Medicine and Health Sciences Commons^™

Silencing Of The Pink1 Gene Expression By Conditional Rnai Does Not Induce Dopaminergic Neuron Death In Mice., Hongxia Zhou, Björn H Falkenburger, Jörg B Schulz, Kim Tieu, Zuoshang Xu, Xu Gang Xia

Kim Tieu

Transgenic RNAi, an alternative to the gene knockout approach, can induce hypomorphic phenotypes that resemble those of the gene knockout in mice. Conditional transgenic RNAi is an attractive choice of method for reverse genetics in vivo because it can achieve temporal and spatial silencing of targeted genes. Pol III promoters such as U6 are widely used to drive the expression of RNAi transgenes in animals. Tested in transgenic mice, a Cre-loxP inducible U6 promoter drove the broad expression of an shRNA against the Pink1 gene whose loss-of-functional mutations cause one form of familial Parkinson's disease. The expression of the shRNA …

Characterization Of A Far-Red Analog Of Ghrelin For Imaging Ghs-R In P19-Derived Cardiomyocytes., Gregory A F Douglas, Rebecca Mcgirr, Carlie L Charlton, Dov B Kagan, Lisa M Hoffman, Leonard G Luyt, Savita Dhanvantari

Lisa Hoffman

Ghrelin and its receptor, the growth hormone secretagogue receptor (GHS-R), are expressed in the heart, and may function to promote cardiomyocyte survival, differentiation and contractility. Previously, we had generated a truncated analog of ghrelin conjugated to fluorescein isothiocyanate for the purposes of determining GHS-R expression in situ. We now report the generation and characterization of a far-red ghrelin analog, [Dpr(3)(octanoyl), Lys(19)(Cy5)]ghrelin (1-19), and show that it can be used to image changes in GHS-R in developing cardiomyocytes. We also generated the des-acyl analog, des-acyl [Lys(19)(Cy5)]ghrelin (1-19) and characterized its binding to mouse heart sections. Receptor binding affinity of Cy5-ghrelin as …

The Glia Response After Peripheral Nerve Injury: A Comparison Between Schwann Cells And Olfactory Ensheathing Cells And Their Uses For Neural Regenerative Therapies, Matthew J Barton, James St John, Alison Wright, Jenny Ekberg

Jenny Ekberg

The peripheral nervous system (PNS) exhibits a much larger capacity for regeneration than the central nervous system (CNS). One reason for this difference is the difference in glial cell types between the two systems. PNS glia respond rapidly to nerve injury by clearing debris from the injury site, supplying essential growth factors and providing structural support; all of which enhances neuronal regeneration. Thus, transplantation of glial cells from the PNS is a very promising therapy for injuries to both the PNS and the CNS. There are two key types of PNS glia: olfactory ensheathing cells (OECs), which populate the olfactory …

Daclatasvir In Combination With Asunaprevir And Beclabuvir For Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis., Andrew J Muir, Fred Poordad, Jacob Lalezari, Gregory Everson, Gregory J Dore, Robert Herring, Aasim Sheikh, Paul Kwo, Christophe Hézode, Paul J Pockros, Albert Tran, Joseph L. Yozviak Do, Facp, Nancy Reau, Alnoor Ramji, Katherine Stuart, Alexander J Thompson, John Vierling, Bradley Freilich, James Cooper, Wayne Ghesquiere, Rong Yang, Fiona Mcphee, Eric A Hughes, E Scott Swenson, Philip D Yin

Joseph L Yozviak DO, FACP

IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis.

OBJECTIVE: All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis.

DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients …

Hysteresis As A Measure Of Ankle Dysfunction, Alissa Cohen, James Mertz, Peggy Stewart, Michael Warner, Michael Kuchera

Michael Kuchera

There is no abstract for this article.

Metastatic Brain Tumors: Current Therapeutic Options And Historical Perspective, Mark Rivkin, Richard Kanoff

Mark Rivkin

Metastatic brain tumors affect more than 150,000 patients annually in the United States. The therapeutic paradigms for these tumors have evolved over the years and currently encompass numerous modalities implemented by treating physicians across several medical disciplines. The armamentarium of brain tumor treatment involves neurosurgical intervention, whole-brain and focused radiation modalities, chemotherapy, and immunotherapy. Patient selection, however, remains critical to achieve maximal therapeutic benefit and depends on functional status, number and location of lesions, and tissue histologic findings. Best outcomes can be expected with a multidisciplinary approach to patient care where state-of-the-art treatment options are readily available.

