Sample records for abuse preclinical models

  1. Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

    PubMed

    Teuns, Greet B A; Geys, Helena M; Geuens, Sonja M A; Stinissen, Piet; Meert, Theo F

    2014-01-01

    Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the

  2. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse

    PubMed Central

    Carnicella, Sebastien; Ron, Dorit; Barak, Segev

    2014-01-01

    One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5–6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders. PMID:24721195

  3. Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse.

    PubMed

    Carnicella, Sebastien; Ron, Dorit; Barak, Segev

    2014-05-01

    One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5-6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Interactions between nicotine and drugs of abuse: A review of preclinical findings

    PubMed Central

    Kohut, Stephen J.

    2017-01-01

    Polysubstance abuse is common among substance use disorder patients and nicotine is one of the most commonly co-used substances. Epidemiological and clinical laboratory studies suggest that nicotine, when combined with other drugs of abuse, increases intake of one or both substances. This review focuses on the preclinical literature regarding nicotine’s interaction with alcohol, stimulants (i.e., cocaine, amphetamines), opioids (i.e., morphine, heroin) and Δ9-tetrahydrocannabinol (THC). The current understanding of how these various classes of abused drugs may interact with nicotine on behavioral, physiological, and pharmacological indices that may be important in maintaining co-use of one or both substances in human populations are highlighted. Suggestions as to future areas of research and gaps in knowledge are offered. PMID:27589579

  5. Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies.

    PubMed

    Gauvin, David V; Zimmermann, Zachary J; Baird, Theodore J

    2015-10-01

    Current regulatory policies of both the US Food and Drug Administration and Drug Enforcement Administration do not delineate automatic exceptions for biologics with respect to preclinical assessments for abuse liability of all new entities. As defined in current guidance documents and drug control policies, an exception may be given upon thorough review of available data, therapeutic target and in consultation with the Controlled Substances Staff within the Center for Drug Evaluation and Research of the FDA, but a blanket exception for all biological entities is not currently available. We review the abuse liability testing of four known biologics with definitive positive abuse liability signals in the three core abuse liability assays, self-administration, drug discrimination, and dependence potential described in the FDA draft guidance document. Interestingly, while all four examplars have positive abuse liability signals in all three assays, two of these biologics are controlled under the Comprehensive Drug Abuse and Control Act (CSA, 1970) and the other two are not currently controlled. Admittedly, these four biologics are small molecule entities. However, there is no reference to "molecular size" in the legally-binding statutory definition of biologics under the FD&C act or in the Controlled Substances Act. Neither of these drug control policy mandates have a bifurcated control status in which to make exceptions based solely on molecular size. With the current pharmaceutical focus on new technologies, such as "Trojan Horses", targeting the active transport of large molecule entities directly into the CNS, an argument to automatically exempt new molecular entities solely on molecular size is untenable. We argue that for the safety and health of general public the current regulatory control status be maintained until definitive criteria for exceptions can be identified and amended to both the FD&CA and CSA, if warranted. Copyright © 2015 Elsevier Inc. All

  6. Modeling the Western Diet for Preclinical Investigations.

    PubMed

    Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

    2018-05-01

    Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

  7. Patient-derived xenografts as preclinical neuroblastoma models.

    PubMed

    Braekeveldt, Noémie; Bexell, Daniel

    2018-05-01

    The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing.

  8. Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

    PubMed Central

    Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

    2015-01-01

    Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

  9. Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder.

    PubMed

    Banks, Matthew L

    2017-04-01

    Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation toward abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., money and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self-administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder. © 2016 New York Academy of Sciences.

  10. Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder

    PubMed Central

    Banks, Matthew L.

    2016-01-01

    Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation towards abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., work and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self-administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder. PMID:27936284

  11. Preclinical Animal Models for Temporomandibular Joint Tissue Engineering.

    PubMed

    Almarza, Alejandro J; Brown, Bryan N; Arzi, Boaz; Ângelo, David Faustino; Chung, William; Badylak, Stephen F; Detamore, Michael

    2018-06-01

    There is a paucity of in vivo studies that investigate the safety and efficacy of temporomandibular joint (TMJ) tissue regeneration approaches, in part due to the lack of established animal models. Review of disease models for study of TMJ is presented herein with an attempt to identify relevant preclinical animal models for TMJ tissue engineering, with emphasis on the disc and condyle. Although degenerative joint disease models have been mainly performed on mice, rats, and rabbits, preclinical regeneration approaches must employ larger animal species. There remains controversy regarding the preferred choice of larger animal models between the farm pig, minipig, goat, sheep, and dog. The advantages of the pig and minipig include their well characterized anatomy, physiology, and tissue properties. The advantages of the sheep and goat are their easier surgical access, low cost per animal, and its high tissue availability. The advantage of the dog is that the joint space is confined, so migration of interpositional devices should be less likely. However, each species has limitations as well. For example, the farm pig has continuous growth until about 18 months of age, and difficult surgical access due to the zygomatic arch covering the lateral aspect of joint. The minipig is not widely available and somewhat costly. The sheep and the goat are herbivores, and their TMJs mainly function in translation. The dog is a carnivore, and the TMJ is a hinge joint that can only rotate. Although no species provides the gold standard for all preclinical TMJ tissue engineering approaches, the goat and sheep have emerged as the leading options, with the minipig as the choice when cost is less of a limitation; and with the dog and farm pig serving as acceptable alternatives. Finally, naturally occurring TMJ disorders in domestic species may be harnessed on a preclinical trial basis as a clinically relevant platform for translation.

  12. Vaccines for Drug Abuse

    PubMed Central

    Shen, Xiaoyun; Orson, Frank M.; Kosten, Thomas R.

    2012-01-01

    Current medications for drug abuse have had only limited success. Anti-addiction vaccines to elicit antibodies that block the pharmacological effects of drugs have great potential for treating drug abuse. We review the status for two vaccines that are undergoing clinical trials (cocaine and nicotine) and two that are still in pre-clinical development (methamphetamine and heroin). We also outline the challenges and ethical concerns for anti-addiction vaccine development and their use as future therapeutics. PMID:22130115

  13. Modeling mania in preclinical settings: a comprehensive review

    PubMed Central

    Sharma, Ajaykumar N.; Fries, Gabriel R.; Galvez, Juan F.; Valvassori, Samira S.; Soares, Jair C.; Carvalho, André F.; Quevedo, Joao

    2015-01-01

    The current pathophysiological understanding of mechanisms leading to onset and progression of bipolar manic episodes remains limited. At the same time, available animal models for mania have limited face, construct, and predictive validities. Additionally, these models fail to encompass recent pathophysiological frameworks of bipolar disorder (BD), e.g. neuroprogression. Therefore, there is a need to search for novel preclinical models for mania that could comprehensively address these limitations. Herein we review the history, validity, and caveats of currently available animal models for mania. We also review new genetic models for mania, namely knockout mice for genes involved in neurotransmission, synapse formation, and intracellular signaling pathways. Furthermore, we review recent trends in preclinical models for mania that may aid in the comprehension of mechanisms underlying the neuroprogressive and recurring nature of BD. In conclusion, the validity of animal models for mania remains limited. Nevertheless, novel (e.g. genetic) animal models as well as adaptation of existing paradigms hold promise. PMID:26545487

  14. Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications

    PubMed Central

    Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong

    2017-01-01

    Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. PMID:28515222

  15. Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications.

    PubMed

    Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong; Searson, Peter C; Lee, Kwan Hyi

    2017-06-30

    Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. © 2017 The Author(s).

  16. Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

    DTIC Science & Technology

    2014-09-01

    AD_________________ Award Number: TITLE: Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...AUG 2013-7 Aug 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...a genetic mouse model of autism -like phenotypes, the Grin1 knockdown mouse. The Grin1 gene encodes the NR1 subunit of the NMDA receptor . In the

  17. SEIIrR: Drug abuse model with rehabilitation

    NASA Astrophysics Data System (ADS)

    Sutanto, Azizah, Afina; Widyaningsih, Purnami; Saputro, Dewi Retno Sari

    2017-05-01

    Drug abuse in the world quite astonish and tend to increase. The increase and decrease on the number of drug abusers showed a pattern of spread that had the same characteristics with patterns of spread of infectious disease. The susceptible infected removed (SIR) and susceptible exposed infected removed (SEIR) epidemic models for infectious disease was developed to study social epidemic. In this paper, SEIR model for disease epidemic was developed to study drug abuse epidemic with rehabilitation treatment. The aims of this paper were to analogize susceptible exposed infected isolated recovered (SEIIrR) model on the drug abusers, to determine solutions of the model, to determine equilibrium point, and to do simulation on β. The solutions of SEIIrR model was determined by using fourth order of Runge-Kutta algorithm, equilibrium point obtained was free-drug equilibrium point. Solutions of SEIIrR showed that the model was able to suppress the spread of drug abuse. The increasing value of contact rate was not affect the number of infected individuals due to rehabilitation treatment.

  18. Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis.

    PubMed

    Kitz, Jenna; Lowes, Lori E; Goodale, David; Allan, Alison L

    2018-04-28

    The majority of cancer deaths occur because of metastasis since current therapies are largely non-curative in the metastatic setting. The use of in vivo preclinical mouse models for assessing metastasis is, therefore, critical for developing effective new cancer biomarkers and therapies. Although a number of quantitative tools have been previously developed to study in vivo metastasis, the detection and quantification of rare metastatic events has remained challenging. This review will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer and the resulting lessons learned about CTC and metastasis biology. We will also discuss how the use of clinically-relevant CTC technologies such as the CellSearch ® and Parsortix™ platforms for preclinical CTC studies can serve to enhance the study of cancer biology, new biomarkers, and novel therapies from the bench to the bedside.

  19. Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

    PubMed Central

    Wu, Fan; Bansal, Loveleena; Bradshaw‐Pierce, Erica; Chan, Jason R.; Liederer, Bianca M.; Mettetal, Jerome T.; Schroeder, Patricia; Schuck, Edgar; Tsai, Alice; Xu, Christine; Chimalakonda, Anjaneya; Le, Kha; Penney, Mark; Topp, Brian; Yamada, Akihiro

    2018-01-01

    A cross‐industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering. PMID:29349875

  20. Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse

    PubMed Central

    Lê, A.D.; Funk, Douglas; Lo, Steven; Coen, Kathleen

    2017-01-01

    Rationale and objectives Alcohol and nicotine are often taken together. In humans, intake of nicotine, via smoked tobacco, increases alcohol drinking, and alcohol increases smoking. Chronic nicotine treatment increases alcohol self-administration (SA) in laboratory animals; the reverse relationship is less clear. Most animal work modeling this has used passive administration, which lacks relevance to human co-abuse. Here, we describe a model based on sequential operant SA of alcohol and nicotine. Methods Animals are first trained on alcohol SA (0.19 ml of 12% w/v/delivery) and then receive separate alcohol (8% w/v) and nicotine (15 μg/kg/infusion) SA sessions on the same day (“daily dual access”). Animals then receive access to alcohol and then to nicotine (or in the reverse order) in alternating 5 min periods in 2h sessions (“alternating access”). We then determine if alternating access modifies the effects of naltrexone on responding for alcohol and nicotine. Results We found that with daily dual access, nicotine significantly increased alcohol SA when alcohol access occurred prior to nicotine access, and that nicotine SA significantly decreased when the alcohol SA session preceded it. During alternating access, nicotine also significantly increased alcohol intake. Naltrexone (0.3 or 1 mg/kg) significantly reduced alcohol SA during these alternating access sessions in animals that also received nicotine SA, but had minimal effects on animals receiving alcohol SA alone. Naltrexone did not affect nicotine SA under any condition. Conclusions This sequential access procedure effectively models the effects of nicotine on alcohol intake noted in humans. PMID:24696081

  1. Adolescent Victims of Abuse: A Treatment Model.

    ERIC Educational Resources Information Center

    Anderson-Merchant, Darlene

    This paper presents a theory and model for treating adolescent victims of physical and sexual abuse and neglect. The theory examines issues related to abuse or neglect and the effect that an abusive history has on adolescent development. Specific issues noted are depression, anger, low self-esteem, self-shame, lack of trust, a sense of…

  2. Models for preclinical studies in aging-related disorders: One is not for all

    PubMed Central

    Santulli, Gaetano; Borras, Consuelo; Bousquet, Jean; Calzà, Laura; Cano, Antonio; Illario, Maddalena; Franceschi, Claudio; Liotta, Giuseppe; Maggio, Marcello; Molloy, William D.; Montuori, Nunzia; O’Caoimh, Rónán; Orfila, Francesc; Rauter, Amelia P.; Santoro, Aurelia; Iaccarino, Guido

    2015-01-01

    Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical. PMID:27042427

  3. Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

    PubMed

    Ng, Samuel Y; Yoshida, Noriaki; Christie, Amanda L; Ghandi, Mahmoud; Dharia, Neekesh V; Dempster, Joshua; Murakami, Mark; Shigemori, Kay; Morrow, Sara N; Van Scoyk, Alexandria; Cordero, Nicolas A; Stevenson, Kristen E; Puligandla, Maneka; Haas, Brian; Lo, Christopher; Meyers, Robin; Gao, Galen; Cherniack, Andrew; Louissaint, Abner; Nardi, Valentina; Thorner, Aaron R; Long, Henry; Qiu, Xintao; Morgan, Elizabeth A; Dorfman, David M; Fiore, Danilo; Jang, Julie; Epstein, Alan L; Dogan, Ahmet; Zhang, Yanming; Horwitz, Steven M; Jacobsen, Eric D; Santiago, Solimar; Ren, Jian-Guo; Guerlavais, Vincent; Annis, D Allen; Aivado, Manuel; Saleh, Mansoor N; Mehta, Amitkumar; Tsherniak, Aviad; Root, David; Vazquez, Francisca; Hahn, William C; Inghirami, Giorgio; Aster, Jon C; Weinstock, David M; Koch, Raphael

    2018-05-22

    T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

  4. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    PubMed

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

    2015-06-01

    Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

  5. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction

    PubMed Central

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S. Stevens

    2015-01-01

    Opinion Statement Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940’s, and during the last 10–15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence. PMID:26009706

  6. Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

    PubMed

    Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen Jma; Raybon, Joseph; Schroeder, Patricia; Schuck, Virna; Suryawanshi, Satyendra; Su, Yaming; Trapa, Patrick; Tsai, Alice; Vakilynejad, Majid; Wang, Shining; Wong, Harvey

    2015-03-01

    The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

  7. Development of computational small animal models and their applications in preclinical imaging and therapy research.

    PubMed

    Xie, Tianwu; Zaidi, Habib

    2016-01-01

    The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

  8. Preclinical models for obesity research

    PubMed Central

    Barrett, Perry; Morgan, Peter J.

    2016-01-01

    ABSTRACT A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity. PMID:27821603

  9. Does physical activity protect against drug abuse vulnerability?

    PubMed

    Bardo, Michael T; Compton, Wilson M

    2015-08-01

    The current review examined recent literature to determine our state of knowledge about the potential ability of physical activity serve as a protectant against drug abuse vulnerability. Both preclinical and clinical studies were examined using either associational or random assignment study designs. In addition to examining drug use as an outcome variable, the potential neural mediators linking physical activity and drug abuse vulnerability were examined. Several important conclusions may be drawn. First, the preclinical evidence is solid in showing that physical activity in various forms is able to serve as both a preventive and treatment intervention that reduces drug use, although voluntary alcohol drinking appears to be an exception to this conclusion. Second, the clinical evidence provides some evidence, albeit mixed, to suggest a beneficial effect of physical activity on tobacco dependent individuals. In contrast, there exists only circumstantial evidence that physical activity may reduce use of drugs other than nicotine, and there is essentially no solid information from random control studies to know if physical activity may prevent initiation of problem use. Finally, both preclinical and clinical evidence shows that various brain systems are altered by physical activity, with the medial prefrontal cortex (mPFC) serving as one potential node that may mediate the putative link between physical activity and drug abuse vulnerability. It is concluded that novel neurobehavioral approaches taking advantage of novel techniques for assessing the physiological impact of physical activity are needed and can be used to inform the longitudinal random control studies that will answer definitively the question posed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

    PubMed

    Siegler, Elizabeth Louise; Wang, Pin

    2018-05-01

    Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

  11. Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

    PubMed Central

    Proetzel, Gabriele; Wiles, Michael V.; Roopenian, Derry C.

    2015-01-01

    The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID:24150980

  12. Preclinical MR fingerprinting (MRF) at 7 T: effective quantitative imaging for rodent disease models.

    PubMed

    Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A; Vincent, Jason A; Dell, Katherine M; Drumm, Mitchell L; Brady-Kalnay, Susann M; Griswold, Mark A; Flask, Chris A; Lu, Lan

    2015-03-01

    High-field preclinical MRI scanners are now commonly used to quantitatively assess disease status and the efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical 7.0-T MRI implementation of the highly novel MR fingerprinting (MRF) methodology which has been described previously for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a fast imaging with steady-state free precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 min. This initial high-field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for the quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. Copyright © 2015 John Wiley & Sons, Ltd.

  13. Healing from Childhood Sexual Abuse: A Theoretical Model

    ERIC Educational Resources Information Center

    Draucker, Claire Burke; Martsolf, Donna S.; Roller, Cynthia; Knapik, Gregory; Ross, Ratchneewan; Stidham, Andrea Warner

    2011-01-01

    Childhood sexual abuse is a prevalent social and health care problem. The processes by which individuals heal from childhood sexual abuse are not clearly understood. The purpose of this study was to develop a theoretical model to describe how adults heal from childhood sexual abuse. Community recruitment for an ongoing broader project on sexual…

  14. Development of computational small animal models and their applications in preclinical imaging and therapy research

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xie, Tianwu; Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch; Geneva Neuroscience Center, Geneva University, Geneva CH-1205

    The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and themore » development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.« less

  15. Imaging technologies for preclinical models of bone and joint disorders

    PubMed Central

    2011-01-01

    Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy. PMID:22214535

  16. Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

    PubMed Central

    Edwardson, Matthew A.; Wang, Ximing; Liu, Brent; Ding, Li; Lane, Christianne J.; Park, Caron; Nelsen, Monica A.; Jones, Theresa A; Wolf, Steven L; Winstein, Carolee J; Dromerick, Alexander W.

    2017-01-01

    Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1 % had lesions resembling proximal MCA or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. Conclusions ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

  17. Beyond abuse: the association among parenting style, abdominal pain, and somatization in IBS patients.

    PubMed

    Lackner, Jeffrey M; Gudleski, Gregory D; Blanchard, Edward B

    2004-01-01

    This study assessed the relative strength of the association between abuse, negative parenting style, and somatization in irritable bowel syndrome (IBS) patients. Drawing from preclinical stress physiology and abuse research identifying the family social climate as a frequently stronger and independent determinant of long-term health effects than abuse-specific variables, we predicted that negative parenting behaviors would more strongly correlate with somatization than abuse. Subjects were 81 consecutively evaluated patients, who at baseline underwent psychological testing, measuring perceived parental style, abuse history, somatization, and pain. Although abuse correlated with maternal and paternal rejection, abuse was not associated with somatization. Higher levels of rejection and/or hostility among fathers (not mothers) were more strongly correlated with somatization than was abuse. Further, paternal parenting behaviors were more predictive of somatization than abuse, age, and gender. The lack of an association between abuse and somatization is discussed in light of limitations of biopsychosocial IBS models, whose strong focus on "pathological stressors" (e.g., abuse, trauma) as risk factors may overlook the importance of "less extreme" parenting variables in influencing somatic complaints. The relationship between parenting and somatization is discussed in the context of broader behavioral science research linking disruptions in the quality of parenting to dramatic and long-term changes in patterns of stress reactivity and brain abnormalities seen in IBS patients.

  18. Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

    PubMed Central

    Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

    2015-01-01

    High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

  19. Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings

    PubMed Central

    Barker, David J.; Simmons, Steven J.; West, Mark O.

    2015-01-01

    The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals’ initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures. PMID:26411762

  20. Current preclinical models for the advancement of translational bladder cancer research.

    PubMed

    DeGraff, David J; Robinson, Victoria L; Shah, Jay B; Brandt, William D; Sonpavde, Guru; Kang, Yibin; Liebert, Monica; Wu, Xue-Ru; Taylor, John A

    2013-02-01

    Bladder cancer is a common disease representing the fifth most diagnosed solid tumor in the United States. Despite this, advances in our understanding of the molecular etiology and treatment of bladder cancer have been relatively lacking. This is especially apparent when recent advances in other cancers, such as breast and prostate, are taken into consideration. The field of bladder cancer research is ready and poised for a series of paradigm-shifting discoveries that will greatly impact the way this disease is clinically managed. Future preclinical discoveries with translational potential will require investigators to take full advantage of recent advances in molecular and animal modeling methodologies. We present an overview of current preclinical models and their potential roles in advancing our understanding of this deadly disease and for advancing care. ©2012 AACR.

  1. A preclinical mouse model of invasive lobular breast cancer metastasis.

    PubMed

    Doornebal, Chris W; Klarenbeek, Sjoerd; Braumuller, Tanya M; Klijn, Christiaan N; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W; Jonkers, Jos; de Visser, Karin E

    2013-01-01

    Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous breast cancer metastasis, which recapitulates key events in its formation and clinical course. Specifically, using the conditional K14cre;Cdh1(F/F);Trp53(F/F) model of de novo mammary tumor formation, we orthotopically transplanted invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once primary tumors were established in recipient mice, we mimicked the clinical course of treatment by conducting a mastectomy. After surgery, recipient mice succumbed to widespread overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Genomic profiling of paired mammary tumors and distant metastases showed that our model provides a unique tool to further explore the biology of metastatic disease. Neoadjuvant and adjuvant intervention studies using standard-of-care chemotherapeutics showed the value of this model in determining therapeutic agents that can target early- and late-stage metastatic disease. In obtaining a more accurate preclinical model of metastatic lobular breast cancer, our work offers advances supporting the development of more effective treatment strategies for metastatic disease.

  2. Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies.

    PubMed

    't Hart, Bert A; Jagessar, S Anwar; Kap, Yolanda S; Haanstra, Krista G; Philippens, Ingrid H C H M; Serguera, Che; Langermans, Jan; Vierboom, Michel

    2014-09-01

    The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. A hypothesized model of Korean women's responses to abuse.

    PubMed

    Choi, Myunghan; Harwood, Jake

    2004-07-01

    Many abused married Korean women have a strong desire to leave their abusive husbands but remain in the abusive situations because of the strong influence of their sociocultural context. The article discusses Korean women's responses to spousal abuse in the context of patriarchal, cultural, and social exchange theory. Age, education, and income as component elements share common effects on the emergent variable, sociostructural power. Gender role attitudes, traditional family ideology, individualism/collectivism, marital satisfaction, and marital conflict predict psychological-relational power as a latent variable. Sociostructural, patriarchal, cultural, and social exchange theories are reconceptualized to generate the model of Korean women's responses to abuse.

  4. Recent Translational Findings on Impulsivity in Relation to Drug Abuse

    PubMed Central

    Weafer, Jessica; Mitchell, Suzanne H.

    2015-01-01

    Impulsive behavior is strongly implicated in drug abuse, as both a cause and a consequence of drug use. To understand how impulsive behaviors lead to and result from drug use, translational evidence from both human and non-human animal studies is needed. Here, we review recent (2009 or later) studies that have investigated two major components of impulsive behavior, inhibitory control and impulsive choice, across preclinical and clinical studies. We concentrate on the stop-signal task as the measure of inhibitory control and delay discounting as the measure of impulsive choice. Consistent with previous reports, recent studies show greater impulsive behavior in drug users compared with non-users. Additionally, new evidence supports the prospective role of impulsive behavior in drug abuse, and has begun to identify the neurobiological mechanisms underlying impulsive behavior. We focus on the commonalities and differences in findings between preclinical and clinical studies, and suggest future directions for translational research. PMID:25678985

  5. Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction.

    PubMed

    Neisewander, J L; Peartree, N A; Pentkowski, N S

    2012-11-01

    Social factors are important determinants of drug dependence and relapse. We reviewed pre-clinical literature examining the role of social experiences from early life through the development of drug dependence and relapse, emphasizing two aspects of these experiences: (1) whether the social interaction is appetitive or aversive and (2) whether the social interaction occurs within or outside of the drug-taking context. The models reviewed include neonatal care, isolation, social defeat, chronic subordination, and prosocial interactions. We review results from these models in regard to effects on self-administration and conditioned place preference established with alcohol, psychostimulants, and opiates. We suggest that in general, when the interactions occur outside of the drug-taking context, prosocial interactions are protective against drug abuse-related behaviors, whereas social stressors facilitate these behaviors. By contrast, positive or negative social interactions occurring within the drug-taking context may interact with other risk factors to enhance or inhibit these behaviors. Despite differences in the nature and complexity of human social behavior compared to other species, the evolving animal literature provides useful models for understanding social influences on drug abuse-related behavior that will allow for research on the behavioral and biological mechanisms involved. The models have contributed to understanding social influences on initiation and maintenance of drug use, but more research is needed to understand social influences on drug relapse.

  6. Emotional valence and context of social influences on drug abuse-related behavior in animal models of social stress and prosocial interaction

    PubMed Central

    Neisewander, J.L.; Peartree, N.A.; Pentkowski, N.S.

    2014-01-01

    Rationale Social factors are important determinants of drug dependence and relapse. Objectives We reviewed preclinical literature examining the role of social experiences from early life through the development of drug dependence and relapse, emphasizing two aspects of these experiences: 1) whether the social interaction is appetitive or aversive and 2) whether the social interaction occurs within or outside of the drug-taking context. Methods The models reviewed include neonatal care, isolation, social defeat, chronic subordination, and prosocial interactions. We review results from these models in regard to effects on self-administration and conditioned place preference established with alcohol, psychostimulants, and opiates. Results We suggest that in general, when the interactions occur outside of the drug-taking context, prosocial interactions are protective against drug abuse-related behaviors whereas social stressors facilitate these behaviors. By contrast, positive or negative social interactions occurring within the drug-taking context may interact with other risk factors to enhance or inhibit these behaviors. Conclusions Despite differences in the nature and complexity of human social behavior compared to other species, the evolving animal literature provides useful models for understanding social influences on drug abuse-related behavior that will allow for research on the behavioral and biological mechanisms involved. The models have contributed to understanding social influences on initiation and maintenance of drug use, but more research is needed to understand social influences on drug relapse. PMID:22955569

  7. Modelling Drug Abuse Epidemics in the Presence of Limited Rehabilitation Capacity.

    PubMed

    Mushanyu, J; Nyabadza, F; Muchatibaya, G; Stewart, A G R

    2016-12-01

    The abuse of drugs is now an epidemic globally whose control has been mainly through rehabilitation. The demand for drug abuse rehabilitation has not been matched with the available capacity resulting in limited placement of addicts into rehabilitation. In this paper, we model limited rehabilitation through the Hill function incorporated into a system of nonlinear ordinary differential equations. Not every member of the community is equally likely to embark on drug use, risk structure is included to help differentiate those more likely (high risk) to abuse drugs and those less likely (low risk) to abuse drugs. It is shown that the model has multiple equilibria, and using the centre manifold theory, the model exhibits the phenomenon of backward bifurcation whose implications to rehabilitation are discussed. Sensitivity analysis and numerical simulations are performed. The results show that saturation in rehabilitation will in the long run lead to the escalation of drug abuse. This means that limited access to rehabilitation has negative implications in the fight against drug abuse where rehabilitation is the main form of control. This suggests that increased access to rehabilitation is likely to lower the drug abuse epidemic.

  8. Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures.

    PubMed

    Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

    2018-01-01

    Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

  9. Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

    PubMed Central

    Ratajczak, Jessica; Gervois, Pascal; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

    2018-01-01

    Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair. PMID:29535784

  10. How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction.

    PubMed

    Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

    2016-01-01

    Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. Published by Elsevier Inc.

  11. How preclinical models evolved to resemble the diagnostic criteria of drug addiction

    PubMed Central

    Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

    2015-01-01

    Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. Despite extensive research, the pathophysiology and aetiology of addiction is only partially understood, due to the gap between current preclinical models of addiction and the clinical criteria of the disorder. Here we give a brief overview, based on selected methodologies, of how behavioral models have evolved over the last fifty years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. These new models will hopefully increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additional, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. PMID:25747744

  12. Challenges for Preclinical Investigations of Human Biofield Modalities

    PubMed Central

    Gronowicz, Gloria; Bengston, William

    2015-01-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

  13. Testing women's propensities to leave their abusive husbands using structural equation modeling.

    PubMed

    Choi, Myunghan; Belyea, Michael; Phillips, Linda R; Insel, Kathleen; Min, Sung-Kil

    2009-01-01

    Many Korean women are just beginning to recognize that what they considered to be normal treatment is actually domestic violence. Many are becoming more intolerant of the abuse and more likely to desire to leave an abusive relationship. The aim of this study was to test, using the framework of sociostructural and psychological-relational power (PRP), a model of Korean women's propensities to leave their abusive husbands. Multigroup structural equation modeling was used to test relationships between variables chosen from the sociostructural power and PRP to explain intolerance to abuse. Married Korean women (n = 184) who self-identified as being abused physically, psychologically, sexually, or financially participated in the study. The multigroup analysis revealed that the relationship of abuse and Hwa-Byung (a culture-bound syndrome that denotes Korean women's anger) with intolerance was supported for women with low education (defined as having an education of high school or less: < or =12 years); also for this group, particularly among the younger women, high power was related to high levels of reported abuse and abuse intolerance. For women in the high-education group (education beyond high school: > or =13 years), high power was related to abuse, Hwa-Byung, and abuse intolerance; age did not influence power. Overall, the multigroup model adequately fitted the sample data (chi2 = 92.057, degree of freedom = 50, p = .000; normal fit index = .926, comparative fix index = .964, root mean square error of approximation = .068, Hoelter's critical number = 152), demonstrating that education is a crucial moderator of Korean women's attitude toward the unacceptability of abuse and propensity to terminate the marriage. This study found support for a model of abuse intolerance using the framework of sociostructural power and PRP, primarily for the low-education group. Hwa-Byung was a mediating factor that contributed to intolerance to abuse in women with low education. This

  14. Preclinical studies on the reinforcing effects of cannabinoids. A tribute to the scientific research of Dr. Steve Goldberg

    PubMed Central

    Tanda, Gianluigi

    2016-01-01

    Rationale The reinforcing effects of most abused drugs have been consistently demonstrated and studied in animal models, although those of marijuana were not, until the demonstration fifteen years ago that THC could serve as a reinforcer in self-administration (SA) procedures in squirrel monkeys. Until then, those effects were inferred using indirect assessments. Objectives The aim of this manuscript is to review the primary preclinical procedures used to indirectly and directly infer reinforcing effects of cannabinoid drugs. Methods Results will be reviewed from studies of cannabinoid-discrimination, intracranial-self-stimulation (ICSS), conditioned place preference (CPP), as well as change in levels of dopamine assessed in brain areas related to reinforcement, and finally from self-administration procedures. For each procedure, an evaluation will be made of the predictive validity in detecting the potential abuse liability of cannabinoids based on seminal papers, with the addition of selected reports from more recent years especially those from Dr. Goldberg’s research group. Results and Conclusions ICSS and CPP do not provide consistent results for the assessment of potential for abuse of cannabinoids. However, drug-discrimination and neurochemistry procedures appear to detect potential for abuse of cannabinoids, as well as several novel “designer cannabinoid drugs.” Though after 15 years it remains somewhat problematic transfer the self-administration model of marijuana abuse from squirrel monkeys to other species, studies with the former species have substantially advanced the field, and several reports have been published with consistent self-administration of cannabinoid agonists in rodents. PMID:27026633

  15. The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

    PubMed

    Marshall, John C

    2005-12-01

    The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design

  16. Monoamine Transporter Inhibitors and Substrates as Treatments for Stimulant Abuse

    PubMed Central

    Howell, Leonard L.; Negus, S. Stevens

    2015-01-01

    The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters in general, and dopamine transporters in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability, and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

  17. Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. | Office of Cancer Genomics

    Cancer.gov

    T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs).

