Medicine and Health Sciences Commons^™

Ideology Masquerading As Science: The Case Of Endocrine Disrupter Screening Programmes, Troy Seidle

Troy Seidle, PhD

The global move to develop novel testing methods and strategies to identify suspected endocrine disrupting chemicals offers a unique opportunity to move away from traditional animal testing paradigms in this new area of regulatory concern. Regrettably, the programmes under development, both in the USA and internationally through the OECD, have thus far failed to consider in vitro and other nonanimal test methods as more than “pre-screening” or “priority-setting” tools in a larger, animal-based testing strategy. Validation efforts to date have focused almost exclusively on the modification of existing animal tests to detect “endocrine effects”, with no demonstrable effort to promote …

Dual Engagement Of The Nlrp3 And Aim2 Inflammasomes By Plasmodium-Derived Hemozoin And Dna During Malaria, Parisa Kalantari, Rosane B. Deoliveira, Jennie Chan, Yolanda Corbett, Vijay A. K. Rathinam, Andrea Stutz, Eicke Latz, Ricardo T. Gazzinelli, Douglas T. Golenbock, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and …

Malaria-Induced Nlrp12/Nlrp3-Dependent Caspase-1 Activation Mediates Inflammation And Hypersensitivity To Bacterial Superinfection, Marco A. Ataide, Warrison A. Andrade, Dario S. Zamboni, Donghai Wang, Maria Do Carmo Souza, Bernardo S. Franklin, Samir Elian, Flaviano S. Martins, Dhelio Pereira, George W. Reed, Katherine A. Fitzgerald, Douglas T. Golenbock, Ricardo T. Gazzinelli

Katherine A. Fitzgerald

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1beta. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-gamma-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1beta expression required a second stimulation with LPS and was also dependent on IFN-gamma-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1beta upon a second …

Increased Risk For Vitamin D Deficiency In Obese Children With Both Celiac Disease And Type 1 Diabetes, Nithya Setty-Shah, Louise S. Maranda, Benjamin U. Nwosu

Benjamin U. Nwosu

Background. It is unknown whether the coexistence of type 1 diabetes (T1D) and celiac disease (CD) increases the risk for vitamin D deficiency.

Aims. To determine the vitamin D status and the risk for vitamin D deficiency in prepubertal children with both T1D and CD compared to controls, TID, and CD.

Subjects and Methods. Characteristics of 62 prepubertal children of age 2–13 y with either CD + T1D (� = 22, 9.9 ± 3.1 y), CD only (� = 18, 8.9 ± 3.3 y), or T1D only (� = 22, 10.1 ± 2.8 y) were compared to 49 controls of …

Health Professionals’ Roles In Animal Agriculture, Climate Change, And Human Health, Aysha Z. Akhtar, Michael Greger, Hope Ferdowsian, Erica Frank

Michael Greger, MD, FACLM

What we eat is rapidly becoming an issue of global concern. With food shortages, the rise in chronic disease, and global warming, the impact of our dietary choices seems more relevant today than ever. Globally, a transition is taking place toward greater consumption of foods of animal origin, in lieu of plantbased diets. With this transition comes intensification of animal agriculture that in turn is associated with the emergence of zoonotic infectious diseases, environmental degradation, and the epidemics of chronic disease and obesity. Health professionals should be aware of these trends and consider them as they promote healthier and more …

The Validity Of Animal Experiments In Medical Research, Gill Langley

Gill Langley, PhD

Other animals, such as mice, rats, rabbits, dogs and monkeys, are widely used as surrogates for humans in fundamental medical research. This involves creating disorders in animals by chemical, surgical or genetic means, with the aim of mimicking selected aspects of human illnesses. It is a truism that any model or surrogate is not identical to the target being modelled. So, in medical research, experiments using animals or cell cultures or even healthy volunteers instead of patients (being the target population with the target illness) will inevitably have limitations, although these will be greater or lesser depending on the model.

