Medicine and Health Sciences Commons^™

Genome-Wide Association Study Of Borderline Personality Disorder Reveals Genetic Overlap With Bipolar Disorder, Major Depression And Schizophrenia, S. H. Witt, F. Streit, M. Jungkunz, J. Frank, Ney Alliey Rodriguez

School of Medicine Publications

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) …

Ovarian Hormones Modify Anxiety Behavior And Glucocorticoid Receptors After Chronic Social Isolation Stress, Dinah L. Ramos-Ortolaza, Raura J. Doreste-Mendez, John K. Alvarado-Torres, Annelyn Torres-Reveron

School of Medicine Publications

Chronic social isolation could lead to a disruption in the Hypothalamic-Pituitary-Adrenal (HPA) axis, resulting in anxiety and depressive-like behaviors but cycling estrogens could modify these behaviors. The aim of this study was to determine if changes in ovarian hormones during the normal cycle could interact with social isolation to alter anxiety and depressive-like behaviors. In parallel, we examined the expression of glucocorticoid receptor (GR) and synaptic vesicle protein synaptophysin in the hippocampus and hypothalamus of Sprague Dawley normal cycling female rats. We assigned rats to either isolated or paired housing for 8 weeks. To assess anxiety and depressive-like behaviors, we …

Heritability And Genetic Correlation Between Gerd Symptoms Severity, Metabolic Syndrome, And Inflammation Markers In Families Living In Mexico City, Arturo Reding-Bernal, Valentin Sánchez-Pedraza, Hortensia Moreno-Macías, Sergio Sobrino-Cossio, María Elizabeth Tejero-Barrera, Ana Isabel Burguete-García, Mireya Leon-Hernandez, María Fabiola Serratos-Canales, Ravi Duggirala, Juan Carlos Lopez Alvarenga

School of Medicine Publications

Objective: The aim of this study was to estimate the heritability (h2) and genetic correlation (ρG) between GERD symptoms severity, metabolic syndrome components, and inflammation markers in Mexican families.

Methods: Cross-sectional study which included 32 extended families resident in Mexico City. GERD symptoms severity was assessed by the ReQuest in Practice questionnaire. Heritability and genetic correlation were determined using the Sequential Oligogenic Linkage Analysis Routines software.

Results: 585 subjects were included, the mean age was 42 (±16.7) years, 57% were women. The heritability of the severity of some GERD symptoms was h2 = 0.27, 0.27, 0.37, and 0.34 (p-value < 1.0x10-5) for acidity complaints, lower abdominal complaints, sleep disturbances, and total ReQuest score, respectively. Heritability of metabolic syndrome components ranged from 0.40 for fasting plasma glucose to 0.61 for body mass index and diabetes mellitus. The heritability for fibrinogen and C-reactive protein was 0.64 and 0.38, respectively. Statistically significant genetic correlations were found between acidity complaints and fasting plasma glucose (ρG = 0.40); sleep disturbances and fasting plasma glucose (ρG = 0.36); acidity complaints and diabetes mellitus (ρG = 0.49) and between total ReQuest score and fasting plasma glucose (ρG = 0.43). The rest of metabolic syndrome components did not correlate with GERD symptoms.

Conclusion: …

Factores De Riesgo Asociados A Recaída De Enfermedad Por Reflujo Gastroesofágico En Pacientes De Primer Nivel De Atención Exitosamente Tratados Con Inhibidor De La Bomba De Protones [Risk Factors Associated With Gastroesophageal Reflux Disease Relapse In Primary Care Patients Successfully Treated With A Proton Pump Inhibitor], Aurelio López-Colombo, M. S. Pacio-Quiterio, L. Y. Jesús-Mejenes, J. E. G. Rodríguez-Aguilar, M. López-Guevara, A. J. Montiel-Jarquín, Juan Carlos Lopez Alvarenga, E. R. Morales-Hernández, V. R. Ortiz-Juárez, L. Ávila-Jiménez

School of Medicine Publications

Resumen

Antecedentes

No existen estudios en primer nivel de atención sobre factores asociados a recaída de enfermedad por reflujo gastroesofágico (ERGE).

Objetivo

Identificar factores de riesgo asociados a recaída de ERGE en pacientes de primer nivel de atención que respondieron adecuadamente a un tratamiento corto con inhibidor de la bomba de protones.