  18. Review of Factors, Methods, and Outcome Definition in Designing Opioid Abuse Predictive Models.

    PubMed

    Alzeer, Abdullah H; Jones, Josette; Bair, Matthew J

    2018-05-01

    Several opioid risk assessment tools are available to prescribers to evaluate opioid analgesic abuse among chronic patients. The objectives of this study are to 1) identify variables available in the literature to predict opioid abuse; 2) explore and compare methods (population, database, and analysis) used to develop statistical models that predict opioid abuse; and 3) understand how outcomes were defined in each statistical model predicting opioid abuse. The OVID database was searched for this study. The search was limited to articles written in English and published from January 1990 to April 2016. This search generated 1,409 articles. Only seven studies and nine models met our inclusion-exclusion criteria. We found nine models and identified 75 distinct variables. Three studies used administrative claims data, and four studies used electronic health record data. The majority, four out of seven articles (six out of nine models), were primarily dependent on the presence or absence of opioid abuse or dependence (ICD-9 diagnosis code) to define opioid abuse. However, two articles used a predefined list of opioid-related aberrant behaviors. We identified variables used to predict opioid abuse from electronic health records and administrative data. Medication variables are the recurrent variables in the articles reviewed (33 variables). Age and gender are the most consistent demographic variables in predicting opioid abuse. Overall, there is similarity in the sampling method and inclusion/exclusion criteria (age, number of prescriptions, follow-up period, and data analysis methods). Intuitive research to utilize unstructured data may increase opioid abuse models' accuracy.

  19. Experimental psychiatric illness and drug abuse models: from human to animal, an overview.

    PubMed

    Edwards, Scott; Koob, George F

    2012-01-01

    Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

  20. Insights from Preclinical Choice Models on Treating Drug Addiction

    PubMed Central

    Banks, Matthew L.; Negus, S. Stevens

    2016-01-01

    Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food ‘choice’ procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. PMID:27916279

  1. Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones.

    PubMed

    Anker, Justin J; Carroll, Marilyn E

    2011-01-01

    Human and animal research indicates the presence of sex differences in drug abuse. These data suggest that females, compared to males, are more vulnerable to key phases of the addiction process that mark transitions in drug use such as initiation, drug bingeing, and relapse. Recent data indicate that the female gonadal hormone estrogen may facilitate drug abuse in women. For example, phases of the menstrual cycle when estrogen levels are high are associated with enhanced positive subjective measures following cocaine and amphetamine administration in women. Furthermore, in animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. This chapter discusses sex differences in and hormonal effects on drug-seeking behaviors in animal models of drug abuse. The neurobiological basis of these differences and effects are also discussed.

  2. Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

  3. Arterial Calcification in Diabetes Mellitus: Preclinical Models and Translational Implications.

    PubMed

    Stabley, John N; Towler, Dwight A

    2017-02-01

    Diabetes mellitus increasingly afflicts our aging and dysmetabolic population. Type 2 diabetes mellitus and the antecedent metabolic syndrome represent the vast majority of the disease burden-increasingly prevalent in children and older adults. However, type 1 diabetes mellitus is also advancing in preadolescent children. As such, a crushing wave of cardiometabolic disease burden now faces our society. Arteriosclerotic calcification is increased in metabolic syndrome, type 2 diabetes mellitus, and type 1 diabetes mellitus-impairing conduit vessel compliance and function, thereby increasing the risk for dementia, stroke, heart attack, limb ischemia, renal insufficiency, and lower extremity amputation. Preclinical models of these dysmetabolic settings have provided insights into the pathobiology of arterial calcification. Osteochondrogenic morphogens in the BMP-Wnt signaling relay and transcriptional regulatory programs driven by Msx and Runx gene families are entrained to innate immune responses-responses activated by the dysmetabolic state-to direct arterial matrix deposition and mineralization. Recent studies implicate the endothelial-mesenchymal transition in contributing to the phenotypic drift of mineralizing vascular progenitors. In this brief overview, we discuss preclinical disease models that provide mechanistic insights-and point to challenges and opportunities to translate these insights into new therapeutic strategies for our patients afflicted with diabetes mellitus and its arteriosclerotic complications. © 2016 American Heart Association, Inc.

  4. Methodological Rigor in Preclinical Cardiovascular Studies

    PubMed Central

    Ramirez, F. Daniel; Motazedian, Pouya; Jung, Richard G.; Di Santo, Pietro; MacDonald, Zachary D.; Moreland, Robert; Simard, Trevor; Clancy, Aisling A.; Russo, Juan J.; Welch, Vivian A.; Wells, George A.

    2017-01-01

    Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in

  5. Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

    PubMed Central

    Cole, Banumathi K.; Issa, Danny; Feaver, Ryan E.

    2018-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, affecting about 1/3 of the US general population and remaining as a significant cause of morbidity and mortality. The hallmark of the disease is the excessive accumulation of fat within the liver cells (hepatocytes), which eventually paves the way to cellular stress, injury and apoptosis. NAFLD is strongly associated with components of the metabolic syndrome and is fast emerging as a leading cause of liver transplant in the USA. Based on clinico-pathologic classification, NAFLD may present as isolated lipid collection (steatosis) within the hepatocytes (referred to as non-alcoholic fatty liver; NAFL); or as the more aggressive phenotype (known as non-alcoholic steatohepatitis; NASH). There are currently no regulatory agency-approved medication for NAFLD, despite the enormous work and resources that have gone into the study of this condition. Therefore, there remains a huge unmet need in developing and utilizing pre-clinical models that will recapitulate the disease condition in humans. In line with progress being made in developing appropriate disease models, this review highlights the cutting-edge preclinical in vitro and animal models that try to recapitulate the human disease pathophysiology and/or clinical manifestations. PMID:29299759

  6. Insights from Preclinical Choice Models on Treating Drug Addiction.

    PubMed

    Banks, Matthew L; Negus, S Stevens

    2017-02-01

    Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse.

    PubMed

    Cross, Sarah J; Lotfipour, Shahrdad; Leslie, Frances M

    2017-03-01

    Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.

  8. Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: evidence from the bench and the bedside.

    PubMed

    Graves, Steven M; Rafeyan, Roueen; Watts, Jeffrey; Napier, T Celeste

    2012-12-01

    Understanding substance use disorders (SUDs) and the problems associated with abstinence has grown in recent years. Nonetheless, highly efficacious treatment targeting relapse prevention has remained elusive, and there remains no FDA-approved pharmacotherapy for psychostimulant dependence. Preclinical and clinical investigations assessing the utility of classical antidepressants, which block monoamine reuptake, show mixed and often contradictory results. Mirtazapine (Remeron®) is a unique FDA-approved antidepressant, with negligible affinity for reuptake proteins, indirectly augments monoamine transmission presumably through antagonist activity at multiple receptors including the norepinephrine (NE)(α2), and serotonin (5-HT)(2A/C) receptors. Historically, mirtazapine was also considered to be a 5-HT(2C) antagonist, but recent evidence indicates that mirtazapine is an inverse agonist at this receptor subtype. Suggesting a promising role for mixed-action serotonergic drugs for addiction pharmacotherapy, mirtazapine attenuates psychostimulant-induced behaviors in several rodent models of substance abuse, and antagonizes methamphetamine-induced biochemical and electrophysiological alterations in rats. Preclinical findings are confirmed through published case studies documenting successful outcomes with mirtazapine therapy across a number of SUDs. To date, a large scale clinical trial assessing the utility of mirtazapine in substance abuse pharmacotherapy has yet to be conducted. However, as reviewed here, accumulating preclinical and clinical evidence argues that mirtazapine, or compounds that emulate aspects of its pharmacological profile, may prove useful in helping treat addictions. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

    PubMed

    Doncel, Gustavo F; Clark, Meredith R

    2010-12-01

    A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. In vivo three-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models.

    PubMed

    Ogunlade, Olumide; Connell, John J; Huang, Jennifer L; Zhang, Edward; Lythgoe, Mark F; Long, David A; Beard, Paul

    2018-06-01

    Noninvasive imaging of the kidney vasculature in preclinical murine models is important for the assessment of renal development, studying diseases and evaluating new therapies but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualizing the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optical Fabry-Perot-based photoacoustic scanner was used to image the abdominal region of mice. High-resolution three-dimensional, noninvasive, label-free photoacoustic images of the mouse kidney and renal vasculature were acquired in vivo. The scanner was also used to visualize and quantify differences in the vascular architecture of the kidney in vivo due to polycystic kidney disease. This study suggests that photoacoustic imaging could be utilized as a novel preclinical imaging tool for studying the biology of renal disease.

  11. Perspectives on the neuroscience of alcohol from the National Institute on Alcohol Abuse and Alcoholism.

    PubMed

    Reilly, Matthew T; Noronha, Antonio; Warren, Kenneth

    2014-01-01

    Mounting evidence over the last 40 years clearly indicates that alcoholism (alcohol dependence) is a disorder of the brain. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has taken significant steps to advance research into the neuroscience of alcohol. The Division of Neuroscience and Behavior (DNB) was formed within NIAAA in 2002 to oversee, fund, and direct all research areas that examine the effects of alcohol on the brain, the genetic underpinnings of alcohol dependence, the neuroadaptations resulting from excessive alcohol consumption, advanced behavioral models of the various stages of the addiction cycle, and preclinical medications development. This research portfolio has produced important discoveries in the etiology, treatment, and prevention of alcohol abuse and dependence. Several of these salient discoveries are highlighted and future areas of neuroscience research on alcohol are presented. © 2014 Elsevier B.V. All rights reserved.

  12. From Bench to Bedside: Utility of the Rabbit Elastase Aneurysm Model in Pre-Clinical Studies of Intracranial Aneurysm Treatment

    PubMed Central

    Brinjikji, Waleed; Ding, Yong H; Kallmes, David F; Kadirvel, Ramanathan

    2016-01-01

    Summary Pre-clinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus, an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss 1) various techniques used to create the aneurysm, 2) complications of aneurysm creation, 3) natural history of the arterial aneurysm, 4) histopathologic and hemodynamic features of the aneurysm 5) devices tested using this model and 6) weaknesses of the model. We demonstrate how pre-clinical studies using this model are applied in treatment of intracranial aneurysms in humans. The model has a similar hemodynamic, morphological and histologic characteristics to human aneurysms and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths however, the model does have many weaknesses including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore the model’s extracranial location affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms however further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms. PMID:25904642

  13. Animal Models of Substance Abuse and Addiction: Implications for Science, Animal Welfare, and Society

    PubMed Central

    Lynch, Wendy J; Nicholson, Katherine L; Dance, Mario E; Morgan, Richard W; Foley, Patricia L

    2010-01-01

    Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models. PMID:20579432

  14. Animal models of substance abuse and addiction: implications for science, animal welfare, and society.

    PubMed

    Lynch, Wendy J; Nicholson, Katherine L; Dance, Mario E; Morgan, Richard W; Foley, Patricia L

    2010-06-01

    Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models.

  15. A multi-dimensional model of groupwork for adolescent girls who have been sexually abused.

    PubMed

    Lindon, J; Nourse, C A

    1994-04-01

    This paper describes a treatment approach for sexually abused adolescent girls using a group work model. The model incorporates three treatment modalities: a skills component, a psychotherapeutic component, and an educative component. The group ran for 16 sessions over a 6-month period and each girl was assessed prior to joining the group. The girls were again assessed at the end of treatment and a 6-months follow-up; all of them showed improvement on self-statements (outcome) and on behavioral measures assessed by others (follow-up). Girls who had been sexually abused demonstrated difficulties in many areas of their lives following abuse. These problems related to their feelings of guilt and helplessness in relation to both themselves and their abuser. Sexually abused children often have poor knowledge of sexual matters and demonstrate confusion over their own body image. Using a multidimensional model the problems following abuse can be addressed.

  16. Sex-related responses after traumatic brain injury: Considerations for preclinical modeling.

    PubMed

    Späni, Claudia B; Braun, David J; Van Eldik, Linda J

    2018-05-18

    Traumatic brain injury (TBI) has historically been viewed as a primarily male problem, since men are more likely to experience a TBI because of more frequent participation in activities that increase risk of head injuries. This male bias is also reflected in preclinical research where mostly male animals have been used in basic and translational science. However, with an aging population in which TBI incidence is increasingly sex-independent due to falls, and increasing female participation in high-risk activities, the attention to potential sex differences in TBI responses and outcomes will become more important. These considerations are especially relevant in designing preclinical animal models of TBI that are more predictive of human responses and outcomes. This review characterizes sex differences following TBI with a special emphasis on the contribution of the female sex hormones, progesterone and estrogen, to these differences. This information is potentially important in developing and customizing TBI treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Using in vitro models for expression profiling studies on ethanol and drugs of abuse.

    PubMed

    Thibault, Christelle; Hassan, Sajida; Miles, Michael

    2005-03-01

    The use of expression profiling with microarrays offers great potential for studying the mechanisms of action of drugs of abuse. Studies with the intact nervous system seem likely to be most relevant to understanding the mechanisms of drug abuse-related behaviours. However, the use of expression profiling with in vitro culture models offers significant advantages for identifying details of cellular signalling actions and toxicity for drugs of abuse. This study discusses general issues of the use of microarrays and cell culture models for studies on drugs of abuse. Specific results from existing studies are also discussed, providing clear examples of relevance for in vitro studies on ethanol, nicotine, opiates, cannabinoids and hallucinogens such as LSD. In addition to providing details on signalling mechanisms relevant to the neurobiology of drugs of abuse, microarray studies on a variety of cell culture systems have also provided important information on mechanisms of cellular/organ toxicity with drugs of abuse. Efforts to integrate genomic studies on drugs of abuse with both in vivo and in vitro models offer the potential for novel mechanistic rigor and physiological relevance.

  18. Alcohol advertising, consumption and abuse: a covariance-structural modelling look at Strickland's data.

    PubMed

    Adlaf, E M; Kohn, P M

    1989-07-01

    Re-analysis employing covariance-structural models was conducted on Strickland's (1983) survey data on 772 drinking students from Grades 7, 9 and 11. These data bear on the relations among alcohol consumption, alcohol abuse, association with drinking peers and exposure to televised alcohol advertising. Whereas Strickland used a just-identified model which, therefore, could not be tested for goodness of fit, our re-analysis tested several alternative models, which could be contradicted by the data. One model did fit his data particularly well. Its major implications are as follows: (1) Symptomatic consumption, negative consequences and self-rated severity of alcohol-related problems apparently reflect a common underlying factor, namely alcohol abuse. (2) Use of alcohol to relieve distress and frequency of intoxication, however, appear not to reflect abuse, although frequent intoxication contributes substantially to it. (3). Alcohol advertising affects consumption directly and abuse indirectly, although peer association has far greater impact on both consumption and abuse. These findings are interpreted as lending little support to further restrictions on advertising.

  19. Translational Animal Models of Atopic Dermatitis for Preclinical Studies



    PubMed Central

    Martel, Britta C.; Lovato, Paola; Bäumer, Wolfgang; Olivry, Thierry

    2017-01-01

    There is a medical need to develop new treatments for patients suffering from atopic dermatitis (AD). To improve the discovery and testing of novel treatments, relevant animal models for AD are needed. Generally, these animal models mimic different aspects of the pathophysiology of human AD, such as skin barrier defects and Th2 immune bias with additional Th1 and Th22, and in some populations Th17, activation. However, the pathomechanistic characterization and pharmacological validation of these animal models are generally incomplete. In this paper, we review animal models of AD in the context of preclinical use and their possible translation to the human disease. Most of these models use mice, but we will also critically evaluate dog models of AD, as increasing information on disease mechanism show their likely relevance for the human disease. PMID:28955179

  20. Monoclonal antibody form and function: manufacturing the right antibodies for treating drug abuse.

    PubMed

    Peterson, Eric; Owens, S Michael; Henry, Ralph L

    2006-05-26

    Drug abuse continues to be a major national and worldwide problem, and effective treatment strategies are badly needed. Antibodies are promising therapies for the treatment of medical problems caused by drug abuse, with several candidates in preclinical and early clinical trials. Monoclonal antibodies can be designed that have customized affinity and specificity against drugs of abuse, and because antibodies can be designed in various forms, in vivo pharmacokinetic characteristics can be tailored to suit specific clinical applications (eg, long-acting for relapse prevention, or short-acting for overdose). Passive immunization with antibodies against drugs of abuse has several advantages over active immunization, but because large doses of monoclonal antibodies may be needed for each patient, efficient antibody production technology is essential. In this minireview we discuss some of the antibody forms that may be effective clinical treatments for drug abuse, as well as several current and emerging production systems that could bridge the gap from discovery to patient use.

  1. The dark side of family communication: a communication model of elder abuse and neglect.

    PubMed

    Lin, Mei-Chen; Giles, Howard

    2013-08-01

    To further address the potential factors that lead up to elder abuse in domestic settings, this paper proposes a model from a communication approach to explain dyadic influences between the family caregiver and the elderly care receiver that give rise to the abuse. That is, dysfunctional communication between the caregivers and care receivers may, therefore, increase the likelihood of elder abuse. Grounded in Bugental and her colleagues' work (1993, 1999, 2002) on child abuse, we propose a power-oriented communication model based, in part, on research in the fields of family violence and intergenerational communication to explain the likelihood of occurrence of elder abuse in family caregiving situations. We argue that certain risk factors pertaining to caregivers' characteristics--those who perceive high stress in caregiving, have mental health issues, have a history of substance abuse, and/or display verbal aggressiveness--may be more likely to attribute considerable power to those elderly under their custodianship. At the same time, such caregivers tend to feel powerless and experience loss of control when interacting with their elderly counterparts. When an elderly care receiver displays noncompliant behaviors, caregivers may be prone to employ abusive behaviors (in our model, it refers to physical abuse, verbal abuse, or communication neglect) to seek such compliance. Consequences of such abuse may result in lower self-esteem or lower confidence in one's ability to manage his/her life. It is suggested that researchers and practitioners investigate both parties' interactions closely and the role of elderly care receivers in order to detect, intervene, and prevent elder abuse.

  2. An Overview of the Effectiveness of Adolescent Substance Abuse Treatment Models.

    ERIC Educational Resources Information Center

    Muck, Randolph; Zempolich, Kristin A.; Titus, Janet C.; Fishman, Marc; Godley, Mark D.; Schwebel, Robert

    2001-01-01

    Describes current approaches to adolescent substance abuse treatment, including the 12-step treatment approach, behavioral treatment approach, family-based treatment approach, and therapeutic community approach. Summarizes research that assesses the effectiveness of these models, offering findings from the Center for Substance Abuse Treatment's…

  3. Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson's disease.

    PubMed

    Paris, Irmgard; Cardenas, Sergio; Lozano, Jorge; Perez-Pastene, Carolina; Graumann, Rebecca; Riveros, Alejandra; Caviedes, Pablo; Segura-Aguilar, Juan

    2007-09-01

    Four decades after L-dopa introduction to PD therapy, the cause of Parkinson's disease (PD) remains unknown despite the intensive research and the discovery of a number of gene mutations and deletions in the pathogenesis of familial PD. Different model neurotoxins have been used as preclinical experimental models to study the neurodegenerative process in PD, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone. The lack of success in identifying the molecular mechanism for the degenerative process in PD opens the question whether the current preclinical experimental models are suitable to understand the degeneration of neuromelanin-containing dopaminergic neurons in PD. We propose aminochrome as a model neurotoxin to study the neurodegenerative processes occurring in neuromelanin-containing dopaminergic neurons in PD. Aminochrome is an endogenous compound formed during dopamine oxidation and it is the precursor of neuromelanin, a substance whose formation is a normal process in mesencephalic dopaminergic neurons. However, aminochrome itself can induce neurotoxicity under certain aberrant conditions such as (i) one-electron reduction of aminochrome catalyzed by flavoenzymes to leukoaminochrome o-semiquinone radical, which is a highly reactive neurotoxin; or (ii) the formation of aminochrome adducts with alpha-synuclein, enhancing and stabilizing the formation of neurotoxic protofibrils. These two neurotoxic pathways of aminochrome are prevented by DT-diaphorase, an enzyme that effectively reduces aminochrome with two-electrons preventing both aminochrome one-electron reduction or formation alpha synuclein protofibrils. We propose to use aminochrome as a preclinical experimental model to study the neurodegenerative process of neuromelanin containing dopaminergic neurons in PD.

  4. An Integrative Spiritual Development Model of Supervision for Substance Abuse Counselors-in-Training

    ERIC Educational Resources Information Center

    Weiss Ogden, Karen R.; Sias, Shari M.

    2011-01-01

    Substance abuse counselors who address clients' spiritual development may provide more comprehensive counseling. This article presents an integrative supervision model designed to promote the spiritual development of substance abuse counselors-in-training, reviews the model, and discusses the implications for counselor education.

  5. Longitudinal histories as predictors of future diagnoses of domestic abuse: modelling study

    PubMed Central

    Kohane, Isaac S; Mandl, Kenneth D

    2009-01-01

    Objective To determine whether longitudinal data in patients’ historical records, commonly available in electronic health record systems, can be used to predict a patient’s future risk of receiving a diagnosis of domestic abuse. Design Bayesian models, known as intelligent histories, used to predict a patient’s risk of receiving a future diagnosis of abuse, based on the patient’s diagnostic history. Retrospective evaluation of the model’s predictions using an independent testing set. Setting A state-wide claims database covering six years of inpatient admissions to hospital, admissions for observation, and encounters in emergency departments. Population All patients aged over 18 who had at least four years between their earliest and latest visits recorded in the database (561 216 patients). Main outcome measures Timeliness of detection, sensitivity, specificity, positive predictive values, and area under the ROC curve. Results 1.04% (5829) of the patients met the narrow case definition for abuse, while 3.44% (19 303) met the broader case definition for abuse. The model achieved sensitive, specific (area under the ROC curve of 0.88), and early (10-30 months in advance, on average) prediction of patients’ future risk of receiving a diagnosis of abuse. Analysis of model parameters showed important differences between sexes in the risks associated with certain diagnoses. Conclusions Commonly available longitudinal diagnostic data can be useful for predicting a patient’s future risk of receiving a diagnosis of abuse. This modelling approach could serve as the basis for an early warning system to help doctors identify high risk patients for further screening. PMID:19789406

  6. A Multivariate Model for the Study of Parental Acceptance-Rejection and Child Abuse.

    ERIC Educational Resources Information Center

    Rohner, Ronald P.; Rohner, Evelyn C.

    This paper proposes a multivariate strategy for the study of parental acceptance-rejection and child abuse and describes a research study on parental rejection and child abuse which illustrates the advantages of using a multivariate, (rather than a simple-model) approach. The multivariate model is a combination of three simple models used to study…

  7. Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

    PubMed Central

    Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

    2014-01-01

    Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. PMID:24128326

  8. Social Cognitive Theory Recommendations for Improving Modeling in Adolescent Substance Abuse Prevention Programs.

    ERIC Educational Resources Information Center

    Cleaveland, Bonnie L.

    1994-01-01

    Current state-of-the-art substance abuse prevention programs are mostly social cognitive theory based. However, there are few publications which review specifically how modeling is applied to adolescent substance abuse prevention programs. This article reviews theoretical considerations for implementing modeling for this purpose. (Author/LKS)

  9. Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

    DTIC Science & Technology

    2015-11-01

    evaluated one synthetic oxytocin agonist, Compound 39, and one oxytocin metabolite, for efficacy against social deficits in BALB/cByJ mice, and we are...currently evaluating a second oxytocin metabolite for prosocial effects. Overall, we have successfully validated three mouse models as preclinical...to, first, prioritize synthetic compounds that activate the oxytocin receptor using cell-based assays, and secondly, evaluate the therapeutic efficacy

  10. Preclinical fluorescent mouse models of pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  11. Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

    PubMed Central

    Bell, Richard L.; Hauser, Sheketha R.; McClintick, Jeanette; Rahman, Shafiqur; Edenberg, Howard J.; Szumlinski, Karen K.; McBride, William J.

    2016-01-01

    Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence. PMID:26809998

  12. The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

    PubMed

    Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

    2017-08-01

    Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Overlaps in the nosology of substance abuse and overeating: the translational implications of "food addiction".

    PubMed

    Avena, Nicole M; Bocarsly, Miriam E; Hoebel, Bartley G; Gold, Mark S

    2011-09-01

    The obesity epidemic has led to the postulation that highly palatable foods may be "addictive" for some individuals. This idea is supported by the fact that there are overlaps in brain circuitry that underlie addictive behavior as well as overeating. In this paper, we discuss the utility of the concept of "food addiction" as it may relate to treating certain disordered eating behaviors. Using criteria set forth in the DSM-IV for substance-use disorders, we review data that have emerged from animal models suggesting that overeating, in the form of binge eating, fits some of the criteria for substance abuse. Further, we discuss preclinical data revealing that the addiction-like behavioral changes observed in response to overeating are concomitant with neurochemical changes that are similar to those observed in response to drugs of abuse. With this background and evidence in mind, we conclude this article with a discussion as to how "food addiction" research may translate into clinical strategies and pharmaceutical treatments useful in curtailing overeating.

  14. Minnelide reduces tumor burden in preclinical models of osteosarcoma.

    PubMed

    Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

    2013-07-28

    Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Application of advanced preclinical models and methods in anesthetic neurotoxicity research.

    PubMed

    Wang, Cheng; Zhang, Xuan; Liu, Fang

    2017-05-01

    Recently, there has been increasing concern regarding the potential of anesthetics to disturb the long-term function of the central nervous system (CNS). The field of anesthesia-related toxicology, therefore, has engaged multiple scientific disciplines and utilized a variety of pre-clinical research models in an attempt to identify the basic characteristics of the anesthetic agents that may produce acute and/or chronic adverse effects on the CNS. This review discusses how the application of advanced research approaches and models, such as the nonhuman primate, neural stem cell-derived organotypic slice cultures and/or organs-on-chips systems, can serve as translational models of infantile anesthetic exposure. Utilization of these models may expeditiously decrease the uncertainty in the risk posed to children by postnatal anesthetic exposure. Copyright © 2017. Published by Elsevier Inc.

  16. Four dimensional optoacoustic imaging of perfusion in preclinical breast tumor model in vivo (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Deán-Ben, Xosé Luís.; Ermolayev, Vladimir; Mandal, Subhamoy; Ntziachristos, Vasilis; Razansky, Daniel

    2016-03-01

    Imaging plays an increasingly important role in clinical management and preclinical studies of cancer. Application of optical molecular imaging technologies, in combination with highly specific contrast agent approaches, eminently contributed to understanding of functional and histological properties of tumors and anticancer therapies. Yet, optical imaging exhibits deterioration in spatial resolution and other performance metrics due to light scattering in deep living tissues. High resolution molecular imaging at the whole-organ or whole-body scale may therefore bring additional understanding of vascular networks, blood perfusion and microenvironment gradients of malignancies. In this work, we constructed a volumetric multispectral optoacoustic tomography (vMSOT) scanner for cancer imaging in preclinical models and explored its capacity for real-time 3D intravital imaging of whole breast cancer allografts in mice. Intrinsic tissue properties, such as blood oxygenation gradients, along with the distribution of externally administered liposomes carrying clinically-approved indocyanine green dye (lipo-ICG) were visualized in order to study vascularization, probe penetration and extravasation kinetics in different regions of interest within solid tumors. The use of v-MSOT along with the application of volumetric image analysis and perfusion tracking tools for studies of pathophysiological processes within microenvironment gradients of solid tumors demonstrated superior volumetric imaging system performance with sustained competitive resolution and imaging depth suitable for investigations in preclinical cancer models.

  17. Hidden Abuse within the Home: Recognizing and Responding to Sibling Abuse

    ERIC Educational Resources Information Center

    Stutey, Diane; Clemens, Elysia V.

    2015-01-01

    Sibling abuse is a serious phenomenon in our society that often goes unaddressed. Victims of sibling abuse experience psychological effects similar to those of child abuse (Caspi, 2012; Wiehe, 2002). The purpose of this article is to provide school counselors with a definition of sibling abuse and a five-step model to recognize and respond. A…

  18. TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

    PubMed Central

    Brabetz, Sebastian; Schmidt, Christin; Groebner, Susanne N.; Mack, Norman; Seker-Cin, Huriye; Jones, David T.W.; Chavez, Lukas; Milde, Till; Witt, Olaf; Leary, Sarah E.; Li, Xiao-Nan; Wechsler-Reya, Robert J.; Olson, James M.; Pfister, Stefan M.; Kool, Marcel

    2017-01-01

    Abstract Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for

  19. Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

    PubMed Central

    Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

    2010-01-01

    Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

  20. Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

    PubMed

    Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

    2010-07-01

    Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

  1. Research design strategies to evaluate the impact of formulations on abuse liability.

    PubMed

    McColl, Shelley; Sellers, Edward M

    2006-06-01

    Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective.

  2. Heuristic Models of Elder Abuse: Implications for the Practitioner.

    ERIC Educational Resources Information Center

    Galbraith, Michael W.; Zdorkowski, R. Todd

    1984-01-01

    Lists some of the more interesting hypotheses that lie unexamined in the elder abuse literature and specifies the kinds of explanations that these hypotheses demand. Includes models that may be useful to practitioners. (JOW)

  3. Improving the Clinical Pharmacologic Assessment of Abuse Potential: Part 1: Regulatory Context and Risk Management.

    PubMed

    Sellers, Edward M

    2018-02-01

    This article brings to the attention of drug developers the Food and Drug Administration's (FDA's) recent final Guidance to Industry on Assessment of Abuse Potential and provides practical suggestions about compliance with the Guidance. The Guidance areas are reviewed, analyzed, and placed in the context of current scientific knowledge and best practices to mitigate regulatory risk. The Guidance provides substantial new detail on what needs to be done at all stages of drug development for central nervous system-active drugs. However, because many psychopharmacologic agents have unique preclinical and clinical features, the plan for each agent needs to be not only carefully prepared but also reviewed and approved by the FDA. Examples are provided where assumptions about interpretation of the Guidance can delay development. If the expertise and experience needed for assessing abuse potential during drug development do not exist within a company, external preclinical and clinical expert should be involved. Consultation with the FDA is encouraged and important because the specific requirements for each drug will vary.

  4. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    PubMed Central

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2008-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component hypotheses were that (a) maladaptive traits would increase risk for inattention/hyperactivity, (b) inattention/hyperactivity would increase risk for disruptive behaviors, and (c) disruptive behaviors would lead to adolescent substance abuse. Participants were 674 children (486 boys) from 321 families in an ongoing, longitudinal high risk study that began when children were three years old. Temperament traits assessed were reactive control, resiliency, and negative emotionality, using examiner ratings on the California Q-Sort. Parent, teacher, and self ratings of inattention/hyperactivity, disruptive behaviors, and substance abuse were also obtained. Low levels of childhood reactive control, but not resiliency or negative emotionality, were associated with adolescent substance abuse, mediated by disruptive behaviors. Using a cascade model, family risk for substance abuse was partially mediated by reactive control, inattention/hyperactivity, and disruptive behavior. Some, but not all, temperament traits in childhood were related to adolescent substance abuse; these effects were mediated via inattentive/hyperactive and disruptive behaviors. PMID:18787942

  5. [Domestic elder abuse and neglect--conclusions from the evaluation of a model project].

