Digital Commons Network^™

Advancing Pharmacometrics And Systems Pharmacology., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Pharmacometrics and systems pharmacology are emerging as principal quantitative sciences within drug development and experimental therapeutics. In recognition of the importance of pharmacometrics and systems pharmacology to the discipline of clinical pharmacology, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), in collaboration with Nature Publishing Group and Clinical Pharmacology & Therapeutics, has established CPT: Pharmacometrics & Systems Pharmacology to inform the field and shape the discipline.

A Four Factor Model Of Systems-Based Practices In Psychiatry., Jules M. Ranz, Michael Weinberg, Melissa R. Arbuckle, Joanna Fried, Anthony Carino, Hunter L. Mcquistion, Glen Davis, Donovan Wong, Sosunmolu O. Shoyinka, Benjamin Brody, Kamala D. Sethi, Anna Skiandos, Wesley Sowers, David Stern, Anne Sullivan, Michael J. Vergare

Department of Psychiatry and Human Behavior Faculty Papers

No abstract provided.

Expanding Delivery System Research In Public Health Settings: Lessons From Practice-Based Research Networks, Glen P. Mays, Rachel A. Hogg

Health and Clinical Sciences Faculty Publications

BACKGROUND: Delivery system research to identify how best to organize, finance, and implement health improvement strategies has focused heavily on clinical practice settings, with relatively little attention paid to public health settings-where research is made more difficult by wide heterogeneity in settings and limited sources of existing data and measures. This study examines the approaches used by public health practice-based research networks (PBRNs) to expand delivery system research and evidence-based practice in public health settings.

METHODS: Practice-based research networks employ quasi-experimental research designs, natural experiments, and mixed-method analytic techniques to evaluate how community partnerships, economic shocks, and policy changes impact …

Molecular Mechanism For Depolarization-Induced Modulation Of Kv Channel Closure, Alain J. Labro, Jerome J. Lacroix, Carlos A. Villalba-Galea, Dirk J. Snyders, Francisco Bezanilla

School of Pharmacy Faculty Articles

Voltage-dependent potassium (Kv) channels provide the repolarizing power that shapes the action potential duration and helps control the firing frequency of neurons. The K(+) permeation through the channel pore is controlled by an intracellularly located bundle-crossing (BC) gate that communicates with the voltage-sensing domains (VSDs). During prolonged membrane depolarizations, most Kv channels display C-type inactivation that halts K(+) conduction through constriction of the K(+) selectivity filter. Besides triggering C-type inactivation, we show that in Shaker and Kv1.2 channels (expressed in Xenopus laevis oocytes), prolonged membrane depolarizations also slow down the kinetics of VSD deactivation and BC gate closure during the …

Escherichia Coli Recg Functionally Suppresses Human Bloom Syndrome Phenotypes, Michael W. Killen, Dawn M. Stults, William A. Wilson, Andrew J. Pierce

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to …

Addressing Appearance-Related Distress Across Clinical Conditions., Alyson Bessell, Emma Dures, Cherith Semple, Sue Jackson

School of Psychology

Evidence is accumulating about the nature and prevalence of appearance-related distress across a variety of clinical populations. Health professionals working with specific patient groups are often aware of these difficulties and their detrimental effect on quality of life and wellbeing. However, many health professionals lack knowledge and skills on how to support patients, either within the team or via referral to relevant service providers who have expertise in managing appearance-related distress. This is mainly owing to a lack of information about screening, assessment measures and available interventions. The aim of this article is to consider how health professionals can support …

Gene Expression Analysis Of A Murine Model With Pulmonary Vascular Remodeling Compared To End-Stage Ipah Lungs, Kayoko Shimodaira, Yoichiro Okubo, Eri Ochiai, Haruo Nakayama, Harutaka Katano, Megumi Wakayama, Minoru Shinozaki, Takao Ishiwatari, Daisuke Sasai, Naobumi Tochigi, Tetsuo Nemoto, Tsutomu Saji, Katsuhiko Kamei, Kazutoshi Shibuya

