Digital Commons Network^™

Human Genome-Wide Association And Mouse Knockout Approaches Identify Platelet Supervillin As An Inhibitor Of Thrombus Formation Under Shear Stress., Leonard C. Edelstein, Elizabeth J. Luna, Ian B. Gibson, Molly Bray, Ying Jin, Altaf Kondkar, Srikanth Nagalla, Nacima Hadjout-Rabi, Tara C. Smith, Daniel Covarrubias, Stephen N. Jones, Firdos Ahmad, Moritz Stolla, Xianguo Kong, Zhiyou Fang, Wolfgang Bergmeier, Chad Shaw, Suzanne M. Leal, Paul Bray

Department of Medicine Faculty Papers

BACKGROUND: High shear force critically regulates platelet adhesion and thrombus formation during ischemic vascular events. To identify genetic factors that influence platelet thrombus formation under high shear stress, we performed a genome-wide association study and confirmatory experiments in human and animal platelets.

METHODS AND RESULTS: Closure times in the shear-dependent platelet function analyzer (PFA)-100 were measured on healthy, nondiabetic European Americans (n=125) and blacks (n=116). A genome-wide association (P

CONCLUSIONS: We show for the first time that (1) platelets contain supervillin; (2) platelet thrombus formation in the PFA-100 is associated with human SVIL variants and low SVIL expression; and (3) …

Effectiveness Of The Project P.A.T.H.S. In Hong Kong: Evaluation Based On Different Strategies And Different Studies Over Time, Daniel T. L. Shek, Hing Keung Ma, Joav Merrick

Pediatrics Faculty Publications

No abstract.

Participants' Evaluation Of The Project P.A.T.H.S.: Are Findings Based On Different Datasets Consistent?, Daniel T. L. Shek, Rachel C. F. Sun

Pediatrics Faculty Publications

Subjective outcome evaluation findings based on the perspective of the participants of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in nine datasets collected from 2005 to 2009 (n = 206, 313 program participants) were examined in this paper. Based on the consolidated data with schools as units, results showed that the participants generally had positive perceptions of the program, implementers, and benefits of the program. More than four-fifths of the participants regarded the program as beneficial to their holistic development. Multiple regression analysis revealed that the perceived qualities of the program and the program implementers predicted perceived …

Selective Impact Of Hiv Disease Progression On The Innate Immune System In The Human Female Reproductive Tract, Timothy Lahey, Mimi Ghosh, John V. Fahey, Zheng Shen, Lucy R. Mukura, Yan Song, Susan Cu-Uvin, Kenneth H. Mayer, Peter F. Wright, John C. Kappes, Christina Ochsenbauer, Charles R. Wira

Dartmouth Scholarship

Background: We have previously demonstrated intrinsic anti-HIV activity in cervicovaginal lavage (CVL) from HIV-infected women with high CD4 counts and not on antiretroviral therapy. However, the impact of HIV disease progression on CVL innate immune responses has not been delineated.

Methods: CVL from 57 HIV-infected women not on antiretroviral therapy were collected by washing the cervicovaginal area with 10 ml of sterile normal saline. We characterized subject HIV disease progression by CD4 count strata: >500 cells/µl, 200-500 cells/µl, or <200 cells/µl of blood. To assess CVL anti-HIV activity, we incubated TZM-bl cells with HIV plus or minus CVL. Antimicrobials, cytokines, chemokines and anti-gp160 HIV IgG antibodies were measured by ELISA and Luminex.

Analysis And Validation Of A Parkinson's Disease Register As A Recruitment Tool For Clinical Studies., Camille Carroll, Amy Palmer, Christine Cosby, John Zajicek

Peninsula Medical School

Promotion of research is a key strategy of the National Health Service (NHS). Currently, many patients are not afforded the opportunity to participate in clinical studies. A register of research-interested patients has the potential to maximise inclusivity. We have established a register of research-interested patients with Parkinson's disease within the South West of England, with pragmatic inclusion criteria and multiple recruitment routes. We undertook an analysis of the register, investigation of its utility as a recruitment tool and a survey of recruiters. There were 529 active participants; 30% were self-referred and 70% were recruited by a healthcare practitioner. Response rate …

Greater Benefits Of Multisensory Integration During Complex Sensorimotor Transformations., Verena N Buchholz, Samanthi C Goonetilleke, W Pieter Medendorp, Brian D Corneil