    PubMed

    Görgen, T; Nägele, B

    2005-02-01

    The main task of a federally funded model project in the German city of Hannover was to develop approaches for prevention and intervention in the field of domestic elder abuse. Over a three year period (1998-2001), different approaches--like a telephone helpline for senior citizens, and social workers operating as counsellors for elderly people and their relatives--were tested at a local level. The paper presents results from the evaluation of the project and draws conclusions for future prevention and intervention in the field. The authors argue that the explicit use of the conceptual framework of "violence"/"abuse" creates potentials for scandalizing the issue and is therefore supportive for media appearance, whereas it can impede the approach to the main target groups (elderly people and their relatives) and reduce accessibility of counselling services for potential clients. In the light of evaluation results the focus of the project ("domestic elder abuse" or "violence against elderly people in close relationships") was too narrow for a local project. Counselling services were used in a relatively small number of cases; analyses of cases show that incidents of domestic elder abuse are often embedded in complex problem constellations. Cases brought to the attention of the model project were multifaceted and not limited to incidents of neglect and abuse of elderly care recipients caused by caregiver overload. Cases of intimate violence in partnerships and of intergenerational violence without any of the participants being dependent on care show the need to develop a broader concept of domestic elder abuse. Integration of the concepts of domestic violence, violence against women, elder abuse/neglect and abuse/neglect in caregiving relationships is necessary on a conceptual level as well as on the level of interagency cooperation of institutions dealing with cases of "elder abuse".

  6. Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization.

    PubMed

    Tuzun, Erdem; Berrih-Aknin, Sonia; Brenner, Talma; Kusner, Linda L; Le Panse, Rozen; Yang, Huan; Tzartos, Socrates; Christadoss, Premkumar

    2015-08-01

    Myasthenia gravis (MG) is an autoimmune disorder characterized by generalized muscle weakness due to neuromuscular junction (NMJ) dysfunction brought by acetylcholine receptor (AChR) antibodies in most cases. Although steroids and other immunosuppressants are effectively used for treatment of MG, these medications often cause severe side effects and a complete remission cannot be obtained in many cases. For pre-clinical evaluation of more effective and less toxic treatment methods for MG, the experimental autoimmune myasthenia gravis (EAMG) induced by Torpedo AChR immunization has become one of the standard animal models. Although numerous compounds have been recently proposed for MG mostly by using the active immunization EAMG model, only a few have been proven to be effective in MG patients. The variability in the experimental design, immunization methods and outcome measurements of pre-clinical EAMG studies make it difficult to interpret the published reports and assess the potential for application to MG patients. In an effort to standardize the active immunization EAMG model, we propose standard procedures for animal care conditions, sampling and randomization of mice, experimental design and outcome measures. Utilization of these standard procedures might improve the power of pre-clinical EAMG experiments and increase the chances for identifying promising novel treatment methods that can be effectively translated into clinical trials for MG. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Pica in Rats as a Preclinical Model of Emesis.

    PubMed

    Davis, T Gregg

    2016-10-03

    The ability to assess the potential for gastrointestinal adverse events in a preclinical setting is a challenge in the development of new drugs, as the vast majority of in vivo research is conducted in rodent species lacking a vomiting reflex. The use of higher species capable of emesis is often limited by cost, technical experience, and relevant efficacy models to define a therapeutic index. Additionally, investigators should be mindful of ethical considerations when using more sentient species when an alternative in lower species is available. This unit describes the use of pica behavior in rodents as an alternative for evaluating emetic potential in vivo. After an acclimation period, the incidence of rats engaging in pica following the administration of a test article can be used to generate a dose-response curve of the pica behavior. When linked with an appropriate efficacy model, this allows compounds to be ranked based on therapeutic index. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

  8. Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

    PubMed

    Tompkins, David Andrew; Lanier, Ryan K; Harrison, Joseph A; Strain, Eric C; Bigelow, George E

    2010-07-01

    Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

  9. ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension.

    PubMed

    Budas, Grant R; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A; Weissmann, Norbert; Seeger, Werner; Liles, John T; Schermuly, Ralph T

    2018-02-01

    Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

  10. MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

    PubMed

    Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

    2011-03-01

    Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A

  11. Preclinical experimental stress studies: protocols, assessment and comparison.

    PubMed

    Bali, Anjana; Jaggi, Amteshwar Singh

    2015-01-05

    Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Vascular physiology and protein disposition in a preclinical model of neurodegeneration.

    PubMed

    Boswell, C Andrew; Mundo, Eduardo E; Johnstone, Bernadette; Ulufatu, Sheila; Schweiger, Michelle G; Bumbaca, Daniela; Fielder, Paul J; Prabhu, Saileta; Khawli, Leslie A

    2013-05-06

    The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently

  13. Wife Abuse and the Wife Abuser: Review and Recommendations.

    ERIC Educational Resources Information Center

    Carden, Ann D.

    1994-01-01

    Reviews clinical, theoretical, and empirical literature on wife abuse/abusers. Presents historical and contextual information, overview of domestic violence, prevalence data, and descriptions of evolution and current status of public and professional awareness and response. Proposes integrative model for understanding etiologic, dynamic, and…

  14. Immunotherapy for the treatment of drug abuse.

    PubMed

    Kosten, Thomas; Owens, S Michael

    2005-10-01

    Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.

  15. Pharmacological enhancement of fear reduction: preclinical models

    PubMed Central

    Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

    2011-01-01

    Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

  16. Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

    PubMed Central

    Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

    2008-01-01

    This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

  17. Study partners should be required in preclinical Alzheimer's disease trials.

    PubMed

    Grill, Joshua D; Karlawish, Jason

    2017-12-06

    In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

  18. Strengths and Weaknesses of Pre-Clinical Models for Human Melanoma Treatment: Dawn of Dogs’ Revolution for Immunotherapy

    PubMed Central

    Barutello, Giuseppina; Rolih, Valeria; Arigoni, Maddalena; Tarone, Lidia; Conti, Laura

    2018-01-01

    Despite several therapeutic advances, malignant melanoma still remains a fatal disease for which novel and long-term curative treatments are needed. The successful development of innovative therapies strongly depends on the availability of appropriate pre-clinical models. For this purpose, several mouse models holding the promise to provide insight into molecular biology and clinical behavior of melanoma have been generated. The most relevant ones and their contribution for the advancement of therapeutic approaches for the treatment of human melanoma patients will be here summarized. However, as models, mice do not recapitulate all the features of human melanoma, thus their strengths and weaknesses need to be carefully identified and considered for the translation of the results into the human clinics. In this panorama, the concept of comparative oncology acquires a priceless value. The revolutionary importance of spontaneous canine melanoma as a translational model for the pre-clinical investigation of melanoma progression and treatment will be here discussed, with a special consideration to the development of innovative immunotherapeutic approaches. PMID:29534457

  19. Estimating attractiveness for abuse of a not-yet-marketed "abuse-deterrent" prescription opioid formulation.

    PubMed

    Butler, Stephen F; Black, Ryan; Grimes Serrano, Jill M; Folensbee, Lesley; Chang, Alan; Katz, Nathaniel

    2010-01-01

    The present study builds on research to model abusers' perceptions of particular analgesics' attractiveness for abuse and extends these methods to derive an estimate of attractiveness for abuse of a not-yet-marketed abuse-deterrent formulation (ADF) of a prescription opioid (Remoxy), Pain Therapeutics, Inc., San Mateo, CA, and King Pharmaceuticals, Inc., Bristol, TN). In a previous study, the Opioid Attractiveness Technology Scaling (OATS) method identified, from a drug abuser's point of view, the particular features of a prescription opioid relevant to its attractiveness for recreational use. A second online sample rated the extent to which these features applied to particular products they had actually used/abused. These data were used to model the abusers' overall preference for prescription opioids they had used/abused. In the present study, this method was applied to a not-yet-marketed ADF using substance abuse counselors as proxies for prescription opioid abusers. Thirty-eight counselors were given materials describing the new ADF along with four known products. Thirty-two counselors demonstrated sufficient agreement with abusers' ratings of the overall attractiveness of these drugs. The overall model yielded a significant pseudo R(2) of 0.15 (P < 0.001), with increasing model fit based on preferred route of administration, from swallowing whole (pseudo R(2) = 0.06; P < 0.001) and best for those who preferred to inject (pseudo R(2) = 0.40; P < 0.001). Data from a cross-validation group of 16 counselors/proxies were used to calculate the OATS scores for the five rated drugs and revealed significant differences between the ADF and OxyContin (Purdue Pharma LP, Stamford, CT), Percocet (Endo Pharmaceuticals, Chadds Ford, PA), and Vicodin (Abbott Laboratories, Abbott Park, IL), but not Talwin NX (Sanofi-aventis, Bridgewater, NJ), which was identified in the prior study as a highly unattractive drug for recreational purposes. The OATS method shows promise for

  20. Preclinical restorative training.

    PubMed

    Ferguson, Michael B; Sobel, Morton; Niederman, Richard

    2002-10-01

    In conjunction with its problem-based learning curriculum, Harvard School of Dental Medicine (HSDM) developed a shortened preclinical restorative training curriculum. This study compared our curriculum with those in other dental schools and examined student reaction to it. Twenty-nine U.S. dental schools responded to a survey regarding the length of their preclinical course in Operative Dentistry. Nationally, preclinical courses ranged from 179 hours to 280 hours (mean +/- SEM = 193 +/- 9 hours; n = 29). In marked contrast, the new seventy-five-hour preclinical curriculum at Harvard was the lowest of any school, and significantly lower than the U.S. average (p < 0.01). In Harvard's previous curriculum, students spent 232 curriculum hours. Reactions of Harvard students to this compact preclinical curriculum were surveyed using a three-topic, three-category survey instrument. Results indicated that, prior to beginning clinical patient care, approximately 80 percent of students felt that the course was too short and 20 percent just right. Conversely, and retrospectively, after completing their dental school training, only 35 percent felt it was too short, and 65 percent felt it was just right. Retrospectively, in terms of clinical preparedness, 55 percent felt adequately prepared and 35 percent felt well prepared to treat their patients. No significant change was noted between Part II National Board scores following the change to the reduced curricula time. The average National Board Part II scores prior to initiating the new curriculum was 86.3, and afterwards, it was 86.2. Further, for the North East Regional Board, HSDM students in the past four years demonstrated a 98 percent overall success rate with 100 percent primary pass in the operative dentistry part of the examination. These results suggest that an abbreviated preclinical training is not only possible, but may make time available for training opportunities in other areas, such as aesthetic dental

  1. A Mixed-Methodological Examination of Investment Model Variables among Abused and Nonabused College Women

    ERIC Educational Resources Information Center

    Dardis, Christina M.; Kelley, Erika L.; Edwards, Katie M.; Gidycz, Christine A.

    2013-01-01

    Objective: This study assessed abused and nonabused women's perceptions of Investment Model (IM) variables (ie, relationship investment, satisfaction, commitment, quality of alternatives) utilizing a mixed-methods design. Participants: Participants included 102 college women, approximately half of whom were in abusive dating relationships.…

  2. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    ERIC Educational Resources Information Center

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component…

  3. The Prevention of Elder Abuse: An Educational Model.

    ERIC Educational Resources Information Center

    Gold, Deborah T.; Gwyther, Lisa P.

    1989-01-01

    Notes that research on elder abuse highlights importance of communication and conflict resolution in families of older people, and that few prevention programs are available for use with community groups. Reviews literature on elder abuse and describes an educational curriculum designed to prevent abuse and neglect in families of the elderly.…

  4. A Protective Factors Model for Alcohol Abuse and Suicide Prevention among Alaska Native Youth

    PubMed Central

    Allen, James; Mohatt, Gerald V.; Fok, Carlotta Ching Ting; Henry, David; Burkett, Rebekah

    2014-01-01

    This study provides an empirical test of a culturally grounded theoretical model for prevention of alcohol abuse and suicide risk with Alaska Native youth, using a promising set of culturally appropriate measures for the study of the process of change and outcome. This model is derived from qualitative work that generated an heuristic model of protective factors from alcohol (Allen at al., 2006; Mohatt, Hazel et al., 2004; Mohatt, Rasmus et al., 2004). Participants included 413 rural Alaska Native youth ages 12-18 who assisted in testing a predictive model of Reasons for Life and Reflective Processes about alcohol abuse consequences as co-occurring outcomes. Specific individual, family, peer, and community level protective factor variables predicted these outcomes. Results suggest prominent roles for these predictor variables as intermediate prevention strategy target variables in a theoretical model for a multilevel intervention. The model guides understanding of underlying change processes in an intervention to increase the ultimate outcome variables of Reasons for Life and Reflective Processes regarding the consequences of alcohol abuse. PMID:24952249

  5. Breaking the cycle: The effects of role model performance and ideal leadership self-concepts on abusive supervision spillover.

    PubMed

    Tu, Min-Hsuan; Bono, Joyce E; Shum, Cass; LaMontagne, Liva

    2018-03-19

    Building on identity theories and social learning theory, we test the notion that new leaders will model the abusive behaviors of their superiors only under certain conditions. Specifically, we hypothesize that new leaders will model abusive supervisory behaviors when (a) abusive superiors are perceived to be competent, based on the performance of their teams and (b) new leaders' ideal leadership self-concepts are high on tyranny or low on sensitivity. Results of an experiment in which we manipulated abusive supervisory behaviors using a professional actor, and created a role change where 93 individuals moved from team member to team leader role, generally support our hypotheses. We found the strongest association between abuse exposure and new leader abuse under conditions where the abusive superior's team performed well and the new team leaders' self-concepts showed low concern for others. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  6. Evaluation of a novel high-intensity focused ultrasound device: preclinical studies in a porcine model.

    PubMed

    Jewell, Mark L; Desilets, Charles; Smoller, Bruce R

    2011-05-01

    High-intensity focused ultrasound (HIFU) has been applied clinically for the noninvasive treatment of pathological conditions in various organs for over 50 years; however, there are little data describing the use of thermal HIFU to ablate fat for body contouring and treatment of collagen-rich layers. A novel device under clinical investigation (LipoSonix; Medicis Technologies Corporation, Bothell, Washington) uses HIFU to eliminate unwanted adipose tissue. The authors describe the results of HIFU treatment in a series of preclinical studies performed in a validated porcine model. Preclinical research included in vivo treatment of the abdominal subcutaneous adipose tissue of swine with transcutaneous HIFU therapy. Endpoint analyses included thermocouple temperature data, full-body necropsy, local pathology and histology studies, clinical hematology, urinalysis, and blood chemistry parameters, including lipid panels. The application of HIFU energy levels of 166 to 372 J/cm(2) generated tissue temperature approaching 70°C, which was restricted to the focal area (n = seven). Application of 68 and 86 J/cm(2) did not produce clinically-significant changes in serum liver function tests, free fatty acids, or cholesterol (n = eight). Gross examination of tissue from various organs showed no evidence of fat emboli or accumulation (n = two). Histology demonstrated well-preserved vasculature and intact nerve fibers within the HIFU focal area (n = three). Following treatment with 85.3 to 270 J/cm(2), normal healing response included the migration of macrophages into the damaged tissue and removal of disrupted cellular debris and lipids (n = 8). In a preclinical swine model, the controlled thermal effect of HIFU appears to provide a safe and effective means for ablating subcutaneous adipose tissue.

  7. Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

    PubMed Central

    Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew; Li, Tong; Worley, Paul F; Troncoso, Juan C; Wong, Phil C; Price, Don L

    2012-01-01

    Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. PMID:21937983

  8. Modeling risk for child abuse and harsh parenting in families with depressed and substance-abusing parents.

    PubMed

    Kelley, Michelle L; Lawrence, Hannah R; Milletich, Robert J; Hollis, Brittany F; Henson, James M

    2015-05-01

    Children with substance abusing parents are at considerable risk for child maltreatment. The current study applied an actor-partner interdependence model to examine how father only (n=52) and dual couple (n=33) substance use disorder, as well as their depressive symptomology influenced parents' own (actor effects) and the partner's (partner effects) overreactivity in disciplinary interactions with their children, as well as their risk for child maltreatment. Parents completed the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977), the overreactivity subscale from the Parenting Scale (Arnold, O'Leary, Wolff, & Acker, 1993), and the Brief Child Abuse Potential Inventory (Ondersma, Chaffin, Mullins, & LeBreton, 2005). Results of multigroup structural equation models revealed that a parent's own report of depressive symptoms predicted their risk for child maltreatment in both father SUD and dual SUD couples. Similarly, a parent's report of their own depressive symptoms predicted their overreactivity in disciplinary encounters both in father SUD and dual SUD couples. In all models, partners' depressive symptoms did not predict their partner's risk for child maltreatment or overreactivity. Findings underscore the importance of a parent's own level of depressive symptoms in their risk for child maltreatment and for engaging in overreactivity during disciplinary episodes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Modeling Risk for Child Abuse and Harsh Parenting in Families with Depressed and Substance-abusing Parents

    PubMed Central

    Kelley, Michelle L.; Lawrence, Hannah R.; Milletich, Robert R.; Hollis, Brittany F.; Henson, James M.

    2015-01-01

    Children with substance abusing parents are at considerable risk for child maltreatment. The current study applied an actor-partner interdependence model to examine how father only (n = 52) and dual couple (n = 33) substance use disorder, as well as their depressive symptomology influenced parents’ own (actor effects) and the partner's (partner effects) overreactivity in disciplinary interactions with their children, as well as their risk for child maltreatment. Parents completed the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977), the overreactivity subscale from the Parenting Scale (Arnold, O'Leary, Wolff, & Acker, 1993), and the Brief Child Abuse Potential Inventory (Ondersma, Chaffin, Mullins, & LeBreton, 2005). Results of multigroup structural equation models revealed that a parent's own report of depressive symptoms predicted their risk for child maltreatment in both father SUD and dual SUD couples. Similarly, a parent's report of their own depressive symptoms predicted their overreactivity in disciplinary encounters both in father SUD and dual SUD couples. In all models, partners’ depressive symptoms did not predict their partner's risk for child maltreatment or overreactivity. Findings underscore the importance of a parent's own levels of depressive symptoms in their risk for child maltreatment and for engaging in overreactivity during disciplinary episodes. PMID:25724658

  10. Quality Assurance in Biobanking for Pre-Clinical Research

    PubMed Central

    Simeon-Dubach, Daniel; Zeisberger, Steffen M.; Hoerstrup, Simon P.

    2016-01-01

    It is estimated that not less than USD 28 billion are spent each year in the USA alone on irreproducible pre-clinical research, which is not only a fundamental loss of investment and resources but also a strong inhibitor of efficiency for upstream processes regarding the translation towards clinical applications and therapies. The issues and cost of irreproducibility has mainly been published on pre-clinical research. In contrast to pre-clinical research, test material is often being transferred into humans in clinical research. To protect treated human subjects and guarantee a defined quality standard in the field of clinical research, the manufacturing and processing infrastructures have to strictly follow and adhere to certain (inter-)national quality standards. It is assumed and suggested by the authors that by an implementation of certain quality standards within the area of pre-clinical research, billions of USD might be saved and the translation phase of promising pre-clinical results towards clinical applications may substantially be improved. In this review, we discuss how an implementation of a quality assurance (QA) management system might positively improve sample quality and sustainability within pre-clinically focused biobank infrastructures. Biobanks are frequently positioned at the very beginning of the biomedical research value chain, and, since almost every research material has been stored in a biobank during the investigated life cycle, biobanking seems to be of substantial importance from this perspective. The role model of a QA-regulated biobank structure can be found in biobanks within the context of clinical research organizations such as in regenerative medicine clusters. PMID:27781023

  11. The Abuse Intervention Model: A Pragmatic Approach to Intervention for Elder Mistreatment.

    PubMed

    Mosqueda, Laura; Burnight, Kerry; Gironda, Melanie W; Moore, Alison A; Robinson, Jehni; Olsen, Bonnie

    2016-09-01

    Ten percent of older adults experience elder mistreatment, and it is much more common in older adults with dementia. It is associated with higher rates of psychological distress, hospitalization, and death and, in the United States, costs billions of dollars each year. Although elder mistreatment is relatively common and costly, it is estimated that fewer than 10% of instances of elder mistreatment are reported. Given these data, there is a great need for research on interventions to mitigate elder mistreatment and for a practical model or framework to use in approaching such interventions. Although many theories have been proposed, adapted, and applied to understand elder mistreatment, there has not been a simple, coherent framework of known risk factors of the victim, perpetrator, and environment that applies to all types of abuse. This article presents a new model to examine the multidimensional and complex relationships between risk factors. Theories of elder mistreatment, research on risk factors for elder mistreatment, and 10 years of experience of faculty and staff at an Elder Abuse Forensics Center who have investigated more than 1,000 cases of elder mistreatment inform this model. It is hoped that this model, the Abuse Intervention Model, will be used to study and intervene in elder mistreatment. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

  12. Dissolution DNP for in vivo preclinical studies

    NASA Astrophysics Data System (ADS)

    Comment, Arnaud

    2016-03-01

    The tremendous polarization enhancement afforded by dissolution dynamic nuclear polarization (DNP) can be taken advantage of to perform preclinical in vivo molecular and metabolic imaging. Following the injection of molecules that are hyperpolarized via dissolution DNP, real-time measurements of their biodistribution and metabolic conversion can be recorded. This technology therefore provides a unique and invaluable tool for probing cellular metabolism in vivo in animal models in a noninvasive manner. It gives the opportunity to follow and evaluate disease progression and treatment response without requiring ex vivo destructive tissue assays. Although its considerable potential has now been widely recognized, hyperpolarized magnetic resonance by dissolution DNP remains a challenging method to implement for routine in vivo preclinical measurements. The aim of this article is to provide an overview of the current state-of-the-art technology for preclinical applications and the challenges that need to be addressed to promote it and allow its wider dissemination in the near future.

  13. The "intoxication state of consciousness": a model for alcohol and drug abuse.

    PubMed

    Galanter, M

    1976-06-01

    The author describes a model of intoxicant use based on altered states of consciousness and reviews his own and others' research on marijuana to illustrate the utility of this model, which is derived from both introspective reports and observed data. The relationship of social behavior and cognitive functioning to the "intoxication state of consciousness" is discussed. This state of consciousness may have an adaptive value in engendering and stabilizing social cohesion. Possible treatment implications include cognitive labeling of cues that precipitate episodes of abuse, training for moderated drug use while patients are intoxicated, and providing abusers with altered consciousness through other means, such as meditation.

  14. Rodent Models of Genetic Contributions to Motivation to Abuse Alcohol

    PubMed Central

    Crabbe, John C.

    2016-01-01

    The distinction between alcohol use (normative) and abuse (unfortunately common) implies dysregulation of motivation directed toward the drug. Genetic contributions to abuse risk are mediated through personality differences, other predispositions to drink excessively, and differences in sensitivity to the acute and chronic consequences of the drug. How to assess motivation in laboratory animals is not straightforward but risk factors for and consequences of alcohol abuse can be modeled with reasonable fidelity in laboratory rodents. Remarkably few rodent studies focus on the genetic contributions to alcohol’s reinforcing value: almost all examine preferential drinking of unflavored alcohol over water. Such studies will likely never avoid the confounding role of taste preferences and most often yield intake levels insufficient to yield a pharmacologically significant blood alcohol level. Genotypes that avoid alcohol probably do so based on pre-ingestive sensory cues; however, post-ingestive consequences are also important. Thus, the quest for improved measures of reinforcing value continues. We have genetic differences aplenty, but still lack evidence that any genotype will readily self-administer alcohol to the devastating extent that many alcoholics will. Encouraging results that are emerging include improved behavioral methods for elevating alcohol intake and inferring alcohol reinforcement, as well as new genetic animal models. Several ingenious assays to index alcohol’s motivational effects have been used extensively. Alcoholic drinking that attempts to prevent or to alleviate withdrawal symptoms has been modeled. Another characteristic of alcoholic drinking is its persistence despite abundant evidence to the drinker of the damaging effects of the excessive drinking on work, relationships, and/or health. Modeling such persistence in rodents has been uncommon to date. New genetic animal models include lines of mice selectively bred for chronic high drinking

  15. Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

    PubMed

    Provencher, Steeve; Archer, Stephen L; Ramirez, F Daniel; Hibbert, Benjamin; Paulin, Roxane; Boucherat, Olivier; Lacasse, Yves; Bonnet, Sébastien

    2018-03-30

    Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from

  16. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

    PubMed

    Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

    2017-05-09

    To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  17. Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

    PubMed

    Hennika, Tammy; Hu, Guo; Olaciregui, Nagore G; Barton, Kelly L; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J; Tsoli, Maria; Ziegler, David S; Carcaboso, Angel M; Becher, Oren J

    2017-01-01

    Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

  18. Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

    PubMed Central

    Tan, Hor-Yue; San-Marina, Serban; Wang, Ning; Hong, Ming; Li, Sha; Li, Lei; Cheung, Fan; Wen, Xiao-Yan; Feng, Yibin

    2016-01-01

    Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID:26941826

  19. Abusive alcohol consumption among adolescents: a predictive model for maximizing early detection and responses.

    PubMed

    de Freitas Ferreira, M; de Moraes, C L; Braga, J U; Reichenheim, M E; da Veiga, G V

    2018-06-01

    To present a predictive model of alcohol abuse among adolescents based on prevalence projections in various population subgroups. Cross-sectional study. The sample consisted of 785 adolescents enrolled in the second year of high school in Rio de Janeiro, Brazil. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test. Socio-economic, demographic, family, individuals, and school-related variables were examined as potential predictors. The logit model was used to estimate the prevalence projections. Model fitting was examined in relation to the observed data set, and in a subset, that was generated from 200 subsamples of individuals via a bootstrap process using general fit estimators, discrimination, and calibration measures. About 25.5% of the adolescents were classified as positive for alcohol abuse. Being male, being 17-19 years old, not living with mothers, presenting symptoms suggestive of binge eating, having used a strategy of weight reduction in the last 3 months, and, especially, being a victim of family violence were important predictors of abusive consumption of alcohol. While the model's prevalence projection in the absence of these features was 8%, it reaches 68% in the presence of all predictors. Knowledge of predictive characteristics of alcohol abuse is essential for screening, early detection of positive cases, and establishing interventions to reduce consumption among adolescents. Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  20. A protective factors model for alcohol abuse and suicide prevention among Alaska Native youth.

    PubMed

    Allen, James; Mohatt, Gerald V; Fok, Carlotta Ching Ting; Henry, David; Burkett, Rebekah

    2014-09-01

    This study provides an empirical test of a culturally grounded theoretical model for prevention of alcohol abuse and suicide risk with Alaska Native youth, using a promising set of culturally appropriate measures for the study of the process of change and outcome. This model is derived from qualitative work that generated an heuristic model of protective factors from alcohol (Allen et al. in J Prev Interv Commun 32:41-59, 2006; Mohatt et al. in Am J Commun Psychol 33:263-273, 2004a; Harm Reduct 1, 2004b). Participants included 413 rural Alaska Native youth ages 12-18 who assisted in testing a predictive model of Reasons for Life and Reflective Processes about alcohol abuse consequences as co-occurring outcomes. Specific individual, family, peer, and community level protective factor variables predicted these outcomes. Results suggest prominent roles for these predictor variables as intermediate prevention strategy target variables in a theoretical model for a multilevel intervention. The model guides understanding of underlying change processes in an intervention to increase the ultimate outcome variables of Reasons for Life and Reflective Processes regarding the consequences of alcohol abuse.

  1. Vaccines against drugs of abuse: a viable treatment option?

    PubMed

    Kantak, Kathleen M

    2003-01-01

    Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice;a lack of an effect on drug craving that predisposes an addict to relapse; and tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically

  2. Using the tidal model of mental health recovery to plan primary health care for women in residential substance abuse recovery.

    PubMed

    Young, Brenda B

    2010-09-01

    Women currently are 30% of the substance abuse recovery population in North America and have gender specific treatment needs as they enter the difficult work of recovery. Important among women's specific needs as they enter recovery is the need for a focus on primary health care. Few models designed to guide the provision of health care for this population are available in the literature. The Tidal Model of Mental Health Recovery and Reclamation is based on the concept of nursing as "caring with" persons in the experience of distress. Given the emphasis in this model on developing a partnership between caregiver and client, it is especially appropriate for women in recovery for substance abuse. The Tidal Model, integrated with the United States Substance Abuse and Mental Health Services' CSAT model for comprehensive alcohol and other drug (AOD) abuse treatment, is used to guide planning for delivery of primary health care in a residential women's substance abuse recovery center in the Midwest. This article describes the Tidal Model, and identifies how the model can improve the delivery of primary care to women in residential substance abuse treatment. Strategies for implementation of the model are proposed. Evaluation and outcome criteria are identified.

  3. Impact Evaluation of a Cognitive Behavioral Group Therapy Model in Brazilian Sexually Abused Girls

    ERIC Educational Resources Information Center

    Habigzang, Luisa Fernanda; Damasio, Bruno Figueiredo; Koller, Silvia Helena

    2013-01-01

    This study evaluated the impact of a cognitive behavioral group therapy model in Brazilian girls who had experienced sexual abuse. The effect of the waiting period before treatment and the enduring effectiveness of the treatment after six and 12 months were also evaluated. Forty-nine female sexual abuse victims between the ages of 9 and 16…

  4. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

    PubMed

    Voorhees, Jaymie R; Rohlman, Diane S; Lein, Pamela J; Pieper, Andrew A

    2016-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

  5. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    PubMed Central

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  6. Preclinical Imaging for the Study of Mouse Models of Thyroid Cancer

    PubMed Central

    Greco, Adelaide; Orlandella, Francesca Maria; Iervolino, Paola Lucia Chiara; Klain, Michele; Salvatore, Giuliana

    2017-01-01

    Thyroid cancer, which represents the most common tumors among endocrine malignancies, comprises a wide range of neoplasms with different clinical aggressiveness. One of the most important challenges in research is to identify mouse models that most closely resemble human pathology; other goals include finding a way to detect markers of disease that common to humans and mice and to identify the most appropriate and least invasive therapeutic strategies for specific tumor types. Preclinical thyroid imaging includes a wide range of techniques that allow for morphological and functional characterization of thyroid disease as well as targeting and in most cases, this imaging allows quantitative analysis of the molecular pattern of the thyroid cancer. The aim of this review paper is to provide an overview of all of the imaging techniques used to date both for diagnosis and theranostic purposes in mouse models of thyroid cancer. PMID:29258188

  7. Substance abuse and quality of life among severely mentally ill consumers: a longitudinal modelling analysis.

    PubMed

    Urbanoski, Karen A; Cairney, John; Adlaf, Edward; Rush, Brian

    2007-10-01

    Evidence suggests that substance abuse negatively affects both psychiatric symptom severity and quality of life (QOL) in people with severe mental illness (SMI). However, these relationships have not been examined simultaneously, nor have they been characterized over time. Thus, it is difficult to appreciate the extent to which substance abuse exerts an enduring effect on psychiatric symptoms and distress and/or QOL in this population. The purpose of this study is to test a conceptual model linking these factors together. Subjects were participants in a longitudinal evaluation of community mental healthcare in Ontario (n = 133). Comprehensive consumer assessments were conducted at treatment entry, and at 9 and 18 months. Subjects were receiving intensive case management or assertive community treatment throughout the 18-month study period. Structural equation modelling was used to examine the concurrent and longitudinal relationships between substance abuse, symptoms and distress, and QOL. The prevalence of substance abuse was 55.0%. The SEM analysis suggested that substance abuse at baseline was associated with elevated symptomatology and distress and lower QOL, and that these effects endured after 18 months of treatment. Psychiatric symptoms and distress mediated the negative relationship between substance abuse and QOL. The mediating role played by symptom and distress levels in the relationship between substance abuse and QOL suggests the importance of closely monitoring changes in these factors among SMI patients with substance problems. Tracking symptom severity and distress levels over time will allow service providers to intervene and potentially improve the QOL of individuals with SMI.

  8. Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models

    PubMed Central

    Báez-Díaz, Claudia; Sánchez-Margallo, Francisco Miguel

    2017-01-01

    Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans. PMID:28725598

  9. Internal working models and adjustment of physically abused children: the mediating role of self-regulatory abilities.