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our …

Cdk Inhibitors (P16/P19/P21) Induce Senescence And Autophagy In Cancer-Associated Fibroblasts, "Fueling" Tumor Growth Via Paracrine Interactions, Without An Increase In Neo-Angiogenesis., Claudia Capparelli, Barbara Chiavarina, Diana Whitaker-Menezes, Timothy G Pestell, Richard Pestell, James Hulit, Sebastiano Andò, Anthony Howell, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, …

Interstage Mortality After The Norwood Procedure: Results Of The Multicenter Single Ventricle Reconstruction Trial., Nancy S. Ghanayem, Kerstin R. Allen, Sarah Tabbutt, Andrew M. Atz, Martha L. Clabby, David S. Cooper, Pirooz Eghtesady, Peter C. Frommelt, Peter J. Gruber, Kevin D. Hill, Jonathan R. Kaltman, Peter C. Laussen, Alan B. Lewis, Karen J. Lurito, L Luann Minich, Richard G. Ohye, Julie V. Schonbeck, Steven M. Schwartz, Rakesh K. Singh, Caren S. Goldberg, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: For infants with single ventricle malformations undergoing staged repair, interstage mortality is reported at 2% to 20%. The Single Ventricle Reconstruction trial randomized subjects with a single morphologic right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt (MBTS) or a right ventricle-to-pulmonary artery shunt (RVPAS). The aim of this analysis was to explore the associations of interstage mortality and shunt type, and demographic, anatomic, and perioperative factors.

METHODS: Participants in the Single Ventricle Reconstruction trial who survived to discharge after the Norwood procedure were included (n = 426). Interstage mortality was defined as death postdischarge after the …

Design Of A Prostate Cancer Patient Navigation Intervention For A Veterans Affairs Hospital, Narissa J. Nonzee, June M. Mckoy, Alfred W. Rademaker, Peter Byer, Thanh H. Luu, Dachao Liu, Elizabeth A. Richey

Dartmouth Scholarship

Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago.

Early Adoption Of Transoral Robotic Surgical Program: Preliminary Outcomes., David Cognetti, Adam Luginbuhl, Anthony L. Nguyen, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVE: The objective of this study is to demonstrate the feasibility and safety of establishing a transoral robotic surgical (TORS) program in the post-Food and Drug Administration (FDA) approval setting. Early outcomes are compared with the previously reported results of pioneering centers.

STUDY DESIGN: Clinical data from a prospective TORS study.

SETTING: Academic university institution.

SUBJECTS AND METHODS: Sixty-one patients treated with 63 TORS procedures. Main outcome measures: intraoperative times, margin status, complications, time to diet, and percutaneous endoscopic gastrostomy (PEG) tube retention rate. The authors also report oncologic outcomes on their first 30 patients.

RESULTS: The spectrum of subsites …

Dermatofibroma: A Curious Tumor., Lawrence Parish, Shideh Yazdanian, W Clark Lambert, Peter C Lambert

Department of Dermatology and Cutaneous Biology Faculty Papers

A tumor, such as a dermatofibroma, causes consternation among many patients, but it rarely creates problems on its own. Also called a histiocytoma, it remains one of the most common mesenchymal growths. Its etiology is unknown with the previous theory that it is a dermal response to injury, such as an insect bite, being challenged. As much as patients like to blame spiders or other arthropods for traumatizing an arm or leg, no definitive explanation is available for its etiology.

