of impressive accomplishments achieved recently by the Connecticut Institute for Clinical and Translational Science (CICATS.) With so much momentum, it’s hard to believe it’s been less than one year since CICATS held its formal launch last fall! True to its mission and goals, CICATS is making great strides to educate and nurture new scientists and increase the number of clinical and translational research projects in the greater Hartford area.

Oral Mucositis: The New Paradigms, Rajesh V. Lalla, Douglas E. Peterson

UCHC Articles - Research

Purpose of review

Mucositis has long been viewed as an unavoidable consequence of high-dose chemotherapy and/or radiation. Management has been directed to supportive care including oral pain control, nutritional support, infection treatment and control of diarrhea. While these interventions have been valuable for clinical management, they have not been collectively directed to molecularly targeted prevention and treatment. This review addresses recent advances regarding mucosal injury in cancer patients, with emphasis on symptom clusters, genetically-based tissue susceptibility and risk prediction, imaging technology, and computational biology.

Recent findings

Modeling of symptom clusters in cancer patients continues to mature. Although integration of mucositis …

Early Signals During Cd8+ T Cell Priming Regulate The Generation Of Central Memory Cells, Joshua J. Obar, Leo Lefrancois

UCHC Articles - Research

The CD8⁺ T cell response to infection is characterized by the appearance of short-lived (CD127^low killer cell lectin-like receptor G 1–high) and memory-precursor (CD127^high killer cell lectin-like receptor G 1–low) effector cells. How and when central-memory T (T_CM; CD62L^high CCR7⁺) cell and effector-memory T(T_EM; CD62L^low CCR7⁻) cell subsets are established remains unclear. We now show that the T_CM cell lineage represents an early developmental branchpoint during the CD8⁺ T cell response to infection. Central-memory CD8⁺ T cells could be identified prior to the peak …

Characterization Of Stem And Progenitor Cells In The Dental Pulp Of Erupted And Unerupted Murine Molars, Anamaria Balic, Hector L. Aguila, Melissa J. Caimano, Victor P. Francone, Mina Mina

UCHC Articles - Research

In the past few years there have been significant advances in the identification of putative stem cells also referred to as “mesenchymal stem cells” (MSC) in dental tissues including the dental pulp. It is thought that MSC in dental pulp share certain similarities with MSC isolated from other tissues. However, cells in dental pulp are still poorly characterized. This study focused on the characterization of progenitor and stem cells in dental pulps of erupted and unerupted mice molars. Our study showed that dental pulps from unerupted molars contain a significant number of cells expressing CD90+/CD45-, CD117+/CD45-, Sca-1+/CD45- and little if …

Effects Of Naltrexone Treatment For Alcohol-Related Disorders On Healthcare Costs In An Insured Population, Henry R. Kranzler

UCHC Articles - Research

Objective To determine the impact of treatment with oral naltrexone on healthcare costs in patients with alcohol-related disorders. Methods Using data from the MarketScan Commercial Claims and Encounters Database for 2000–2004, we identified a Naltrexone Group (with an alcohol-related diagnosis and at least one pharmacy claim for oral naltrexone) and two control groups. Alcohol Controls had an alcohol-related diagnosis and were not prescribed an alcoholism treatment medication. Non-Alcohol Controls had no alcohol-related diagnosis and no prescription for an alcoholism treatment medication. The control groups were matched three to one to the naltrexone group on demographic and other relevant measures. Healthcare …

Mitochondria-Centric Activation Induced Cell Death Of Cytolytic T Lymphocytes And Its Implications For Cancer Immunotherapy, Arvind Chhabra

UCHC Articles - Research

Premature death of the adoptively transferred cytolytic T lymphocytes (CTL) by means of activation induced cell death (AICD) represents one of the major constraints in devising an effective anti-cancer immune intervention strategy. Understanding the mechanism of AICD is, therefore, critical for developing methods to interfere with this death process. Although the existing paradigm on AICD centers around the initiation of the cascade of events originating from the engagement of death receptors leading to the activation of effector caspases and eventually resulting in cell death, recent findings have questioned the universal role of caspases as the cell death executioners. We here …

A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship, Grace Chan, Henry R. Kranzler

UCHC Articles - Research

Context

Although the prevalence of depression among medical interns substantially exceeds that of the general population, the specific factors responsible are not well understood. Recent reports of a moderating effect of a genetic polymorphism (5-HTTLPR) in the serotonin transporter protein gene on the likelihood that life stress will precipitate depression may help to understand the development of mood symptoms in medical interns.