Prepubertal Organochlorine Pesticide Concentrations And Age Of Pubertal Onset Among Russian Boys, Thuy Lam, Paige Williams, Mary Lee, Susan Korrick, Linda Birnbaum, Jane Burns, Oleg Sergeyev, Boris Revich, Larisa Altshul, Donald Patterson, Wayman Turner, Russ Hauser

Mary M. Lee

BACKGROUND: In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent. OBJECTIVE: To evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)] with male pubertal onset. METHODS: In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8-9 year old boys with measured OCPs were enrolled during 2003-2005 and were followed annually for eight years. We evaluated three measures of pubertal onset: testicular volume (TV) > 3 mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). We used multivariable interval-censored models to …

Association Between Chlorinated Pesticides In The Serum Of Prepubertal Russian Boys And Longitudinal Biomarkers Of Metabolic Function, Jane Burns, Paige Williams, Susan Korrick, Russ Hauser, Oleg Sergeyev, Boris Revich, Thuy Lam, Mary Lee

Mary M. Lee

Organochlorine pesticides (OCPs) have been linked to adult metabolic disorders; however, few studies have examined these associations in childhood. We prospectively evaluated the associations of baseline serum OCPs (hexachlorobenzene, beta-hexachlorocyclohexane, and p,p'-dichlorodiphenyldichloroethylene) in Russian boys with subsequent repeated measurements of serum glucose, insulin, lipids, leptin, and calculated homeostatic model assessment of insulin resistance (IR). During 2003-2005, we enrolled 499 boys aged 8-9 years in a prospective cohort; 318 had baseline serum OCPs and serum biomarkers measured at ages 10-13 years. Multivariable generalized estimating equation and mediation regression models were used to examine associations and direct and indirect (via body mass …

Xk Aprosencephaly And Anencephaly In Sibs, Phillip Townes, Karen Reuter, E. Rosquete, B. Magee

B. Dale Magee

Recent studies have suggested a causal and pathogenetic relationship between holoprosencephaly and anencephaly. In support of the proposed relationship we report a sibship that includes anencephalic male twins and a female infant with a severe form of alobar holoprosencephaly, radial aplasia, and oligodactyly. The upper limb and brain malformations are considered to represent aprosencephaly syndrome. The coexistence of anencephaly and aprosencephaly within a sibship suggests that XK aprosencephaly syndrome may be an autosomal recessive disorder.

Hippocampal Functional Connectivity Patterns During Spatial Working Memory Differ In Right Versus Left Temporal Lobe Epilepsy., Gaelle Eve Doucet, Karol Osipowicz, Ashwini Sharan Md, Michael R Sperling, Joseph I Tracy

Gaelle Eve Doucet

Temporal lobe epilepsy (TLE), affecting the medial temporal lobe, is a disorder that affects not just episodic memory but also working memory (WM). However, the exact nature of hippocampal-related network activity in visuospatial WM remains unclear. To clarify this, we utilized a functional connectivity (FC) methodology to investigate hippocampal network involvement during the encoding phase of a functional magnetic resonance imaging (fMRI) visuospatial WM task in right and left TLE patients. Specifically, we assessed the relation between FC within right and left hippocampus-seeded networks, and patient performance (rate of correct responses) during the encoding phase of a block span WM …

A Culture Of One. Every Healthcare Encounter Is A Cultural Encounter, Debbie Salas-Lopez

Debbie Salas-Lopez MD, MPH

No abstract provided.

Striving For Cultural Competence In An Hiv Program: The Transformative Impact Of A Microsystem In A Larger Health Network, Judith N Sabino, Timothy Friel, Lynn Deitrick, Debbie Salas-Lopez

Debbie Salas-Lopez MD, MPH

No abstract provided.

