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Perioperative Care Of The Geriatric Patient For Noncardiac Surgery, Jonathan D Wolfe, Natasha K Wolfe, Michael W Rich

Open Access Publications

Adults age 65 and over are the fastest growing segment of the population in the United States and around the world. As the size of this population expands, the number of older adults referred for surgical procedures will continue to increase. Due to the physiologic changes of aging and the increased frequency of comorbidities, older adults are at increased risk for adverse outcomes, and perioperative care is inherently more complex than in younger individuals. In this review, we discuss the physiologic changes of aging relevant to the surgical patient, comprehensive preoperative assessment, and postoperative management of common complications in older …

Circulating Ceramide Ratios And Risk Of Vascular Brain Aging And Dementia, Emer R Mcgrath, Jayandra J Himali, Vanessa Xanthakis, Meredith S Duncan, Jean E Schaffer, Daniel S Ory, Linda R Peterson, Charles Decarli, Matthew P Pase, Claudia L Satizabal, Ramachandran S Vasan, Alexa S Beiser, Sudha Seshadri

Open Access Publications

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.

METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.

RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were …

Zika Virus Infection In The Developing Mouse Produces Dramatically Different Neuropathology Dependent On Viral Strain, Kevin K. Noguchi, Brant S. Swiney, Sasha L. Williams, Jacob N. Huffman, Katherine Lucas, Sophie H. Wang, Kayla M. Kapral, Amber Li, Krikor T. Dikranian

Open Access Publications

Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and …

Clinical Controversies In Anticoagulation Monitoring And Antithrombin Supplementation For Ecmo, Meghan M Chlebowski, Sirine Baltagi, Mel Carlson, Jerrold H Levy, Philip C Spinella

Open Access Publications

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One …

Atomistic Basis Of Opening And Conduction In Mammalian Inward Rectifier Potassium (Kir2.2) Channels, Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Grigory Maksaev, Harald Bernsteiner, Feifei Ren, Peng Yuan, Anna Stary-Weinzinger, Colin G. Nichols

Open Access Publications

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This "forced open" mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP2), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP2 bound, or 2.8 Å in complex with …

Splicing Factor Sf3b1 Promotes Endometrial Cancer Progression Via Regulating Ksr2 Rna Maturation, Pooja Popli, Megan M. Richters, Sangappa B. Chadchan, Tae Hoon Kim, Eric Tycksen, Obi Griffith, Premal H. Thaker, Malachi Griffith, Ramakrishna Kommagani

Open Access Publications

No abstract provided.

Diffusion Basis Spectrum Imaging Detects Axonal Loss After Transient Dexamethasone Treatment In Optic Neuritis Mice, Tsen-Hsuan Lin, Jie Zhan, Chunyu Song, Michael Wallendorf, Peng Sun, Xuan Niu, Ruimeng Yang, Anne H Cross, Sheng-Kwei Song

Open Access Publications

Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after …

A Pilot Study Of Cardiac Mri In Breast Cancer Survivors After Cardiotoxic Chemotherapy And Three-Dimensional Conformal Radiotherapy, Carmen Bergom, Jason Rubenstein, J Frank Wilson, Aimee Welsh, El-Sayed H Ibrahim, Phillip Prior, Aronne M Schottstaedt, Daniel Eastwood, Mei-Jie Zhang, Adam Currey, Lindsay Puckett, Jennifer L Strande, Julie A Bradley, Julia White

Open Access Publications

Purpose/Objectives: Node-positive breast cancer patients often receive chemotherapy and regional nodal irradiation. The cardiotoxic effects of these treatments, however, may offset some of the survival benefit. Cardiac magnetic resonance (CMR) is an emerging modality to assess cardiac injury. This is a pilot trial assessing cardiac damage using CMR in patients who received anthracycline-based chemotherapy and three-dimensional conformal radiotherapy (3DCRT) regional nodal irradiation using heart constraints.

Materials and Methods: Node-positive breast cancer patients (2000-2008) treated with anthracycline-based chemotherapy and 3DCRT regional nodal irradiation (including the internal mammary chain nodes) with heart ventricular constraints (V25 < 10%) were invited to participate. Cardiac tissues were contoured and analyzed separately for whole heart (pericardium) and for combined ventricles and left atrium (myocardium). CMR obtained ventricular function/dimensions, late gadolinium enhancement (LGE), global longitudinal strain (GLS), and extracellular volume fraction (ECV) as measures of cardiac injury and/or early fibrosis. CMR parameters were correlated with dose-volume constraints using Spearman correlations.