Pacientes y métodos

Estudio de cohorte, se incluyeron casos incidentes de ERGE. Se dio tratamiento con omeprazol durante 4 semanas. Se aplicó ReQuest y un cuestionario de factores de riesgo. Se determinó la tasa de éxito terapéutico y de recaída a las 4 y 12 semanas después de …

The Lipidome In Major Depressive Disorder: Shared Genetic Influence For Ether-Phosphatidylcholines, A Plasma-Based Phenotype Related To Inflammation, And Disease Risk, Emma E. M. Knowles, Kevin Huynh, Peter J. Meikle, Harald H. H. Goring, Rene L. Olvera, Samuel R. Mathias, Ravi Duggirala, Laura Almasy, John Blangero, Joanne E. Curran, David C. Glahn

School of Medicine Publications

Background

The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated.

Methods

In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3–80), we used mass-spectrometry lipidomic measures to evaluate the genetic …

Maternal Serum Markers Of Lipid Metabolism In Relation To Neonatal Anthropometry, Nansi S. Boghossian, Pauline Mendola, Aiyi Liu, Candace Robledo, Edwina H. Yeung

School of Medicine Publications

Objective: The objective of this study is to examine associations between lipids (high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides and lipoprotein (a)) measured on average three time points during pregnancy and neonatal anthropometrics.

Study design: Stored samples from a preeclampsia trial measured as part of a case-control study from five US centers (1992 to 1995) were used. The sample included women without pregnancy complications (n=136) and cases of gestational diabetes (n=93), abnormal glucose tolerance (AGT; n=76), gestational hypertension (n=170) and preeclampsia (n=177). Linear regression and linear mixed-effects models estimated adjusted associations between lipids and birth weight z-score, ponderal index (PI), …

Use Of Brca Mutation Test In The Us, 2004-2014, Fangjian Guo, Jacqueline M. Hirth, Yu-Li Lin, Gwyn Richardson, Lyuba Levine, Abbey B. Berenson, Yong-Fang Kuo

School of Medicine Publications

Introduction

BRCA mutation testing has been used for screening women at high risk of breast and ovarian cancer and for selecting the best treatment for those with breast cancer. To optimize the infrastructure and medical resources allocation for genetic testing, it is important to understand the use of BRCA mutation testing in the U.S. health system.

Methods

This retrospective cohort study included 53,254 adult women with insurance claims for BRCA mutation testing between 2004 and 2014 from ClinformaticsTM Data Mart Database. Data analysis was performed in 2016. This study assessed trends in the use of BRCA mutation testing in women …

Genetic Correlation Of The Plasma Lipidome With Type 2 Diabetes, Prediabetes And Insulin Resistance In Mexican American Families, Hemant Kulkarni, Manju Mamtani, Gerard Wong, Jacquelyn M. Weir, Christopher K. Barlow, Thomas D. Dyer, Laura Almasy, Michael Mahaney, Anthony G. Comuzzie, Ravindranath Duggirala, Peter J. Meikle, John Blangero, Joanne E. Curran

School of Medicine Publications

Background

Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits.

Results

We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, …

Comparative Analysis Of Immune Checkpoint Molecules And Their Potential Role In The Transmissible Tasmanian Devil Facial Tumor Disease, Andrew S. Flies, Nicholas B. Blackburn, Alan Bruce Lyons, John D. Hayball, Gregory M. Woods

School of Medicine Publications

Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory …

Epigenetic Age Acceleration Assessed With Human White-Matter Images, Karen Hodgson, Melanie A. Carless, Hemant Kulkarni, Joanne E. Curran, Emma Sprooten, Emma E. Knowles, Samuel R. Mathias, Harald H. H. Goring, Nailin Yao, Rene L. Olvera, Laura Almasy, Ravindranath Duggirala, John Blangero, David C. Glahn

School of Medicine Publications

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic …

How Many More? Sample Size Determination In Studies Of Morphological Integration And Evolvability, Mark Grabowski, Arthur Porto

School of Medicine Publications

1. The variational properties of living organisms are an important component of current evolutionary theory. As a consequence, researchers working on the field of multivariate evolution have increasingly used integration and evolvability statistics as a way of capturing the potentially complex patterns of trait association and their effects over evolutionary trajectories. Little attention has been paid, however, to the cascading effects that inaccurate estimates of trait covariance have on these widely used evolutionary statistics.