Defining And Targeting Health Care Access Barriers, J Carrillo, Victor Carrillo, Hector Perez, Debbie Salas-Lopez, Ana Natale-Pereira, Alex Byron

Debbie Salas-Lopez MD, MPH

The impact of social and economic determinants of health status and the existence of racial and ethnic health care access disparities have been well-documented. This paper describes a model, the Health Care Access Barriers Model (HCAB), which provides a taxonomy and practical framework for the classification, analysis and reporting of those modifiable health care access barriers that are associated with health care disparities. The model describes three categories of modifiable health care access barriers: financial, structural, and cognitive. The three types of barriers are reciprocally reinforcing and affect health care access individually or in concert. These barriers are associated with …

Barriers And Facilitators For Colorectal Cancer Screening Practices In The Latino Community: Perspectives From Community Leaders, Ana Natale-Pereira, Jonnie Marks, Marielos Vega, Dawne Mouzon, Shawna Hudson, Debbie Salas-Lopez

Debbie Salas-Lopez MD, MPH

BACKGROUND: Colorectal cancer (CRC) is the second-leading cause of cancer-related death in the United States and the third most commonly diagnosed cancer among Latinos. While Latinos represent one of the fastest-growing ethnic groups in the United States, their participation in cancer prevention and treatment trials is low. METHODS: Thirty-six Latino community leaders participated in five focus groups that examined factors affecting CRC screening practices among Latinos. RESULTS: The top four barriers identified were low knowledge and awareness of CRC, language barriers, lack of insurance, and undocumented legal status. Additional barriers included seeking health care only when sick, fatalism, fear, denial …

Perspectives On Cancer Screening Among Latino Community Members And Internal Medicine Residents, Debbie Salas-Lopez, Dawne Mouzon, Jonnie Marks, Neil Kothari, Ana Natale-Pereira

Debbie Salas-Lopez MD, MPH

BACKGROUND: Latinos have lower rates of cancer screening, partially because of cultural beliefs that conflict with those of health care professionals. Moreover, established programs for training physicians in cultural competency often fail to incorporate input from the community.

METHODS: To explore beliefs about cancer and cancer screening among Latino community members and internal medicine residents. Three focus groups of Latino community members (n = 31) and one focus group of internal medicine residents (n = 9) were conducted to compare ideas regarding cancer and cancer screening.

RESULTS: We identified clear disconnects between residents and Latino community members regarding their understandings …

Cultural Competency In New Jersey: Evolution From Planning To Law, Debbie Salas-Lopez, Linda Holmes, Dawne Mouzon, Maria Soto-Greene

Debbie Salas-Lopez MD, MPH

No abstract provided.

Access To Hospital Interpreter Services For Limited English Proficient Patients In New Jersey: A Statewide Evaluation, Glenn Flores, Sylvia Torres, Linda Holmes, Debbie Salas-Lopez, Mara Youdelman, Sandra Tomany-Korman

Debbie Salas-Lopez MD, MPH

CONTEXT/OBJECTIVES: We surveyed New Jersey (NJ) hospitals to assess current language services and identify policy recommendations on meeting limited English proficiency (LEP) patients' needs.

METHODS: Survey with 37 questions regarding hospital/patient features, interpreter services, and resources/policies needed to provide quality interpreter services.

RESULTS: Sixty-seven hospitals responded (55% response rate). Most NJ hospitals have no interpreter services department, 80% provide no staff training on working with interpreters, 31% lack multilingual signs, and 19% offer no written translation services. Only 3% of hospitals have full-time interpreters, a ratio of 1 interpreter:240,748 LEP NJ residents. Most hospitals stated third-party reimbursement for interpreters would …

National Trauma Institute Prospective Evaluation Of The Ventilator Bundle In Trauma Patients: Does It Really Work?, Martin A. Croce Md, Karen J. Brasel Md, Mph, Raul Coimbra Md, Phd, Charles A. Adams Jr, Md, Preston R. Miller Md, Michael D. Pasquale Md, Facs, Fccm, Chanchai S. Mcdonald Phd, Somchan Vuthipadadon Phd, Timothy C. Fabian Md, Elizabeth A. Tolley Phd

Michael D Pasquale MD, FACS, FCCM

BACKGROUND: Since its introduction by the Institute for Healthcare Improvement, the ventilator bundle (VB) has been credited with a reduction in ventilator-associated pneumonia (VAP). The VB consists of stress ulcer prophylaxis, deep venous thrombosis prophylaxis, head-of-bed elevation, and daily sedation vacation with weaning assessment. While there is little compelling evidence that the VB is effective, it has been widely accepted. The Centers for Medical and Medicaid Services has suggested that VAP should be a "never event" and may reduce payment to providers. To provide evidence of its efficacy, the National Trauma Institute organized a prospective multi-institutional trial to evaluate the …

