Medicine and Health Sciences Commons^™

Survival Associated Pathway Identification With Group Lp Penalized Global Auc Maximization., Zhenqiu Liu, Laurence S Magder, Terry Hyslop, Li Mao

Department of Pharmacology and Experimental Therapeutics Faculty Papers

It has been demonstrated that genes in a cell do not act independently. They interact with one another to complete certain biological processes or to implement certain molecular functions. How to incorporate biological pathways or functional groups into the model and identify survival associated gene pathways is still a challenging problem. In this paper, we propose a novel iterative gradient based method for survival analysis with group Lp penalized global AUC summary maximization. Unlike LASSO, Lp (p < 1) (with its special implementation entitled adaptive LASSO) is asymptotic unbiased and has oracle properties 1. We first extend Lp for individual gene identification to group Lp penalty for pathway selection, and then develop a novel iterative gradient algorithm for penalized global AUC summary maximization (IGGAUCS). This method incorporates the genetic pathways into global AUC summary maximization and identifies survival associated pathways instead of individual genes. The tuning parameters are determined using 10-fold cross validation with training data only. The prediction performance is evaluated using test data. We apply the proposed method to survival outcome analysis with gene expression profile and identify multiple pathways simultaneously. Experimental results with simulation and gene expression data demonstrate that the proposed procedures can be used for identifying important biological pathways that are related to survival phenotype and for building a parsimonious model for predicting the survival times.

The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B. Jekabsons, Tyler A. Johnson, Koneni V. Sashidhara, Phillip Crews, Dale G. Nagle, Yu-Dong Zhou

Natural Sciences and Mathematics | Faculty Scholarship

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound …

S-Glutathionylation Activates Stim1 And Alters Mitochondrial Homeostasis., Brian J Hawkins, Krishna M Irrinki, Karthik Mallilankaraman, Yu-Chin Lien, Youjun Wang, Cunnigaiper D Bhanumathy, Ramasamy Subbiah, Michael F Ritchie, Jonathan Soboloff, Yoshihiro Baba, Tomohiro Kurosaki, Suresh K Joseph, Donald L Gill, Muniswamy Madesh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Oxidant stress influences many cellular processes, including cell growth, differentiation, and cell death. A well-recognized link between these processes and oxidant stress is via alterations in Ca(2+) signaling. However, precisely how oxidants influence Ca(2+) signaling remains unclear. Oxidant stress led to a phenotypic shift in Ca(2+) mobilization from an oscillatory to a sustained elevated pattern via calcium release-activated calcium (CRAC)-mediated capacitive Ca(2+) entry, and stromal interaction molecule 1 (STIM1)- and Orai1-deficient cells are resistant to oxidant stress. Functionally, oxidant-induced Ca(2+) entry alters mitochondrial Ca(2+) handling and bioenergetics and triggers cell death. STIM1 is S-glutathionylated at cysteine 56 in response to …

Growth, Immune And Viral Responses In Hiv Infected African Children Receiving Highly Active Antiretroviral Therapy: A Prospective Cohort Study., Philippa M. Musoke, Peter Mudiope, Linda N. Barlow-Mosha, Patrick Ajuna, Danstan Bagenda, Michael M. Mubiru, Thorkild Tylleskar, Mary G. Fowler

Journal Articles: Epidemiology

BACKGROUND: Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes.

METHODS: A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ), weight and height-for-age z scores (WAZ & HAZ) were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both …

Harnessing The Effect Of Adoptively Transferred Tumor-Reactive T Cells On Endogenous (Host-Derived) Antitumor Immunity, Yolanda Nesbeth, Jose R. Conejo-Garcia

Dartmouth Scholarship

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, and ex vivo expansion procedure of tumor-reactive T cells to be adoptively transferred influence their in vivo effectiveness and may need to be adapted for different types of cancer and host …

Diaphragm Weakness And Mechanical Ventilation – What's The Critical Issue?, Leigh Ann Callahan, Gerald S. Supinski

Internal Medicine Faculty Publications

While animal studies indicate that controlled mechanical ventilation (MV) induces diaphragm weakness and myofiber atrophy, there are no data in humans that confirm MV per se produces diaphragm weakness. Whether or not diaphragm weakness results from MV, sepsis, corticosteroids, hyperglycemia, or a combination of these factors, however, is not the most important issue raised by the recent study from Hermans and colleagues. This study makes an important contribution by providing additional evidence that many critically ill patients have profound diaphragm weakness. If diaphragm weakness of this magnitude is present in most mechanically ventilated patients, a strong argument can be made …