    PubMed

    Hawkins, Amy L; Haskett, Mary E

    2014-01-01

    Abused children's internal working models (IWM) of relationships are known to relate to their socioemotional adjustment, but mechanisms through which negative representations increase vulnerability to maladjustment have not been explored. We sought to expand the understanding of individual differences in IWM of abused children and investigate the mediating role of self-regulation in links between IWM and adjustment. Cluster analysis was used to subgroup 74 physically abused children based on their IWM. Internal working models were identified by children's representations, as measured by a narrative story stem task. Self-regulation was assessed by teacher report and a behavioral task, and adjustment was measured by teacher report. Cluster analyses indicated two subgroups of abused children with distinct patterns of IWMs. Cluster membership predicted internalizing and externalizing problems. Associations between cluster membership and adjustment were mediated by children's regulation, as measured by teacher reports of many aspects of regulation. There was no support for mediation when regulation was measured by a behavioral task that tapped more narrow facets of regulation. Abused children exhibit clinically relevant individual differences in their IWMs; these models are linked to adjustment in the school setting, possibly through children's self-regulation. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

  10. Non-invasive molecular imaging for preclinical cancer therapeutic development

    PubMed Central

    O'Farrell, AC; Shnyder, SD; Marston, G; Coletta, PL; Gill, JH

    2013-01-01

    Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development. PMID:23488622

  11. Sexual maturation and control issues among sexually abused and non-abused anorexia patients.

    PubMed

    Walsh, J; Burns, F

    2000-09-01

    To assess the relative salience of the maintenance of control and the avoidance of sexual maturation as sources of motivation for maintaining pathological eating behaviours among sexually abused anorexic patients. A two-factor mixed experimental design was employed. Three independent groups (sexually abused anorexics (N = 12); non-abused anorexics (N = 9); non-anorexic/non-abused controls (N = 12)) constituted the between-subjects factor. Allocation to abuse/non-abuse group was dependent upon replies to a questionnaire-based measure of unwanted sexual experience. The within-subjects factor comprised three conditions in which words of various colours were presented to participants for colour-naming (Stroop, 1935). The conditions were represented by lists of neutral words, sexual maturation words, and control-related words. Two trials were carried out in each condition and mean response times were measured. Within-group analyses revealed that interference was greater from sexual maturation words than from control-related words among the sexually-abused anorexics, but of equal magnitude among non-abused counterparts. Between-groups analyses found that abused patients experienced marginally greater cognitive interference from sexual maturation words than the non-abused patients. Theoretically, support is offered for elaborated schematic models of cognitive processing. Clinically, treatment interventions may need to pay particular attention to issues of sexual maturation among sexually abused anorexic patients.

  12. Psychiatric symptoms in preclinical behavioural-variant frontotemporal dementia in MAPT mutation carriers.

    PubMed

    Cheran, Gayathri; Silverman, Hannah; Manoochehri, Masood; Goldman, Jill; Lee, Seonjoo; Wu, Liwen; Cines, Sarah; Fallon, Emer; Kelly, Brendan Desmond; Olszewska, Diana Angelika; Heidebrink, Judith; Shair, Sarah; Campbell, Stephen; Paulson, Henry; Lynch, Timothy; Cosentino, Stephanie; Huey, Edward D

    2018-05-01

    To characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness. The present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers' lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported. Non-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder. Findings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  13. Paradoxical Neurobehavioral Rescue by Memories of Early-Life Abuse: The Safety Signal Value of Odors Learned during Abusive Attachment

    PubMed Central

    Raineki, Charlis; Sarro, Emma; Rincón-Cortés, Millie; Perry, Rosemarie; Boggs, Joy; Holman, Colin J; Wilson, Donald A; Sullivan, Regina M

    2015-01-01

    Caregiver-associated cues, including those learned in abusive attachment, provide a sense of safety and security to the child. Here, we explore how cues associated with abusive attachment, such as maternal odor, can modify the enduring neurobehavioral effects of early-life abuse. Two early-life abuse models were used: a naturalistic paradigm, where rat pups were reared by an abusive mother; and a more controlled paradigm, where pups underwent peppermint odor-shock conditioning that produces an artificial maternal odor through engagement of the attachment circuit. Animals were tested for maternal odor preference in infancy, forced swim test (FST), social behavior, and sexual motivation in adulthood—in the presence or absence of maternal odors (natural or peppermint). Amygdala odor-evoked local field potentials (LFPs) via wireless electrodes were also examined in response to the maternal odors in adulthood. Both early-life abuse models induced preference for the maternal odors in infancy. In adulthood, these early-life abuse models produced FST deficits and decreased social behavior, but did not change sexual motivation. Presentation of the maternal odors rescued FST and social behavior deficits induced by early-life abuse and enhanced sexual motivation in all animals. In addition, amygdala LFPs from both abuse animal models showed unique activation within the gamma frequency (70–90 Hz) bands in response to the specific maternal odor present during early-life abuse. These results suggest that attachment-related cues learned during infancy have a profound ability to rescue neurobehavioral dysregulation caused by early-life abuse. Paradoxically, abuse-associated cues seem to acquire powerful and enduring antidepressive properties and alter amygdala modulation. PMID:25284320

  14. Paradoxical neurobehavioral rescue by memories of early-life abuse: the safety signal value of odors learned during abusive attachment.

    PubMed

    Raineki, Charlis; Sarro, Emma; Rincón-Cortés, Millie; Perry, Rosemarie; Boggs, Joy; Holman, Colin J; Wilson, Donald A; Sullivan, Regina M

    2015-03-01

    Caregiver-associated cues, including those learned in abusive attachment, provide a sense of safety and security to the child. Here, we explore how cues associated with abusive attachment, such as maternal odor, can modify the enduring neurobehavioral effects of early-life abuse. Two early-life abuse models were used: a naturalistic paradigm, where rat pups were reared by an abusive mother; and a more controlled paradigm, where pups underwent peppermint odor-shock conditioning that produces an artificial maternal odor through engagement of the attachment circuit. Animals were tested for maternal odor preference in infancy, forced swim test (FST), social behavior, and sexual motivation in adulthood-in the presence or absence of maternal odors (natural or peppermint). Amygdala odor-evoked local field potentials (LFPs) via wireless electrodes were also examined in response to the maternal odors in adulthood. Both early-life abuse models induced preference for the maternal odors in infancy. In adulthood, these early-life abuse models produced FST deficits and decreased social behavior, but did not change sexual motivation. Presentation of the maternal odors rescued FST and social behavior deficits induced by early-life abuse and enhanced sexual motivation in all animals. In addition, amygdala LFPs from both abuse animal models showed unique activation within the gamma frequency (70-90 Hz) bands in response to the specific maternal odor present during early-life abuse. These results suggest that attachment-related cues learned during infancy have a profound ability to rescue neurobehavioral dysregulation caused by early-life abuse. Paradoxically, abuse-associated cues seem to acquire powerful and enduring antidepressive properties and alter amygdala modulation.

  15. Long-term tolerance to kidney allografts in a preclinical canine model.

    PubMed

    Kuhr, Christian S; Yunusov, Murad; Sale, George; Loretz, Carol; Storb, Rainer

    2007-08-27

    Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

  16. Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics.

    PubMed

    Jain, Shweta; Khaiser, Imran M; Thakur, Sophia; Jain, Shikha

    2014-05-01

    Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases.

  17. Rat animal model for preclinical testing of microparticle urethral bulking agents.

    PubMed

    Mann-Gow, Travis K; Blaivas, Jerry G; King, Benjamin J; El-Ghannam, Ahmed; Knabe, Christine; Lam, Michael K; Kida, Masatoshi; Sikavi, Cameron S; Plante, Mark K; Krhut, Jan; Zvara, Peter

    2015-04-01

    To develop an economic, practical and readily available animal model for preclinical testing of urethral bulking therapies, as well as to establish feasible experimental methods that allow for complete analysis of hard microparticle bulking agents. Alumina ceramic beads suspended in hyaluronic acid were injected into the proximal urethra of 15 female rats under an operating microscope. We assessed overall lower urinary tract function, bulking material intraurethral integrity and local host tissue response over time. Microphotographs were taken during injection and again 6 months postoperatively, before urethral harvest. Urinary flow rate and voiding frequency were assessed before and after injection. At 6 months, the urethra was removed and embedded in resin. Hard tissue sections were cut using a sawing microtome, and processed for histological analysis using scanning electron microscopy, light microscopy and immunohistochemistry. Microphotographs of the urethra showed complete volume retention of the bulking agent at 6 months. There was no significant difference between average urinary frequency and mean urinary flow rate at 1 and 3 months postinjection as compared with baseline. Scanning electron microscopy proved suitable for evaluation of microparticle size and integrity, as well as local tissue remodeling. Light microscopy and immunohistochemistry allowed for evaluation of an inflammatory host tissue reaction to the bulking agent. The microsurgical injection technique, in vivo physiology and novel hard tissue processing for histology, described in the present study, will allow for future comprehensive preclinical testing of urethral bulking therapy agents containing microparticles made of a hard material. © 2015 The Japanese Urological Association.

  18. A conceptual model of the risk of elder abuse posed by incontinence and care dependence.

    PubMed

    Ostaszkiewicz, Joan

    2017-12-08

    To describe and critically analyse the thinking that led to the concept of an association between incontinence, care dependence and elder abuse. Coercive or abusive continence care practices include chastising a person for their incontinence and overriding their attempts to resist continence care. Neglect in continence care is characterised by withholding or delaying responding to requests for help to maintain continence or to manage incontinence, and restricting a person's access to toileting assistance, incontinence aids or hygiene care. Contemporary biomedical understandings about incontinence and influencing concepts from the fields of sociology, psychology and nursing were analysed to inform the design of a conceptual model that elucidates possible associations between incontinence, care dependence and elder abuse. Ideas generated from an analysis of the concepts led to the development of a model termed the "Model of Attributes to Abuse of Dependent Elders in Continence Care" (MADE-CC). The MADE-CC theorises factors that cause and contribute to abuse in continence care. Carer factors include physical and emotional exhaustion, frustration related to the inability to control or predict incontinence, resentment associated with constraints imposed by care dependence, disgust associated with physical contact with urine/faeces, limited knowledge and skills about incontinence and ethical conflicts concerning care. Care recipient factors include frequent and severe incontinence, cognitive impairment and a history of physical or psychological trauma. Social factors that are theorised include the stigmatised nature of incontinence, social taboos and cultural norms and the private nature of continence care. The MADE-CC illuminates the potential risk of elder abuse posed by incontinence and care dependence. It should be used to improve ethical care of older people and stimulate debate about everyday ethics in the care of older people who are care dependent and to optimise

  19. Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

    PubMed Central

    Dohmen, Amy J. C.; Swartz, Justin E.; Van Den Brekel, Michiel W. M.; Willems, Stefan M.; Spijker, René; Neefjes, Jacques; Zuur, Charlotte L.

    2015-01-01

    Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well. PMID:26343729

  20. Addressing elder abuse: the Waterloo restorative justice approach to elder abuse project.

    PubMed

    Groh, Arlene; Linden, Rick

    2011-04-01

    The Community Care Access Centre (CCAC) of Waterloo Region, in partnership with a number of other social service agencies, designed and implemented a restorative justice model applicable to older adults who have been abused by an individual in a position of trust. The project was very successful in building partnerships, as many community agencies came together to deal with the problem of elder abuse. The program also raised the profile of elder abuse in the community. However, despite intensive efforts, referrals to the restorative justice program were quite low. Because of this, the program moved to a new organizational model, the Elder Abuse Response Team (EART), which has retained the guiding philosophy of restorative justice but has broadened the mandate. The team has evolved into a conflict management system that has multiple points of entry for cases and multiple options for dealing with elder abuse. The team has developed a broad range of community partners who can facilitate referrals to the EART and also can help to provide an individualized response to each case. The transition to the EART has been successful, and the number of referrals has increased significantly. Copyright © Taylor & Francis Group, LLC

  1. Joint influences of individual and work unit abusive supervision on ethical intentions and behaviors: a moderated mediation model.

    PubMed

    Hannah, Sean T; Schaubroeck, John M; Peng, Ann C; Lord, Robert G; Trevino, Linda K; Kozlowski, Steve W J; Avolio, Bruce J; Dimotakis, Nikolaos; Doty, Joseph

    2013-07-01

    We develop and test a model based on social cognitive theory (Bandura, 1991) that links abusive supervision to followers' ethical intentions and behaviors. Results from a sample of 2,572 military members show that abusive supervision was negatively related to followers' moral courage and their identification with the organization's core values. In addition, work unit contexts with varying degrees of abusive supervision, reflected by the average level of abusive supervision reported by unit members, moderated relationships between the level of abusive supervision personally experienced by individuals and both their moral courage and their identification with organizational values. Moral courage and identification with organizational values accounted for the relationship between abusive supervision and followers' ethical intentions and unethical behaviors. These findings suggest that abusive supervision may undermine moral agency and that being personally abused is not required for abusive supervision to negatively influence ethical outcomes. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  2. Feasibility of spatial frequency domain imaging (SFDI) for optically characterizing a preclinical oncology model.

    PubMed

    Tabassum, Syeda; Zhao, Yanyu; Istfan, Raeef; Wu, Junjie; Waxman, David J; Roblyer, Darren

    2016-10-01

    Determination of chemotherapy efficacy early during treatment would provide more opportunities for physicians to alter and adapt treatment plans. Diffuse optical technologies may be ideally suited to track early biological events following chemotherapy administration due to low cost and high information content. We evaluated the use of spatial frequency domain imaging (SFDI) to characterize a small animal tumor model in order to move towards the goal of endogenous optical monitoring of cancer therapy in a controlled preclinical setting. The effects of key measurement parameters including the choice of imaging spatial frequency and the repeatability of measurements were evaluated. The precision of SFDI optical property extractions over repeat mouse measurements was determined to be within 3.52% for move and replace experiments. Baseline optical properties and chromophore values as well as intratumor heterogeneity were evaluated over 25 tumors. Additionally, tumor growth and chemotherapy response were monitored over a 45 day longitudinal study in a small number of mice to demonstrate the ability of SFDI to track treatment effects. Optical scattering and oxygen saturation increased as much as 70% and 25% respectively in treated tumors, suggesting SFDI may be useful for preclinical tracking of cancer therapies.

  3. Three-dimensional thermal finite element modeling of lithium-ion battery in thermal abuse application

    NASA Astrophysics Data System (ADS)

    Guo, Guifang; Long, Bo; Cheng, Bo; Zhou, Shiqiong; Xu, Peng; Cao, Binggang

    In order to better understand the thermal abuse behavior of high capacities and large power lithium-ion batteries for electric vehicle application, a three-dimensional thermal model has been developed for analyzing the temperature distribution under abuse conditions. The model takes into account the effects of heat generation, internal conduction and convection, and external heat dissipation to predict the temperature distribution in a battery. Three-dimensional model also considers the geometrical features to simulate oven test, which are significant in larger cells for electric vehicle application. The model predictions are compared to oven test results for VLP 50/62/100S-Fe (3.2 V/55 Ah) LiFePO 4/graphite cells and shown to be in great agreement.

  4. The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

    PubMed

    Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

    2017-07-01

    Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Effectiveness of Different Models of Case Management for Substance-Abusing Populations

    PubMed Central

    Vanderplasschen, Wouter; Wolf, Judith; Rapp, Richard C.; Broekaert, Eric

    2007-01-01

    Case management has been implemented in substance abuse treatment to improve (cost-) effectiveness, but controversy exists about its potential to realize this objective. A systematic and comprehensive review of peer-reviewed articles (n = 48) published between 1993 and 2003 is presented, focusing on the effects of different models of case management among various substance-abusing populations. Results show that several studies have reported positive effects, but only some randomized and controlled trials have demonstrated the effectiveness of case management compared with other interventions. Longitudinal effects of this intervention remain unclear. Although no compelling evidence was found for the effectiveness of case management, some evidence is available about the (differential) effectiveness of intensive case management and assertive community treatment for homeless and dually-diagnosed substance abusers. Strengths-based and generalist case management have proven to be relatively effective for substance abusers in general. Most positive effects concern reduced use of inpatient services and increased utilization of community-based services, prolonged treatment retention, improved quality of life, and high client satisfaction. Outcomes concerning drug use and psychosocial functioning are less consistent, but seem to be mediated by retention in treatment and case management. Further research is required to learn more about the extent of the effects of this intervention, how long these are sustained and what specific elements cause particular outcomes. PMID:17523588

  6. Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury.

    PubMed

    Fiorentino, Marco; Kellum, John A

    2018-05-23

    Several cellular and molecular targets and mechanisms have been investigated in preclinical studies of acute kidney injury (AKI), but translation in successful clinical studies has failed to date. This article reviews many issues that have limited this and the potential future perspectives in AKI prevention and treatment. Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success. © 2018 S. Karger AG, Basel.

  7. Internal Working Models and Adjustment of Physically Abused Children: The Mediating Role of Self-Regulatory Abilities

    ERIC Educational Resources Information Center

    Hawkins, Amy L.; Haskett, Mary E.

    2014-01-01

    Background: Abused children's internal working models (IWM) of relationships are known to relate to their socioemotional adjustment, but mechanisms through which negative representations increase vulnerability to maladjustment have not been explored. We sought to expand the understanding of individual differences in IWM of abused children and…

  8. Preclinical Magnetic Resonance Imaging and Systems Biology in Cancer Research

    PubMed Central

    Albanese, Chris; Rodriguez, Olga C.; VanMeter, John; Fricke, Stanley T.; Rood, Brian R.; Lee, YiChien; Wang, Sean S.; Madhavan, Subha; Gusev, Yuriy; Petricoin, Emanuel F.; Wang, Yue

    2014-01-01

    Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy. PMID:23219428

  9. Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts.

    PubMed

    Ambrogio, Chiara; Carmona, Francisco J; Vidal, August; Falcone, Mattia; Nieto, Patricia; Romero, Octavio A; Puertas, Sara; Vizoso, Miguel; Nadal, Ernest; Poggio, Teresa; Sánchez-Céspedes, Montserrat; Esteller, Manel; Mulero, Francisca; Voena, Claudia; Chiarle, Roberto; Barbacid, Mariano; Santamaría, David; Villanueva, Alberto

    2014-11-01

    Cancer evolution is a process that is still poorly understood because of the lack of versatile in vivo longitudinal studies. By generating murine non-small cell lung cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations, and the appearance of naturally occurring intratumor heterogeneity, thus recapitulating the stochastic nature of human cancer development. This approach combines the robustness of genetically engineered cancer models with the flexibility of allograft methodology. We have applied this tool for the preclinical evaluation of therapeutic approaches. This system can be implemented to improve the design of future treatments for patients with NSCLC. ©2014 American Association for Cancer Research.

  10. The utility of micro-CT and MRI in the assessment of longitudinal growth of liver metastases in a preclinical model of colon carcinoma.

    PubMed

    Pandit, Prachi; Johnston, Samuel M; Qi, Yi; Story, Jennifer; Nelson, Rendon; Johnson, G Allan

    2013-04-01

    Liver is a common site for distal metastases in colon and rectal cancer. Numerous clinical studies have analyzed the relative merits of different imaging modalities for detection of liver metastases. Several exciting new therapies are being investigated in preclinical models. But, technical challenges in preclinical imaging make it difficult to translate conclusions from clinical studies to the preclinical environment. This study addresses the technical challenges of preclinical magnetic resonance imaging (MRI) and micro-computed tomography (CT) to enable comparison of state-of-the-art methods for following metastatic liver disease. We optimized two promising preclinical protocols to enable a parallel longitudinal study tracking metastatic human colon carcinoma growth in a mouse model: T2-weighted MRI using two-shot PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) and contrast-enhanced micro-CT using a liposomal contrast agent. Both methods were tailored for high throughput with attention to animal support and anesthesia to limit biological stress. Each modality has its strengths. Micro-CT permitted more rapid acquisition (<10 minutes) with the highest spatial resolution (88-micron isotropic resolution). But detection of metastatic lesions requires the use of a blood pool contrast agent, which could introduce a confound in the evaluation of new therapies. MRI was slower (30 minutes) and had lower anisotropic spatial resolution. But MRI eliminates the need for a contrast agent and the contrast-to-noise between tumor and normal parenchyma was higher, making earlier detection of small lesions possible. Both methods supported a relatively high-throughput, longitudinal study of the development of metastatic lesions. Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.

  11. Affective preclinical modeling of psychiatric disorders: taking imbalanced primal emotional feelings of animals seriously in our search for novel antidepressants

    PubMed Central

    Panksepp, Jaak

    2015-01-01

    Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong—to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states. During the past decade, the use of such affective neuroscience-based animal modeling has yielded three novel antidepressants (i) via the alleviation of psychic pain with low doses of buprenorphine; (ii) via the amplification of enthusiasm by direct stimulation of the medial forebrain bundle); and (iii) via the facilitation of the capacity for social joy with play facilitators such as rapastinel (GLYX13). All have progressed to successful human testing. For optimal progress, it may be useful for preclinical investigators to focus on the evolved affective foundations of psychiatrically relevant brain emotional disorders for optimal animal modeling. PMID:26869838

  12. Vaginal wall weakness in parous ewes: a potential preclinical model of pelvic organ prolapse.

    PubMed

    Young, Natharnia; Rosamilia, Anna; Arkwright, John; Lee, Joseph; Davies-Tuck, Miranda; Melendez, Joan; Werkmeister, Jerome; Gargett, Caroline E

    2017-07-01

    Ewes develop pelvic organ prolapse (POP) and may be a suitable model for preclinical studies evaluating cell-based therapies for POP. The aim of this study was to establish a clinical score of vaginal weakness and to compare POP Quantification System (POP-Q) values in conscious nulliparous and parous ewes and determine whether ewes are a suitable POP model. Ewes (n = 114) were examined while conscious, without sedation, and standing in a V conveyer by adapting the human POP-Q measurement. Ovine POP was defined as descent to the introitus from POP-Q points Aa 3 cm above the introitus on the anterior wall, Ap 3 cm above the introitus on the posterior wall, or increased Ba anterior wall descent above the urethra (≥0). A test-retest showed good inter- and intrarater reliability. There was no evidence of tissue mobility at Aa, Ap, Ba (all -3 cm) in nulliparous ewes (n = 14). In contrast, multiparous ewes had a median of -1 and interquartile range (IQR) (-2 to 0) for Aa, [0 (-1 to 0)] for Ap and [0 (-2.75 to 0)] for Ba (n = 33; P < 0.0001 in comparison with nulliparous) ewes. Ovine vaginal displacement was seen in 50.9 % of parous ewes and was strongly associated with parity (P = 0.003). A modified POP-Q in conscious ewes was established showing that the vaginal wall of parous animals has similar regions of weakness as do women and may be similarly related to parity. Ewes appear to be a representative preclinical model of human vaginal prolapse.

  13. A Model of Sexual Risk Behaviors Among Young Gay and Bisexual Men: Longitudinal Associations of Mental Health, Substance Abuse, Sexual Abuse, and the Coming-Out Process

    PubMed Central

    Rosario, Margaret; Schrimshaw, Eric W.; Hunter, Joyce

    2011-01-01

    Sexual risk behaviors of young gay and bisexual men must be understood within the context of other health concerns (e.g., anxiety, substance abuse), population-specific factors (i.e., the coming-out process and gay-related stress), childhood sexual abuse, and other theoretical factors (e.g., safer sex intentions). The current report proposes and longitudinally examines a model of risk factors for subsequent sexual risk behaviors among young gay and bisexual men in New York City. As hypothesized, more negative attitudes toward homosexuality, more substance abuse symptoms, and poorer intentions for safer sex were directly associated with a greater likelihood of unprotected anal sex over the following year. Further, lower self-esteem, more anxious symptoms, and childhood sexual abuse were related to more unprotected anal sex indirectly through more sexual partners, sexual encounters, and substance abuse symptoms. These findings suggest that interventions targeting sexual risk behaviors of young gay and bisexual men may be more effective if they also address mental health concerns and aspects of the coming-out process. PMID:17067255

  14. Child Abuse & Neglect in the Mexican American Community. Course Model.

    ERIC Educational Resources Information Center

    Camacho, Rosie Lee

    Consisting of three units, the course model aims to prepare students to address the problem of abuse and/or neglect in the Mexican American community. Unit one focuses on the two major parts of the informal helping system in the Mexican American community, the barrio and the family. Unit two concentrates on the traditional child welfare system and…

  15. The basics of preclinical drug development for neurodegenerative disease indications.

    PubMed

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  16. The basics of preclinical drug development for neurodegenerative disease indications

    PubMed Central

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  17. Cardiac AAV9-S100A1 gene therapy rescues postischemic heart failure in a preclinical large animal model

    PubMed Central

    Pleger, Sven T.; Shan, Changguang; Ksienzyk, Jan; Bekeredjian, Raffi; Boekstegers, Peter; Hinkel, Rabea; Schinkel, Stefanie; Leuchs, Barbara; Ludwig, Jochen; Qiu, Gang; Weber, Christophe; Kleinschmidt, Jürgen A.; Raake, Philip; Koch, Walter J.; Katus, Hugo A.; Müller, Oliver J.; Most, Patrick

    2014-01-01

    As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the pre-clinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure. PMID:21775667

  18. A Systems Dynamic Model for Drug Abuse and Drug-Related Crime in the Western Cape Province of South Africa

    PubMed Central

    Coetzee, Lezanie

    2017-01-01

    The complex problem of drug abuse and drug-related crimes in communities in the Western Cape province cannot be studied in isolation but through the system they are embedded in. In this paper, a theoretical model to evaluate the syndemic of substance abuse and drug-related crimes within the Western Cape province of South Africa is constructed and explored. The dynamics of drug abuse and drug-related crimes within the Western Cape are simulated using STELLA software. The simulation results are consistent with the data from SACENDU and CrimeStats SA, highlighting the usefulness of such a model in designing and planning interventions to combat substance abuse and its related problems. PMID:28555161

  19. Ficus deltoidea Prevented Bone Loss in Preclinical Osteoporosis/Osteoarthritis Model by Suppressing Inflammation.

    PubMed

    Che Ahmad Tantowi, Nur Adeelah; Lau, Seng Fong; Mohamed, Suhaila

    2018-05-28

    Osteoporosis (OP) and osteoarthritis (OA) are debilitating musculoskeletal diseases of the elderly. Ficus deltoidea (FD) or mistletoe fig, a medicinal plant, was pre-clinically evaluated against OP- and OA-related bone alterations, in postmenopausal OA rat model. Thirty twelfth-week-old female rats were divided into groups (n = 6). Four groups were bilateral ovariectomized (OVX) and OA-induced by intra-articular monosodium iodoacetate (MIA) injection into the right knee joints. The Sham control and OVX-OA non-treated groups were given deionized water. The three other OVX-OA groups were orally administered daily with FD extract (200, 400 mg/kg) or diclofenac (5 mg/kg) for 4 weeks. The rats' bones and blood were evaluated for protein and mRNA expressions of osteoporosis and inflammatory indicators, and micro-CT computed tomography for bone microstructure. The non-treated OVX-OA rats developed severe OP bone loss and bone microstructural damage in the subchondral and metaphyseal regions, supported by reduced serum bone formation markers (osteocalcin, osteoprotegerin) and increased bone resorption markers (RANKL and CTX-I). The FD extract significantly (p < 0.05) mitigated these bone microstructural and biomarker changes by dose-dependently down-regulating pro-inflammatory NF-κβ, TNF-α, and IL-6 mRNA expressions. The FD extract demonstrated good anti-osteoporotic properties in this OP/OA preclinical model by stimulating bone formation and suppressing bone resorption via anti-inflammatory pathways. This is among the few reports relating the subchondral bone plate and trabecular thickening with the metaphyseal trabecular osteopenic bone loss under osteoporotic-osteoarthritis conditions, providing some insights on the debated inverse relationship between osteoporosis and osteoarthritis.

  20. Effect of drugs of abuse on social behaviour: a review of animal models.

    PubMed

    Blanco-Gandía, Maria C; Mateos-García, Ana; García-Pardo, Maria P; Montagud-Romero, Sandra; Rodríguez-Arias, Marta; Miñarro, José; Aguilar, María A

    2015-09-01

    Social behaviour is disturbed in many substance abuse and psychiatric disorders. Given the consensus that social behaviours of lower mammals may help to understand some human emotional reactions, the aim of the present work was to provide an up-to-date review of studies on the changes in social behaviour induced by drugs of abuse. Various animal models have been used to study the relationship between drugs of abuse and social behaviour. Herein, we describe the effects of different substances of abuse on the three most commonly used animal models of social behaviour: the social play test, the social interaction test and the resident-intruder paradigm. The first is the most widely used test to assess adolescent behaviour in rodents, the second is generally used to evaluate a wide repertoire of behaviours in adulthood and the latter is specific to aggressive behaviour. Throughout the review we will explore the most relevant studies carried out to date to evaluate the effects of alcohol, cocaine, opioids, 3,4-methylenedioxymethamphetamine (MDMA), cannabinoids, nicotine and other drugs of abuse on these three paradigms, taking into account the influence of different variables, such as social history, age and type of exposure. Drugs of diverse pharmacological classes induce alterations in social behaviour, although they can be contrasting depending on several factors (drug, individual differences and environmental conditions). Ethanol and nicotine increase social interaction at low doses but reduce it at high doses. Psychostimulants, MDMA and cannabinoids reduce social interaction, whereas opiates increase it. Ethanol and psychostimulants enhance aggression, whereas MDMA, opiates, cannabinoids and nicotine reduce it. Prenatal drug exposure alters social behaviour, whereas drug withdrawal decreases sociability and enhances aggression. As a whole, this evidence has improved our understanding of the social dimension of drug addiction.

  1. From lead optimization to NDA approval for a new antimicrobial: Use of pre-clinical effect models and pharmacokinetic/pharmacodynamic mathematical modeling.

    PubMed

    Drusano, G L

    2016-12-15

    Because of our current crisis of resistance, particularly in nosocomial pathogens, the discovery and development of new antimicrobial agents has become a societal imperative. Changes in regulatory pathways by the Food and Drug Administration and the European Medicines Agency place great emphasis on the use of preclinical models coupled with pharmacokinetic/pharmacodynamic analysis to rapidly and safely move new molecular entities with activity against multi-resistant pathogens through the approval process and into the treatment of patients. In this manuscript, the use of the murine pneumonia system and the Hollow Fiber Infection Model is displayed and the way in which the mathematical analysis of the data arising from these models contributes to the robust choice of dose and schedule for Phase 3 clinical trials is shown. These data and their proper analysis act to de-risk the conduct of Phase 3 trials for anti-infective agents. These trials are the most expensive part of drug development. Further, given the seriousness of the infections treated, they represent the riskiest element for patients. Consequently, these preclinical model systems and their proper analysis have become a central part of accelerated anti-infective development. A final contention of this manuscript is that it is possible to embed these models and in particular, the Hollow Fiber Infection Model earlier in the drug discovery/development process. Examples of 'dynamic driver switching' and the impact of this phenomenon on clinical trial outcome are provided. Identifying dynamic drivers early in drug discovery may lead to improved decision making in the lead optimization process, resulting in the best molecules transitioning to clinical development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models

    PubMed Central

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-01-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

  3. Rosalie Wolf Memorial Lecture: A logic model to measure the impacts of World Elder Abuse Awareness Day.

    PubMed

    Stein, Karen

    2016-01-01

    This commentary discusses the need to evaluate the impact of World Elder Abuse Awareness Day activities, the elder abuse field's most sustained public awareness initiative. A logic model is proposed with measures for short-term, medium-term, and long-term outcomes for community-based programs.

  4. Novel target for high-risk neuroblastoma identified in pre-clinical research | Center for Cancer Research

    Cancer.gov

    Pre-clinical research by investigators at the Center for Cancer Research and their colleagues have identified a number of novel epigenetic targets for high-risk neuroblastoma and validated a promising new targeted inhibitor in pre-clinical models.  Read more...