Brain and Mind Institute Researchers' Publications

Multisensory integration enables rapid and accurate behavior. To orient in space, sensory information registered initially in different reference frames has to be integrated with the current postural information to produce an appropriate motor response. In some postures, multisensory integration requires convergence of sensory evidence across hemispheres, which would presumably lessen or hinder integration. Here, we examined orienting gaze shifts in humans to visual, tactile, or visuotactile stimuli when the hands were either in a default uncrossed posture or a crossed posture requiring convergence across hemispheres. Surprisingly, we observed the greatest benefits of multisensory integration in the crossed posture, as indexed …

A Prospective Observational Study Of Mycophenolate Mofetil Treatment In Progressive Diffuse Cutaneous Systemic Sclerosis Of Recent Onset., Fabian A. Mendoza, Md, Sarah J. Nagle, Jason B. Lee, Md, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset.

METHODS: Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients.

RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR …

Does The Load-Sharing Classification Predict Ligamentous Injury, Neurological Injury, And The Need For Surgery In Patients With Thoracolumbar Burst Fractures?: Clinical Article., Kristen Radcliff, Christopher K Kepler, Todd A Rubin, Motasem Maaieh, Alan S Hilibrand, James Harrop, Jeffrey A Rihn, Todd J Albert, Alexander R Vaccaro

Department of Orthopaedic Surgery Faculty Papers

OBJECT: The load-sharing score (LSS) of vertebral body comminution is predictive of results after short-segment posterior instrumentation of thoracolumbar burst fractures. Some authors have posited that an LSS > 6 is predictive of neurological injury, ligamentous injury, and the need for surgical intervention. However, the authors of the present study hypothesized that the LSS does not predict ligamentous or neurological injury.

METHODS: The prospectively collected spinal cord injury database from a single institution was queried for thoracolumbar burst fractures. Study inclusion criteria were acute (< 24 hours) burst fractures between T-10 and L-2 with preoperative CT and MRI. Flexion-distraction injuries and pathological fractures were excluded. Four experienced spine surgeons determined the LSS and posterior ligamentous complex (PLC) integrity. Neurological status was assessed from a review of the medical records.

RESULTS: Forty-four patients were included in the study. There were 4 patients for whom all observers …

Effect Of Oxidative Stress On Protein Tyrosine Phosphatase 1b In Scleroderma Dermal Fibroblasts., Pei-Suen Tsou, Nadine N. Talia, Adam J. Pinney, Ann Kendzicky, Sonsoles Piera-Velazquez, Sergio A. Jimenez, James R. Seibold, Kristine Phillips, Alisa E Koch

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: Platelet-derived growth factor (PDGF) and its receptor, PDGFR, promote fibrosis in systemic sclerosis (SSc; scleroderma) dermal fibroblasts, and such cells in scleroderma skin lesions produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and is dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. This study was undertaken to determine whether the thiol-sensitive PTP1B is affected by ROS in SSc dermal fibroblasts, thereby enhancing the phosphorylation of PDGFR and synthesis of type I collagen. This study also sought to investigate the effect of a thiol antioxidant, N-acetylcysteine (NAC), in SSc.

METHODS: Fibroblasts were isolated from the skin …

Resolution Of Bilateral Ptosis After Reduction Of Unilaterally Elevated Intraocular Pressure In A Child With Axenfeld-Reiger Spectrum Disorder., Ketki Soin, Alex V. Levin

Wills Eye Hospital Papers

We report a 9-month-old boy with bilateral pseudoptosis associated with elevated IOP. The patient had previously undergone bilateral trabeculectomies and Ahmed tube placement and right cataract extraction and penetrating keratoplasty. At presentation, the right eye IOP was 24 mm Hg and the left eye IOP was 32 mm Hg. Approximately 2 weeks after dorzolamide was added to the treatment regimen for the left eye, the mother reported that the ptosis had resolved. We suggest several explanations for the resolution of the ptosis.

Technical Desiderata For The Integration Of Genomic Data Into Electronic Health Records., Daniel R Masys, Gail P Jarvik, Neil F Abernethy, Nicholas R Anderson, George J Papanicolaou, Dina N Paltoo, Mark A Hoffman, Isaac S Kohane, Howard P Levy

Manuscripts, Articles, Book Chapters and Other Papers

The era of "Personalized Medicine," guided by individual molecular variation in DNA, RNA, expressed proteins and other forms of high volume molecular data brings new requirements and challenges to the design and implementation of Electronic Health Records (EHRs). In this article we describe the characteristics of biomolecular data that differentiate it from other classes of data commonly found in EHRs, enumerate a set of technical desiderata for its management in healthcare settings, and offer a candidate technical approach to its compact and efficient representation in operational systems.