How Do We Change Practice When We Have The Evidence?, Janice P Burke, Laura N. Gitlin

Department of Occupational Therapy Faculty Papers

Translating research findings into practice includes myriad pragmatic realities, including understanding the suitability of the data to a particular patient group, writing new guidelines for occupational therapy practitioners, facilitating adoption of the guidelines, and instituting new patterns of care for patients. The process is more than a matter of disseminating the information to practitioners and expecting immediate change in patient treatment. Indeed, the field of implementation science is devoted to the identification of the numerous barriers and supports that constrain or expedite practice change in response to research. Moving forward and adopting evidence-based findings will require a focused understanding of …

Exosome-Mediated Shuttling Of Microrna-29 Regulates Hiv Tat And Morphine-Mediated Neuronal Dysfunction., Guoku Hu, H Yao, A D. Chaudhuri, Sowmya V. Yelamanchili, H Wen, P D. Cheney, Howard S. Fox, Shilpa J. Buch

Journal Articles: Pharmacology & Experimental Neuroscience

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance …

Psychometrics Of The Scale Of Attitudes Toward Physician-Pharmacist Collaboration: A Study With Medical Students., Mohammadreza Hojat, John Spandorfer, Gerald A. Isenberg, Michael J. Vergare, Reza Fassihi, Joseph S. Gonnella

Department of Psychiatry and Human Behavior Faculty Papers

BACKGROUND: Despite the emphasis placed on interdisciplinary education and interprofessional collaboration between physicians and pharmacologists, no psychometrically sound instrument is available to measure attitudes toward collaborative relationships.

AIM: This study was designed to examine psychometrics of an instrument for measuring attitudes toward physician-pharmacist collaborative relationships for administration to students in medical and pharmacy schools and to physicians and pharmacists.

METHODS: The Scale of Attitudes Toward Physician-Pharmacist Collaboration was completed by 210 students at Jefferson Medical College. Factor analysis and correlational methods were used to examine psychometrics of the instrument.

RESULTS: Consistent with the conceptual framework of interprofessional collaboration, three underlying …

Validation Of Food Store Environment Secondary Data Source And The Role Of Neighborhood Deprivation In Appalachia, Kentucky, Alison A. Gustafson, Sarah Lewis, Corey Wilson, Stephanie Jilcott-Pitts

Dietetics and Human Nutrition Faculty Publications

BACKGROUND: Based on the need for better measurement of the retail food environment in rural settings and to examine how deprivation may be unique in rural settings, the aims of this study were: 1) to validate one commercially available data source with direct field observations of food retailers; and 2) to examine the association between modified neighborhood deprivation and the modified retail food environment score (mRFEI).

METHODS: Secondary data were obtained from a commercial database, InfoUSA in 2011, on all retail food outlets for each census tract. In 2011, direct observation identifying all listed food retailers was conducted in 14 …

Reflective Journals Of Students Taking A Positive Youth-Development Course In A University Context In Hong Kong, Daniel T. L. Shek, Florence K. Y. Wu

Pediatrics Faculty Publications

To promote the holistic development of university students, a course entitled "Tomorrow's Leaders" was developed and offered at The Hong Kong Polytechnic University. Based on a case study approach, reflective journals of five outstanding students of the course are presented and analyzed (i.e., thick description), with several themes emerging from the reflection. First, the students liked the course, and they identified many positive attributes. Second, the students appreciated the instructors. Third, the students viewed that the course contributed to different aspects of their development. Fourth, some areas of improvements were proposed. In conjunction with other evaluation mechanisms, the present findings …

Plant Calcium Content: Ready To Remodel, Jian Yang, Tracy Punshon, Mary Lou Guerinot, Kendal D. Hirschi

Dartmouth Scholarship

By identifying the relationship between calcium location in the plant cell and nutrient bioavailability, the plant characteristics leading to maximal calcium absorption by humans can be identified. Knowledge of plant cellular and molecular targets controlling calcium location in plants is emerging. These insights should allow for better strategies for increasing the nutritional content of foods. In particular, the use of preparation-free elemental imaging technologies such as synchrotron X-ray fluorescence (SXRF) microscopy in plant biology may allow researchers to understand the relationship between subcellular location and nutrient bioavailability. These approaches may lead to better strategies for altering the location of calcium …