  5. Mitigating risk in academic preclinical drug discovery.

    PubMed

    Dahlin, Jayme L; Inglese, James; Walters, Michael A

    2015-04-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

  6. Preclinical Alzheimer's Disease: Implications for Refinement of the Concept.

    PubMed

    Vos, Stephanie J B; Visser, Pieter Jelle

    2018-05-23

    Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

  7. Preclinical Biokinetic Modelling of Tc-99m Radiophamaceuticals Obtained from Semi-Automatic Image Processing.

    PubMed

    Cornejo-Aragón, Luz G; Santos-Cuevas, Clara L; Ocampo-García, Blanca E; Chairez-Oria, Isaac; Diaz-Nieto, Lorenza; García-Quiroz, Janice

    2017-01-01

    The aim of this study was to develop a semi automatic image processing algorithm (AIPA) based on the simultaneous information provided by X-ray and radioisotopic images to determine the biokinetic models of Tc-99m radiopharmaceuticals from quantification of image radiation activity in murine models. These radioisotopic images were obtained by a CCD (charge couple device) camera coupled to an ultrathin phosphorous screen in a preclinical multimodal imaging system (Xtreme, Bruker). The AIPA consisted of different image processing methods for background, scattering and attenuation correction on the activity quantification. A set of parametric identification algorithms was used to obtain the biokinetic models that characterize the interaction between different tissues and the radiopharmaceuticals considered in the study. The set of biokinetic models corresponded to the Tc-99m biodistribution observed in different ex vivo studies. This fact confirmed the contribution of the semi-automatic image processing technique developed in this study.

  8. Micro-ultrasound for preclinical imaging

    PubMed Central

    Foster, F. Stuart; Hossack, John; Adamson, S. Lee

    2011-01-01

    Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency ‘micro-ultrasound’ has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

  9. Abusive families and character formation.

    PubMed

    McCarthy, J B

    1990-06-01

    Family research studies confirm that abusive parents tend to be undifferentiated partners who compete with each other and with their children for attention and nurturance. More or less healthy parents make demands on children to counteract their own injured narcissism, but they do so largely without devaluation and the sadistic use of projective identification. Under sufficient stress abusive parents attack the child who fails to gratify their needs, thereby giving vent to longstanding frustrations and feelings of being threatened by the child's individuation and competency. The emotional atmosphere in such families facilitates ego deficits like those of the borderline personality as it molds the child's efforts to avoid anxiety. Devaluation, loss, and defenses against mourning partially account for depression and paranoid traits in abused youngsters. Early neglect and abuse exposes them to influential models who act out rage and primitive defenses. Some abused individuals project their rage and later become paranoid or antisocial, whereas others fragment or retain infantile defenses. The destructiveness of severe psychological abuse lies in the constriction of the experiencing self and healthy character development, together with the conditioning to repeat abusive relationships and to avoid intimacy. Achieving individuation under these circumstances entails overcoming the internalized abusive relationships and relinquishing the unconscious wish to be transformed from the abused into the abuser.

  10. Clinical Supervision in Alcohol and Drug Abuse Counseling: Principles, Models, Methods.

    ERIC Educational Resources Information Center

    Powell, David J.

    A case is made for professionalism in clinical training as substance abuse counseling becomes a unique field. Part 1, "Principles," includes: (1) "A Historical Review of Supervision"; (2) "A Working Definition of Supervision"; (3) "Leadership Principles for Supervisors" and; (4) "Traits of an Effective Clinical Supervisor." Part 2, "Models,"…

  11. HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

    PubMed Central

    Larochelle, Andre; Dunbar, Cynthia E.

    2013-01-01

    The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

  12. A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies

    PubMed Central

    Majumder, Kaustav; Arora, Nivedita; Modi, Shrey; Chugh, Rohit; Nomura, Alice; Giri, Bhuwan; Dawra, Rajinder; Ramakrishnan, Sundaram; Banerjee, Sulagna; Saluja, Ashok; Dudeja, Vikas

    2017-01-01

    A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as KrasG12D; Trp53R172H; Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies. PMID:26582596

  13. Comprehensive preclinical evaluation of a multi-physics model of liver tumor radiofrequency ablation.

    PubMed

    Audigier, Chloé; Mansi, Tommaso; Delingette, Hervé; Rapaka, Saikiran; Passerini, Tiziano; Mihalef, Viorel; Jolly, Marie-Pierre; Pop, Raoul; Diana, Michele; Soler, Luc; Kamen, Ali; Comaniciu, Dorin; Ayache, Nicholas

    2017-09-01

    We aim at developing a framework for the validation of a subject-specific multi-physics model of liver tumor radiofrequency ablation (RFA). The RFA computation becomes subject specific after several levels of personalization: geometrical and biophysical (hemodynamics, heat transfer and an extended cellular necrosis model). We present a comprehensive experimental setup combining multimodal, pre- and postoperative anatomical and functional images, as well as the interventional monitoring of intra-operative signals: the temperature and delivered power. To exploit this dataset, an efficient processing pipeline is introduced, which copes with image noise, variable resolution and anisotropy. The validation study includes twelve ablations from five healthy pig livers: a mean point-to-mesh error between predicted and actual ablation extent of 5.3 ± 3.6 mm is achieved. This enables an end-to-end preclinical validation framework that considers the available dataset.

  14. Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis

    PubMed Central

    Sharma, Raman; Al Jayoussi, Ghaith; Tyrer, Hayley E.; Gamble, Joanne; Hayward, Laura; Priestley, Richard S.; Murphy, Emma A.; Davies, Jill; Waterhouse, David; Cook, Darren A. N.; Clare, Rachel H.; Cassidy, Andrew; Steven, Andrew; Johnston, Kelly L.; McCall, John; Ford, Louise; Hemingway, Janet; Ward, Stephen A.

    2017-01-01

    Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles. PMID:29078351

  15. Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

    PubMed Central

    Burd, Christin E.; Gill, Matthew S.; Niedernhofer, Laura J.; Robbins, Paul D.; Austad, Steven N.; Barzilai, Nir

    2016-01-01

    Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. PMID:27535964

  16. Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms.

    PubMed

    Burd, Christin E; Gill, Matthew S; Niedernhofer, Laura J; Robbins, Paul D; Austad, Steven N; Barzilai, Nir; Kirkland, James L

    2016-11-01

    Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

  17. Leaving an Abusive Dating Relationship: A Prospective Analysis of the Investment Model and Theory of Planned Behavior.

    PubMed

    Edwards, Katie M; Gidycz, Christine A; Murphy, Megan J

    2015-10-01

    The purpose of the current study was to build on the existing literature to better understand young women's leaving processes in abusive dating relationships using a prospective design. Two social psychological models-the investment model and theory of planned behavior-were tested. According to the investment model, relationship continuation is predicted by commitment, which is a function of investment, satisfaction, and low quality of alternatives. The theory of planned behavior asserts that a specific behavior is predicted by an individual's intention to use a behavior, which is a function of the individual's attitudes toward the behavior, the subjective norms toward the behavior, and the individual's perceived behavioral control over the behavior. College women (N = 169 young women in abusive relatinships) completed surveys at two time points, approximately 4 months apart, to assess initially for the presence of intimate partner violence (IPV) in a current relationship and investment model and theory of planned behavior variables; the purpose of the 4-month follow-up session was to determine if women had remained in or terminated their abusive relationship. Path analytic results demonstrated that both the theory of planned behavior and investment models were good fits to the data in prospectively predicting abused women's stay/leave decisions. However, the theory of planned behavior was a better fit to the data than the investment model. Implications for future research and intervention are discussed. © The Author(s) 2014.

  18. Synchrotron radiation microimaging in rabbit models of cancer for preclinical testing

    NASA Astrophysics Data System (ADS)

    Umetani, Keiji; Uesugi, Kentaro; Kobatake, Makito; Yamamoto, Akira; Yamashita, Takenori; Imai, Shigeki

    2009-10-01

    Preclinical laboratory animal imaging modalities such as microangiography and micro-computed tomography (micro-CT) have been developed at the SPring-8 BL20B2 bending magnet beamline. The objective of this paper is to demonstrate the usefulness of microangiography systems for physiological examinations of live animals and micro-CT systems for postmortem morphological examinations. Synchrotron radiation microangiography and micro-CT with contrast agents present the main advantageous capability of depicting the anatomy of small blood vessels with tens of micrometers' diameter. This paper reports two imaging instrument types and their respective applications to preclinical imaging of tumor angiogenic blood vessels in tumor-bearing rabbits, where tumor angiogenesis is characterized morphologically by an increased number of blood vessels. A microangiography system with spatial resolution around 10 μm has been used for therapeutically evaluating angiogenic vessels in a rabbit model of cancer for evaluating embolization materials in transcatheter arterial embolization and for radiation therapy. After an iodine contrast agent was injected into an artery, in vivo imaging was carried out using a high-resolution real-time detector incorporating an X-ray direct-conversion-type SATICON pickup tube. On the other hand, a micro-CT system capably performed three-dimensional visualization of tumor angiogenic blood vessels using tumor-transplanted rabbit specimens with a barium sulfate contrast agent injected into the blood vessels. For specimen imaging, a large-field high-resolution micro-CT system based on a 10-megapixel CCD camera was developed to study tumor-associated alterations in angioarchitecture. Evidence of increased vascularity by tumor angiogenesis and decreased vascularity by tumor treatments was achieved by physiological evaluation of angiogenic small blood vessels in microangiographic imaging and by morphological assessment in micro-CT imaging. These results

  19. Intergenerational Transmission of Abuse of Incarcerated Fathers: A Study of the Measurement of Abuse

    ERIC Educational Resources Information Center

    Ball, Jeremy D.

    2009-01-01

    Research on the intergenerational transmission of abuse hypothesis often only examined the "existence" of abuse. The current study utilizes retrospective recalls of incarcerated male defendants (N = 414), using questions formulated from the modified Conflict Tactics Scales. Five logistic regression models are run, representing a different physical…

  20. Mitigating risk in academic preclinical drug discovery

    PubMed Central

    Dahlin, Jayme L.; Inglese, James; Walters, Michael A.

    2018-01-01

    The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

  1. Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research.

    PubMed

    Galuschka, Claudia; Proynova, Rumyana; Roth, Benjamin; Augustin, Hellmut G; Müller-Decker, Karin

    2017-05-15

    The devastating diseases of human cancer are mimicked in basic and translational cancer research by a steadily increasing number of tumor models, a situation requiring a platform with standardized reports to share model data. Models in Translational Oncology (MiTO) database was developed as a unique Web platform aiming for a comprehensive overview of preclinical models covering genetically engineered organisms, models of transplantation, chemical/physical induction, or spontaneous development, reviewed here. MiTO serves data entry for metastasis profiles and interventions. Moreover, cell lines and animal lines including tool strains can be recorded. Hyperlinks for connection with other databases and file uploads as supplementary information are supported. Several communication tools are offered to facilitate exchange of information. Notably, intellectual property can be protected prior to publication by inventor-defined accessibility of any given model. Data recall is via a highly configurable keyword search. Genome editing is expected to result in changes of the spectrum of model organisms, a reason to open MiTO for species-independent data. Registered users may deposit own model fact sheets (FS). MiTO experts check them for plausibility. Independently, manually curated FS are provided to principle investigators for revision and publication. Importantly, noneditable versions of reviewed FS can be cited in peer-reviewed journals. Cancer Res; 77(10); 2557-63. ©2017 AACR . ©2017 American Association for Cancer Research.

  2. Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs

    PubMed Central

    Neisewander, J. L.; Kelly, T. H.

    2013-01-01

    The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse. PMID:23343975

  3. A rationale and model for addressing tobacco dependence in substance abuse treatment.

    PubMed

    Richter, Kimber P; Arnsten, Julia H

    2006-08-14

    Most persons in drug treatment smoke cigarettes. Until drug treatment facilities systematically treat their patients' tobacco use, millions will flow through the drug treatment system, overcome their primary drug of abuse, but die prematurely from tobacco-related illnesses. This paper reviews the literature on the health benefits of quitting smoking for drug treatment patients, whether smoking causes relapse to other drug or alcohol abuse, the treatment of tobacco dependence, and good and bad times for quitting smoking among drug treatment patients. It also presents a conceptual model and recommendations for treating tobacco in substance abuse treatment, and provides references to internet and paper-copy tools and information for treating tobacco dependence. At present, research on tobacco treatment in drug treatment is in its infancy. Although few drug treatment programs currently offer formal services, many more will likely begin to treat nicotine dependence as external forces and patient demand for these services increases. In the absence of clear guidelines and attention to quality of care, drug treatment programs may adopt smoking cessation services based on cost, convenience, or selection criteria other than efficacy. Because research in this field is relatively new, substance abuse treatment professionals should adhere to the standards of care for the general population, but be prepared to update their practices with emerging interventions that have proven to be effective for patients in drug treatment.

  4. A Stress and Coping Approach to Intervention with Abused Women.

    ERIC Educational Resources Information Center

    Carlson, Bonnie E.

    1997-01-01

    Presents an ecological model of intervention for physical abuse based on the Lazarus and Folkman conceptualization of stress and coping. Claims that the model identifies the stages that abused women may experience in their appraisal of the abuse experience. Focuses on barriers to ending abuse, stress and coping, and effective interventions. (RJM)

  5. The Association Between Childhood Abuse and Elder Abuse Among Chinese Adult Children in the United States.

    PubMed

    Dong, XinQi; Li, Ge; Simon, Melissa A

    2017-07-01

    The previous researchers have postulated that an abused child may abuse his or her abuser parent when the parent is getting old, also known as the intergenerational transmission of violence. However, few studies use data to support this model, and it has yet to be examined in the U.S. Chinese community. This study aims to examine the association between childhood abuse and elder abuse reported by Chinese adult children in the United States. Guided by a community-based participatory research approach, 548 Chinese adult children aged 21 years and older participated in this study. Childhood abuse was assessed by four-item Hurt-Insult-Threaten-Scream (HITS) scale. Elder abuse was assessed by a 10-item instrument derived from the Caregiver Abuse Screen (CASE). Logistic regression analysis was performed. Childhood abuse was associated with caregiver abuse screen results (odds ratio = 1.92, 95% confidence interval = 1.24-2.95). Being physically hurt (r = .13, p < .01), insulted (r = .15, p < .001), threatened (r = .12, p < .01), and screamed at (r = .18, p < .001) as a child were significantly correlated with caregiver abuse screen results. This study suggests that childhood abuse is associated with increased risk of elder abuse among Chinese adult children in the United States. Longitudinal research should be conducted to explore the mechanisms through which childhood abuse and its subtypes links with elder abuse. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  6. Contrast-Enhanced Sonography Depicts Spontaneous Ovarian Cancer at Early Stages in a Preclinical Animal Model

    PubMed Central

    Barua, Animesh; Bitterman, Pincas; Bahr, Janice M.; Basu, Sanjib; Sheiner, Eyal; Bradaric, Michael J.; Hales, Dale B.; Luborsky, Judith L.; Abramowicz, Jacques S.

    2011-01-01

    Objective Our goal was to examine the feasibility of using laying hens, a preclinical model of human spontaneous ovarian cancer, in determining the kinetics of an ultrasound contrast agent indicative of ovarian tumor-associated neoangiogenesis in early-stage ovarian cancer. Methods Three-year-old White Leghorn laying hens with decreased ovarian function were scanned before and after intravenous injection of a human serum albumin–perflutren contrast agent at a dose of 5 µL/kg body weight. Gray scale morphologic characteristics, Doppler indices, the arrival time, peak intensity, and wash-out of the contrast agent were recorded and archived on still images and video clips. Hens were euthanized thereafter; sonographic predictions were compared at gross examination; and ovarian tissues were collected. Archived clips were analyzed to determine contrast parameters and Doppler intensities of vessels. A time-intensity curve per hen was drawn, and the area under the curve was derived. Tumor types and the density of ovarian microvessels were determined by histologic examination and immunohistochemistry and compared to sonographic predictions. Results The contrast agent significantly (P < .05) enhanced the visualization of microvessels, which was confirmed by immunohistochemistry. Contrast parameters, including the time of wash-out and area under the curve, were significantly different (P < .05) between ovaries of normal hens and hens with ovarian cancer and correctly detected cancer at earlier stages than the time of peak intensity. Conclusions The laying hen may be a useful animal model for determining ovarian tumor-associated vascular kinetics diagnostic of early-stage ovarian cancer using a contrast agent. This model may also be useful for testing the efficacy of different contrast agents in a preclinical setting. PMID:21357555

  7. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

    PubMed

    Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

    2013-09-01

    Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  8. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

    PubMed

    Barajaz, Ashley M; Kliethermes, Christopher L

    2017-12-01

    Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. A crowdsourcing model for creating preclinical medical education study tools.

    PubMed

    Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

    2013-06-01

    During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning.

  10. Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α.

    PubMed

    Lowery, Caitlin D; Blosser, Wayne; Dowless, Michele; Knoche, Shelby; Stephens, Jennifer; Li, Huiling; Surguladze, David; Loizos, Nick; Luffer-Atlas, Debra; Oakley, Gerard J; Guo, Qianxu; Iyer, Seema; Rubin, Brian P; Stancato, Louis

    2018-02-15

    Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors. Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor. Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin. Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847-57. ©2017 AACR . ©2017 American Association for Cancer Research.

  11. Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review.

    PubMed

    Maze, Mervyn

    2016-02-01

    The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury. Databases of the published literature (MEDLINE® and EMBASE™) were appraised for peer-reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators' declarations in the National Institutes of Health clinical trials website were considered. While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon's neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon's efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care. According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility.

  12. Representations of self and other in the narratives of neglected, physically abused, and sexually abused preschoolers.

    PubMed

    Toth, S L; Cicchetti, D; Macfie, J; Emde, R N

    1997-01-01

    The MacArthur Story Stem Battery was used to examine maternal and self-representations in neglected, physically abused, sexually abused, and nonmaltreated comparison preschool children. The narratives of maltreated children contained more negative maternal representations and more negative self-representations than did the narratives of nonmaltreated children. Maltreated children also were more controlling with and less responsive to the examiner. In examining the differential impact of maltreatment subtype differences on maternal and self-representations, physically abused children evidenced the most negative maternal representations; they also had more negative self-representations than nonmaltreated children. Sexually abused children manifested more positive self-representations than neglected children. Despite these differences in the nature of maternal and self-representations, physically and sexually abused children both were more controlling and less responsive to the examiner. The investigation adds to the corpus of knowledge regarding disturbances in the self-system functioning of maltreated children and provides support for relations between representational models of self and other and the self-organizing function that these models exert on children's lives.

  13. Methodological Rigor in Preclinical Cardiovascular Studies: Targets to Enhance Reproducibility and Promote Research Translation.

    PubMed

    Ramirez, F Daniel; Motazedian, Pouya; Jung, Richard G; Di Santo, Pietro; MacDonald, Zachary D; Moreland, Robert; Simard, Trevor; Clancy, Aisling A; Russo, Juan J; Welch, Vivian A; Wells, George A; Hibbert, Benjamin

    2017-06-09

    Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and

  14. Foodstuffs for Preventing Cancer: The Preclinical and Clinical Development of Berries

    PubMed Central

    Stoner, Gary D.

    2009-01-01

    Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents, such as anthocyanins and ellagitannins, that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems; for determining these compounds’ mechanisms of action; and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts or individual constituents (anthocyanins) for cancer prevention are also discussed. PMID:19258544

  15. Foodstuffs for preventing cancer: the preclinical and clinical development of berries.

    PubMed

    Stoner, Gary D

    2009-03-01

    Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.

  16. Methamphetamine blood concentrations in human abusers: application to pharmacokinetic modeling.

    PubMed

    Melega, William P; Cho, Arthur K; Harvey, Dennis; Laćan, Goran

    2007-04-01

    Characterization of methamphetamine's (METH) dose-dependent effects on brain neurochemistry may represent a critical component for better understanding the range of resultant behavioral pathologies. Most human studies, however, have assessed only the effects of long term, high dose METH abuse (e.g., greater than 1000 mg/day) in individuals meeting DSM-IV criteria for METH dependence. Yet, for the majority of METH abusers, their patterns of METH exposure that consist of lower doses remain less well-characterized. In this study, blood samples were obtained from 105 individuals detained by police for possible criminal activity and testing positive for stimulants by EMIT assay. METH blood concentrations were subsequently quantified by GC-MS and were predominantly in the low micromolar range (0.1-11.1 microM), with median and mean values of 1.3 microM (0.19 mg/l) and 2 microM (0.3 mg/l), respectively. Pharmacokinetic calculations based on these measured values were used to estimate initial METH body burdens, the median value being 52 mg. Modeling a 52 mg dose for a 4 day-METH maintenance exposure pattern of 4 doses/day at 4 h intervals showed that blood concentrations remained between 1 and 4 microM during this period. Collectively, these data present evidence for a METH exposure pattern distinct from high dose-METH abuse and provide the rationale for assessing potential brain pathology associated with such lower dose-METH exposure.

  17. Inhalant abuse among adolescents: neurobiological considerations

    PubMed Central

    Lubman, D I; Yücel, M; Lawrence, A J

    2008-01-01

    Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABAA, glycine and 5HT3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABAA receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development. PMID:18332858

  18. A mouse model for chronic pain-induced increase in ethanol consumption.

    PubMed

    Butler, Ryan K; Knapp, Darin J; Ulici, Veronica; Longobardi, Lara; Loeser, Richard F; Breese, George R

    2017-03-01

    Chronic pain conditions are often comorbid with alcohol abuse. "Self-medication" with alcohol introduces a host of problems associated with the abuse of alcohol which over time has the potential of exacerbating the painful condition. Despite the prevalence of chronic pain being associated with alcohol abuse, rodent models which mimic the comorbid conditions are lacking. In this study, we model osteoarthritis (OA) in C57BL/6J mice by surgically destabilizing the medial meniscus (DMM). Sham-operated mice served as controls. Thirteen weeks after surgery, DMM but not sham-operated mice exhibited pronounced incapacitance of the surgically manipulated hind limb compared with the nonsurgically manipulated hind limb. At this time, the mice were exposed to the 2-bottle ethanol choice, beginning with 2.5% with a gradual increasing to 20%. Compared with sham controls, DMM mice consumed more EtOH and preferred EtOH over water at the 20% EtOH concentration. Histological analysis verified that the DMM mice exhibited significant damage to the articular cartilage and osteophyte growth compared with sham controls and these measures of the severity of OA correlated with the amount of ethanol intake. Thus, the combination of the DMM model of OA with the enhanced two-bottle ethanol choice is a potential preclinical approach in mice by which the basis of the comorbid association of alcohol abuse and chronic pain conditions can be explored.

  19. Histological Characterization of the Irritative Zones in Focal Cortical Dysplasia Using a Preclinical Rat Model.

    PubMed

    Deshmukh, Abhay; Leichner, Jared; Bae, Jihye; Song, Yinchen; Valdés-Hernández, Pedro A; Lin, Wei-Chiang; Riera, Jorge J

    2018-01-01

    Current clinical practice in focal epilepsy involves brain source imaging (BSI) to localize brain areas where from interictal epileptiform discharges (IEDs) emerge. These areas, named irritative zones , have been useful to define candidate seizures-onset zones during pre-surgical workup. Since human histological data are mostly available from final resected zones, systematic studies characterizing pathophysiological mechanisms and abnormal molecular/cellular substrates in irritative zones-independent of them being epileptogenic-are challenging. Combining BSI and histological analysis from all types of irritative zones is only possible through the use of preclinical animal models. Here, we recorded 32-channel spontaneous electroencephalographic data from rats that have focal cortical dysplasia (FCD) and chronic seizures. BSI for different IED subtypes was performed using the methodology presented in Bae et al. (2015). Post-mortem brain sections containing irritative zones were stained to quantify anatomical, functional, and inflammatory biomarkers specific for epileptogenesis, and the results were compared with those obtained using the contralateral healthy brain tissue. We found abnormal anatomical structures in all irritative zones (i.e., larger neuronal processes, glioreactivity, and vascular cuffing) and larger expressions for neurotransmission (i.e., NR2B) and inflammation (i.e., ILβ1, TNFα and HMGB1). We conclude that irritative zones in this rat preclinical model of FCD comprise abnormal tissues disregarding whether they are actually involved in icto-genesis or not. We hypothesize that seizure perpetuation happens gradually; hence, our results could support the use of IED-based BSI for the early diagnosis and preventive treatment of potential epileptic foci. Further verifications in humans are yet needed.

  20. Draft Model Curriculum in Nursing Education for Alcohol and Other Drug Abuse.

    ERIC Educational Resources Information Center

    Naegle, Madeline A.; Burns, Elizabeth M.

    This document contains three model curricula in nursing education for alcohol and other drug abuse, one graduate and one baccalaureate level from New York University's (NYU) Division of Nursing, and the third combining graduate and undergraduate level curricula for Ohio State University (OSU). The NYU undergraduate curriculum contains a pilot test…

  1. Workplace abuse: finding solutions.

    PubMed

    Christmas, Kate

    2007-01-01

    The atmosphere within the work setting speaks volumes about your culture, and is often a primary factor in recruitment and retention (or turnover) of staff. Workplace tension and abuse are significant contributing factors as to why nurses are exiting workplaces--and even leaving the profession. Abuse can take many forms from inappropriate interpersonal communication to sexual harassment and even violence. Administrators should adopt a zero tolerance policy towards abusive communication. Addressing peer behavior is essential, but positive behavior must also be authentically modeled from the CNO and other nursing leaders. Raising awareness and holding individuals accountable for their behavior can lead to a safer and more harmonious work environment.

  2. Prior childhood sexual abuse in mothers of sexually abused children.

    PubMed

    Oates, R K; Tebbutt, J; Swanston, H; Lynch, D L; O'Toole, B I

    1998-11-01

    To see if mothers who were sexually abused in their own childhood are at increased risk of their children being sexually abused and to see if prior sexual abuse in mothers affects their parenting abilities. Sixty-seven mothers whose children had been sexually abused by others and 65 control mothers were asked about sexual abuse in their own childhood. The sexually abused children of mothers who had been sexually abused in their own childhood were compared with the sexually abused children of mothers who had not suffered child sexual abuse as children. Comparisons were made on self-esteem, depression and behavior in the children. Thirty-four percent of mothers of sexually abused children gave a history of sexual abuse in their own childhoods, compared with 12% of control mothers. Assessment of the sexually abused children for self-esteem, depression and behavior at the time of diagnosis, after 18 months and after 5 years showed no difference in any of these measures at any of the three time intervals between those whose mothers had suffered child sexual abuse and those whose mothers had not been abused. In this study, sexual abuse in a mother's own childhood was related to an increased risk of sexual abuse occurring in the next generation, although prior maternal sexual abuse did not effect outcome in children who were sexually abused.

  3. Psychiatric disorders, spouse abuse and child abuse.

    PubMed

    Bland, R C; Orn, H

    1986-01-01

    The results of 2000 standardized psychiatric diagnostic interviews of randomly selected adult household residents of Edmonton showed that having had any psychiatric diagnosis increased the risk for being involved in spouse and child abuse, particularly for those with alcohol abuse/dependence plus anti-social personality or depression. Altogether 56% of spouse abusers and 69% of child abusers had a lifetime psychiatric diagnosis.

  4. Elder abuse.

    PubMed

    Kurrle, Susan

    2004-10-01

    Elder abuse is a common and yet often unrecognised problem in our community. With up to 5% of the community dwelling older population being victims of abuse, the general practitioner has a pivotal role in identifying this abuse. This article provides an outline of the definition of elder abuse, describes the types of abuse seen and the reasons for occurrence of abuse. It summarises the role of the GP in the identification and management of abuse and provides guidance on intervention strategies. Case studies are used to illustrate the issues discussed. Elder abuse is defined as any pattern of behaviour which causes physical, psychological, financial or social harm to an older person. The role of the GP in identifying abuse is critical. The vast majority of older people visit their GP at least once a year, and the GP often has a long standing relationship with their patient and the patient's family. They are therefore ideally placed to identify elder abuse.

  5. Cognitive and Emotional Differences between Abusive and Non-Abusive Fathers

    ERIC Educational Resources Information Center

    Francis, Karen J.; Wolfe, David A.

    2008-01-01

    Objective: Abusive fathers perpetrate a substantial portion of child physical abuse. Despite this, little is known about how they differ from non-abusive fathers. This study compared a broad range of cognitive and affective factors between physically abusive and non-abusive fathers. Methods: Abusive (n = 24) and non-abusive (n = 25) fathers…

  6. Abuse of Older Men in Seven European Countries: A Multilevel Approach in the Framework of an Ecological Model.

    PubMed

    Melchiorre, Maria Gabriella; Di Rosa, Mirko; Lamura, Giovanni; Torres-Gonzales, Francisco; Lindert, Jutta; Stankunas, Mindaugas; Ioannidi-Kapolou, Elisabeth; Barros, Henrique; Macassa, Gloria; Soares, Joaquim J F

    2016-01-01

    Several studies on elder abuse indicate that a large number of victims are women, but others report that men in later life are also significantly abused, especially when they show symptoms of disability and poor health, and require help for their daily activities as a result. This study focused on the prevalence of different types of abuse experienced by men and on a comparison of male victims and non-victims concerning demographic/socio-economic characteristics, lifestyle/health variables, social support and quality of life. Additionally, the study identified factors associated with different types of abuse experienced by men and characteristics associated with the victims. The cross-sectional data concerning abuse in the past 12 months were collected by means of interviews and self-response during January-July 2009, from a sample of 4,467 not demented individuals aged between 60-84 years living in seven European countries (Germany, Greece, Italy, Lithuania, Portugal, Spain and Sweden). We used a multilevel approach, within the framework of an Ecological Model, to explore the phenomenon of abuse against males as the complex result of factors from multiple levels: individual, relational, community and societal. Multivariate analyses showed that older men educated to higher levels, blue-collar workers and men living in a rented accommodation were more often victims than those educated to lower levels, low-rank white-collar workers and home owners, respectively. In addition, high scores for factors such as somatic and anxiety symptoms seemed linked with an increased probability of being abused. Conversely, factors such as increased age, worries about daily expenses (financial strain) and greater social support seemed linked with a decreased probability of being abused. Male elder abuse is under-recognized, under-detected and under-reported, mainly due to the vulnerability of older men and to social/cultural norms supporting traditional male characteristics of

  7. Abuse of Older Men in Seven European Countries: A Multilevel Approach in the Framework of an Ecological Model

    PubMed Central

    Melchiorre, Maria Gabriella; Di Rosa, Mirko; Lamura, Giovanni; Torres-Gonzales, Francisco; Lindert, Jutta; Stankunas, Mindaugas; Ioannidi-Kapolou, Elisabeth; Barros, Henrique; Macassa, Gloria; Soares, Joaquim J. F.

    2016-01-01

    Background Several studies on elder abuse indicate that a large number of victims are women, but others report that men in later life are also significantly abused, especially when they show symptoms of disability and poor health, and require help for their daily activities as a result. This study focused on the prevalence of different types of abuse experienced by men and on a comparison of male victims and non-victims concerning demographic/socio-economic characteristics, lifestyle/health variables, social support and quality of life. Additionally, the study identified factors associated with different types of abuse experienced by men and characteristics associated with the victims. Methods The cross-sectional data concerning abuse in the past 12 months were collected by means of interviews and self-response during January-July 2009, from a sample of 4,467 not demented individuals aged between 60–84 years living in seven European countries (Germany, Greece, Italy, Lithuania, Portugal, Spain and Sweden). We used a multilevel approach, within the framework of an Ecological Model, to explore the phenomenon of abuse against males as the complex result of factors from multiple levels: individual, relational, community and societal. Results Multivariate analyses showed that older men educated to higher levels, blue-collar workers and men living in a rented accommodation were more often victims than those educated to lower levels, low-rank white-collar workers and home owners, respectively. In addition, high scores for factors such as somatic and anxiety symptoms seemed linked with an increased probability of being abused. Conversely, factors such as increased age, worries about daily expenses (financial strain) and greater social support seemed linked with a decreased probability of being abused. Conclusions Male elder abuse is under-recognized, under-detected and under-reported, mainly due to the vulnerability of older men and to social/cultural norms supporting

  8. Optimized design and analysis of preclinical intervention studies in vivo

    PubMed Central

    Laajala, Teemu D.; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-01-01

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

  9. Optimized design and analysis of preclinical intervention studies in vivo.

    PubMed

    Laajala, Teemu D; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

    2016-08-02

    Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions.