Objective

To identify psychological, demographic and residency program factors that associate with depression among interns and use medical internship as a model to study the moderating effects of this polymorphism using a prospective, within-subject design that addresses the …

Progesterone Inhibits Apoptosis In Part By Pgrmc1-Regulated Gene Expression, John J. Peluso, Xiufang Liu, A Gawkowska, Valentina Lodde, Carol A. Wu

UCHC Articles - Research

Progesterone Receptor Membrane Component-1 (PGRMC1) is present in both the cytoplasm and nucleus of spontaneously immortalized granulosa cells (SIGCs). PGRMC1 is detected as a monomer in the cytoplasm and a DTT-resistant PGRMC1 dimer in the nucleus. Transfected PGRMC1-GFP localizes mainly to the cytoplasm and does not form a DTT-resistant dimer. Moreover, forced expression of PGRMC1-GFP increases the sensitivity of the SIGCs to progesterone (P4) 's anti-apoptotic action, indicating that the PGRMC1 monomer is functional. However, when endogenous PGRMC1 is depleted by siRNA treatment and replaced with PGRMC1-GFP, P4 responsiveness is not enhanced, although overall levels of PGRMC1 are increased. P4's …

The Core Circadian Gene Cryptochrome 2 Influences Breast Cancer Risk, Possibly By Mediating Hormone Signaling, Richard G. Stevens

UCHC Articles - Research

As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing, and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six SNPs in CRY2 were identified for genotyping in a case-control population (N=441 cases and N=479 controls), and three SNPs (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status (dominant model for …

Trpm7-Mediated Ca2+ Signals Confer Fibrogenesis In Human Atrial Fibrillation, Jianyang Du, Jia Xie, Zheng Zhang, Hiroto Tsujikawa, Daniel Fusco, David Silverman, Bruce Liang, Lixia Yue

UCHC Articles - Research

Rationale—Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown.
Objective—To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF.
Methods and Results—We demonstrate that the transient receptor potential melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human …

Welcome To Tomorrow, Edward F. Rossomando

UCHC Articles - Research

It is always a delight to see an idea become a reality. We recognized that there was a need for a dental journal for those to publish a tentative explanation for a phenomenon, an explanation that could be used as a basis for further investigation. Early in the planning, it was necessary to address the question: Is there a need for a journal for dental hypothesis? A detailed examination of dental journals now published revealed that most if not all published research findings - this research might be in various scientific disciplines or in education but all contained results of …

Should The Concentration Of Vitamin D Be Measured In All Patients With Hypertension?, Angela Boldo, Patrick Campbell, Pooja Luthra, William B. White

UCHC Articles - Research

With mounting evidence indicating the direct effect of vitamin D on the vascular smooth muscle cell, endothelial function and the renin-angiotensin-aldosterone system, it is clear that randomized trials of vitamin D replacement and renin and angiotensin inhibition in patients with hypertension and vitamin D deficiency are warranted. Preliminary research has shown an inverse relationship between BP and vitamin D levels, and supplementation appears promising. To that end, we have just initiated a randomized clinical trial evaluating the effects of vitamin D and/or a renin inhibitor on ambulatory and clinic BP in vitamin D deficient patients with hypertension (clinical trials.gov identifier …

Genetic Influences On The Dynamics Of Pain And Affect In Fibromyalgia, Howard A. Tennen, Jonathan Covault

UCHC Articles - Research

Objective The purpose of the present investigation was to determine if variation in the catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes is associated with pain-related positive affective regulation in fibromyalgia (FM). Design Forty-six female FM patients completed an electronic diary that included daily assessments of positive affect and pain. Between- and within-person analyses were conducted with multilevel modeling. Main Outcome Measure Daily positive affect was the primary outcome measure. Results Analyses revealed a significant gene × experience interaction for COMT, such that individuals with met/met genotype experienced a greater decline in positive affect on days …

Feasibility Of Using Interactive Voice Response To Monitor Daily Drinking, Moods And Relationship Processes On A Daily Basis In Alcoholic Couples, Howard A. Tennen

UCHC Articles - Research

Background

Daily process research on alcohol involvement has used paper-and-pencil and electronic data collection methods, but no studies have yet tested the feasibility of using Interactive Voice Response (IVR) technology to monitor drinking, affective, and social interactional processes among alcoholic (ALC) couples. This study tested the feasibility of using IVR with n=54 ALC couples.

Methods

Participants were n=54 couples (probands who met criteria for a past one-year alcohol use disorder and their partners) recruited from a substance abuse treatment center and the local community. Probands and their partners reported on their daily drinking, marital interactions, and moods once a day …

Inhibitory Role Of Sphingosine 1-Phosphate Receptor 2 In Macrophage Recruitment During Inflammation, Jason Michaud, Timothy Hla, Dong-Soon Im

UCHC Articles - Research

Macrophage recruitment to sites of inflammation is an essential step in host defense. However, the mechanisms preventing excessive accumulation of macrophages remain relatively unknown. The lysophospholipid sphingosine 1-phosphate (S1P) promotes T and B cell egress from lymphoid organs by acting on S1P receptor 1 (S1P₁R). More recently, S1P₅R was shown to regulate NK cell mobilization during inflammation, raising the possibility that S1P regulates the trafficking of other leukocyte lineages. In this study, we show that S1P₂R inhibits macrophage migration in vitro and that S1P₂R-deficient mice have enhanced macrophage recruitment during thioglycollate peritonitis. …