Comparison Of Insulin Infusion Protocols Targeting 110-140 Mg/Dl In Patients After Cardiac Surgery., Vasudev Magaji, Shriddha Nayak, Amy Donihi, Lauren Willard, Srinivasa Jampana, Parachur Nivedita, Raymond Eder, Jann Johnston, Mary Korytkowski

Vasudev G Magaji MD, MS

BACKGROUND: Continuous intravenous insulin infusion (CII) following coronary artery bypass graft (CABG) surgery reduces postoperative complications and hospitalization duration. Because of limited data evaluating outcomes of CII with revised glycemic targets (110-140 mg/dL) in cardiac surgery, this study compared efficacy and safety of two different CII protocols having revised targets. SUBJECTS AND METHODS: This is a retrospective study comparing two different protocols between August 2009 and March 2010. Protocol 1 consists of four algorithms, and Protocol 2 is a table to adjust CII. Blood glucose (BG) and CII rates were recorded for 48 h postoperatively or CII discontinuation. Efficacy was …

Angiographic Recognition Of Ostial Left Main Coronary Artery Stenosis: Case Report., R M Macmillan, Bruce Feldman, V Maranhao

Bruce A. Feldman DO

Ostial left main coronary stenosis has a poor prognosis and increased mortality rate with coronary arteriography. Due to its anatomic location, visualization of the stenosis may be difficult. A high index of suspicion based upon only a few signs should prompt the physician to perform certain maneuvers to obtain the correct diagnosis. Four illustrative cases are presented and discussed.

Emergence Of Bimodal Cell Population Responses From The Interplay Between Analog Single-Cell Signaling And Protein Expression Noise., Marc R Birtwistle, Jens Rauch, Anatoly Kiyatkin, Edita Aksamitiene, Maciej Dobrzyński, Jan Hoek, Walter Kolch, Babatunde A Ogunnaike, Boris N Kholodenko

Anatoly Kiyatkin

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses. RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally …

Addressing The Controversy Of Rate-Versus-Rhythm Control In Atrial Fibrillation, Tahmeed Contractor, Vadim Levin, Ravi Desai, Francis E Marchlinski

Vadim A Levin MD

Atrial fibrillation is the most common sustained cardiac arrhythmia and significantly increases patient risk of stroke, cardiomyopathy, and mortality. Rate versus rhythm control as the "best" treatment strategy remains an issue of considerable, ongoing debate. A multitude of clinical trials have compared the 2 strategies and have not shown any benefit of one approach over the other. However, the trials were conducted in specific subgroups of patients and demonstrated low success rates with antiarrhythmic drug (AAD) therapy and a high incidence of adverse AAD effects. Sub-analyses of the trials have confirmed that successful rhythm control with sinus rhythm restoration is …

Addressing The Controversy Of Rate-Versus-Rhythm Control In Atrial Fibrillation, Tahmeed Contractor, Vadim Levin, Ravi Desai, Francis E Marchlinski

Ravi V Desai MD

Atrial fibrillation is the most common sustained cardiac arrhythmia and significantly increases patient risk of stroke, cardiomyopathy, and mortality. Rate versus rhythm control as the "best" treatment strategy remains an issue of considerable, ongoing debate. A multitude of clinical trials have compared the 2 strategies and have not shown any benefit of one approach over the other. However, the trials were conducted in specific subgroups of patients and demonstrated low success rates with antiarrhythmic drug (AAD) therapy and a high incidence of adverse AAD effects. Sub-analyses of the trials have confirmed that successful rhythm control with sinus rhythm restoration is …

Human Monoclonal Antibodies Directed Against Toxins A And B Prevent Clostridium Difficile-Induced Mortality In Hamsters, Gregory Babcock, Teresa Broering, Hector Hernandez, Robert Mandell, Katherine Donahue, Naomi Boatright, Anne Stack, Israel Lowy, Robert Graziano, Deborah Molrine, Donna Ambrosino, William Thomas

William D Thomas Jr

Clostridium difficile is the leading cause of nosocomial antibiotic-associated diarrhea, and recent outbreaks of strains with increased virulence underscore the importance of identifying novel approaches to treat and prevent relapse of Clostridium difficile-associated diarrhea (CDAD). CDAD pathology is induced by two exotoxins, toxin A and toxin B, which have been shown to be cytotoxic and, in the case of toxin A, enterotoxic. In this report we describe fully human monoclonal antibodies (HuMAbs) that neutralize these toxins and prevent disease in hamsters. Transgenic mice carrying human immunoglobulin genes were used to isolate HuMAbs that neutralize the cytotoxic effects of either toxin …