2. Here, we analyze the relationship between sampling effort and inaccuracy in evolvability and integration statistics calculated from 10-trait matrices with varying patterns of covariation and …

Improvement Of Cardiometabolic Markers After Fish Oil Intervention In Young Mexican Adults And The Role Of Pparα L162v And Pparγ2 P12a, Aristea Binia, Carolina Vargas-Martínez, Mónica Ancira-Moreno, Laura M. Gosoniu, Ivan Montoliu, Elí Gámez-Valdez, Diana C. Soria-Contreras, Adriana Angeles-Quezada, Rocío Gonzalez-Alberto, Juan Carlos Lopez Alvarenga

School of Medicine Publications

Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and …

Ophthalmic Manifestations Of Congenital Zika Syndrome In Colombia And Venezuela, Juan B. Yepez, Felipe A. Murati, Michele Petitto, Carlos F. Peñaranda, J. Fernando Arevalo, Gladys E. Maestre

School of Medicine Publications

IMPORTANCE The ocular manifestations and sequelae of Zika virus infection are not well known. Recently, the World Health Organization changed the declaration of Zika as a public health emergency and designated the viral outbreak and related microcephaly clusters as a long-term program of work. This change indicates the urgent need to evaluate and document ophthalmic manifestations in patients for timely management of this disease. In addition, confirmation whether the public health problem in Brazil extends to other regions in South America is needed.

OBJECTIVE To report the ocular manifestations of congenital Zika syndrome with microcephaly in Colombia and Venezuela.

DESIGN, …

Opossum Apobec1 Is A Dna Mutator With Retrovirus And Retroelement Restriction Activity, Terumasa Ikeda, Mayuko Shimoda, Diako Ebrahimi, John L. Vandeberg, Reuben S. Harris, Atsushi Koito, Kazuhiko Maeda

School of Medicine Publications

APOBEC3s (A3s) are single-stranded DNA cytosine deaminases that provide innate immune defences against retroviruses and mobile elements. A3s are specific to eutherian mammals because no direct homologs exist at the syntenic genomic locus in metatherian (marsupial) or prototherian (monotreme) mammals. However, the A3s in these species have the likely evolutionary precursors, the antibody gene deaminase AID and the RNA/DNA editing enzyme APOBEC1 (A1). Here, we used cell culture-based assays to determine whether opossum A1 restricts the infectivity of retroviruses including human immunodeficiency virus type 1 (HIV-1) and the mobility of LTR/non-LTR retrotransposons. Opossum A1 partially inhibited HIV-1, as well as …

Transcriptome Sequencing Study Implicates Immune-Related Genes Differentially Expressed In Schizophrenia: New Data And A Meta-Analysis, Alan R. Sanders, Eugene I. Drigalenko, Jubao Duan, Jessica Freda, Harald H. H. Goring, Pablo V. Gejman

School of Medicine Publications

We undertook an RNA sequencing (RNAseq)-based transcriptomic profiling study on lymphoblastoid cell lines of a European ancestry sample of 529 schizophrenia cases and 660 controls, and found 1058 genes to be differentially expressed by affection status. These differentially expressed genes were enriched for involvement in immunity, especially the 697 genes with higher expression in cases. Comparing the current RNAseq transcriptomic profiling to our previous findings in an array-based study of 268 schizophrenia cases and 446 controls showed a highly significant positive correlation over all genes. Fifteen (18%) of the 84 genes with significant (false discovery rateo0.05) expression differences between cases …

Genome-Wide Physical Activity Interactions In Adiposity ― A Meta-Analysis Of 200,452 Adults, Mariaelisa Graff, Robert A. Scott, Anne E. Justice, Kristin L. Young, Mary F. Feitosa, Llilda Barata, Thomas W. Winkler, Audrey Y. Chu, Anubha Mahajan, John Blangero

School of Medicine Publications

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which …

Fast Genome-Wide Qtl Association Mapping On Pedigree And Population Data, Hua Zhou, John Blangero, Thomas D. Dyer, Kei-Hang K. Chan, Kenneth Lange, Eric M. Sobel