Cross-Reactivity Of Antibodies Against Leptospiral Recurrent Uveitis-Associated Proteins A And B (Lrua And Lrub) With Eye Proteins, Ashutosh Verma, Pawan Kumar, Kelly Babb, John F. Timoney, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Infection by Leptospira interrogans has been causally associated with human and equine uveitis. Studies in our laboratories have demonstrated that leptospiral lipoprotein LruA and LruB are expressed in the eyes of uveitic horses, and that antibodies directed against LruA and LruB react with equine lenticular and retinal extracts, respectively. These reactivities were investigated further by performing immunofluorescent assays on lenticular and retinal tissue sections. Incubation of lens tissue sections with LruA-antiserum and retinal sections with LruB-antiserum resulted in positive fluorescence. By employing two-dimensional gel analyses followed by immunoblotting and mass spectrometry, lens proteins cross-reacting with LruA antiserum were identified to …

Hyperpolarized (3)He Magnetic Resonance Imaging-Derived Pulmonary Pressure-Volume Curves, Stephen Choy, Andrew Wheatley, David G Mccormack, Grace Parraga

Medical Biophysics Publications

We aimed to evaluate the potential for the use of hyperpolarized helium-3 magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) surrogates of alveolar size, together with literature-based morphological parameters in a theoretical model of lung mechanics to simulate noninvasive transpulmonary pressure-volume curves. Fourteen ex-smokers with chronic obstructive pulmonary disease (COPD) (n = 8 stage II, n = 6 stage III/IV COPD) and five age-matched never-smokers, provided written, informed consent and were evaluated at baseline and 26 + or - 2 mo later (n = 15 subjects) using plethysmography, spirometry, and (3)He MRI at 3.0 T. Total lung capacity, residual volume, …

A Smac Mimetic Reduces Tnf Related Apoptosis Inducing Ligand (Trail)-Induced Invasion And Metastasis Of Cholangiocarcinoma Cells., Christian D. Fingas, Boris R.A. Blechacz, Rory L. Smoot, Maria E. Guicciardi, Justin L. Mott, Steve F. Bronk, Nathan W. Werneburg, Alphonse E. Sirica, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that, failing to kill CCA cells, instead promotes their tumorigenicity and especially the metastatic behaviors of cell migration and invasion. Second mitochondria-derived activator of caspase (smac) mimetics are promising cancer therapeutic agents that enhance proapoptotic death receptor signaling by causing cellular degradation of inhibitor of apoptosis (IAP) proteins. Our aim was to examine the in vitro and in vivo effects of the smac mimetic JP1584 in CCA. Despite JP1584-mediated loss of cellular inhibitor of apoptosis-1 (cIAP-1) and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, …

The Perils Of The Imperfect Expectation Of The Perfect Baby., Frank A Chervenak, Laurence B Mccullough, Robert L Brent

Department of Pediatrics Faculty Papers

Advances in modern medicine invite the assumption that medicine can control human biology. There is a perilous logic that leads from expectations of medicine's control over reproductive biology to the expectation of having a perfect baby. This article proposes that obstetricians should take a preventive ethics approach to the care of pregnant women with expectations for a perfect baby. We use Nathaniel Hawthorne's classic short story, "The Birthmark," to illustrate the perils of the logic of control and perfection through science and then identify possible contemporary sources of the expectation of the perfect baby. We propose that the informed consent …

Asian Race/Ethnicity As A Risk Factor For Bile Duct Injury During Cholecystectomy., Stephanie R. Downing, Ghazala Datoo, Tolulope A. Oyetunji, Terrence Fullum, David C. Chang, Nita Ahuja

Manuscripts, Articles, Book Chapters and Other Papers

Iatrogenic bile duct injury (BDI) is an uncommon but serious complication of cholecystectomy, with identified risk factors of acute cholecystitis, male sex, older age, and aberrant biliary anatomy. The Nationwide Inpatient Sample (1998-2006) was queried for cholecystectomy performed on hospital day 0 or 1. Bile duct injury repair procedure codes were used as a surrogate for BDI. We identified 377,424 patients who underwent cholecystectomy, with 1124 BDIs (0.3%). On multivariate logistic regression analysis, Asian race/ethnicity was a significant risk factor for BDI (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.59-3.23; P < .001). This persisted for laparoscopic (OR, 2.62; 95% CI, 1.28-5.39; P = .009) and open (2.21; 1.59-3.07; P < .001) cholecystectomies. No other race/ethnicity was identified as a risk factor for BDI. We report a new finding that Asian race/ethnicity is a significant risk factor for BDI in laparoscopic and open cholecystectomies.