Gucy2c Opposes Systemic Genotoxic Tumorigenesis By Regulating Akt-Dependent Intestinal Barrier Integrity, Jieru Egeria Lin, Adam Eugene Snook, Peng Li, Brian Arthur Stoecker, Gilbert Won Kim, Michael Sullivan Magee, Alex Vladimir Mejia Garcia, Michael Anthony Valentino, Terry Hyslop, Stephanie Schulz, Scott Arthur Waldman

Adam E Snook

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous …

Advanced Molecular Biologic Techniques In Toxicologic Disease, Jeanine Ward, Gyongyi Szabo, David Mcmanus, Edward Boyer

Gyongyi Szabo

The advancement of molecular biologic techniques and their capabilities to answer questions pertaining to mechanisms of pathophysiologic events have greatly expanded over the past few years. In particular, these opportunities have provided researchers and clinicians alike the framework from with which to answer clinical questions not amenable for elucidation using previous, more antiquated methods. Utilizing extremely small molecules, namely microRNA, DNA, protein, and nanoparticles, we discuss the background and utility of these approaches to the progressive, practicing physician. Finally, we consider the application of these tools employed as future bedside point of care tests, aiding in the ultimate goal of …

Stent Placement Compared With Balloon Angioplasty For Obstructed Coronary Bypass Grafts. Saphenous Vein De Novo Trial Investigators., M P Savage, J S Douglas, D L Fischman, C J Pepine, S B King, J A Werner, S R Bailey, P A Overlie, S H Fenton, J A Brinker, M B Leon, S Goldberg

Michael P Savage M.D.

BACKGROUND: Treatment of stenosis in saphenous-vein grafts after coronary-artery bypass surgery is a difficult challenge. The purpose of this study was to compare the effects of stent placement with those of balloon angioplasty on clinical and angiographic outcomes in patients with obstructive disease of saphenous-vein grafts.

METHODS: A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later.

RESULTS: As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate …

Transcriptional Regulatory Network Analysis During Epithelial-Mesenchymal Transformation Of Retinal Pigment Epithelium., Craig H Pratt, Rajanikanth Vadigepalli, Praveen Chakravarthula, Gregory E Gonye, Nancy J Philp, Gerald B Grunwald

Rajanikanth Vadigepalli

PURPOSE: Phenotypic transformation of retinal pigment epithelial (RPE) cells contributes to the onset and progression of ocular proliferative disorders such as proliferative vitreoretinopathy (PVR). The formation of epiretinal membranes in PVR may involve an epithelial-mesenchymal transformation (EMT) of RPE cells as part of an aberrant wound healing response. While the underlying mechanism remains unclear, this likely involves changes in RPE cell gene expression under the control of specific transcription factors (TFs). Thus, the purpose of the present study was to identify TFs that may play a role in this process. METHODS: Regulatory regions of genes that are differentially regulated during …

A Glycosylated Recombinant Human Granulocyte Colony Stimulating Factor Produced In A Novel Protein Production System (Avi-014) In Healthy Subjects: A First-In Human, Single Dose, Controlled Study., Roslyn Varki, Ed Pequignot, Mark C Leavitt, Andres Ferber, Walter K Kraft

walter k Kraft

BACKGROUND: AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014. METHODS: 24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion. RESULTS: The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0-72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0-72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, …

Role Of Hypoxia And Glycolysis In The Development Of Multi-Drug Resistance In Human Tumor Cells And The Establishment Of An Orthotopic Multi-Drug Resistant Tumor Model In Nude Mice Using Hypoxic Pre-Conditioning, Lara Milane, Zhenfeng Duan, Mansoor M. Amiji

Mansoor M. Amiji

Background The development of multi-drug resistant (MDR) cancer is a significant challenge in the clinical treatment of recurrent disease. Hypoxia is an environmental selection pressure that contributes to the development of MDR. Many cancer cells, including MDR cells, resort to glycolysis for energy acquisition. This study aimed to explore the relationship between hypoxia, glycolysis, and MDR in a panel of human breast and ovarian cancer cells. A second aim of this study was to develop an orthotopic animal model of MDR breast cancer. Methods Nucleic and basal protein was extracted from a panel of human breast and ovarian cancer cells; …