  10. Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma

    PubMed Central

    Krytska, Kateryna; Ryles, Hannah T.; Sano, Renata; Raman, Pichai; Infarinato, Nicole R.; Hansel, Theodore D.; Makena, Monish R.; Song, Michael M.; Reynolds, C. Patrick; Mossé, Yael P.

    2015-01-01

    Purpose The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. Experimental Design The sensitivity of human neuroblastoma-derived cell lines, cell line-derived and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. Results In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free-survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). Conclusions Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multi-agent therapy for ALK-aberrant neuroblastoma patients. PMID:26438783

  11. Reproducibility of preclinical animal research improves with heterogeneity of study samples

    PubMed Central

    Vogt, Lucile; Sena, Emily S.; Würbel, Hanno

    2018-01-01

    Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research. PMID:29470495

  12. Customizing Monoclonal Antibodies for the Treatment of Methamphetamine Abuse: Current and Future Applications

    PubMed Central

    Peterson, Eric C.; Gentry, W. Brooks

    2015-01-01

    Monoclonal antibody-based medications designed to bind (+)-methamphetamine (METH) with high affinity are among the newest approaches to the treatment of METH abuse, and the associated medical complications. The potential clinical indications for these medications include treatment of overdose, reduction of drug dependence, and protection of vulnerable populations from METH-related complications. Research designed to discover and conduct preclinical and clinical testing of these antibodies suggest a scientific vision for how intact mAb (singular and plural) or small antigen binding fragments of mAb could be engineered to optimize the proteins for specific therapeutic applications. In this review we discuss keys to success in this development process including choosing predictors of specificity, efficacy, duration of action, and safety of the medications in disease models of acute and chronic drug abuse. We consider important aspects of METH-like hapten design and how hapten structural features influence specificity and affinity, with an example of a high-resolution x-ray crystal structure of a high affinity antibody to demonstrate this structural relationship. Additionally, several prototype anti-METH mAb forms such as antigen binding fragments (Fab) and single chain variable fragments (scFv) are under development. Unique, customizable aspects of these fragments are presented with specific possible clinical indications. Finally, we discuss clinical trial progress of the first in kind anti-METH mAb, for which the METH is the disease target instead of vulnerable central nervous system networks of receptors, binding sites and neuronal connections. PMID:24484976

  13. Therapeutic Hypothermia and Hypoxia-Ischemia in the Term-equivalent Neonatal Rat: Characterization of a Translational Pre-clinical Model

    PubMed Central

    Patel, Shyama D.; Pierce, Leslie; Ciardiello, Amber; Hutton, Alexandra; Paskewitz, Samuel; Aronowitz, Eric; Voss, Henning U.; Moore, Holly; Vannucci, Susan J.

    2015-01-01

    Background Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity in survivors. Therapeutic hypothermia (TH) is the only available intervention, but the protection is incomplete. Preclinical studies of HIE/TH in the rodent have relied on the postnatal day (P) 7 rat whose brain approximates a 32–36 week gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational. Methods P10–11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 hours recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 hours, 2 and 12 weeks. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition. Results Neuroprotection with TH was apparent at 2 and 12 weeks in both moderately and severely damaged animals. TH improved motor function in moderate, but not severe damage. Impaired object recognition occurred with severe damage with no evidence of protection of TH. Conclusion This adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed longitudinally to provide a useful translational preclinical model. PMID:25996893

  14. Preclinical testing for aortic endovascular grafts: results of a Food and Drug Administration workshop.

    PubMed

    Abel, Dorothy B; Beebe, Hugh G; Dedashtian, Mark M; Morton, Michael C; Moynahan, Megan; Smith, Loius J; Weinberg, Steven L

    2002-05-01

    Since their introduction into clinical trials in the United States, endovascular aortic grafts have shown various types of problems. Although details of design and construction vary between different endovascular grafts and failure modes have had a variety of causes and clinical effects, the inability of preclinical testing to predict these failures remains common to all endovascular grafts. The need to improve preclinical testing in an attempt to reduce clinical device failures resulted in a Food and Drug Administration-sponsored workshop on endovascular graft preclinical testing held in Rockville, Md, from July 31 to August 1, 2001. FORMAT: The workshop was not designed as a consensus conference. Instead, it provided a forum for bringing stakeholders together to define problems and identify areas of agreement and disagreement. The workshop had 34 invited participants who represented device manufacturers, the medical community, the Food and Drug Administration, and testing facilities, and international attendance was more than 120 people. Discussion centered on: 1, defining the physiologic, anatomic, and morphologic characteristics of abdominal aortic aneurysms before and after endovascular graft treatment; 2, identifying the types of failures that have been observed clinically; and 3, determining which characteristics should be considered during preclinical modeling to better predict clinical performance. Attendees agreed to the need to better define and address anatomic characteristics and changes in the aneurysm after endograft treatment to optimize preclinical testing. Much discussion and little agreement occurred on the importance of flow-related forces on graft performance or the need or ability to define and model physiologic compliance during durability testing. The discussion and conclusions are summarized in this paper and are provided in detail at: http://www.fda.gov/cdrh/meetings/073101workshop.html. The workshop raised awareness of significant

  15. Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review

    PubMed Central

    Deane, Kevin D.

    2014-01-01

    Multiple studies demonstrate that there is a period of development of rheumatoid arthritis (RA) during which there are elevations of disease-related biomarkers, including autoantibodies, in the absence of and prior to the development of RA; this period can be termed ‘preclinical RA’. These ‘preclinical’ autoantibodies including rheumatoid factor and antibodies to citrullinated protein antigens, and more recent studies have also identified a wider variety of autoantibodies and a wide range of inflammatory biomarkers. These findings in conjunction with established and emerging data about genetic and environmental risk factors for RA support a model of disease development where certain factors lead to an initial triggering of RA-related autoimmunity that expands over time to the point where symptomatic arthritis classifiable as RA develops. Herein will be reviewed updates in the field, as well as a discussion of current limitations of our understanding of preclinical RA, and potential future directions for study. PMID:24643396

  16. Long-term correlates of childhood abuse among adults with severe mental illness: adult victimization, substance abuse, and HIV sexual risk behavior.

    PubMed

    Meade, Christina S; Kershaw, Trace S; Hansen, Nathan B; Sikkema, Kathleen J

    2009-04-01

    The prevalence of childhood sexual and physical abuse among persons with severe mental illness (SMI) is disproportionately high. Adults with SMI also engage in high rates of HIV risk behaviors. This study examined the association between childhood abuse and adult victimization, substance abuse, and lifetime HIV sexual risk in a sample of 152 adults with SMI receiving community mental health services. Structured interviews assessed psychiatric, psychosocial, and behavioral risk factors. Seventy percent reported childhood physical and/or sexual abuse, and 32% reported both types of abuse. Participants with childhood abuse were more likely to report adult victimization and greater HIV risk. A structural equation model found that childhood abuse was directly and indirectly associated with HIV risk through drug abuse and adult vicitimization. Integrated treatment approaches that address interpersonal violence and substance abuse may be necessary for HIV risk reduction in this population.

  17. Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

    PubMed Central

    Bell, Richard L.; Sable, Helen J.K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

    2012-01-01

    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID:22841890

  18. Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM).

    PubMed

    Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M

    2016-07-01

    In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical

  19. Benefits and costs of substance abuse treatment programs for state prison inmates: results from a lifetime simulation model.

    PubMed

    Zarkin, Gary A; Cowell, Alexander J; Hicks, Katherine A; Mills, Michael J; Belenko, Steven; Dunlap, Laura J; Houser, Kimberly A; Keyes, Vince

    2012-06-01

    Reflecting drug use patterns and criminal justice policies throughout the 1990s and 2000s, prisons hold a disproportionate number of society's drug abusers. Approximately 50% of state prisoners meet the criteria for a diagnosis of drug abuse or dependence, but only 10% receive medically based drug treatment. Because of the link between substance abuse and crime, treating substance abusing and dependent state prisoners while incarcerated has the potential to yield substantial economic benefits. In this paper, we simulate the lifetime costs and benefits of improving prison-based substance abuse treatment and post-release aftercare for a cohort of state prisoners. Our model captures the dynamics of substance abuse as a chronic disease; estimates the benefits of substance abuse treatment over individuals' lifetimes; and tracks the costs of crime and criminal justice costs related to policing, adjudication, and incarceration. We estimate net societal benefits and cost savings to the criminal justice system of the current treatment system and five policy scenarios. We find that four of the five policy scenarios provide positive net societal benefits and cost savings to the criminal justice system relative to the current treatment system. Our study demonstrates the societal gains to improving the drug treatment system for state prisoners. Copyright © 2011 John Wiley & Sons, Ltd.

  20. BENEFITS AND COSTS OF SUBSTANCE ABUSE TREATMENT PROGRAMS FOR STATE PRISON INMATES: RESULTS FROM A LIFETIME SIMULATION MODEL

    PubMed Central

    ZARKIN, GARY A.; COWELL, ALEXANDER J.; HICKS, KATHERINE A.; MILLS, MICHAEL J.; BELENKO, STEVEN; DUNLAP, LAURA J.; HOUSER, KIMBERLY A.; KEYES, VINCE

    2011-01-01

    SUMMARY Reflecting drug use patterns and criminal justice policies throughout the 1990s and 2000s, prisons hold a disproportionate number of society’s drug abusers. Approximately 50% of state prisoners meet the criteria for a diagnosis of drug abuse or dependence, but only 10% receive medically based drug treatment. Because of the link between substance abuse and crime, treating substance abusing and dependent state prisoners while incarcerated has the potential to yield substantial economic benefits. In this paper, we simulate the lifetime costs and benefits of improving prison-based substance abuse treatment and post-release aftercare for a cohort of state prisoners. Our model captures the dynamics of substance abuse as a chronic disease; estimates the benefits of substance abuse treatment over individuals’ lifetimes; and tracks the costs of crime and criminal justice costs related to policing, adjudication, and incarceration. We estimate net societal benefits and cost savings to the criminal justice system of the current treatment system and five policy scenarios. We find that four of the five policy scenarios provide positive net societal benefits and cost savings to the criminal justice system relative to the current treatment system. Our study demonstrates the societal gains to improving the drug treatment system for state prisoners. PMID:21506193

  1. Teen dating abuse: recognition and interventions.

    PubMed

    Freeman, Sally Ann; Rosenbluth, Barri; Cotton, Laura

    2013-03-01

    Teen dating abuse, also known as teen dating violence, is a significant public health issue. Adolescents with a history of dating abuse may struggle academically and experience increased risk for serious injury or even death. They may engage in risky sexual behavior, substance abuse, and unhealthy dieting and exhibit suicidal behaviors. School nurses may be the first adults that teens confide in when experiencing dating abuse and may lack the knowledge and skills to intervene with teens involved in unhealthy dating relationships. Beginning in 2008, Dell Children s Medical Center in Austin, Texas, partnered with SafePlace (a local nonprofit that serves survivors of sexual and domestic violence) to address dating abuse. This collaboration is part of Start Strong Austin, one of 11 communities nationwide participating in the Start Strong: Building Healthy Teen Relationships Initiative funded by the Robert Wood Johnson Foundation. The Start Strong model employs innovative strategies in education, community engagement, policy change, and social marketing to prevent dating abuse before it starts.

  2. Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using Diffuse and Mechanical TBI Animal Models

    DTIC Science & Technology

    2016-05-01

    Award Number: PT075653 (grant) W81XWH-08-2-0153 (contract) TITLE: Treatment of TBI with Hormonal and Pharmacological Support, Preclinical...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-08-2-0153 Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using...rats. Our in vivo tests also included MRI imaging, focusing on edema resolution and reduction of diffuse axonal damage (fractional anisotropy

  3. QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome

    PubMed Central

    Chen, Xian; Cass, Jessica D; Bradley, Jenifer A; Dahm, Corinn M; Sun, Zhuoqian; Kadyszewski, Edmund; Engwall, Michael J; Zhou, Jun

    2005-01-01

    Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration-dependent, and 100 μM (∼18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects. PMID:16158069

  4. Child Abuse

    MedlinePlus

    ... puts a child at risk of harm. Child abuse can be physical, sexual or emotional. Neglect, or not providing for a child's needs, is also a form of abuse. Most abused children suffer greater emotional than physical damage. An abused child may become ...

  5. Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.

    PubMed

    Rea, Domenica; Coppola, Carmela; Barbieri, Antonio; Monti, Maria Gaia; Misso, Gabriella; Palma, Giuseppe; Bimonte, Sabrina; Zarone, Mayra Rachele; Luciano, Antonio; Liccardo, Davide; Maiolino, Piera; Cittadini, Antonio; Ciliberto, Gennaro; Arra, Claudio; Maurea, Nicola

    2016-01-01

    In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography. We generated a mouse model of cardiotoxicity induced by doxorubicin. C57BL 6 mice were divided into two groups, treated for 7 days by intraperitoneal injections of placebo (vehicle) or doxorubicin (2.17 mg/kg), in order to characterize the cardiac phenotype in vivo. We demonstrated that doxorubicin caused ealy remodeling of the left ventricle: after two days of therapy, the radial, circumferential and strain rates were reduced respectively by 35%, 34%, and 39% (p-value ≤0.001). Moreover, histological analysis revealed that doxorubicin treatment increased fibrosis, cardiomyocyte diameter and apoptosis. In a murine model of doxorubicin-induced cardiac injury, we detected left ventricular dysfunction followed by alterations in conventional echocardiographic indices. Our study suggests that a change in strain could be an effective early marker of myocardial dysfunction for new anticancer treatments and, in preclinical studies, it might also be a valuable indicator for the assessment of activity of cardioprotective agents. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  6. Substance abuse associated with elder abuse in the United States.

    PubMed

    Jogerst, Gerald J; Daly, Jeanette M; Galloway, Lara J; Zheng, Shimin; Xu, Yinghui

    2012-01-01

    Substance abuse by either victim or perpetrator has long been associated with violence and abuse. Sparse research is available regarding elder abuse and its association with substance abuse. The objective of this study was to evaluate the association of state-reported domestic elder abuse with regional levels of substance abuse. Census demographic and elder abuse data were sorted into substate regions to align with the substance use treatment-planning regions for 2269 US counties. From the 2269 US counties there were 229 substate regions in which there were 213,444 investigations of abuse. For the other Ns (reports and substantiations) there were fewer counties and regions. See first sentence of data analyses and first sentence of results. Elder abuse report rates ranged from .03 to .41% (80 regions), investigation rates .001 to .34% (229 regions), and substantiation rates 0 to .22% (184 regions). Elder abuse investigations and substantiations were associated with various forms of substance abuse. Higher investigation rates were significantly associated with a higher rate of any illicit drug use in the past month, a lower median household income, lower proportion of the population graduated high school, and higher population of Hispanics. Higher substantiation rates were significantly associated with higher rate of illicit drug use in the past month and higher population of Hispanics. It may be worthwhile for administrators of violence programs to pay particular attention to substance abuse among their clients and in their community's environment, especially if older persons are involved. Measures of documented elder abuse at the county level are minimal. To be able to associate substance abuse with elder abuse is a significant finding, realizing that the substance abuse can be by the victim or the perpetrator of elder abuse.

  7. Screening for childhood physical and sexual abuse among outpatient substance abusers.

    PubMed

    Simpson, T L; Westerberg, V S; Little, L M; Trujillo, M

    1994-01-01

    Research demonstrates that substance-abusing individuals report substantially higher rates of childhood sexual and physical abuse than the general population. This study sought to test a method of identifying substance-abusing clients with histories of childhood sexual and/or physical abuse and to explore the differences between those reporting childhood abuse and those not. Files of substance abusing clients from two distinct time periods were examined for reports of childhood abuse. At Time 1 (n = 399) clients were not systematically asked about experiences of childhood abuse, and at Time 2 (n = 305) clients were routinely asked about this issue. Results indicate that significantly more male and female clients disclosed childhood abuse at Time 2. Additionally, male clients reporting childhood abuse appeared more distressed than those not reporting abuse; female clients reporting childhood abuse did not appear more distressed than their counterparts.

  8. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    PubMed

    Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

    2015-10-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. ©2015 American Association for Cancer Research.

  9. Effect of insurance parity on substance abuse treatment.

    PubMed

    Azzone, Vanessa; Frank, Richard G; Normand, Sharon-Lise T; Burnam, M Audrey

    2011-02-01

    This study examined the impact of insurance parity on the use, cost, and quality of substance abuse treatment. The authors compared substance abuse treatment spending and utilization from 1999 to 2002 for continuously enrolled beneficiaries covered by Federal Employees Health Benefit (FEHB) plans, which require parity coverage of mental health and substance use disorders, with spending and utilization among beneficiaries in a matched set of health plans without parity coverage. Logistic regression models estimated the probability of any substance abuse service use. Conditional on use, linear models estimated total and out-of-pocket spending. Logistic regression models for three quality indicators for substance abuse treatment were also estimated: identification of adult enrollees with a new substance abuse diagnosis, treatment initiation, and treatment engagement. Difference-in-difference estimates were computed as (postparity - preparity) differences in outcomes in plans without parity subtracted from those in FEHB plans. There were no significant differences between FEHB and non-FEHB plans in rates of change in average utilization of substance abuse services. Conditional on service utilization, the rate of substance abuse treatment out-of-pocket spending declined significantly in the FEHB plans compared with the non-FEHB plans (mean difference=-$101.09, 95% confidence interval [CI]=-$198.06 to -$4.12), whereas changes in total plan spending per user did not differ significantly. With parity, more patients had new diagnoses of a substance use disorder (difference-in-difference risk=.10%, CI=.02% to .19%). No statistically significant differences were found for rates of initiation and engagement in substance abuse treatment. Findings suggest that for continuously enrolled populations, providing parity of substance abuse treatment coverage improved insurance protection but had little impact on utilization, costs for plans, or quality of care.

  10. Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse.

    PubMed

    Martínez-Alfaro, Minerva; Cárabez-Trejo, Alfonso; Gallegos-Corona, Marco-Antonio; Pedraza-Aboytes, Gustavo; Hernández-Chan, Nancy Georgina; Leo-Amador, Guillermo Enrique

    2010-04-01

    Humans can come into contact with thinner by occupational exposure or by intentional inhalation abuse. Numerous studies of workers for genotoxic effects of thinner exposure have yielded conflicting results, perhaps because co-exposure to variable other compounds cannot be avoided in workplace exposure studies. In contrast, there is no data concerning the genotoxic effects of intentional inhalation abuse. The aim of this project was to examine the genotoxic effects of thinner inhalation in an animal model of thinner abuse (rats exposed to 3000 ppm toluene, a high solvent concentration over a very short, 15 min time period, twice a day for 6 weeks). The data presented here provides evidence that thinner inhalation in our experimental conditions is able to induce weight loss, lung abnormalities and oxidative stress. This oxidative stress induces oxidative DNA damage that is not a characteristic feature of genotoxic damage. No significant difference in DNA damage and DNA repair (biomarkers of genotoxicity) in lymphocytes from thinner-treated and control rats was found. Lead treatment was used as a positive control in these assays. Finally, bone marrow was evaluated as a biomarker of cellular alteration associated with thinner inhalation. The observed absence of hemopoietic and genetic toxicity could be explained in part by the absence of benzene, the only carcinogenic component of thinner; however, benzene is no longer a common component of thinner. In conclusion, thinner did not cause genotoxic effects in an experimental model of intentional abuse despite the fact that thinner inhalation induces oxidative stress. (c) 2009 John Wiley & Sons, Ltd.

  11. Stress in adolescence and drugs of abuse in rodent models: Role of dopamine, CRF, and HPA axis

    PubMed Central

    Burke, Andrew R.; Miczek, Klaus A.

    2014-01-01

    Rationale Research on adolescence and drug abuse increased substantially in the past decade. However, drug-addiction related behaviors following stressful experiences during adolescence are less studied. We focus on rodent models of adolescent stress cross-sensitization to drugs of abuse. Objectives Review the ontogeny of behavior, dopamine, corticotropin-releasing factor (CRF), and the hypothalamic pituitary adrenal (HPA) axis in adolescent rodents. We evaluate evidence that stressful experiences during adolescence engender hypersensitivity to drugs of abuse and offer potential neural mechanisms. Results and Conclusions Much evidence suggests that final maturation of behavior, dopamine systems, and HPA axis occurs during adolescence. Stress during adolescence increases amphetamine- and ethanol-stimulated locomotion, preference, and self-administration under many conditions. The influence of adolescent stress on subsequent cocaine- and nicotine-stimulated locomotion and preference is less clear. The type of adolescent stress, temporal interval between stress and testing, species, sex, and the drug tested are key methodological determinants for successful cross-sensitization procedures. The sensitization of the mesolimbic dopamine system is proposed to underlie stress cross-sensitization to drugs of abuse in both adolescents and adults through modulation by CRF. Reduced levels of mesocortical dopamine appear to be a unique consequence of social stress during adolescence. Adolescent stress may reduce the final maturation of cortical dopamine through D2 dopamine receptor regulation of dopamine synthesis or glucocorticoid-facilitated pruning of cortical dopamine fibers. Certain rodent models of adolescent adversity are useful for determining neural mechanisms underlying the cross-sensitization to drugs of abuse. PMID:24370534

  12. [Modeling the academic performance of medical students in basic sciences and pre-clinical courses: a longitudinal study].

    PubMed

    Zúñiga, Denisse; Mena, Beltrán; Oliva, Rose; Pedrals, Nuria; Padilla, Oslando; Bitran, Marcela

    2009-10-01

    The study of predictors of academic performance is relevant for medical education. Most studies of academic performance use global ratings as outcome measure, and do not evaluate the influence of the assessment methods. To model by multivariate analysis, the academic performance of medical considering, besides academic and demographic variables, the methods used to assess students' learning and their preferred modes of information processing. Two hundred seventy two students admitted to the medical school of the Pontificia Universidad Católica de Chile from 2000 to 2003. Six groups of variables were studied to model the students' performance in five basic science courses (Anatomy, Biology, Calculus, Chemistry and Physics) and two pre-clinical courses (Integrated Medical Clinic I and IT). The assessment methods examined were multiple choice question tests, Objective Structured Clinical Examination and tutor appraisal. The results of the university admission tests (high school grades, mathematics and biology tests), the assessment methods used, the curricular year and previous application to medical school, were predictors of academic performance. The information processing modes influenced academic performance, but only in interaction with other variables. Perception (abstract or concrete) interacted with the assessment methods, and information use (active or reflexive), with sex. The correlation between the real and predicted grades was 0.7. In addition to the academic results obtained prior to university entrance, the methods of assessment used in the university and the information processing modes influence the academic performance of medical students in basic and preclinical courses.

  13. Photobiomodulation (PBM) with 20 W at 640 nm: pre-clinical results and propagation model

    NASA Astrophysics Data System (ADS)

    Gendron, Denis J.; Ménage, Alexander R.

    2017-02-01

    A novel treatment modality for photobiomodulation (PBM) is introduced called High Intensity Physio Light (HIPL) Therapy with a light source at 640 nm wavelength, 20 nm bandwidth, and up to 20 W in large 10 cm flat beam. This report exemplifies the efficacy performance of this method with three pre-clinical cases: (i) ankle: sport injury, (ii) foot: bone fractures, and (iii) shoulder: musculoskeletal disorder (MSD). In all cases, the patients systematically experienced a significant pain reduction (by 2 / 10 - 4 / 10) on a visual pain scale. In case (ii) and (iii), a steady improvement and complete recovery of the patient was respectfully obtained. This report describes the experimental treatment condition for each case, and introduces an intensity-dependant propagation model to explain our observation.

  14. Social-relational risk factors for predicting elder physical abuse: an ecological bi-focal model.

    PubMed

    von Heydrich, Levente; Schiamberg, Lawrence B; Chee, Grace

    2012-01-01

    Annually in the United States, 1 to 5 million older adults, 65 and above, are physically or sexually injured or mistreated by their caregivers in family settings. This study examined the prevalence and risk factors involved in elder physical abuse by adult child caregivers, moving from the immediate elderly parent/adult child relationship context to more distal social support contexts, utilizing a subsample of 203 elderly participants from the Midlife Development in the United States study (MIDUS II, 2004-2006). LISREL modeling examined causal pathways between elderly demographic characteristics, physical/emotional health, and behavioral and contextual characteristics from an ecological perspective. Data modeling was accomplished using Mplus, PAXW, and SYSTAT statistical software packages. Results indicate that latent factors including older adult health, social isolation of the older adult, and adult child characteristics were significantly associated with elder physical abuse, as mediated by the quality of the elderly parent/adult child relationship.

  15. Association of Drug Abuse and Child Abuse.

    ERIC Educational Resources Information Center

    Jaudes, Paula Kienberger; And Others

    1995-01-01

    Children born to mothers who used illicit drugs during pregnancy were assessed for subsequent abuse or neglect. Of the 513 children exposed inutero to drugs, 102 were substantiated as abused or neglected. Infants exposed inutero to drugs had a higher than expected risk of subsequent abuse compared to children in the general population. (Author/SW)

  16. The Genesis of Pedophilia: Testing the "Abuse-to-Abuser" Hypothesis.

    ERIC Educational Resources Information Center

    Fedoroff, J. Paul; Pinkus, Shari

    1996-01-01

    This study tested three versions of the "abuse-to-abuser" hypothesis by comparing men with personal histories of sexual abuse and men without sexual abuse histories. There was a statistically non-significant trend for assaulted offenders to be more likely as adults to commit genital assaults on children. Implications for the abuse-to-abuser…

  17. Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.

    PubMed

    Fancher, R Marcus; Zhang, Hongjian; Sleczka, Bogdan; Derbin, George; Rockar, Richard; Marathe, Punit

    2011-07-01

    A preclinical canine model capable of predicting a compound's potential for pH-dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra-animal variability. Pretreatment of pentagastrin (6 µg/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

  18. An Interprofessional Model for Serving Youth at Risk for Substance Abuse: The Team Case Study.

    ERIC Educational Resources Information Center

    Cobia, Debra C.; And Others

    1995-01-01

    Three models of interprofessional education appropriate for serving youth at risk for substance abuse are described. The evaluation of the team case study model indicated that the participants were more sensitive to the needs of the youths, experienced increased comfort in consulting other agents, and were more confident in their ability to select…

  19. National Cancer Institute Pediatric Preclinical Testing Program: Model Description for In Vitro Cytotoxicity Testing

    PubMed Central

    Kang, Min H.; Smith, Malcolm A.; Morton, Christopher L.; Keshelava, Nino; Houghton, Peter J.; Reynolds, C. Patrick

    2010-01-01

    Background The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. Procedures In vitro cytotoxicity testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC50, absolute IC50, and Ymin values The panel of 23 pediatric cancer cell lines included leukemia (n=6), lymphoma (n=2), rhabdomyosarcoma (n=4), brain tumors (n=3), Ewing family of tumors (EFT, n=4), and neuroblastoma (n=4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. Results We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under preclinical investigation for cancer. To date, the PPTP has completed in vitro testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various “standard” chemotherapy drugs. Conclusions This robust in vitro cytotoxicity testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. PMID:20922763

  20. Design and implementation of an empowerment model to prevent elder abuse: a randomized controlled trial

    PubMed Central

    Estebsari, Fatemeh; Dastoorpoor, Maryam; Mostafaei, Davoud; Khanjani, Narges; Khalifehkandi, Zahra Rahimi; Foroushani, Abbas Rahimi; Aghababaeian, Hamidreza; Taghdisi, Mohammad Hossein

    2018-01-01

    Background Older adults are more vulnerable to health risks than younger people and may get exposed to various dangers, including elder abuse. This study aimed to design and implement an empowerment educational intervention to prevent elder abuse. Methods This parallel randomized controlled trial was conducted in 2014–2016 for 18 months on 464 older adults aged above 60 years who visited health houses of 22 municipalities in Tehran. Data were collected using standard questionnaires, including the Elder Abuse-Knowledge Questionnaire, Health-Promoting Behavior Questionnaire, Health-Promoting Lifestyle Profile II, Barriers to Healthy Lifestyle, Perceived Social Support, Perceived Self-Efficacy, Loneliness Scale, Geriatric Depression Scale, Multidimensional Health Locus of Control Scale, and the SCARED (stress, coping, argument, resources, events, and dependence) tool. The intervention was done in twenty 45- to 60-minute training sessions over 6 months. Data analysis were performed using χ2 tests, multiple linear and logistic regression, and structural equation modeling (SEM). Results The frequency of knowledge of elder abuse, self-efficacy, social support and health promoting lifestyle before the intervention was similar in the two groups. However, the frequency of high knowledge of elder abuse (94.8% in the intervention group and 46.6% in the control group), high self-efficacy (82.8% and 7.8%, respectively), high social support (97.0% and 10.3%, respectively) and high health promoting lifestyle (97.0% and 10.3%, respectively) was significantly higher (P<0.001) and the frequency of elder abuse risk (28.0% and 49.6%, respectively) was significantly less in the intervention group after the intervention. SEM standardized beta (Sβ) showed that the intervention had the highest impact on increase social support (Sβ=0.80, β=48.64, SE=1.70, P<0.05), self-efficacy (Sβ=0.76, β=13.32, SE=0.52, P<0.05) and health promoting behaviors (Sβ=0.48, β=33.08, SE=2.26, P<0

  1. Design and implementation of an empowerment model to prevent elder abuse: a randomized controlled trial.

    PubMed

    Estebsari, Fatemeh; Dastoorpoor, Maryam; Mostafaei, Davoud; Khanjani, Narges; Khalifehkandi, Zahra Rahimi; Foroushani, Abbas Rahimi; Aghababaeian, Hamidreza; Taghdisi, Mohammad Hossein

    2018-01-01

    Older adults are more vulnerable to health risks than younger people and may get exposed to various dangers, including elder abuse. This study aimed to design and implement an empowerment educational intervention to prevent elder abuse. This parallel randomized controlled trial was conducted in 2014-2016 for 18 months on 464 older adults aged above 60 years who visited health houses of 22 municipalities in Tehran. Data were collected using standard questionnaires, including the Elder Abuse-Knowledge Questionnaire, Health-Promoting Behavior Questionnaire, Health-Promoting Lifestyle Profile II, Barriers to Healthy Lifestyle, Perceived Social Support, Perceived Self-Efficacy, Loneliness Scale, Geriatric Depression Scale, Multidimensional Health Locus of Control Scale, and the SCARED (stress, coping, argument, resources, events, and dependence) tool. The intervention was done in twenty 45- to 60-minute training sessions over 6 months. Data analysis were performed using χ 2 tests, multiple linear and logistic regression, and structural equation modeling (SEM). The frequency of knowledge of elder abuse, self-efficacy, social support and health promoting lifestyle before the intervention was similar in the two groups. However, the frequency of high knowledge of elder abuse (94.8% in the intervention group and 46.6% in the control group), high self-efficacy (82.8% and 7.8%, respectively), high social support (97.0% and 10.3%, respectively) and high health promoting lifestyle (97.0% and 10.3%, respectively) was significantly higher ( P <0.001) and the frequency of elder abuse risk (28.0% and 49.6%, respectively) was significantly less in the intervention group after the intervention. SEM standardized beta (Sβ) showed that the intervention had the highest impact on increase social support (Sβ=0.80, β=48.64, SE=1.70, P <0.05), self-efficacy (Sβ=0.76, β=13.32, SE=0.52, P <0.05) and health promoting behaviors (Sβ=0.48, β=33.08, SE=2.26, P <0.05), respectively. The

  2. The Role of Digital 3D Scanned Models in Dental Students' Self-Assessments in Preclinical Operative Dentistry.

    PubMed

    Lee, Cliff; Kobayashi, Hiro; Lee, Samuel R; Ohyama, Hiroe

    2018-04-01

    The aim of this study was to determine how dental student self-assessment and faculty assessment of operative preparations compared for conventional visual assessment versus assessment of scanned digital 3D models. In 2016, all third-year students in the Class of 2018 (N=35) at Harvard School of Dental Medicine performed preclinical exams of Class II amalgam preparations (C2AP) and Class III composite preparations (C3CP) and completed self-assessment forms; in 2017, all third-year students in the Class of 2019 (N=34) performed the same exams. Afterwards, the prepared typodont teeth were digitally scanned. Students self-assessed their preparations digitally, and four faculty members graded the preparations conventionally and digitally. The results showed that, overall, the students assessed their preparations higher than the faculty assessments. The mean student-faculty gaps for C2AP and C3CP in the conventional assessments were 11% and 5%, respectively. The mean digital student-faculty gap for C2AP and C3CP were 8% and 2%, respectively. In the conventional assessments, preclinical performance was negatively correlated with the student-faculty gap (r=-0.47, p<0.001). The correlations were not statistically significant with the digital assessments (p=0.39, p=0.26). Students in the bottom quartile significantly improved their self-assessment accuracy using digital self-assessments over conventional assessments (C2AP 10% vs. 17% and C3CP 3% vs. 10%, respectively). These results suggest that digital assessments offered a significant learning opportunity for students to critically self-assess themselves in operative preclinical dentistry. The lower performing students benefitted the most, improving their assessment ability to the level of the rest of the class.