Perspectives On: Sgp Symposium On Mitochondrial Physiology And Medicine: Mitochondria Take Center Stage., Shey-Shing Sheu, Robert T Dirksen, Edward N Pugh

Center for Translational Medicine Faculty Papers

No abstract provided.

Perspectives On: Sgp Symposium On Mitochondrial Physiology And Medicine: Molecular Identities Of Mitochondrial Ca2+ Influx Mechanism: Updated Passwords For Accessing Mitochondrial Ca2+-Linked Health And Disease., Jin O-Uchi, Shi Pan, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

No abstract provided.

Management Of Hyperglycemia In Type 2 Diabetes: A Patient-Centered Approach: Position Statement Of The American Diabetes Association (Ada) And The European Association For The Study Of Diabetes (Easd)., Silvio E Inzucchi, Richard M Bergenstal, John B Buse, Michaela Diamant, Ele Ferrannini, Michael Nauck, Anne L Peters, Apostolos Tsapas, Richard Wender, David R. Matthews

Department of Family & Community Medicine Faculty Papers

No abstract provided.

The Quest For The Perfect Prostate Biopsy Continues, Leonard G. Gomella

Kimmel Cancer Center Faculty Papers

No abstract provided.

Acceptability Of Narratives To Promote Colorectal Cancer Screening In An Online Community, Kevin O Hwang, Amber W Trickey, Amanda L Graham, Eric J Thomas, Richard L Street, Jennifer L Kraschnewski, Sally W Vernon

Faculty, Staff and Student Publications

OBJECTIVE: To assess the acceptability of narratives to promote colorectal cancer (CRC) screening among members of an online weight loss community.

METHOD: Members of online weight loss community completed an Internet survey in 2010. Multiple logistic regression models examined demographic and attitudinal correlates of interest in sharing and receiving CRC screening narratives.

RESULTS: Participants (n=2386) were 92% female with mean (SD) age 58 (6) years; 68% were up-to-date with CRC screening. Among those who were up-to-date, 39% were interested in sharing their narratives with other members. African-Americans were more likely than other racial groups to be interested in sharing narratives …

Collaborative Learning About E-Health For Mental Health Professionals And Service Users In A Structured Anonymous Online Short Course: Pilot Study., Emily J. Ashurst, Ray B. Jones, Graham R. Williamson, Tobit Emmens, Jon Perry

School of Nursing and Midwifery

BACKGROUND: Professionals are interested in using e-health but implementation of new methods is slow. Barriers to implementation include the need for training and limited awareness or experience. Research may not always convince mental health professionals (MHPs). Adding the 'voice' of mental health service users (MHSUs) in collaborative learning may help. Involving MHSUs in face-face education can be difficult. We had previously been unable to engage MHPs in online discussion with MHSUs. Here we assessed the feasibility of short online courses involving MHSUs and MHPs. METHODS: We ran three e-health courses, comprising live interactive webcast, week's access to a discussion forum, …

Does Initial Shunt Type For The Norwood Procedure Affect Echocardiographic Measures Of Cardiac Size And Function During Infancy?: The Single Vventricle Reconstruction Trial., Peter C. Frommelt, Lin T. Guey, L Luann Minich, Majeed Bhat, Tim J. Bradley, Steve D. Colan, Greg Ensing, Jessica Gorentz, Haleh Heydarian, J Blaine John, Wyman W. Lai, Jami C. Levine, William T. Mahle, Stephen G. Miller, Richard G. Ohye, Gail D. Pearson, Girish S. Shirali, Pierre C. Wong, Meryl S. Cohen, Pediatric Heart Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle-pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age.

METHODS AND RESULTS: A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5 ± 13.4 days), before stage II procedure (age 4.8 ± 1.8 months), and at 14 …

Cdc42-Dependent Activation Of Nadph Oxidase Is Involved In Ethanol-Induced Neuronal Oxidative Stress, Xin Wang, Zunji Ke, Gang Chen, Mei Xu, Kimberly A. Bower, Jacqueline A. Frank, Zhuo Zhang, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