Results: Fifteen left-sided and five right-sided patients …

Patient-Controlled Intravenous Morphine Analgesia Combined With Transcranial Direct Current Stimulation For Post-Thoracotomy Pain: A Cost-Effectiveness Study And A Feasibility For Its Future Implementation, Nemanja Rancic, Katarina Mladenovic, Nela V Ilic, Viktorija Dragojevic-Simic, Menelaos Karanikolas, Tihomir V Ilic, Dusica M Stamenkovic

Open Access Publications

This prospective randomized study aims to evaluate the feasibility and cost-effectiveness of combining transcranial direct current stimulation (tDCS) with patient controlled intravenous morphine analgesia (PCA-IV) as part of multimodal analgesia after thoracotomy. Patients assigned to the active treatment group (a-tDCS,

The Cartilage Matrisome In Adolescent Idiopathic Scoliosis, Carol A. Wise, Diane Sepich, Aki Ushiki, Anas M. Khanshour, Yared H. Kidane, Nadja Makki, Christina A. Gurnett, Ryan S. Gray, Jonathan J. Rios, Nadav Ahituv, Lila Solnica-Krezel

Open Access Publications

No abstract provided.

Histopathologic, Immunophenotypic, And Proteomics Characteristics Of Low-Grade Phyllodes Tumor And Fibroadenoma: More Similarities Than Differences, Lingxin Zhang, Chen Tang, John D. Pfeifer, Richard M. Caprioli, Audra M. Judd, Nathan H. Patterson, Michelle L. Reyzer, Jeremy L. Norris, Horacio M. Maluf

Open Access Publications

No abstract provided.

Design And Rationale Of The Hapin Study: A Multicountry Randomized Controlled Trial To Assess The Effect Of Liquefied Petroleum Gas Stove And Continuous Fuel Distribution, Thomas Clasen, Victor G. Davila-Roman, Et Al.

Open Access Publications

No abstract provided.

Midkine Activation Of Cd8+ T Cells Establishes A Neuron–Immune–Cancer Axis Responsible For Low-Grade Glioma Growth, Xiaofan Guo, Yuan Pan, Min Xiong, Shilpa Sanapala, Corina Anastasaki, Olivia Cobb, Sonika Dahiya, David H. Gutmann

Open Access Publications

No abstract provided.

Association Of Ptsd Symptom Groups With Functional Impairment And Distress In Trauma-Exposed Disaster Survivors, Carol S North, Erin Van Enkevort, Barry A Hong, Alina M Surís

Open Access Publications

BACKGROUND: In the nearly a quarter of a century since the addition of the clinically significant distress/impairment criterion to the definition of PTSD in DSM-IV, little research has been done to examine the association of this criterion with symptom group criteria and with the numbing subgroup specifically. This study was conducted to examine these relationships in a large database of disaster survivors consistently studied across 12 different incidents of the full range of disaster typology.

METHODS: Analysis was conducted on a merged database representing 1187 trauma-exposed survivors of 12 different disasters studied systematically. DSM-IV-TR criteria for disaster-related PTSD were assessed …

Ldha-Mediated Ros Generation In Chondrocytes Is A Potential Therapeutic Target For Osteoarthritis, Manoj Arra, Gaurav Swarnkar, Ke Ke, Jesse E. Otero, Jun Ying, Xin Duan, Takashi Maruyama, Muhammad Farooq Rai, Regis J. O'Keefe, Gabriel Mbalaviele, Jie Shen, Yousef Abu-Amer

Open Access Publications

No abstract provided.

Ancestry Specific Associations Of Fto Gene Variant And Metabolic Syndrome: A Longitudinal Aric Study, Dale S. Hardy, Jane T. Garvin, Tesfaye B. Mersha, Susan B. Racette

Open Access Publications

No abstract provided.

Proteomic Resistance Biomarkers For Pi3k Inhibitor In Triple Negative Breast Cancer Patient-Derived Xenograft Models, Zhanfang Guo, Tina Primeau, Jingqin Luo, Cynthia Zhang, Hua Sun, Jeremy Hoog, Feng Gao, Shixia Huang, Dean P Edwards, Sherri R Davies, Rebecca Aft, Li Ding, Matthew J Ellis, Shunqiang Li, Cynthia X Ma

Open Access Publications

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth …

A Ventrolateral Medulla-Midline Thalamic Circuit For Hypoglycemic Feeding, B. Sofia Beas, Xinglong Gu, Yan Leng, Omar Koita, Shakira Rodriguez-Gonzalez, Morgan Kindel, Bridget A. Matikainen-Ankney, Rylan S. Larsen, Alexxai V. Kravitz, Mark A. Hoon, Mario A. Penzo

Open Access Publications

No abstract provided.

Rates Of Brain Atrophy Across Disease Stages In Familial Frontotemporal Dementia Associated With Mapt, Grn, And C9orf72 Pathogenic Variants, Adam M. Staffaroni, Nupur Ghoshal, Et Al

Open Access Publications

Importance: Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect.

Objective: To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia.