Distribution Of Left Ventricular Ejection Fraction In Angina Patients With Severe Coronary Artery Disease Not Amenable To Revascularization., Shuchita Gupta, Gregg S. Pressman, D Lynn Morris, Vincent M. Figueredo, M.D.

Division of Cardiology Faculty Papers

BACKGROUND: As the number of angina patients with severe coronary artery disease not amenable to revascularization increases, new therapies will be developed. How patients with depressed compared to normal left ventricular ejection fraction (LVEF) will respond to new therapies may differ.

HYPOTHESIS: We conducted a retrospective chart review to determine the distribution of LVEF in angina patients with severe coronary artery disease (three-vessel disease with >50% stenosis major epicardial vessels or >50% stenosis left main) not amenable to revascularization.

METHODS: Patients underwent cardiac catheterization between 2004 and 2009. LVEF, measured by echocardiography, nuclear-gated imaging or radioventriculography within 6 months of …

Multiple Mechanisms Of Consciousness: The Neural Correlates Of Emotional Awareness., Jayna M Amting, Steven G Greening, Derek G V Mitchell

Brain and Mind Institute Researchers' Publications

Emotional stimuli, including facial expressions, are thought to gain rapid and privileged access to processing resources in the brain. Despite this access, we are conscious of only a fraction of the myriad of emotion-related cues we face everyday. It remains unclear, therefore, what the relationship is between activity in neural regions associated with emotional representation and the phenomenological experience of emotional awareness. We used functional magnetic resonance imaging and binocular rivalry to delineate the neural correlates of awareness of conflicting emotional expressions in humans. Behaviorally, fearful faces were significantly more likely to be perceived than disgusted or neutral faces. Functionally, …

Enalapril In Infants With Single Ventricle: Results Of A Multicenter Randomized Trial., Daphne T. Hsu, Victor Zak, Lynn Mahony, Lynn A. Sleeper, Andrew M. Atz, Jami C. Levine, Piers C. Barker, Chitra Ravishankar, Brian W. Mccrindle, Richard V. Williams, Karen Altmann, Nancy S. Ghanayem, Renee Margossian, Wendy K. Chung, William L. Border, Gail D. Pearson, Mario P. Stylianou, Seema Mital, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown.

METHODS AND RESULTS: The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg . kg(-1) . d(-1)) or placebo who were followed up until 14 months of age. The primary end …

Deltanp63 Transcriptionally Regulates Atm To Control P53 Serine-15 Phosphorylation., Ashley L. Craig, Jitka Holcakova, Lee E. Finlan, Marta Nekulova, Roman Hrstka, Nuri Gueven, James Direnzo, Graeme Smith, Ted R. Hupp, Borivoj Vojtesek

Dartmouth Scholarship

Background: ΔNp63α is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-dam age induced p53 phosphorylation is confined to ΔNp63α-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylatio n of the p53 tumour suppressor is po sitively regulated by ΔNp63α in immortalised human keratinocytes. ΔNp63α depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of ΔNp63α in p63-null tumour cells stimulates ATM transcription and p53 Seri ne-15 phosphorylation. We show that AT M is a …

Passive Transfer Of Igg Anti-Gm1 Antibodies Impairs Peripheral Nerve Repair, Pablo H Lopez, Gang Zhang, Jiangyang Zhang, Helmar C Lehmann, John W Griffin, Ronald L Schnaar, Kazim A Sheikh

Faculty, Staff and Student Publications

Anti-GM1 antibodies are present in some patients with autoimmune neurological disorders. These antibodies are most frequently associated with acute immune neuropathy called Guillain-Barré syndrome (GBS). Some clinical studies associate the presence of these antibodies with poor recovery in GBS. The patients with incomplete recovery have failure of nerve repair, particularly axon regeneration. Our previous work indicates that monoclonal antibodies can inhibit axon regeneration by engaging cell surface gangliosides (Lehmann et al., 2007). We asked whether passive transfer of human anti-GM1 antibodies from patients with GBS modulate axon regeneration in an animal model. Human anti-GM1 antibodies were compared with other GM1 …

The Role Of Gender In Single Vs Married Individuals With Bipolar Disorder., Daniel Z Lieberman, Suena H Massey, Frederick K Goodwin

Psychiatry and Behavioral Sciences Faculty Publications

BACKGROUND: Despite the importance of marriage as a source of social support, it has been largely neglected in studies of bipolar disorder; and differential effects on men and women have not been explored.