A Digital X-Ray Tomosynthesis Coupled Near Infrared Spectral Tomography System For Dual-Modality Breast Imaging, Venkataramanan Krishnaswamy, Kelly E. Michaelsen, Brian W. Pogue, Steven P. Poplack, Ian Shaw, Ken Defrietas, Ken Brooks, Keith D. Paulsen

Dartmouth Scholarship

A Near Infrared Spectral Tomography (NIRST) system has been developed and integrated into a commercial Digital Breast Tomosynthesis (DBT) scanner to allow structural and functional imaging of breast in vivo. The NIRST instrument uses an 8-wavelength continuous wave (CW) laser-based scanning source assembly and a 75-element silicon photodiode solid-state detector panel to produce dense spectral and spatial projection data from which spectrally constrained 3D tomographic images of tissue chromophores are produced. Integration of the optical imaging system into the DBT scanner allows direct co-registration of the optical and DBT images, while also facilitating the synergistic use of x-ray contrast as …

Hormonal Induction Of Polo-Like Kinases (Plks) And Impact Of Plk2 On Cell Cycle Progression In The Rat Ovary, Feixue Li, Misung Jo, Thomas E. Curry, Jing Liu

Obstetrics and Gynecology Faculty Publications

The highly conserved polo-like kinases (Plks) are potent regulators of multiple functions in the cell cycle before and during mitotic cell division. We investigated the expression pattern of Plk genes and their potential role(s) in the rat ovary during the periovulatory period. Plk2 and Plk3 were highly induced both in intact ovaries and granulosa cells in vivo after treatment with the luteinizing hormone (LH) agonist, human chorionic gonadotropin (hCG). In vitro, hCG stimulated the expression of Plk2 in granulosa cells, but not Plk3. This induction of Plk2 expression was mimicked by both forskolin and phorbol 12 myristate 13-acetate (PMA). Moreover, …

Family And Personal Adjustment Of Economically Disadvantaged Chinese Adolescents In Hong Kong, Daniel T. L. Shek, Pik Fong Tsui

Pediatrics Faculty Publications

This study attempted to examine the relationship between poverty and adolescent developmental outcomes in the family and personal domains in 3,328 Chinese secondary school students in Hong Kong. Developmental outcomes included positive youth development constructs, problem behaviors, perceived family interaction, and parental parenting. Results showed that adolescents experiencing poverty did not differ from nonpoor adolescents in terms of risk behavior and in most indicators of positive youth development. On the other hand, adolescents with economic disadvantage displayed lower levels of positive identity, family interaction, and perceived paternal parenting than did those without economic disadvantage.

Subjective Outcome Evaluation Of The Project P.A.T.H.S. In Different Cohorts Of Students, Daniel T. L. Shek, Cecilia M. S. Ma

Pediatrics Faculty Publications

The project P.A.T.H.S. is an indigenously developed positive youth development program in Hong Kong. In the extension phase (2009/2010 school year), subjective outcome evaluation data were collected from 231 schools involving 89,068 participants after completion of the curricula-based Tier 1 Program. With schools as the units of analysis, results showed that participants generally had positive perceptions of the program content and implementers, with over four-fifth of the participants regarded the program as helpful to them. There were some significant grade differences in the subjective outcome evaluation findings, although the related effect size was not strong. Multiple regression analyses revealed that …

Student Classroom Misbehavior: An Exploratory Study Based On Teachers' Perceptions, Rachel C. F. Sun, Daniel T. L. Shek

Pediatrics Faculty Publications

This study aimed to examine the conceptions of junior secondary school student misbehaviors in classroom, and to identify the most common, disruptive, and unacceptable student problem behaviors from teachers' perspective. Twelve individual interviews with teachers were conducted. A list of 17 student problem behaviors was generated. Results showed that the most common and disruptive problem behavior was talking out of turn, followed by nonattentiveness, daydreaming, and idleness. The most unacceptable problem behavior was disrespecting teachers in terms of disobedience and rudeness, followed by talking out of turn and verbal aggression. The findings revealed that teachers perceived student problem behaviors as …

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens And Patient Outcomes: An Individual Patient Data Meta-Analysis Of 9,153 Patients, Shama D. Ahuja, David Ashkin, Monika Avendano, Rita Banerjee, Melissa Bauer, Jamie N. Bayona

Dartmouth Scholarship

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.