  3. CHILD SEXUAL ABUSE, BULLYING, CYBERBULLYING, AND MENTAL HEALTH PROBLEMS AMONG HIGH SCHOOLS STUDENTS: A MODERATED MEDIATED MODEL

    PubMed Central

    Hébert, Martine; Cénat, Jude Mary; Blais, Martin; Lavoie, Francine; Guerrier, Mireille

    2017-01-01

    Child sexual abuse is associated with adverse outcomes, including heightened vulnerability that may translate into risk of revictimization. The aims of the study were: (1) to explore the direct and indirect links between child sexual abuse and cyberbullying, bullying, and mental health problems and (2) to study maternal support as a potential protective factor. Methods: Teenagers involved in the two first waves of the Quebec Youths’ Romantic Relationships Survey (N = 8,194 and 6,780 at Wave I and II, respectively) completed measures assessing child sexual abuse and maternal support at Wave I. Cyberbullying, bullying, and mental health problems (self-esteem, psychological distress, and suicidal ideations) were evaluated 6 months later. Results: Rates of cyberbullying in the past 6 months were twice as high in sexually abused teens compared to nonvictims both for girls (33.47 vs. 17.75%) and boys (29.62 vs. 13.29%). A moderated mediated model revealed a partial mediation effect of cyberbullying and bullying in the link between child sexual abuse and mental health. Maternal support acted as a protective factor as the conditional indirect effects of child sexual abuse on mental health via cyberbullying and bullying were reduced in cases of high maternal support. Conclusions: Results have significant relevance for prevention and intervention in highlighting the heightened vulnerability of victims of child sexual abuse to experience both bullying and cyberbullying. Maternal support may buffer the risk of developing mental health distress, suggesting that intervention programs for victimized youth may profit by fostering parent involvement. PMID:27037519

  4. CHILD SEXUAL ABUSE, BULLYING, CYBERBULLYING, AND MENTAL HEALTH PROBLEMS AMONG HIGH SCHOOLS STUDENTS: A MODERATED MEDIATED MODEL.

    PubMed

    Hébert, Martine; Cénat, Jude Mary; Blais, Martin; Lavoie, Francine; Guerrier, Mireille

    2016-07-01

    Child sexual abuse is associated with adverse outcomes, including heightened vulnerability that may translate into risk of revictimization. The aims of the study were: (1) to explore the direct and indirect links between child sexual abuse and cyberbullying, bullying, and mental health problems and (2) to study maternal support as a potential protective factor. Teenagers involved in the two first waves of the Quebec Youths' Romantic Relationships Survey (N = 8,194 and 6,780 at Wave I and II, respectively) completed measures assessing child sexual abuse and maternal support at Wave I. Cyberbullying, bullying, and mental health problems (self-esteem, psychological distress, and suicidal ideations) were evaluated 6 months later. Rates of cyberbullying in the past 6 months were twice as high in sexually abused teens compared to nonvictims both for girls (33.47 vs. 17.75%) and boys (29.62 vs. 13.29%). A moderated mediated model revealed a partial mediation effect of cyberbullying and bullying in the link between child sexual abuse and mental health. Maternal support acted as a protective factor as the conditional indirect effects of child sexual abuse on mental health via cyberbullying and bullying were reduced in cases of high maternal support. Results have significant relevance for prevention and intervention in highlighting the heightened vulnerability of victims of child sexual abuse to experience both bullying and cyberbullying. Maternal support may buffer the risk of developing mental health distress, suggesting that intervention programs for victimized youth may profit by fostering parent involvement. © 2016 Wiley Periodicals, Inc.

  5. Abuse Characteristics and Psychiatric Consequences Associated with Online Sexual Abuse.

    PubMed

    Say, Gökçe Nur; Babadağı, Zehra; Karabekiroğlu, Koray; Yüce, Murat; Akbaş, Seher

    2015-06-01

    The current study examined the rate and psychiatric correlates of sexual abuse involving the use of digital technologies by the offender in a wide sample of juvenile victims. Sociodemographic, abuse, and psychiatric characteristics of 662 sexually abused children and adolescents were evaluated. Of these, 93 reported that digital devices were used by the offender in several ways to facilitate the sexual abuse. The offender-victim relationship was initiated through the Internet in 39 victims. Involvement of digital technologies in sexual abuse was significantly associated with penetrative and recurrent form of sexual abuse commited by multiple offenders with coexisting violence. Additionally, victims of sexual abuse with a digital component were 4.21 times more likely to develop any psychopathology, 3.77 times more likely to have depression, and 2.14 times more likely to have post-traumatic stress disorder as a result of sexual abuse. These results indicated that the offender's use of digital technology may aid the initiation and facilitation of the sexual abuse of youths and may relate to more severe outcomes. This study revealed the importance of raising the awareness of professionals and the community about the potential risks associated with digital technologies and sexual abuse. Mental health professionals should consider this additional form of victimization, especially when dealing with sexual abuse victims.

  6. Preclinical Alzheimer's disease and longitudinal driving decline.

    PubMed

    Roe, Catherine M; Babulal, Ganesh M; Head, Denise M; Stout, Sarah H; Vernon, Elizabeth K; Ghoshal, Nupur; Garland, Brad; Barco, Peggy P; Williams, Monique M; Johnson, Ann; Fierberg, Rebecca; Fague, M Scot; Xiong, Chengjie; Mormino, Elizabeth; Grant, Elizabeth A; Holtzman, David M; Benzinger, Tammie L S; Fagan, Anne M; Ott, Brian R; Carr, David B; Morris, John C

    2017-01-01

    Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 . Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

  7. Prescription Drug Abuse

    MedlinePlus

    ... drug abuse. And it's illegal, just like taking street drugs. Why Do People Abuse Prescription Drugs? Some people abuse prescription drugs ... common risk of prescription drug abuse is addiction . People who abuse ... as if they were taking street drugs. That's one reason most doctors won't ...

  8. Elder Abuse

    MedlinePlus

    ... homes. The mistreatment may be Physical, sexual, or emotional abuse Neglect or abandonment Financial abuse - stealing of money or belongings Possible signs of elder abuse include unexplained bruises, burns, and injuries. There ...

  9. Volatile Solvents as Drugs of Abuse: Focus on the Cortico-Mesolimbic Circuitry

    PubMed Central

    Beckley, Jacob T; Woodward, John J

    2013-01-01

    Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system's ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology. PMID:23954847

  10. Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression

    PubMed Central

    Candolfi, Marianela; Curtin, James F.; Stephen Nichols, W.; Muhammad, AKM. G.; King, Gwendalyn D.; Elizabeth Pluhar, G.; McNiel, Elizabeth A.; Ohlfest, John R.; Freese, Andrew B.; Moore, Peter F.; Lerner, Jonathan; Lowenstein, Pedro R.

    2008-01-01

    Although rodent glioblastoma (GBM) models have been used for over 30 years, the extent to which they recapitulate the characteristics encountered in human GBMs remains controversial. We studied the histopathological features of dog GBM and human xenograft GBM models in immune-deficient mice (U251 and U87 GBM in nude Balb/c), and syngeneic GBMs in immune-competent rodents (GL26 cells in C57BL/6 mice, CNS-1 cells in Lewis rats). All GBMs studied exhibited neovascularization, pleomorphism, vimentin immunoreactivity, and infiltration of T-cells and macrophages. All the tumors showed necrosis and hemorrhages, except the U87 human xenograft, in which the most salient feature was its profuse neovascularization. The tumors differed in the expression of astrocytic intermediate filaments: human and dog GBMs, as well as U251 xenografts expressed glial fibrillary acidic protein (GFAP) and vimentin, while the U87 xenograft and the syngeneic rodent GBMs were GFAP− and vimentin+. Also, only dog GBMs exhibited endothelial proliferation, a key feature that was absent in the murine models. In all spontaneous and implanted GBMs we found histopathological features compatible with tumor invasion into the non-neoplastic brain parenchyma. Our data indicate that murine models of GBM appear to recapitulate several of the human GBM histopathological features and, considering their reproducibility and availability, they constitute a valuable in vivo system for preclinical studies. Importantly, our results indicate that dog GBM emerges as an attractive animal model for testing novel therapies in a spontaneous tumor in the context of a larger brain. PMID:17874037

  11. PREVENTION AND OUTCOMES FOR VICTIMS OF CHILDHOOD SEXUAL ABUSE

    PubMed Central

    Ulibarri, Monica D.; Ulloa, Emilio C.; Salazar, Marissa

    2015-01-01

    This study examined self-reported sexually abusive experiences in childhood and adulthood as correlates of current drug use, alcohol abuse, and depression and posttraumatic stress disorder (PTSD) symptoms. Participants were 204 Latina women 18–34 years old. Results indicated significant relationships between history of sexual abuse (regardless of age of occurrence), depression symptoms, PTSD symptoms, alcohol abuse, and drug use. When examined separately, childhood sexual abuse was associated with symptoms of depression, PTSD, and substance use but not alcohol abuse behaviors. Experiencing sexual abuse in adulthood was associated with symptoms of depression, alcohol abuse behaviors, and substance use but not PTSD symptoms. Structural equation modeling showed that substance use partially mediated the relationship between sexual abuse and mental health outcomes. These findings suggest mental health and substance use services should incorporate treatment for trauma, which may be the root of comorbid mental health and substance use issues. PMID:25635897

  12. Suicide attempts among men with histories of child sexual abuse: examining abuse severity, mental health, and masculine norms.

    PubMed

    Easton, Scott D; Renner, Lynette M; O'Leary, Patrick

    2013-06-01

    Men who were sexually abused during childhood are at risk for a variety of long-term mental health problems, including suicidality. However, little is known about which factors are related to recent suicide attempts for this vulnerable, under-researched population. The purpose of this study was to examine the relationship between abuse severity, mental health, masculine norms and recent suicide attempts among men with histories of child sexual abuse (CSA). We analyzed survey data gathered from a purposive sample of 487 men who were sexually abused during childhood. The age of the sample ranged from 19 to 84 years (μ = 50.4 years). Recent suicide attempts served as the dependent variable in the study. Self-reported measures of sexual abuse severity, child physical abuse, mental health, masculine norms, and demographic information (age, race) represented the independent variables. The results from logistic regression modeling found that five variables - duration of the sexual abuse, use of force during the sexual abuse, high conformity to masculine norms, level of depressive symptoms, and suicidal ideation - increased the odds of a suicide attempt in the past 12 months. To improve mental health services for men with histories of CSA, mental health practitioners should incorporate sexual abuse severity, current mental health, and adherence to masculine norms into assessment and treatment planning. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. An Advanced Preclinical Mouse Model for Acute Myeloid Leukemia Using Patients' Cells of Various Genetic Subgroups and In Vivo Bioluminescence Imaging

    PubMed Central

    Vick, Binje; Rothenberg, Maja; Sandhöfer, Nadine; Carlet, Michela; Finkenzeller, Cornelia; Krupka, Christina; Grunert, Michaela; Trumpp, Andreas; Corbacioglu, Selim; Ebinger, Martin; André, Maya C.; Hiddemann, Wolfgang; Schneider, Stephanie; Subklewe, Marion; Metzeler, Klaus H.; Spiekermann, Karsten; Jeremias, Irmela

    2015-01-01

    Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups. PMID:25793878

  14. An Integrative Social-Cognitive Developmental Model of Supervision for Substance Abuse Counselors-in-Training

    ERIC Educational Resources Information Center

    Sias, Shari M.; Lambie, Glenn W.

    2008-01-01

    Substance abuse counselors (SACs) at higher levels of social-cognitive maturity manage complex situations and perform counselor-related tasks more effectively than individuals at lower levels of development. This article presents an integrative clinical supervision model designed to promote the social-cognitive maturity (ego development;…

  15. On the Role of Imitation on Adolescence Methamphetamine Abuse Dynamics.

    PubMed

    Mushanyu, J; Nyabadza, F; Muchatibaya, G; Stewart, A G R

    2017-03-01

    Adolescence methamphetamine use is an issue of considerable concern due to its correlation with later delinquency, divorce, unemployment and health problems. Understanding how adolescents initiate methamphetamine abuse is important in developing effective prevention programs. We formulate a mathematical model for the spread of methamphetamine abuse using nonlinear ordinary differential equations. It is assumed that susceptibles are recruited into methamphetamine use through imitation. An epidemic threshold value, [Formula: see text], termed the abuse reproduction number, is proposed and defined herein in the drug-using context. The model is shown to exhibit the phenomenon of backward bifurcation. This means that methamphetamine problems may persist in the population even if [Formula: see text] is less than one. Sensitivity analysis of [Formula: see text] was performed to determine the relative importance of different parameters in methamphetamine abuse initiation. The model is then fitted to data on methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse in the treatment centres of Cape Town and parameter values that give the best fit are chosen. Results show that the proportion of methamphetamine users less than 20 years old reporting methamphetamine as their primary substance of abuse will continue to decrease in Cape Town of South Africa. The results suggest that intervention programs targeted at reducing adolescence methamphetamine abuse, are positively impacting methamphetamine abuse.

  16. Cognitive and emotional differences between abusive and non-abusive fathers.

    PubMed

    Francis, Karen J; Wolfe, David A

    2008-12-01

    Abusive fathers perpetrate a substantial portion of child physical abuse. Despite this, little is known about how they differ from non-abusive fathers. This study compared a broad range of cognitive and affective factors between physically abusive and non-abusive fathers. Abusive (n=24) and non-abusive (n=25) fathers completed standard measures assessing their experience and expression of anger, mental health, parenting stress, and their empathy and perceptions of children's socio-emotional signals. Abusive fathers differed from comparisons on almost all constructs. They experienced more anger and were more likely to express that anger aggressively. They reported more mental health concerns (such as depression, hostility, and paranoid ideation), more stress in parenting, and significantly less empathy for their children. They were also more likely to perceive children's emotional expressions as depicting negative emotions, such as anger and disgust. Abusive fathers struggle with a myriad of difficulties that likely contribute to their problematic parenting. These difficulties are both inter- and intra-personal in nature. The findings suggest that abusive fathers require comprehensive assessment that includes mental health screening. Interventions should be selected carefully to target abusive fathers' high levels of negative affect and negative perceptions. Treatment strategies should address problems related to parenting style (e.g., managing stress and interpretation of children's socioemotional signals) as well as their personal adjustment (e.g., cognitive behavioral strategies for regulating affect and cognitive distortions).

  17. Successful reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of type 1 diabetes.

    PubMed

    Thomas, J M; Contreras, J L; Smyth, C A; Lobashevsky, A; Jenkins, S; Hubbard, W J; Eckhoff, D E; Stavrou, S; Neville, D M; Thomas, F T

    2001-06-01

    The recent focus on islet transplantation as primary therapy for type 1 diabetes has heightened interest in the reversal of type 1 diabetes in preclinical models using minimal immunosuppression. Here, we demonstrated in a preclinical rhesus model a consistent reversal of all measured glycemic patterns of streptozotocin-induced type 1 diabetes. The model used single-donor islet transplantation with induction of operational tolerance. The term "operational tolerance" is used to indicate durable survival of single-donor major histocompatibility complex (MHC)-mismatched islet allografts without maintenance immunosuppressive therapy and without rejection or loss of functional islet mass or insulin secretory reserve. In this operational tolerance model, all immunosuppression was discontinued after day 14 posttransplant, and recipients recovered with excellent health. The operational tolerance induction protocol combined peritransplant anti-CD3 immunotoxin to deplete T-cells and 15-deoxyspergualin to arrest proinflammatory cytokine production and maturation of dendritic cells. T-cell deficiency was specific but temporary, in that T-cell-dependent responses in long-term survivors recovered to normal, and there was no evidence of increased susceptibility to infection. Anti-donor mixed lymphocyte reaction responses were positive in the long-term survivors, but all showed clear evidence of systemic T-helper 2 deviation, suggesting that an immunoregulatory rather than a deletional process underlies this operational tolerance model. This study provides the first evidence that operational tolerance can protect MHC nonhuman primate islets from rejection as well as loss of functional islet mass. Such an approach has potential to optimize individual recipient recovery from diabetes as well as permitting more widespread islet transplantation with the limited supply of donor islets.

  18. Developmental experiences of child sexual abusers and rapists.

    PubMed

    Simons, Dominique A; Wurtele, Sandy K; Durham, Robert L

    2008-05-01

    The aim of this study is to identify the distinct developmental experiences associated with child sexual abuse and rape. For 269 sexual offenders (137 rapists and 132 child sexual abusers), developmental experiences were recorded from a behavioral checklist, a parental-bonding survey, and a sexual history questionnaire. Offender classification was obtained from official records and verified through polygraph examinations. Compared to rapists, child sexual abusers reported more frequent experiences of child sexual abuse (73%), early exposure to pornography (65% before age 10), an earlier onset of masturbation (60% before age 11), and sexual activities with animals (38%). In contrast to child sexual abusers, rapists reported more frequent experiences of physical abuse (68%), parental violence (78%), emotional abuse (70%), and cruelty to animals (68%). Both child sexual abusers and rapists (>93%) reported frequent exposure to violent media during their childhood. Most offenders (94%) described having insecure parental attachment bonds; 76% of rapists reported avoidant parental attachments and 62% of child sexual abusers reported anxious parental attachments. Findings from this study support the role of specific developmental experiences as etiological factors in differential sexual offending. Child sexual abusers' developmental histories were characterized by heightened sexuality; whereas rapists' childhood histories were more indicative of violence. These findings have implications for the treatment of sexual abusers and the prevention of sexual abuse. This study's findings suggest that sexual offenders have been socialized to satisfy human needs of intimacy and sexuality through maladaptive means, which implies that a risk management approach may not be sufficient treatment. Although risk models teach offenders skills to avoid high-risk situations, they fail to address the maladaptive strategies that they may have developed for satisfying needs. Instead, the focus

  19. Customizing monoclonal antibodies for the treatment of methamphetamine abuse: current and future applications.

    PubMed

    Peterson, Eric C; Gentry, W Brooks; Owens, S Michael

    2014-01-01

    Monoclonal antibody-based medications designed to bind (+)-methamphetamine (METH) with high affinity are among the newest approaches to the treatment of METH abuse and the associated medical complications. The potential clinical indications for these medications include treatment of overdose, reduction of drug dependence, and protection of vulnerable populations from METH-related complications. Research designed to discover and conduct preclinical and clinical testing of these antibodies suggests a scientific vision for how intact monoclonal antibody (mAb) (singular and plural) or small antigen-binding fragments of mAb could be engineered to optimize the proteins for specific therapeutic applications. In this review, we discuss keys to success in this development process including choosing predictors of specificity, efficacy, duration of action, and safety of the medications in disease models of acute and chronic drug abuse. We consider important aspects of METH-like hapten design and how hapten structural features influence specificity and affinity, with an example of a high-resolution X-ray crystal structure of a high-affinity antibody to demonstrate this structural relationship. Additionally, several prototype anti-METH mAb forms such as antigen-binding fragments and single-chain variable fragments are under development. Unique, customizable aspects of these fragments are presented with specific possible clinical indications. Finally, we discuss clinical trial progress of the first in kind anti-METH mAb, for which METH is the disease target instead of vulnerable central nervous system networks of receptors, binding sites, and neuronal connections. © 2014 Elsevier Inc. All rights reserved.

  20. CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

    PubMed

    Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N; Lopera, Francisco; Bateman, Randall J; Morris, John C; Sperling, Reisa A; Aisen, Paul S; Roses, Allen D; Welsh-Bohmer, Kathleen A; Carrillo, Maria C; Weninger, Stacie

    2016-01-01

    If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

  1. Providing competency-based family medicine residency training in substance abuse in the new millennium: a model curriculum.

    PubMed

    Seale, J Paul; Shellenberger, Sylvia; Clark, Denice Crowe

    2010-05-11

    This article, developed for the Betty Ford Institute Consensus Conference on Graduate Medical Education (December, 2008), presents a model curriculum for Family Medicine residency training in substance abuse. The authors reviewed reports of past Family Medicine curriculum development efforts, previously-identified barriers to education in high risk substance use, approaches to overcoming these barriers, and current training guidelines of the Accreditation Council for Graduate Medical Education (ACGME) and their Family Medicine Residency Review Committee. A proposed eight-module curriculum was developed, based on substance abuse competencies defined by Project MAINSTREAM and linked to core competencies defined by the ACGME. The curriculum provides basic training in high risk substance use to all residents, while also addressing current training challenges presented by U.S. work hour regulations, increasing international diversity of Family Medicine resident trainees, and emerging new primary care practice models. This paper offers a core curriculum, focused on screening, brief intervention and referral to treatment, which can be adapted by residency programs to meet their individual needs. The curriculum encourages direct observation of residents to ensure that core skills are learned and trains residents with several "new skills" that will expand the basket of substance abuse services they will be equipped to provide as they enter practice. Broad-based implementation of a comprehensive Family Medicine residency curriculum should increase the ability of family physicians to provide basic substance abuse services in a primary care context. Such efforts should be coupled with faculty development initiatives which ensure that sufficient trained faculty are available to teach these concepts and with efforts by major Family Medicine organizations to implement and enforce residency requirements for substance abuse training.

  2. The relationship between childhood sexual abuse and alcohol abuse in women--a case-control study.

    PubMed

    Fleming, J; Mullen, P E; Sibthorpe, B; Attewell, R; Bammer, G

    1998-12-01

    The aim of this paper was to examine the association between reporting childhood sexual abuse (CSA) and alcohol abuse in a community sample of women using multivariate analysis which took into account a range of potential confounding variables (such as a family history of alcoholism) and effect modifiers (such as having an alcoholic partner). A two-stage retrospective case-control study was used to investigate the relationship between reporting CSA and alcohol abuse in women. Seven hundred and ten women randomly selected from the Australian federal electoral rolls. The Alcohol Use Disorders Identification Test (AUDIT) was used to measure alcohol abuse. A series of questions based on those developed by Wyatt (1985) were used to ascertain the prevalence of CSA. The final model showed that the relationship between a history of CSA and alcohol abuse reflected a complex interaction between CSA and a range of other factors in a woman's background. CSA was not by itself a significant predictor of alcohol abuse (OR = 0.61; 95% CI = 0.31-1.20). However, a history of CSA became significant in combination with co-factors which included: having a mother who was perceived as cold and uncaring; having an alcoholic partner; and believing that alcohol is a sexual disinhibitor. This study indicates that CSA alone is not a causative factor in the development of alcohol abuse among women and highlights the importance of examining the family background of women with alcohol problems.

  3. Types of abuse and risk factors associated with elder abuse.

    PubMed

    Simone, Lacher; Wettstein, Albert; Senn, Oliver; Rosemann, Thomas; Hasler, Susann

    2016-01-01

    Detecting elder abuse is challenging because it is a taboo, and many cases remain unreported. This study aimed to identify types of elder abuse and to investigate its associated risk factors. Retrospective analyses of 903 dossiers created at an Independent Complaints Authority for Old Age in the Canton of Zurich, Switzerland, from January 1, 2008 to October 31, 2012. Characteristics of victims and perpetrators, types of abuse, and associated risk factors related to the victim or the perpetrator were assessed. Bi- and multivariate analysis were used to identify abuse and neglect determinants. A total of 150 cases reflected at least one form of elder abuse or neglect; 104 cases were categorised as abuse with at least one type of abuse (overall 135 mentions), 46 cases were categorised as neglect (active or passive). Psychological abuse was the most reported form (47%), followed by financial (35%), physical (30%) and anticonstitutional abuse (18%). In 81% of the 150 cases at least two risk factors existed. In 13% no associated risk factor could be identified. Compared with neglect, elders with abuse were less likely to be a nursing home resident than living at home (odds ratio [OR] 0.02, 95% confidence interval [CI] 0.00-0.19). In addition, they were more likely to be cohabiting with their perpetrators (OR 18.01, 95% CI 4.43-73.19). For the majority of the reported elder abuse cases at least two associated risk factors could be identified. Knowledge about these red flags and a multifaceted strategy are needed to identify and prevent elder abuse.

  4. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

    PubMed Central

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

    2015-01-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

  5. KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models

    PubMed Central

    Kenessey, István; Kói, Krisztina; Horváth, Orsolya; Cserepes, Mihály; Molnár, Dávid; Izsák, Vera; Dobos, Judit; Hegedűs, Balázs

    2016-01-01

    Background In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines. Results We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras. In case of in vitro proliferation, the KRAS-mutant human NSCLC cell lines showed resistance to zoledronic acid wild-type KRAS-cells proved to be sensitive. Combinatory application of zoledronic acid enhanced the cytostatic effect of cisplatin. Zoledronic acid did not induce significant apoptosis. In xenograft model, zoledronic acid significantly reduced the weight of wild type KRAS-EGFR-expressing xenograft tumor by decreasing the proliferative capacity. Futhermore, zoledronic acid induced VEGF expression and improved in vivo tumor vascularization. Materials and methods Membrane association of K-Ras was examined by Western-blot. In vitro cell viability, apoptotic cell death and migration were measured in NSCLC lines with different molecular background. The in vivo effect of zoledronic acid was investigated in a SCID mouse subcutaneous xenograft model. Conclusions The in vitro and in vivo inhibitory effect of zoledronic acid was based on the blockade of cell cycle in wild type KRAS-expressing human NSCLC cells. The zoledronic acid induced vascularization supported in vivo cytostatic effect. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy. PMID:27780929

  6. Risk Assessment in Child Sexual Abuse Cases

    ERIC Educational Resources Information Center

    Levenson, Jill S.; Morin, John W.

    2006-01-01

    Despite continuing improvements in risk assessment for child protective services (CPS) and movement toward actuarial prediction of child maltreatment, current models have not adequately addressed child sexual abuse. Sexual abuse cases present unique and ambiguous indicators to the investigating professional, and risk factors differ from those…

  7. Establishment of a large panel of patient-derived preclinical models of human renal cell carcinoma.

    PubMed

    Lang, Hervé; Béraud, Claire; Bethry, Audrey; Danilin, Sabrina; Lindner, Véronique; Coquard, Catherine; Rothhut, Sylvie; Massfelder, Thierry

    2016-09-13

    The objective of the present work was to establish a large panel of preclinical models of human renal cell carcinoma (RCC) directly from patients, faithfully reproducing the biological features of the original tumor. RCC tissues (all stages/subtypes) were collected for 8 years from 336 patients undergoing surgery, xenografted subcutaneously in nude mice, and serially passaged into new mice up to 13 passages. Tissue samples from the primary tumor and tumors grown in mice through passages were analyzed for biological tissue stability by histopathology, mRNA profiling, von Hippel-Lindau gene sequencing, STR fingerprinting, growth characteristics and response to current therapies. Metastatic models were also established by orthotopic implantation and analyzed by imagery. We established a large panel of 30 RCC models (passage > 3, 8.9% success rate). High tumor take rate was associated with high stage and grade. Histopathologic, molecular and genetic characteristics were preserved between original tumors and case-matched xenografts. The models reproduced the sensitivity to targeted therapies observed in the clinic. Overall, these models constitute an invaluable tool for the clinical design of efficient therapies, the identification of predictive biomarkers and translational research.

  8. TFA Systems: A Unique Group Treatment of Spouse Abusers.

    ERIC Educational Resources Information Center

    Clow, Daniel R.; And Others

    1992-01-01

    Presents a group treatment model using Thought-Feeling-Action (TFA) Systems, an offense- and offender-specific group treatment for abusers. Describes use of TFA Systems in group of court-referred male spouse-abusers. Reviews evolution of TFA Systems, then focuses on TFA Systems treatment of spouse abusers. Notes that system can be adapted to other…

  9. Variability in symptom expression among sexually abused girls: developing multivariate models.

    PubMed

    Spaccarelli, S; Fuchs, C

    1997-03-01

    Examined which of several apparent risk variables were predictors of internalizing and externalizing problems in 48 girls who were referred for therapy after disclosing sexual abuse. Specifically, the effects of abuse characteristics, support from nonoffending parents, victims' coping strategies, and victims' cognitive appraisals on symptomatology were assessed. As hypothesized, results indicated that internalizing and externalizing problems were associated with different sets of predictor variables. Victims' self-reports of depression and anxiety were related to lower perceived support from nonoffending parents, more use of cognitive avoidance coping, and more negative appraisals of the abuse. These results were partially replicated when using parent-report measures of depression, but were not replicated for parent reports of victim anxiety. Incest was the only variable that was significantly related to parent-reported anxiety. Parent-reported aggressive behaviors were predicted by level of abuse-related stress; and aggression, social problems, and sexual problems were all related to the tendency to cope by controlling others. Social problems were also related to coping by self-distraction. Regression analyses were done for each dependent variable to examine which predictors accounted for unique variance when controlling for other significant zero-order correlates. Implications of these results for understanding variability in symptom expression among sexual abuse victims are discussed.

  10. Adolescent Abuse.

    ERIC Educational Resources Information Center

    Foreman, Susan; Seligman, Linda

    1983-01-01

    Discusses legal and developmental aspects of adolescent abuse, as distinguished from child abuse. The role of the school counselor in identifying and counseling abused adolescents and their families is discussed and several forms of intervention and support services are described. (JAC)

  11. Drug Abuse

    MedlinePlus

    ... drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms ...

  12. Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options.

    PubMed

    Gallmeier, Eike; Calhoun, Eric S; Rago, Carlo; Brody, Jonathan R; Cunningham, Steven C; Hucl, Tomas; Gorospe, Myriam; Kohli, Manu; Lengauer, Christoph; Kern, Scott E

    2006-06-01

    How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models. We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance. FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer. Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.

  13. [On the relationship between emotional dependency and abuse].

    PubMed

    Leemans, C; Loas, S

    2016-01-01

    Abuse is a complex psychosocial issue with multiple implications. This paper takes a look at the physical and psychological manifestations of domestic violence, i.e. between adult (romantic) partners as well as abuse of the elderly. Past studies have looked at the relationship between emotional dependency, the occurence and sustainability of abuse and the likehood that a victimized person will terminate a relationship. Indeed, individuals with Dependent Personality Disorder (DPD) or with dependent characteristics present a higher risk of becoming abusive (both physically and mentally) as well as becoming a victim of abuse. Regarding the elderly, the concept of "reverse violence"--where the current abuser was the victim of the senior who is being abused-, also entails dependent relationships. We identified three concepts that are necessary in the understanding of how dependent relationships underpin abuse: Rusbult's model of commitment in intimate relationships, the notion of dependency-possessiveness and Murphy et al's notion of escalating affective dependency. Thus, it is imperative that future studies in the field of domestic violence look at the dynamics of dyads rather than the individuals alone.