School of Medicine Publications

Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. …

Examining The Prevalence Rates Of Preexisting Maternal Medical Conditions And Pregnancy Complications By Source: Evidence To Inform Maternal And Child Research, Candace A. Robledo, Edwina H. Yeung, Pauline Mendola, Rajeshwari Sundaram, Nansi S. Boghossian, Erin M. Bell, Charlotte Druschel

School of Medicine Publications

Objectives—We sought to examine whether there are systematic differences in ascertainment of preexisting maternal medical conditions and pregnancy complications from three common data sources used in epidemiologic research

Methods—Diabetes mellitus, chronic hypertension, gestational diabetes mellitus (GDM), gestational hypertensive disorders (GHD), placental abruption and premature rupture of membranes (PROM) among 4821 pregnancies were identified via birth certificates, maternal self-report at approximately 4 months postpartum and by discharge codes from the Statewide Planning and Research Cooperative System (SPARCS), a mandatory New York State hospital reporting system. The kappa statistic (k) was estimated to ascertain beyond chance agreement of outcomes between birth certificates …

Genetic Pleiotropy Between Age-Related Macular Degeneration And 16 Complex Diseases And Traits, Felix Grassmann, Christina Kiel, Martina E. Zimmermann, Mathias Gorski, Veronika Grassmann, Klaus Stark, Iris M. Heid, Bernhard H.F. Weber, Lars G. Fritsche, John Blangero

School of Medicine Publications

Background: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. Methods: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases …

Targeted Disruption Of Tc-Ptp In The Proliferative Compartment Augments Stat3 And Akt Signaling And Skin Tumor Development, Hyunseung Lee, Mihwa Kim, Minwoo Baek, Liza D. Morales, Ik-Soon Jang, Thomas J. Slaga, John Digiovanni, Dae Joon Kim

School of Medicine Publications

Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness …

Faculty Development In Family Medicine Education: What Is Needed?, Brian Johnson, William Edward Cayley, Bich-May Nguyen, Paul Larson, Maria Del C Colon-Gonzalez, Christine Gibson, Ann Evensen

School of Medicine Publications

A growing number of countries are embracing graduate training in the specialty of Family Medicine as a core component of global health systems reform. One significant challenge for new programs is to adequately prepare for educational excellence and leadership. Promising residents are often encouraged to remain in their program as faculty, but may not have had the benefit of specific training in teaching, curriculum development, learner assessment or educational leadership. Faculty Development is a potential avenue to providing these skills to new Family Medicine Faculty and to encourage new graduates to consider teaching. We are currently seeking to further clarify …

A Murine Model To Study Epilepsy And Sudep Induced By Malaria Infection, Paddy Ssentongo, Anna E. Robuccio, Godfrey Thuku, Derek G. Sim, Ali Nabi, Fatemeh Bahari, Balaji Shanmugasundaram, Myles W. Billard, Andrew Geronimo, Frank Gilliam

School of Medicine Publications

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy …

Sympathetic Nervous System Activity And Anti-Lipolytic Response To Iv-Glucose Load In Subcutaneous Adipose Tissue Of Obese And Obese Type 2 Diabetic Subjects, Uwe Schumann, Christopher P. Jenkinson, Andreas Alt, Martina Zügel, Jürgen M. Steinacker, Marion Flechtner-Mors

School of Medicine Publications

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10-4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three …

Analysis Of Whole Exome Sequencing With Cardiometabolic Traits Using Family-Based Linkage And Association In The Iras Family Study, Keri L. Tabb, Jacklyn N. Hellwege, Nicholette D. Palmer, Latchezar Dimitrov, Satria Sajuthi, Kent D. Taylor, Maggie C.Y. Ng, Gregory A. Hawkins, Yii-Der Ida Chen, John Blangero

School of Medicine Publications

Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1,205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 LOD scores with 1,148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD …

The Effect Size Of Type 2 Diabetes Mellitus On Tuberculosis Drug Resistance And Adverse Treatment Outcomes, Lucia Monserrat Perez-Navarro, Blanca I. Restrepo, Francisco Javier Fuentes-Dominguez, Ravi Duggirala, Jaime Morales-Romero, Juan Carlos Lopez Alvarenga, Iñaki Comas, Roberto Zenteno-Cuevas

School of Medicine Publications

Objective

To evaluate the effect size of type 2 diabetes mellitus (T2DM) on tuberculosis (TB) treatment outcomes and multi drug resistance (MDR).