METHODS: Data on episodes of depression, mania, and mixed states were collected for the previous 2 years from a sample of 282 bipolar individuals using the National Institute of Mental Health Life Chart Methodology.

RESULTS: Effects unique to women included the following: Bipolar women were significantly more likely to be married. Married women had fewer episodes of depression during the past 2 years than never-married women, and …

Chronic Obstructive Pulmonary Disease: Longitudinal Hyperpolarized (3)He Mr Imaging, Miranda Kirby, Lindsay Mathew, Andrew Wheatley, Giles E Santyr, David G Mccormack, Grace Parraga

Medical Biophysics Publications

PURPOSE: To quantitatively evaluate a small pilot group of ex-smokers with chronic obstructive pulmonary disease (COPD) and healthy volunteers during approximately 2 years by using hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging.

MATERIALS AND METHODS: All subjects provided written informed consent to the study protocol, which was approved by the local research ethics board and Health Canada and was compliant with the Personal Information Protection and Electronic Documents Act and HIPAA. Hyperpolarized (3)He MR imaging, hydrogen 1 MR imaging, spirometry, and plethysmography were performed in 15 ex-smokers with COPD and five healthy volunteers (with the same mean age and …

Deficits In Attention To Emotional Stimuli Distinguish Youth With Severe Mood Dysregulation From Youth With Bipolar Disorder., Brendan A Rich, Melissa A Brotman, Daniel P Dickstein, Derek G V Mitchell, R James R Blair, Ellen Leibenluft

Brain and Mind Institute Researchers' Publications

Studying attention in the context of emotional stimuli may aid in differentiating pediatric bipolar disorder (BD) from severe mood dysregulation (SMD). SMD is characterized by chronic irritability, arousal, and hyper-reactivity; SMD youth frequently receive a BD diagnosis although they do not meet DSM-IV criteria for BD because they lack manic episodes. We compared 57 BD (14.4 +/- 2.9 years old, 56% male), 41 SMD (12.6 +/- 2.6 years old, 66% male), and 33 control subjects (13.7 +/- 2.5 years old, 52% male) using the Emotional Interrupt task, which examines how attention is impacted by positive, negative, or neutral distracters. We …

A Randomized Comparison Of Online And Paper Mood Charts For People With Bipolar Disorder., Daniel Z Lieberman, Tammas F Kelly, Lanny Douglas, Frederick K Goodwin

Psychiatry and Behavioral Sciences Faculty Publications

BACKGROUND: Longitudinal mood instability is the essential feature of bipolar disorder, however most rating scales are cross sectional in nature, and focus on acute symptoms. By contrast, the NIMH Life Chart Methodology (LCM) characterizes in detail the severity, duration, and frequency of mood episodes. Adherence to daily rating, however, tends to be low. In this study an online version of the LCM, designed to enhance adherence, was compared to the standard paper version.

METHODS: Patients from a mood disorders specialty clinic were randomized to the standard LCM or an online, open-source adaptation. The online version used hypertext links embedded in …

Dopaminergic Neurons Derived From Human Induced Pluripotent Stem Cells Survive And Integrate Into 6-Ohda-Lesioned Rats., Jingli Cai, Ming Yang, Elizabeth Poremsky, Sarah Kidd, Jay S Schneider, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from …

Tubercular Pancreatic Abscess Presenting As Fever And Cystic Pancreatic Lesion With Endoscopic Management., Jonathan M. Fenkel, Maya Spodik, Bheema S. Singu, Anthony Infantolino, Sandeep P. Deshmukh, David E. Loren

Division of Gastroenterology and Hepatology Faculty Papers

Isolated pancreatic tuberculosis is a rare presentation of tubercular infection. There are few reported cases of pancreatic tuberculosis diagnosed by endoscopic ultrasound with fine-needle aspiration (EUS FNA), though EUS is often used in the evaluation of pancreatic cystic lesions. We present a case of a tubercular pancreatic abscess presenting as a cystic lesion in a patient with undiagnosed immunodeficiency. The abscess was aspirated by EUS FNA and treated with endoscopic drainage and anti-mycobacterial medications.

Human Papillomavirus And Survival Of Patients With Oropharyngeal Cancer., K Kian Ang, Jonathan Harris, Richard Wheeler, Randal Weber, David I Rosenthal, Phuc Felix Nguyen-Tân, William H Westra, Christine H Chung, Richard C Jordan, Charles Lu, Harold Kim, Rita S. Axelrod, Md, C Craig Silverman, Kevin P Redmond, Maura L Gillison

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.

METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive …

Postoperative Complications Of Powered Intracapsular Tonsillectomy And Monopolar Electrocautery Tonsillectomy In Teens Versus Adults., Douglas R Johnston, Michael Gaslin, Maurits Boon, Edmund Pribitkin, David Rosen

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVES: This study was performed to determine whether teens have different rates of posttonsillectomy hemorrhage, admission for dehydration, or recurrent tonsillitis compared to adults. Specifically, these parameters were compared within two groups: patients who underwent powered intracapsular tonsillectomy (PIT) and those who underwent monopolar electrocautery tonsillectomy (MET).

METHODS: In a retrospective review of 579 patients at least 12 years of age from January 2000 to July 2006 in a tertiary referral center, outcome measures of reoperation for hemorrhage, readmission or emergency room visit for dehydration, and postoperative tonsillitis were compared for 200 patients 12 to 19 years of age and …

Clinical And Economic Impact Of Infusion Reactions In Patients With Colorectal Cancer Treated With Cetuximab., K A Foley, P F Wang, B L Barber, S R Long, J E Bagalman, V Wagner, X Song, Z Zhao

College of Population Health Faculty Papers

BACKGROUND: Systemic agents in cancer treatment were often associated with possible infusion reactions (IRs). This study estimated the incidence of IRs requiring medical intervention and assessed the clinical and economic impacts of IRs in patients with colorectal cancer (CRC) treated with cetuximab.

PATIENTS AND METHODS: Details on patients with CRC receiving cetuximab in 2004-2006 were extracted from a large USA administrative claims database. IRs were identified based on the occurrence of outpatient treatment, emergency room (ER) visit, and/or hospitalization for hypersensitivity and allergic reactions. Multivariate regressions were used to examine potential risk factors and quantify the economic impact of IRs. …

Breast Cancer Dna Methylation Profiles Are Associated With Tumor Size And Alcohol And Folate Intake, Brock C. Christensen, Karl T. Kelsey, Shichun Zheng, E. Andres Houseman, Carmen J. Marsit, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas

Dartmouth Scholarship

Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05) associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02) and tumor size (P<0.001) in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001) associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …

Hypertension In Children And Adolescents: Epidemiology And Natural History., Bonita Falkner

Department of Medicine Faculty Papers

Primary hypertension is detectable in children and adolescents and, as in adults, is associated with a positive family history of hypertension, obesity, and life-style factors. Owing to the well-established childhood obesity epidemic, the population prevalence of high blood pressure (BP) in the young is increasing. Hypertension in childhood is commonly associated with other cardiovascular risk factors as well as obesity. Although death and cardiovascular disability do not occur in hypertensive children, intermediate markers of target organ damage, such as left ventricular hypertrophy, thickening of the carotid vessel wall, retinal vascular changes, and even subtle cognitive changes, are detectable in children …

Updating The Dermatologic Nomenclature: Names That Are Good Or Bad., Lawrence Charles Parish, Joseph A. Witkowski

Department of Dermatology and Cutaneous Biology Faculty Papers

Dermatology probably has the largest vocabulary of any of the medical specialties,¹ a statement to which we can attest when we reviewed aspects of the Dermatology Lexicon project. Some terms are derived from the Latin or Greek and present spelling problems to all but a select few. Examples include acrokeratosis verruciformis and pterigium. Other diseases carry names that are such a mouthful that few can call them out without the interruption of breathing. These might include erosio interdigitalis blastomycetica and dermatitis exudative discoid and lichenoid of Sulzberger and Garbe. No wonder the former is now referred to simply as …

Anti-Hiv Activity In Cervical-Vaginal Secretions From Hiv-Positive And -Negative Women Correlate With Innate Antimicrobial Levels And Igg Antibodies, Mimi Ghosh, John V. Fahey, Zheng Shen, Timothy Lahey, Susan Cu-Uvin, Zhijin Wu, Kenneth Mayer, Peter F. Wright, John C. Kappes, Christina Ochsenbauer, Charles R. Wira

Dartmouth Scholarship

Background: We investigated the impact of antimicrobials in cervicovaginal lavage (CVL) from HIV(+) and HIV(2) women on target cell infection with HIV. Since female reproductive tract (FRT) secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+) and (2) women inhibit HIV infection.

Methodology/Principal Findings: CVL from 32 HIV(+) healthy women with high CD4 counts and 15 healthy HIV(2) women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti- HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and …