Design, Setting, and Participants: This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between …

Marrowquant Across Aging And Aplasia: A Digital Pathology Workflow For Quantification Of Bone Marrow Compartments In Histological Sections, Josefine Tratwal, Erica L Scheller, Et Al

Open Access Publications

The bone marrow (BM) exists heterogeneously as hematopoietic/red or adipocytic/yellow marrow depending on skeletal location, age, and physiological condition. Mouse models and patients undergoing radio/chemotherapy or suffering acute BM failure endure rapid adipocytic conversion of the marrow microenvironment, the so-called "red-to-yellow" transition. Following hematopoietic recovery, such as upon BM transplantation, a "yellow-to-red" transition occurs and functional hematopoiesis is restored. Gold Standards to estimate BM cellular composition are pathologists' assessment of hematopoietic cellularity in hematoxylin and eosin (H&E) stained histological sections as well as volumetric measurements of marrow adiposity with contrast-enhanced micro-computerized tomography (CE-μCT) upon osmium-tetroxide lipid staining. Due to user-dependent …

Genetic Architecture Of Circulating Very-Long-Chain (C24:0 And C22:0) Ceramide Concentrations, Sharon Cresci, Ruibo Zhang, Qiong Yang, Meredith S Duncan, Vanessa Xanthakis, Xuntian Jiang, Ramachandran S Vasan, Jean E Schaffer, Linda R Peterson

Open Access Publications

OBJECTIVE: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.

METHODS: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.

RESULTS: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides …

The At(N) Framework For Alzheimer's Disease In Adults With Down Syndrome, Michael S Rafii, Beau M Ances, Et Al

Open Access Publications

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which …

Eflornithine Plus Sulindac For Prevention Of Progression In Familial Adenomatous Polyposis, Carol A. Burke, Paul E. Wise, Et Al

Open Access Publications

No abstract provided.

Differentiating Among Stages Of Cognitive Impairment In Aging: Version 3 Of The Uniform Data Set (Uds) Neuropsychological Test Battery And Moca Index Scores, Hiroko H Dodge, John C Morris, Et Al

Open Access Publications

Introduction: Federally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.

Methods: First, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared …

Effects Of Cyp46a1 Inhibition On Long-Term-Depression In Hippocampal Slices Ex Vivo And 24s-Hydroxycholesterol Levels In Mice In Vivo, Michael Popiolek, Yukitoshi Izumi, Allen T Hopper, Jing Dai, Silke Miller, Hong-Jin Shu, Charles F Zorumski, Steven Mennerick

Open Access Publications

The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous system is CYP46A1, a brain enriched enzyme responsible for metabolism of cholesterol into 24S-hydroxycholesterol. Inhibition of this enzyme may negatively modulate NMDARs as 24S-hydroxycholesterol was shown to enhance NMDAR function. In addition, alterations of local cholesterol or other changes mediated by CYP46A1 activity could have important influences on central nervous system function. Here we demonstrate that humans and mice display brain region specific and similar CYP46A1 and …

Cerebral Small Vessel Disease Genomics And Its Implications Across The Lifespan, Muralidharan Sargurupremraj, Andrew C. Heath, Pamela A.F. Madden, Et Al.

Open Access Publications

No abstract provided.

Antibodies Targeting Epitopes On The Cell-Surface Form Of Ns1 Protect Against Zika Virus Infection During Pregnancy, Alex W. Wessel, Nurgun Kose, Robin G. Bombardi, Vicky Roy, Warangkana Chantima, Juthathip Mongkolsapaya, Melissa A. Edeling, Christopher A. Nelson, Irene Bosch, Galit Alter, Gavin R. Screaton, David H. Fremont, James E. Crowe Jr, Michael S. Diamond

Open Access Publications

No abstract provided.

Mapping Language Function With Task-Based Vs. Resting-State Functional Mri, Ki Yun Park, John J. Lee, Donna Dierker, Laura M. Marple, Carl D. Hacker, Jarod L. Roland, Daniel S. Marcus, Mikhail Milchenko, Michelle M. Miller-Thomas, Tammie L. Benzinger, Joshua S. Shimony, Abraham Z. Snyder, Eric C. Leuthardt

Open Access Publications

BACKGROUND: Use of functional MRI (fMRI) in pre-surgical planning is a non-invasive method for pre-operative functional mapping for patients with brain tumors, especially tumors located near eloquent cortex. Currently, this practice predominantly involves task-based fMRI (T-fMRI). Resting state fMRI (RS-fMRI) offers an alternative with several methodological advantages. Here, we compare group-level analyses of RS-fMRI vs. T-fMRI as methods for language localization.

PURPOSE: To contrast RS-fMRI vs. T-fMRI as techniques for localization of language function.

METHODS: We analyzed data obtained in 35 patients who had both T-fMRI and RS-fMRI scans during the course of pre-surgical evaluation. The RS-fMRI data were analyzed …

Genetic Loci Associated With Prevalent And Incident Myocardial Infarction And Coronary Heart Disease In The Cohorts For Heart And Aging Research In Genomic Epidemiology (Charge) Consortium, Julie Hahn, Mary F. Feitosa, Et Al.

Open Access Publications

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants …

Adherence To Updated Childcare Nutrition Regulations In Colorado, United States, Amy A Eyler, Cheryl R Valko, Katherine A Curoe, Ramya Ramadas, Jamie F Chriqui

Open Access Publications

No abstract provided.