Classroom Misbehavior In The Eyes Of Students: A Qualitative Study, Rachel C. F. Sun, Daniel T. L. Shek

Pediatrics Faculty Publications

Using individual interviews, this study investigated perceptions of classroom misbehaviors among secondary school students in Hong Kong (N = 18). Nineteen categories of classroom misbehaviors were identified, with talking out of turn, disrespecting teacher, and doing something in private being most frequently mentioned. Findings revealed that students tended to perceive misbehaviors as those actions inappropriate in the classroom settings and even disrupting teachers' teaching and other students' learning. Among various misbehaviors, talking out of turn and disrespecting teacher were seen as the most disruptive and unacceptable. These misbehaviors were unacceptable because they disturbed teaching and learning, and violated the values …

Postlecture Evaluation Of A Positive Youth Development Subject For University Students In Hong Kong, Daniel T. L. Shek

Pediatrics Faculty Publications

The purpose of this study was to examine the postlecture evaluation by the students taking a course (Tomorrow's Leaders) that attempted to promote their leadership qualities and intrapersonal competencies at The Hong Kong Polytechnic University in Hong Kong. Except for the last lecture, students were invited to respond to a 12-item postlecture questionnaire after each lecture. Results showed that the students had positive perceptions of the subject, class, and teacher attributes, and they had positive global evaluation of the teacher and the subject. The postlecture evaluation questionnaire was found to possess good psychometric properties. Multiple regression analyses showed that subject, …

Modeling Of Pharmacokinetics Of Cocaine In Human Reveals The Feasibility For Development Of Enzyme Therapies For Drugs Of Abuse, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly …

Management Of Periprosthetic Joint Infection: The Current Knowledge: Aaos Exhibit Selection., Javad Parvizi, Bahar Adeli, Benjamin Zmistowski, Camilo Restrepo, Alan Seth Greenwald

Rothman Institute Papers

Periprosthetic joint infection continues to frustrate the medical community. Although the demand for total joint arthroplasty is increasing, the burden of such infections is increasing even more rapidly, and they pose a unique challenge because their accurate diagnosis and eradication can prove elusive. This review describes the current knowledge regarding diagnosis and treatment of periprosthetic joint infection. A number of tools are available to aid in establishing a diagnosis of periprosthetic joint infection. These include the erythrocyte sedimentation rate, serum C-reactive protein concentration, synovial white blood-cell count and differential, imaging studies, tissue specimen culturing, and histological analysis. Multiple definitions of …

The Human Phosphotyrosine Signaling Network: Evolution And Hotspots Of Hijacking In Cancer., Lei Li, Chabane Tibiche, Cong Fu, Tomonori Kaneko, Michael F. Moran, Martin Schiller, Shawn Shun-Cheng Li, Edwin Wang

Life Sciences Faculty Research

Phosphotyrosine (pTyr) signaling, which plays a central role in cell-cell and cell-environment interactions, has been considered to be an evolutionary innovation in multicellular metazoans. However, neither the emergence nor the evolution of the human pTyr signaling system is currently understood. Tyrosine kinase (TK) circuits, each of which consists of a TK writer, a kinase substrate, and a related reader, such as Src homology (SH) 2 domains and pTyr-binding (PTB) domains, comprise the core machinery of the pTyr signaling network. In this study, we analyzed the evolutionary trajectories of 583 literature-derived and 50,000 computationally predicted human TK circuits in 19 representative …

Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?, Fabian A. Mendoza, Md, Lynette L Keyes-Elstein, Sergio A. Jimenez

Scleroderma Center Faculty Papers

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should …