Missed Opportunities In Hpv Vaccination, B. Dale Magee, Autumn S. Davidson, Leslie Regh

B. Dale Magee

Objective: To use the 3 dose Human Papillomavirus (HPV) vaccine administration (given at 0, 1-2 and 6 months) to quantify opportunities to improve efficacy in the delivery of preventive health services. Methods: This was a retrospective, claims-based analysis using data provided by a single managed care plan. Female patients aged 9-26 who were continuously enrolled between 2009 through 2011 and received ≥ dose of the HPV vaccine during 2010 were analyzed. The proportion of initiators who did and did not completed the vaccine series, the timing and location of doses, and the number of outpatient visits during which the vaccine …

F1000research: Tics Welcomes You To 21st Century Biomedical Publishing [V1; Ref Status: Not Peer Reviewed, Http://F1000r.Es/4o1], Kevin J. Black

Kevin J. Black, MD

Tics are repeated, usually suppressible movements or vocalizations. They are the defining features of tic disorders including Tourette syndrome, but many people have them for shorter durations at some point in childhood. This editorial marks the beginning of the F1000Research: Tics specialty section, an effort to provide a single portal to modern research on tics and tic disorders. Publications in F1000Research: Tics benefit from F1000Research’s novel approach to publishing, in which articles can be published within days of submission. Peer review happens after publication and is fully open. When the submitted article or a revision is approved, it is promptly …

Rare Case Of Klinefelters Syndrome With 48xxyy, Vasudev G. Magaji Md, Ms, Deborah Feden Crnp, Gretchen Perilli Md

Vasudev G Magaji MD, MS

No abstract provided.

Imp3 Expression Is Associated With Poor Outcome And Epigenetic Deregulation In Intrahepatic Cholangiocarcinoma, Yuanyuan Gao, Michelle Yang, Zhong Jiang, Bruce A. Woda, Arthur M. Mercurio, Jianjie Qin, Xinli Huang, Feng Zhang

Arthur M. Mercurio

IMP3 is a fetal protein not expressed in normal adult tissues. IMP3 is an oncoprotein and a useful biomarker for a variety of malignancies and is associated with reduced overall survival of a number of them. IMP3 expression and its prognostic value for patients with intrahepatic cholangiocarcinoma (ICC) have not been well investigated. The molecular mechanism underlying IMP3 expression in human cancer cells remains to be elucidated. Here we investigated IMP3 expression in ICC and adjacent nonneoplastic liver in 72 unifocal primary ICCs from a single institute by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction. IMP3 was specifically expressed in …

Regulated Splicing Of The Alpha6 Integrin Cytoplasmic Domain Determines The Fate Of Breast Cancer Stem Cells, Hira Lal Goel, Tatiana Gritsko, Bryan Pursell, Cheng Chang, Leonard D. Shultz, Dale L. Greiner, Jens Henrik Norum, Rune Toftgard, Leslie M. Shaw, Arthur M. Mercurio

Arthur M. Mercurio

Although the alpha6beta1 integrin has been implicated in the function of breast and other cancer stem cells (CSCs), little is known about its regulation and relationship to mechanisms involved in the genesis of CSCs. We report that a CD44(high)/CD24(low) population, enriched for CSCs, is comprised of distinct epithelial and mesenchymal populations that differ in expression of the two alpha6 cytoplasmic domain splice variants: alpha6A and alpha6B. alpha6Bbeta1 expression defines the mesenchymal population and is necessary for CSC function, a function that cannot be executed by alpha6A integrins. The generation of alpha6Bbeta1 is tightly controlled and occurs as a consequence of …

A Pilot Study Of Basal Ganglia And Thalamus Structure By High Dimensional Mapping In Children With Tourette Syndrome, Alton C. Williams, Marie E. Mcneely, Deanna J. Greene, Jessica A. Church, Stacie L. Warren, Johanna M. Hartlein, Bradley L. Schlaggar, Kevin J. Black, Lei Wang

Kevin J. Black, MD

No abstract provided.

Trends And Characteristics Associated With The Risk Of Re-Hospitalization In Patients Discharged From The Hospital After Acute Myocardial Infarction, Mayra Tisminetzky, Han-Yang Chen, Edgard A. Granillo, Joel M. Gore, Jorge L. Yarzebski, Darleen M. Lessard, Robert J. Goldberg

Jorge L. Yarzebski

BACKGROUND: Despite encouraging declines in short-term mortality in patients hospitalized with acute myocardial infarction (AMI), repeat hospitalizations among those discharged from the hospital after AMI remain a major clinical and public health concern. Few studies, however, have described the relatively contemporary magnitude, factors associated with, as well as decade long trends in repeat hospitalizations for cardiovascular disease (CVD) and other causes in patients discharged from the hospital after AMI. METHODS: We reviewed the medical records of 6,018 residents of the Worcester (MA) metropolitan area who were hospitalized for AMI in 6 biennial periods between 1999 and 2009. Re-hospitalizations for any …

Keynote Speaker Presentations: 5th Annual Umass Center For Clinical And Translational Research Retreat (Video), Robert H. Brown Jr., Thomas Grisso

Thomas Grisso

This video features the full keynote presentations from the 5th Annual UMass Center for Clinical and Translational Science Research Retreat at the University of Massachusetts Medical School (UMMS) in Worcester, MA, on May 20, 2014.