Methods

A cohort with 507 individuals with diagnosed TB included 183 with coexistence of T2DM and TB (TB-T2DM). Participants were identified at the time of TB diagnosis and followed during the course of TB treatment. Then we computed relative risks and adjustments by Cox proportional hazards for outcome variables (drug resistance, death, relapse, treatment failure), and the size of their effect as Cohen's-d.

Results

Patients with TB-T2DM were more likely to remain positive for acid-fast bacilli after …

Serum Phosphatidylinositol As A Biomarker For Bipolar Disorder Liability, Emma E. M. Knowles, Peter J. Meikle, Kevin Huynh, Harald H. H. Goring, Rene L. Olvera, Samuel R. Mathias, Ravi Duggirala, Laura Almasy, John Blangero, Joanne E. Curran, David C. Glahn

School of Medicine Publications

Objectives

Individuals with bipolar disorder (BPD) exhibit alterations in their phospholipid levels. It is unclear whether these alterations are a secondary consequence of illness state, or if phospholipids and illness risk overlap genetically. If the latter were true, then phospholipids might provide key insights into the pathophysiology of the illness. Therefore, we rank-ordered phospholipid classes by their genetic overlap with BPD risk in order to establish which class might be most informative in terms of increasing our understanding of illness pathophysiology.

Methods

Analyses were conducted in a sample of 558 individuals, unselected for BPD, from 38 extended pedigrees (average family …

Investigating Resting-State Functional Connectivity In The Cervical Spinal Cord At 3t, Falk Eippert, Yazhuo Kong, Anderson M. Winkler, Jesper L. Andersson, Jürgen Finsterbusch, Christian Büchel, Jonathan C. Brooks, Irene Tracey

School of Medicine Publications

The study of spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra-high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting-state connectivity between the dorsal horns as well as between the ventral horns, and a study in non-human primates has shown that these resting-state signals are impacted by spinal cord injury. As these studies were carried out at ultra-high field strengths using region-of-interest (ROI) based analyses, we investigated whether such resting-state signals could also be observed at the clinically more prevalent field strength …

Adam19: A Novel Target For Metabolic Syndrome In Humans And Mice, Lakshini Weerasekera, Caroline Rudnicka, Qing-Xiang Sang, Joanne E. Curran, Matthew P. Johnson, Eric K. Moses, Harald H. H. Goring, John Blangero, Jana Hricova, Markus Schlaich, Vance B. Matthews

School of Medicine Publications

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced …

Cordycepin Induces Apoptosis By Caveolin-1-Mediated Jnk Regulation Of Foxo3a In Human Lung Adenocarcinoma, Jong Cheon Joo, Jung-Hoo Hwang, Eunbi Jo, Young-Rang Kim, Dae Joon Kim, Kyung-Bok Lee, Soo Jung Park, Ik-Soon Jang

School of Medicine Publications

Forkhead transcription factor (Foxo3a) is a downstream effector of JNK-induced tumor suppression. However, it is not clear whether the caveolin-1 (CAV1)-mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK) and subsequent Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK, whereas CAV1 siRNA downregulated p-JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which downregulated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax …

Cynomolgus Macaques Naturally Infected With Trypanosoma Cruzi-I Exhibit An Overall Mixed Pro-Inflammatory/Modulated Cytokine Signature Characteristic Of Human Chagas Disease, Danielle Marquete Vitelli-Avelar, Renato Sathler-Avelar, Armanda Moreira Mattoso-Barbosa, Nicolas Gouin, Marcelo Perdigão-De-Oliveira, Leydiane Valério-Dos-Reis, Ronaldo Peres Costa, Silvana Maria Elói-Santos, Jane F. Vandeberg, John Vandeberg

School of Medicine Publications

Background: Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease.

Methods and findings: In this cross-sectional study design, flow cytometry and systems biology approaches were used to characterize the ex vivo and in vitro T. cruzi-specific functional cytokine signature …