It has been suggested that excessive reactive oxygen species (ROS) and oxidative stress play an important role in ethanol-induced damage to both the developing and mature central nervous system (CNS). The mechanisms underlying ethanol-induced neuronal ROS, however, remain unclear. In this study, we investigated the role of NADPH oxidase (NOX) in ethanol-induced ROS generation. We demonstrated that ethanol activated NOX and inhibition of NOX reduced ethanol-promoted ROS generation. Ethanol significantly increased the expression of p47^phox and p67^phox, the essential subunits for NOX activation in cultured neuronal cells and the cerebral cortex of infant mice. Ethanol caused serine …

Process Evaluation Of A Positive Youth Development Program In Hong Kong Based On Different Cohorts, Ben M. F. Law, Daniel T. L. Shek

Pediatrics Faculty Publications

There are only a few process evaluation studies on positive youth development programs, particularly in the Chinese context. This study aims to examine the quality of implementation of a positive youth development program (the Project P.A.T.H.S.: Positive Adolescent Training through Holistic Social Programmes) and investigate the relationships among program adherence, process factors, implementation quality, and perceived program success. Process evaluation of 97 classroom-based teaching units was conducted in 62 schools from 2005 to 2009. Findings based on different cohorts generally showed that there were high overall program adherence and implementation quality. Program adherence and implementation process were highly correlated with …

Interim Evaluation Of The Project P.A.T.H.S.: Findings Based On Different Datasets, Daniel T. L. Shek, Lu Yu

Pediatrics Faculty Publications

Interim evaluation studies were carried out in order to examine the implementation details of the Tier 1 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in Hong Kong. Quantitative results of the interim evaluation findings based on eight datasets collected from 2006 to 2009 are reported in this paper. Three hundred and seventy-eight schools were randomly selected to provide information on the implementation details of the program via face-to-face interviews, telephone interviews, and self-completed questionnaires. Results showed that a majority of the workers perceived that the students had positive responses to the program and the program …

Qualitative Evaluation Of Project P.A.T.H.S.: An Integration Of Findings Based On Program Participants, Daniel T. L. Shek, Rachel C. F. Sun

Pediatrics Faculty Publications

An integration of the qualitative evaluation findings collected in different cohorts of students who participated in Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) (n = 252 students in 29 focus groups) was carried out. With specific focus on how the informants described the program, results showed that the descriptions were mainly positive in nature, suggesting that the program was well received by the program participants. When the informants were invited to name three metaphors that could stand for the program, positive metaphors were commonly used. Beneficial effects of the program in different psychosocial domains were also voiced by …

Imaging Prior Information In The Brain, Scott Gorlin, Ming Meng, Jitendra Sharma, Hiroki Sugihara

Dartmouth Scholarship

In making sense of the visual world, the brain's processing is driven by two factors: the physical information provided by the eyes (“bottom-up” data) and the expectancies driven by past experience (“top-down” influences). We use degraded stimuli to tease apart the effects of bottom-up and top-down processes because they are easier to recognize with prior knowledge of undegraded images. Using machine learning algorithms, we quantify the amount of information that brain regions contain about stimuli as the subject learns the coherent images. Our results show that several distinct regions, including high-level visual areas and the retinotopic cortex, contain more information …

Interleukin-1Β Mediates Metalloproteinase-Dependent Renal Cell Carcinoma Tumor Cell Invasion Through The Activation Of Ccaat Enhancer Binding Protein Β, Brenda L. Petrella, Matthew P. P. Vincenti

Dartmouth Scholarship

Effective treatment of metastatic renal cell carcinoma (RCC) remains a major medical concern, as these tumors are refractory to standard therapies and prognosis is poor. Although molecularly targeted therapies have shown some promise in the treatment of this disease, advanced RCC tumors often develop resistance to these drugs. Dissecting the molecular mechanisms underlying the progression to advanced disease is necessary to design alternative and improved treatment strategies. Tumor-associated macrophages (TAMs) found in aggressive RCC tumors produce a variety of inflammatory cytokines, including interleukin-1 b (IL-1b). Moreover, the presence of TAMs and high serum levels of IL-1b in RCC patients correlate …

Deciphering Mechanisms Of Staphylococcal Biofilm Evasion Of Host Immunity., Mark L. Hanke, Tammy Kielian

Journal Articles: Pathology and Microbiology

Biofilms are adherent communities of bacteria contained within a complex matrix. Although host immune responses to planktonic staphylococcal species have been relatively well-characterized, less is known regarding immunity to staphylococcal biofilms and how they modulate anti-bacterial effector mechanisms when organized in this protective milieu. Previously, staphylococcal biofilms were thought to escape immune recognition on the basis of their chronic and indolent nature. Instead, we have proposed that staphylococcal biofilms skew the host immune response away from a proinflammatory bactericidal phenotype toward an anti-inflammatory, pro-fibrotic response that favors bacterial persistence. This possibility is supported by recent studies from our laboratory using …