Beginning at 12:40

1st Keynote Speaker: Robert H. Brown, Jr., MD, D.Phil, Chair, Department of Neurology, UMMS. “Lou Gehrig Disease: From Mapping to Medicines”

Beginning at 1:22:19

2nd Keynote Speaker: Thomas Grisso, PhD, Director, Law and Psychiatry Program and Professor, Department of Psychiatry, UMMS. Recipient, Chancellor’s Medal for Distinguished Scholarship. “Translational Research in Law and Psychiatry”

Also included is a brief introductory presentation with updates …

Does Functional Gain And Pain Relief After Tkr And Thr Differ By Patient Obese Status?, Wenjun Li, Jeffrey Lange, Leslie R. Harrold, Jeroan J. Allison, Courtland Lewis, Thomas Bowen, David C. Ayers, Patricia D. Franklin

Jeroan J. Allison

Introduction: Obesity is an important predictor of functional status and pain after total knee (TKR) and total hip (THR) replacement. However, variations in pre-post TKR and THR changes in function and pain by obesity status remain to be examined.

Material & Methods: Pre- and 6 month post surgery data were collected on 2,964 primary TKR and 2,040 primary THR patients between 5/2011 and 3/2013. Data included demographics, comorbidities, operative joint pain severity based on the Knee Injury or Hip Disability and Osteoarthritis Outcome Score (KOOS/HOOS), WOMAC pain (higher is better), physical function (SF-36 PCS, higher is better), mental health (SF-36 …

Does Helicobacter Pylori Protect Against Eosinophilic Esophagitis In Children?, Yoram Elitsur Md, Baraa Alabd Alrazzak, Deborah L. Preston, Yulia Demetieva

Deborah L Preston

Does Helicobacter Pylori Protect Against Eosinophilic Esophagitis In Children?, Yoram Elitsur Md, Baraa Alabd Alrazzak, Deborah L. Preston, Yulia Demetieva

Yoram Elitsur

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Katherine A. Fitzgerald

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …

Acute Binge Drinking Increases Serum Endotoxin And Bacterial Dna Levels In Healthy Individuals, Shashi Bala, Miguel Marcos, Arijeet Gattu, Donna Catalano, Gyongyi Szabo

Gyongyi Szabo

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to …

Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1beta). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-kappaB (NF-kappaB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric …

High Fat Diet Feeding Results In Gender Specific Steatohepatitis And Inflammasome Activation, Michal Ganz, Timea Csak, Gyongyi Szabo

Gyongyi Szabo

AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge. METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o …

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Gyongyi Szabo

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …

Vitamin D Status Is Associated With Early Markers Of Cardiovascular Disease In Prepubertal Children, Benjamin U. Nwosu, Louise Maranda, Karen Cullen, Carol A. Ciccarelli, Mary M. Lee

Mary M. Lee

Background: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. Objective: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. Subjects and methods: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3 ± 2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D/mL; overweight as body mass index (BMI) ≥ 85 th but …

Parental Mastery Of Continuous Subcutaneous Insulin Infusion Skills And Glycemic Control In Youth With Type 1 Diabetes, Kathleen Mitchell, Kimberley Johnson, Karen Cullen, Mary M. Lee, Olga T. Hardy

Mary M. Lee

OBJECTIVE: The purpose of this study is to determine whether parental knowledge of the continuous subcutaneous insulin infusion (CSII) device affects glycemic control as measured by hemoglobin A1c (A1C) level. SUBJECTS AND METHODS: Parents of children with type 1 diabetes mellitus (T1DM) using CSII completed a 14-item questionnaire. Questions 1-10 were knowledge-based questions that required the parent to extract specific information from their child's CSII device. Questions 11-14 asked parents to provide a self-assessment of their CSII knowledge. RESULTS: Twenty-two parents of youth with T1DM participated in the study. Ten of the youth were in the Low-A1C group (A1C/=8%). Parents …