Dna Methylation Arrays As Surrogate Measures Of Cell Mixture Distribution, Eugene Houseman, William P. Accomando, Devin C. Koestler, Brock C. Christensen, Carmen J. Marsit

Dartmouth Scholarship

There has been a long-standing need in biomedical research for a method that quantifies the normally mixed composition of leukocytes beyond what is possible by simple histological or flow cytometric assessments. The latter is restricted by the labile nature of protein epitopes, requirements for cell processing, and timely cell analysis. In a diverse array of diseases and following numerous immune-toxic exposures, leukocyte composition will critically inform the underlying immuno-biology to most chronic medical conditions. Emerging research demonstrates that DNA methylation is responsible for cellular differentiation, and when measured in whole peripheral blood, serves to distinguish cancer cases from controls.

Improved Tumor Contrast Achieved By Single Time Point Dual-Reporter Fluorescence Imaging, Kenneth M. Tichauer, Kimberley S. Samkoe, Kristian J. Sexton, Jason R. Gunn, Tayyaba Hasan, Brian W. Pogue

Dartmouth Scholarship

In this study, we demonstrate a method to quantify biomarker expression that uses an exogenous dual-reporter imaging approach to improve tumor signal detection. The uptake of two fluorophores, one nonspecific and one targeted to the epidermal growth factor receptor (EGFR), were imaged at 1 h in three types of xenograft tumors spanning a range of EGFR expression levels (n  =  6 in each group). Using this dual-reporter imaging methodology, tumor contrast-to-noise ratio was amplified by >6 times at 1 h postinjection and >2 times at 24 h. Furthermore, by as early as 20 min postinjection, the dual-reporter imaging signal …

Factor Structure Of A Multidimensional Gender Identity Scale In A Sample Of Chinese Elementary School Children, Lu Yu, Dong Xie, Daniel T. L. Shek

Pediatrics Faculty Publications

This study examined the factor structure of a scale based on the four-dimensional gender identity model (Egan and Perry, 2001) in 726 Chinese elementary school students. Exploratory factor analyses suggested a three-factor model, two of which corresponded to "Felt Pressure" and "Intergroup Bias" in the original model. The third factor "Gender Compatibility" appeared to be a combination of "Gender Typicality" and "Gender Contentment" in the original model. Follow-up confirmatory factor analysis (CFA) indicated that, relative to the initial four-factor structure, the three-factor model fits the current Chinese sample better. These results are discussed in light of cross-cultural similarities and differences …

Pv1 Down-Regulation Via Shrna Inhibits The Growth Of Pancreatic Adenocarcinoma Xenografts, Sophie J. Deharvengt, Dan Tse, Olga Sideleva, Caitlin Mcgarry, Jason R. Gunn, Daniel S. Longnecker, Catherine Carriere, Radu V. Stan

Dartmouth Scholarship

PV1 is an endothelial-specific protein with structural roles in the formation of diaphragms in endothelial cells of normal vessels. PV1 is also highly expressed on endothelial cells of many solid tumours. On the basis of in vitro data, PV1 is thought to actively participate in angiogenesis. To test whether or not PV1 has a function in tumour angiogenesis and in tumour growth in vivo, we have treated pancreatic tumour-bearing mice by single-dose intratumoural delivery of lentiviruses encoding for two different shRNAs targeting murine PV1. We find that PV1 down-regulation by shRNAs inhibits the growth of established tumours derived from two …

The Meaning Of Parenteral Hydration To Family Caregivers And Patients With Advanced Cancer Receiving Hospice Care., Marlene Z. Cohen, Isabel Torres-Vigil, Beth E. Burbach, Allison De La Rosa, Eduardo Bruera

Journal Articles: College of Nursing

CONTEXT: In the U.S., patients with advanced cancer who are dehydrated or have decreased oral intake almost always receive parenteral hydration in acute care facilities but rarely in the hospice setting.

OBJECTIVES: To describe the meaning of hydration for terminally ill cancer patients in home hospice care and for their primary caregivers.

METHODS: Phenomenological interviews were conducted at two time points with 85 patients and 84 caregivers enrolled in a randomized, double-blind, controlled trial examining the efficacy of parenteral hydration in patients with advanced cancer receiving hospice care in the southern U.S. Transcripts were analyzed hermeneutically by the interdisciplinary research …