Acceptance Of Simulated Oral Rabies Vaccine Baits By Urban Raccoons, John Hadidian, Suzanne R. Jenkins, David H. Johnston, Peter J. Savarie, Victor F. Nettles, David M. Manski, George M. Baer

John Hadidian, PhD

In summer 1986, a study was conducted to evaluate raccoon (Procyon lotor) acceptance of oral baits that could be used for rabies vaccination, One thousand wax-coated sponge bait cubes were filled with 5 mg of a seromarker (iophenoxic acid), placed in polyethylene bags, and hand-distributed in an 80 ha area within an urban National Park in Washington, D.C. (USA), After 3 wk, target and nontarget animals were trapped and blood samples collected to evaluate bait uptake. Thirty-three of 52 (63%) raccoons had elevated blood iodine levels indicating they had eaten at least one bait, 13 (25%) were negative, and six …

Circulating Microrna Profiles In Human Patients With Acetaminophen Hepatotoxicity Or Ischemic Hepatitis, Jeanine Ward, Chitra Kanchagar, Isana Veksler-Lublinsky, Rosalind C. Lee, Mitchell R. Mcgill, Hartmut Jaeschke, Steven C. Curry, Victor R. Ambros

Victor R. Ambros

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as …

A Revised Method For Measuring Distraction By Tactile Stimulation [V1; Ref Status: Indexed, Http://F1000r.Es/42o], Jacqueline R. Schechter, Deanna J. Greene, Jonathan M. Koller, Kevin J. Black

Kevin J. Black, MD

Sensory hypersensitivity (SH) refers to the tendency to attend to subtle stimuli, to persist in attending to them, and to find them noxious. SH is relatively common in several developmental disorders including Tourette Syndrome and Chronic Tic Disorder (TS/CTD). This study was an attempt to quantify the extent to which a mild tactile stimulus distracts one’s attention in TS/CTD. Fourteen adults with TS/CTD and 14 tic-free control subjects completed questionnaires regarding SH and ADHD, and TS/CTD subjects completed self-report measures of current and past tic disorder symptoms and of current obsessions and compulsions. All subjects performed a sustained attention choice …

Prediction Of Dengue Disease Severity Among Pediatric Thai Patients Using Early Clinical Laboratory Indicators, James A. Potts, Robert V. Gibbons, Alan L. Rothman, Anon Srikiatkhachorn, Stephen J. Thomas, Pra-On Supradish, Stephenie C. Lemon, Daniel H. Libraty, Sharone Green, Siripen Kalayanarooj

Alan Rothman

BACKGROUND: Dengue virus is endemic in tropical and sub-tropical resource-poor countries. Dengue illness can range from a nonspecific febrile illness to a severe disease, Dengue Shock Syndrome (DSS), in which patients develop circulatory failure. Earlier diagnosis of severe dengue illnesses would have a substantial impact on the allocation of health resources in endemic countries. METHODS AND FINDINGS: We compared clinical laboratory findings collected within 72 hours of fever onset from a prospective cohort children presenting to one of two hospitals (one urban and one rural) in Thailand. Classification and regression tree analysis was used to develop diagnostic algorithms using different …

The Vitamin D Status In Inflammatory Bowel Disease, Lauren Veit, Louise Maranda, Jay G. Fong, Benjamin U. Nwosu

Benjamin U. Nwosu

CONTEXT: There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

AIM: To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

HYPOTHESIS: Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

SUBJECTS AND METHODS: A case-controlled retrospective study of subjects with IBD (n = 58) of 2-20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n …

Hiv/Sti Risk Factors Among African-American Students Attending Predominantly White Universities, Marya L. Shegog, Lisa Lindley, Melva Thompson-Robinson, David Simmons, Donna Richter

David Simmons

Introduction: The majority of African American college students in the U.S. attend predominantly white institutions (PWIs). However, there is minimal research examining this population’s HIV/STI risk behaviors. The purpose of this investigation was to assess HIV/STI behavioral risk factors among African American college students (aged 18 – 24years) attending PWIs. (n = 2,568) Methods: Backwards step-wise logistic regression analyses were conducted to determine factors associated with a positive HIV/STI diagnosis (past year) among sexually active African American college students who participated in the Spring, 2006 National College Health Assessment. Findings: Nine factors were significantly associated with an HIV/STI diagnosis among …