  14. Preclinical electrogastrography in experimental pigs

    PubMed Central

    Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

    2010-01-01

    Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

  15. The development of neural stimulators: a review of preclinical safety and efficacy studies.

    PubMed

    Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

    2018-05-14

    Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to

  16. CAP—advancing the evaluation of preclinical Alzheimer disease treatments

    PubMed Central

    Reiman, Eric M.; Langbaum, Jessica B.; Tariot, Pierre N.; Lopera, Francisco; Bateman, Randall J.; Morris, John C.; Sperling, Reisa A.; Aisen, Paul S.; Roses, Allen D.; Welsh-Bohmer, Kathleen A.; Carrillo, Maria C.; Weninger, Stacie

    2016-01-01

    If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer’s Prevention (CAP)—a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact—and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. PMID:26416539

  17. Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

    PubMed

    Holzgrefe, Henry; Ferber, Georg; Champeroux, Pascal; Gill, Michael; Honda, Masaki; Greiter-Wilke, Andrea; Baird, Theodore; Meyer, Olivier; Saulnier, Muriel

    2014-01-01

    In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the

  18. A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel.

    PubMed

    Zhou, X; Kurowski, S; Wu, W; Desai, K; Chu, L; Gutstein, D E; Seiffert, D; Wang, X

    2016-09-01

    Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals. Potential translational value of this preclinical model of MES was demonstrated. Objectives Cerebral microembolic signals (MESs) detected by transcranial Doppler (TCD) ultrasound constitute an independent predictor of stroke risk and prognosis. The aim of this study was to develop a novel preclinical model of MESs to facilitate translational research. Methods A clinical TCD ultrasound machine was used to detect MESs in the cerebral circulation of New Zealand White rabbits. Technical feasibility was assessed for the measurement of MESs in the middle cerebral artery (MCA) by TCD. FeCl3 -induced carotid arterial thrombosis was optimized for the generation of endogenous microemboli. Ascending doses of two antithrombotic agents (aspirin and clopidogrel) were evaluated individually and in combination for their effects on both arterial thrombosis and MESs in a 30% FeCl3 -induced carotid arterial thrombosis model, along with ex vivo functional assays. Results Dose-dependent FeCl3 -induced arterial thrombosis studies showed that 30% FeCl3 resulted in the most consistent and reproducible MESs in the MCA (3.3 ± 0.7 MESs h(-1) ). Ascending-dose studies showed that the effective doses for 50% inhibition (ED50 ) of thrombus formation, based on integrated blood flow and thrombus weight, respectively, were 3.1 mg kg(-1) and 4.2 mg kg(-1) orally for aspirin, and 0.3 mg kg(-1) and 0.28 mg kg(-1) orally for clopidogrel. The ED50 values for MES incidence were 12.7 mg kg(-1) orally for aspirin, and 0.25 mg kg(-1) orally for clopidogrel. Dual treatment with aspirin (5 mg kg(-1) ) and clopidogel (0.3 mg kg(-1) ) resulted in significant reductions in cerebral MESs (P < 0.05) as compared with monotherapy with either agent. Conclusions Our study

  19. The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

    PubMed Central

    Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-01-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

  20. The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

    PubMed

    Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

    2015-07-01

    When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. [Validity evidence of the Health-Related Quality of Life for Drug Abusers Test based on the Biaxial Model of Addiction].

    PubMed

    Lozano, Oscar M; Rojas, Antonio J; Pérez, Cristino; González-Sáiz, Francisco; Ballesta, Rosario; Izaskun, Bilbao

    2008-05-01

    The aim of this work is to show evidence of the validity of the Health-Related Quality of Life for Drug Abusers Test (HRQoLDA Test). This test was developed to measure specific HRQoL for drugs abusers, within the theoretical addiction framework of the biaxial model. The sample comprised 138 patients diagnosed with opiate drug dependence. In this study, the following constructs and variables of the biaxial model were measured: severity of dependence, physical health status, psychological adjustment and substance consumption. Results indicate that the HRQoLDA Test scores are related to dependency and consumption-related problems. Multiple regression analysis reveals that HRQoL can be predicted from drug dependence, physical health status and psychological adjustment. These results contribute empirical evidence of the theoretical relationships established between HRQoL and the biaxial model, and they support the interpretation of the HRQoLDA Test to measure HRQoL in drug abusers, thus providing a test to measure this specific construct in this population.

  2. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles.

    PubMed

    Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B; Østergaard, Michael E; Gu, Xiaofeng; Kordasiewicz, Holly B; Kay, Chris; Cheung, Daphne; Xie, Yuanyun; Waltl, Sabine; Dal Cengio, Louisa; Findlay-Black, Hailey; Doty, Crystal N; Petoukhov, Eugenia; Iworima, Diepiriye; Slama, Ramy; Ooi, Jolene; Pouladi, Mahmoud A; Yang, X William; Swayze, Eric E; Seth, Punit P; Hayden, Michael R

    2017-03-15

    Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Childhood Experiences of Sexual Abuse and Later Parenting Practices among Non-Offending Mothers of Sexually Abused and Comparison Girls

    ERIC Educational Resources Information Center

    Kim, Kihyun; Trickett, Penelope K.; Putnam, Frank W.

    2010-01-01

    Objective: The primary goal of this study was to explore the relationship between childhood sexual abuse and parenting practices among non-offending mothers of sexually abused girls. Guided by a developmental-ecological perspective of parenting, several models with different potential pathways starting from the mothers' childhood experiences of…

  4. Psychiatric Disorders of Children Living with Drug-Abusing, Alcohol-Abusing, and Non-Substance-Abusing Fathers.

    ERIC Educational Resources Information Center

    Kelley, Michelle L.; Fals-Stewart, William

    2004-01-01

    Objective: The present study examined lifetime psychiatric disorders and current emotional and behavioral problems of 8- to 12-year-old children living with drug-abusing (DA) fathers compared to children living in demographically matched homes with alcohol-abusing (AA) or non-substance-abusing fathers. Method: Children's lifetime psychiatric…

  5. Preclinical profile of cabazitaxel

    PubMed Central

    Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil

    2014-01-01

    First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated

  6. Robotic Cholecystectomy Using the Newly Developed Korean Robotic Surgical System, Revo-i: A Preclinical Experiment in a Porcine Model.

    PubMed

    Kang, Chang Moo; Chong, Jae Uk; Lim, Jin Hong; Park, Dong Won; Park, Sung Jun; Gim, Suhyeon; Ye, Hye Jin; Kim, Se Hoon; Lee, Woo Jung

    2017-09-01

    One Korean company recently successfully produced a robotic surgical system prototype called Revo-i (MSR-5000). We, therefore, conducted a preclinical study for robotic cholecystectomy using Revo-i, and this is a report of the first case of robotic cholecystectomy performed using the Revo-i system in a preclinical porcine model. Revo-i consists of a surgeon console (MSRC-5000), operation cart (MSRO-5000) and vision cart (MSRV-5000), and a 40 kg-healthy female porcine was prepared for robotic cholecystectomy with general anesthesia. The primary end point was the safe completion of these procedures using Revo-i: The total operation time was 88 minutes. The dissection time was defined as the time from the initial dissection of the Calot area to the time to complete gallbladder detachment from the liver bed: The dissection time required 14 minutes. The surgical console time was 45 minutes. There was no gallbladder perforation or significant bleeding noted during the procedure. The porcine survived for two weeks postoperatively without any complications. Like the da Vinci surgical system, the Revo-i provides a three-dimensional operative view and allows for angulated instrument motion (forceps, needle-holders, clip-appliers, scissors, bipolar energy, and hook monopolar energy), facilitating an effective laparoscopic procedure. Our experience suggests that robotic cholecystectomy can be safely completed in a porcine model using Revo-i. © Copyright: Yonsei University College of Medicine 2017.

  7. Child-related cognitions and affective functioning of physically abusive and comparison parents.

    PubMed

    Haskett, Mary E; Smith Scott, Susan; Grant, Raven; Ward, Caryn Sabourin; Robinson, Canby

    2003-06-01

    The goal of this research was to utilize the cognitive behavioral model of abusive parenting to select and examine risk factors to illuminate the unique and combined influences of social cognitive and affective variables in predicting abuse group membership. Participants included physically abusive parents (n=56) and a closely-matched group of comparison parents (n=62). Social cognitive risk variables measured were (a) parent's expectations for children's abilities and maturity, (b) parental attributions of intentionality of child misbehavior, and (c) parents' perceptions of their children's adjustment. Affective risk variables included (a) psychopathology and (b) parenting stress. A series of logistic regression models were constructed to test the individual, combined, and interactive effects of risk variables on abuse group membership. The full set of five risk variables was predictive of abuse status; however, not all variables were predictive when considered individually and interactions did not contribute significantly to prediction. A risk composite score computed for each parent based on the five risk variables significantly predicted abuse status. Wide individual differences in risk across the five variables were apparent within the sample of abusive parents. Findings were generally consistent with a cognitive behavioral model of abuse, with cognitive variables being more salient in predicting abuse status than affective factors. Results point to the importance of considering diversity in characteristics of abusive parents.

  8. Adjuvants for Vaccines to Drugs of Abuse and Addiction

    PubMed Central

    Alving, Carl R.; Matyas, Gary R.; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2015-01-01

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA. PMID:25111169

  9. Validation of a Simulation Model of Intrinsic Lutetium-176 Activity in LSO-Based Preclinical PET Systems

    NASA Astrophysics Data System (ADS)

    McIntosh, Bryan

    The LSO scintillator crystal commonly used in PET scanners contains a low level of intrinsic radioactivity due to a small amount of Lu-176. This is not usually a concern in routine scanning but can become an issue in small animal imaging, especially when imaging low tracer activity levels. Previously there had been no systematic validation of simulations of this activity; this thesis discusses the validation of a GATE model of intrinsic Lu-176 against results from a bench-top pair of detectors and a Siemens Inveon preclinical PET system. The simulation results matched those from the bench-top system very well, but did not agree as well with results from the complete Inveon system due to a drop-off in system sensitivity at low energies that was not modelled. With this validation the model can now be used with confidence to predict the effects of Lu-176 activity in future PET systems.

  10. Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

    PubMed Central

    Schütte, Moritz; Risch, Thomas; Abdavi-Azar, Nilofar; Boehnke, Karsten; Schumacher, Dirk; Keil, Marlen; Yildiriman, Reha; Jandrasits, Christine; Borodina, Tatiana; Amstislavskiy, Vyacheslav; Worth, Catherine L.; Schweiger, Caroline; Liebs, Sandra; Lange, Martin; Warnatz, Hans- Jörg; Butcher, Lee M.; Barrett, James E.; Sultan, Marc; Wierling, Christoph; Golob-Schwarzl, Nicole; Lax, Sigurd; Uranitsch, Stefan; Becker, Michael; Welte, Yvonne; Regan, Joseph Lewis; Silvestrov, Maxine; Kehler, Inge; Fusi, Alberto; Kessler, Thomas; Herwig, Ralf; Landegren, Ulf; Wienke, Dirk; Nilsson, Mats; Velasco, Juan A.; Garin-Chesa, Pilar; Reinhard, Christoph; Beck, Stephan; Schäfer, Reinhold; Regenbrecht, Christian R. A.; Henderson, David; Lange, Bodo; Haybaeck, Johannes; Keilholz, Ulrich; Hoffmann, Jens; Lehrach, Hans; Yaspo, Marie-Laure

    2017-01-01

    Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab. PMID:28186126

  11. Male-initiated partner abuse during marital separation prior to divorce.

    PubMed

    Toews, Michelle L; McKenry, Patrick C; Catlett, Beth S

    2003-08-01

    The purpose of this study was to assess predictors of male-initiated psychological and physical partner abuse during the separation process prior to divorce among a sample of 80 divorced fathers who reported no physical violence during their marriages. The predictor variables examined were male gender-role identity, female-initiated divorces, dependence on one's former wife, depression, anxiety, and coparental conflict. Through ordinary least square (OLS) regression techniques, it was found that male gender-role identity was positively related to male-initiated psychological abuse during separation. Logistic regression analyses revealed that male-initiated psychological abuse, anxiety level, coparental conflict, and dependence on one's former spouse increased the odds of a man engaging in physical abuse. However, depression decreased the odds of separation physical abuse. The models predicting both male-initiated psychological abuse (F = 2.20, p < .05, R2 = .15) and physical violence during the separation process were significant (Model chi2 = 35.00, df= 7, p < .001).

  12. Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes

    PubMed Central

    Ergul, Adviye; Hafez, Sherif; Fouda, Abdelrahman; Fagan, Susan C.

    2016-01-01

    Human ischemic stroke is very complex and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients. As such, more and more disease models are being incorporated into the research design. This review highlights the major strengths and weaknesses of the most commonly used animal models of these conditions in preclinical stroke research. The goal is to provide guidance in choosing, reporting and executing appropriate disease models that will be subjected to different models of stroke injury. PMID:27026092

  13. Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy

    PubMed Central

    Wert, Katherine J; Mahajan, Vinit B; Zhang, Lijuan; Yan, Yuanqing; Li, Yao; Tosi, Joaquin; Wei Hsu, Chun; Nagasaki, Takayuki; Janisch, Kerstin M; Grant, Maria B; Mahajan, MaryAnn; Bassuk, Alexander G; Tsang, Stephen H

    2016-01-01

    Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders. PMID:27195131

  14. Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration.

    PubMed

    Trachtenberg, Jordan E; Vo, Tiffany N; Mikos, Antonios G

    2015-03-01

    Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth.

  15. Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration

    PubMed Central

    Trachtenberg, Jordan E.; Vo, Tiffany N.; Mikos, Antonios G.

    2014-01-01

    Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth. PMID:25319726

  16. Prevention or treatment of ARDS with aspirin: a review of preclinical models and meta- analysis of clinical studies

    PubMed Central

    Panka, Bernardo Amisa; de Grooth, Harm-Jan; Spoelstra–de Man, Angeliquè; Looney, Mark; Tuinman, Pieter-Roel

    2016-01-01

    Background The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself, have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. Methods We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. MEDLINE, EMBASE AND COCHRANE databases were searched. Results The literature search yielded 1314 unique articles. Fifteen pre-clinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g. ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps and prostaglandins. High dose ASA may be the drug of choice. A meta-analysis of 3 clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36–0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. Conclusion This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models is being evaluated to guide optimal timing and dose

  17. Maladaptive Decision Making in Adults with a History of Adolescent Alcohol use, in a Preclinical Model, Is Attributable to the Compromised Assignment of Incentive Value during Stimulus-Reward Learning.

    PubMed

    Kruse, Lauren C; Schindler, Abigail G; Williams, Rapheal G; Weber, Sophia J; Clark, Jeremy J

    2017-01-01

    According to recent WHO reports, alcohol remains the number one substance used and abused by adolescents, despite public health efforts to curb its use. Adolescence is a critical period of biological maturation where brain development, particularly the mesocorticolimbic dopamine system, undergoes substantial remodeling. These circuits are implicated in complex decision making, incentive learning and reinforcement during substance use and abuse. An appealing theoretical approach has been to suggest that alcohol alters the normal development of these processes to promote deficits in reinforcement learning and decision making, which together make individuals vulnerable to developing substance use disorders in adulthood. Previously we have used a preclinical model of voluntary alcohol intake in rats to show that use in adolescence promotes risky decision making in adulthood that is mirrored by selective perturbations in dopamine network dynamics. Further, we have demonstrated that incentive learning processes in adulthood are also altered by adolescent alcohol use, again mirrored by changes in cue-evoked dopamine signaling. Indeed, we have proposed that these two processes, risk-based decision making and incentive learning, are fundamentally linked through dysfunction of midbrain circuitry where inputs to the dopamine system are disrupted by adolescent alcohol use. Here, we test the behavioral predictions of this model in rats and present the findings in the context of the prevailing literature with reference to the long-term consequences of early-life substance use on the vulnerability to develop substance use disorders. We utilize an impulsive choice task to assess the selectivity of alcohol's effect on decision-making profiles and conditioned reinforcement to parse out the effect of incentive value attribution, one mechanism of incentive learning. Finally, we use the differential reinforcement of low rates of responding (DRL) task to examine the degree to which

  18. Maladaptive Decision Making in Adults with a History of Adolescent Alcohol use, in a Preclinical Model, Is Attributable to the Compromised Assignment of Incentive Value during Stimulus-Reward Learning

    PubMed Central

    Kruse, Lauren C.; Schindler, Abigail G.; Williams, Rapheal G.; Weber, Sophia J.; Clark, Jeremy J.

    2017-01-01

    According to recent WHO reports, alcohol remains the number one substance used and abused by adolescents, despite public health efforts to curb its use. Adolescence is a critical period of biological maturation where brain development, particularly the mesocorticolimbic dopamine system, undergoes substantial remodeling. These circuits are implicated in complex decision making, incentive learning and reinforcement during substance use and abuse. An appealing theoretical approach has been to suggest that alcohol alters the normal development of these processes to promote deficits in reinforcement learning and decision making, which together make individuals vulnerable to developing substance use disorders in adulthood. Previously we have used a preclinical model of voluntary alcohol intake in rats to show that use in adolescence promotes risky decision making in adulthood that is mirrored by selective perturbations in dopamine network dynamics. Further, we have demonstrated that incentive learning processes in adulthood are also altered by adolescent alcohol use, again mirrored by changes in cue-evoked dopamine signaling. Indeed, we have proposed that these two processes, risk-based decision making and incentive learning, are fundamentally linked through dysfunction of midbrain circuitry where inputs to the dopamine system are disrupted by adolescent alcohol use. Here, we test the behavioral predictions of this model in rats and present the findings in the context of the prevailing literature with reference to the long-term consequences of early-life substance use on the vulnerability to develop substance use disorders. We utilize an impulsive choice task to assess the selectivity of alcohol’s effect on decision-making profiles and conditioned reinforcement to parse out the effect of incentive value attribution, one mechanism of incentive learning. Finally, we use the differential reinforcement of low rates of responding (DRL) task to examine the degree to which

  19. Childhood family dysfunction and associated abuse in patients with nonepileptic seizures: towards a causal model.

    PubMed

    Salmon, Peter; Al-Marzooqi, Suad M; Baker, Gus; Reilly, James

    2003-01-01

    A history of childhood sexual abuse is thought to characterize patients with nonepileptic seizures (NES). We tested the hypotheses: 1) that history of sexual abuse is more prevalent in patients with NES than in controls with epilepsy; 2) that such abuse is associated with NES, not directly but because it is a marker of family dysfunction; and 3) that family dysfunction and abuse are, in turn, linked to NES because they increase a general tendency to somatize. We compared 81 patients with NES with 81 case-matched epilepsy patients, using questionnaires to elicit recollections of sexual, physical, and psychological abuse and family atmosphere and to quantify current somatization. Although each form of abuse was more prevalent in NES patients, only child psychological abuse uniquely distinguished NES from epilepsy. However, its association with NES was explained by family dysfunction. A general tendency to somatize explained part of the relationship of abuse to NES. Abuse therefore seems to be a marker for aspects of family dysfunction that are associated with--and may therefore cause--somatization and, specifically, NES.

  20. Sexual abuses.

    PubMed

    Abel, G G; Rouleau, J L

    1995-03-01

    The sexual abuses described in this article are occurring so frequently that they constitute a public health problem. Superficially they appear to be quite dissimilar because they involve individuals of different ages, different settings, and different power relationships. Basic to each of them, however, is an absence of consent by the victim and the misuse of power by the perpetrator in order to accomplish the abuse. We now have an adequate understanding of each of these abuses and it is now time to make a concerted effort to stop these abuses. This will require the combined efforts of the education of the public, improved identification of the abuses, treatment of the victims, and an appropriate criminal justice response combined with treatment of the perpetrator.

  1. Spouse Abuse, Child Abuse, and Substance Abuse Among Army Facilities: Co-Occurrence, Correlations and Service Delivery Issues

    DTIC Science & Technology

    2006-03-01

    refer spouse abuse or child abuse offenders with identified alcohol or other drug involvement to the on-base counseling center for a substance...abuse assessment. The military’s response to combat substance abuse involves a combination of education, prevention, random testing for illicit drug ...data from three Army sources: the Army Central Registry (ACR), the Drug and Alcohol Management Information System (DAMIS), and Army personnel data

  2. The nature of outsourced preclinical research--the example of chemical synthesis.

    PubMed

    Festel, Gunter W

    2013-09-01

    The possibility to buy standardized external services or even new and innovative methods within drug discovery has increased dramatically during the last decades. Service providers are able to provide timely and efficient solutions to any given problem within preclinical research. The outsourcing behavior depends on the specific company type. Generally, the outsourcing level of emerging pharmaceutical and biotechnology companies is much higher than established companies due to low or missing internal resources. Whereas the "make-or-buy" decisions of large and fully integrated pharmaceutical companies are mainly competency driven, those of mid-size and small pharmaceutical, as well as biotech companies show a specific combination of cost/capacity and competency. The three different cooperation models "price competition", "project selection," and "strategic partnership" were identified. For all types of companies, the cooperation model of "strategic partnership" offers access to high-level expertise while reducing fixed costs and complexity. This was shown using chemical synthesis as an example but is also true for other areas of preclinical research.

  3. Preclinical magnetic resonance imaging and systems biology in cancer research: current applications and challenges.

    PubMed

    Albanese, Chris; Rodriguez, Olga C; VanMeter, John; Fricke, Stanley T; Rood, Brian R; Lee, YiChien; Wang, Sean S; Madhavan, Subha; Gusev, Yuriy; Petricoin, Emanuel F; Wang, Yue

    2013-02-01

    Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  4. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    PubMed

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  5. Mesenchymal stem cell therapy promotes the improvement and recovery of renal function in a preclinical model

    PubMed Central

    Urt-Filho, Antônio; Oliveira, Rodrigo Juliano; Hermeto, Larissa Correa; Pesarini, João Renato; de David, Natan; Cantero, Wilson de Barros; Falcão, Gustavo; Marks, Guido; Antoniolli-Silva, Andréia Conceição Milan Brochado

    2016-01-01

    Abstract Acute renal failure (ARF) is an extremely important public health issue in need of novel therapies. The present study aimed to evaluate the capacity of mesenchymal stem cell (MSC) therapy to promote the improvement and recovery of renal function in a preclinical model. Wistar rats were used as the experimental model, and our results show that cisplatin (5mg/kg) can efficiently induce ARF, as measured by changes in biochemical (urea and creatinine) and histological parameters. MSC therapy performed 24h after the administration of chemotherapy resulted in normalized plasma urea and creatinine levels 30 and 45d after the onset of kidney disease. Furthermore, MSC therapy significantly reduced histological changes (intratubular cast formation in protein overload nephropathy and tubular hydropic degeneration) in this ARF model. Thus, considering that current therapies for ARF are merely palliative and that MSC therapy can promote the improvement and recovery of renal function in this model system, we suggest that innovative/alternative therapies involving MSCs should be considered for clinical studies in humans to treat ARF. PMID:27275667

  6. Substance abuse as a symptom of childhood sexual abuse.

    PubMed

    Teusch, R

    2001-11-01

    The recovery process of a 37-year-old woman with adult onset posttraumatic stress disorder (PTSD) is presented. The patient had suffered childhood sexual abuse and had self-medicated for many years with drugs and alcohol to maintain the dissociation of memories of abuse and to facilitate interpersonal functioning. Upon onset of PTSD, the patient's substance abuse became a full-blown addiction that was highly resistant to treatment. It became evident that her substance abuse symbolically repeated her traumatization. In reexperiencing the affects associated with her earlier trauma (despair, denial, shame, and helplessness) as part of her substance abuse and in the transference, the patient was able to gain mastery over these affects and, subsequently, was able to achieve a stable recovery from both illnesses.

  7. Other Drugs of Abuse

    MedlinePlus

    ... People Abuse » Other Drugs of Abuse Other Drugs of Abuse Listen There are many other drugs of abuse, ... and Rehab Resources About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  8. Abuse behavior of high-power, lithium-ion cells

    NASA Astrophysics Data System (ADS)

    Spotnitz, R.; Franklin, J.

    Published accounts of abuse testing of lithium-ion cells and components are summarized, including modeling work. From this summary, a set of exothermic reactions is selected with corresponding estimates of heats of reaction. Using this set of reactions, along with estimated kinetic parameters and designs for high-rate batteries, models for the abuse behavior (oven, short-circuit, overcharge, nail, crush) are developed. Finally, the models are used to determine that fluorinated binder plays a relatively unimportant role in thermal runaway.

  9. Self-Esteem and Attitudes toward Love in Abused and Non-Abused Women.

    ERIC Educational Resources Information Center

    Chambliss, Catherine; And Others

    This study sought to identify personality differences in abused versus non-abused women. Abused women (N=25) were from several centers for abused women and non-abused women (N=39) were students in evening psychology classes. All subjects completed Rubin's Love Scale, the abbreviated Dominance and Romanticism Scale, Rosenberg's Self-Esteem Scale,…

  10. Student Assistance Programs: New Approaches for Reducing Adolescent Substance Abuse.

    ERIC Educational Resources Information Center

    Moore, David D.; Forster, Jerald R.

    1993-01-01

    Describes school-based Student Assistance Programs (SAPs), which are designed to reduce adolescents' substance abuse. Notes that SAPs, modeled after Employee Assistance Programs in workplace, are identifying, assessing, referring, and managing cases of substance-abusing students. Sees adoption of SAP model as accelerating in response to growing…

  11. Attributional style as a mediator between parental abuse risk and child internalizing symptomatology.

    PubMed

    Rodriguez, Christina M

    2006-05-01

    This study examined a model wherein children's attributional style mediates the relationship between parental physical child-abuse risk and children's internalizing problems. Using structural equation modeling, three indices of abuse risk were selected (child abuse potential, physical discipline use, and dysfunctional parenting style) and two indices of children's internalizing problems (depression and anxiety). The sample included 75 parent-child dyads, in which parents reported on their abuse risk and children independently completed measures of depressive and anxious symptomatology and a measure on their attributional style. Findings supported the model that children's attributional style for positive events (but not negative events) partially mediated the relationship between abuse risk and internalizing symptoms, with significant direct and indirect effects of abuse risk on internalizing symptomatology. Future directions to continue evaluating additional mediators and other possible contextual variables are discussed.

  12. Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

    PubMed

    Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

    2015-04-06

    In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key

  13. Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk.

    PubMed

    Gintant, Gary A

    2008-08-01

    The successful development of novel drugs requires the ability to detect (and avoid) compounds that may provoke Torsades-de-Pointes (TdeP) arrhythmia while endorsing those compounds with minimal torsadogenic risk. As TdeP is a rare arrhythmia not readily observed during clinical or post-marketing studies, numerous preclinical models are employed to assess delayed or altered ventricular repolarization (surrogate markers linked to enhanced proarrhythmic risk). This review evaluates the advantages and limitations of selected preclinical models (ranging from the simplest cellular hERG current assay to the more complex in vitro perfused ventricular wedge and Langendorff heart preparations and in vivo chronic atrio-ventricular (AV)-node block model). Specific attention is paid to the utility of concentration-response relationships and "risk signatures" derived from these studies, with the intention of moving beyond predicting clinical QT prolongation and towards prediction of TdeP risk. While the more complex proarrhythmia models may be suited to addressing questionable or conflicting proarrhythmic signals obtained with simpler preclinical assays, further benchmarking of proarrhythmia models is required for their use in the robust evaluation of safety margins. In the future, these models may be able to reduce unwarranted attrition of evolving compounds while becoming pivotal in the balanced integrated risk assessment of advancing compounds.

  14. Vaccines for cocaine abuse.

    PubMed

    Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Kosten, Thomas R

    2009-04-01

    Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

  15. Excessive Aggression as Model of Violence: A Critical Evaluation of Current Preclinical Methods

    PubMed Central

    Miczek, Klaus A.; de Boer, Sietse F.; Haller, Jozsef

    2013-01-01

    Rationale Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area. Objectives How valid, reliable, productive and informative are the most frequently used animal models of excessive aggressive behavior? Methods The rationale, key methodological features, supporting data and arguments as well as their disadvantages and limitations of the most frequently used animal models for excessive aggressive behavior are summarized and their validity and reliability are evaluated. Results Excessive aggressive behavior is validly and reliably seen in (1) a proportion of feral-derived rats and selectively bred mice, (2) rats with compromised adrenal function resulting in a hypoglucocorticoid state, (3) a significant minority of mice, rats and monkeys after consumption of a moderate dose of alcohol, and (4) resident animals of various species after social instigation. Limitations of these procedures include restrictive animal research regulations, the requirement of expertise in surgical, pharmacological and behavioral techniques, and the behaviorally impoverished mouse strains that are used in molecular genetics research. Promising recent initiatives for novel experimental models include aggressive behaviors that are evoked by optogenetic stimulation and induced by the manipulation of early social experiences such as isolation rearing or social stress. Conclusions One of the most significant challenges for animal models of excessive, potentially abnormal aggressive behavior is the characterization of distinctive neurobiological mechanisms that differ from those governing species-typical aggressive behavior. Identifying novel targets for effective intervention requires increased understanding of the distinctive molecular, cellular and circuit mechanisms for each type of abnormal aggressive behavior. PMID:23430160

  16. Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

    PubMed Central

    Sudres, Muriel; Maurer, Marie; Robinet, Marieke; Bismuth, Jacky; Truffault, Frédérique; Girard, Diane; Dragin, Nadine; Attia, Mohamed; Fadel, Elie; Santelmo, Nicola; Sicsic, Camille; Brenner, Talma

    2017-01-01

    Myasthenia gravis (MG) with anti–acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro–preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell–related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases. PMID:28405609

  17. Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia.

    PubMed

    Caldwell, Matthew; Moroz, Tracy; Hapuarachchi, Tharindi; Bainbridge, Alan; Robertson, Nicola J; Cooper, Chris E; Tachtsidis, Ilias

    2015-01-01

    Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue.

  18. Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia

    PubMed Central

    Bainbridge, Alan; Robertson, Nicola J.; Cooper, Chris E.

    2015-01-01

    Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. PMID:26445281

  19. [Drinking and drug abuse among gymnasium students in Szczecin].

    PubMed

    Musiał, Barbara; Czaja-Bulsa, Grazyna; Szechter-Grycewicz, Aneta; Brodzińska, Beata; Marasz, Agata

    2012-01-01

    The aim of this work was to determine the extent and causes of drinking and drug abuse by the youth. A questionnaire was administered to 918 students aged 13-16 years from five gymnasia in Stettin. The results were analyzed statistically. In the group of 918 students, 76% were alcohol drinkers and 15% abused psychoactive substances. Among causes of drinking and drug abuse were family and personal problems, impressing colleagues, fashion, advertisements, and stress. Alcohol drinking and drug abuse are not only a response to personal and family problems, but also the result of role models accepted by gymnasium students. Lack of control and support within the family are factors liberating alcohol consumption and drug abuse among the youth.

  20. SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shang, M; Sands, M; Bolch, W

    2015-06-15

    Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adultmore » beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.« less

  1. NCI Pediatric Preclinical Testing Consortium

    Cancer.gov

    NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

  2. Sponge-supported cultures of primary head and neck tumors for an optimized preclinical model.

    PubMed

    Dohmen, Amy J C; Sanders, Joyce; Canisius, Sander; Jordanova, Ekaterina S; Aalbersberg, Else A; van den Brekel, Michiel W M; Neefjes, Jacques; Zuur, Charlotte L

    2018-05-18

    Treatment of advanced head and neck cancer is associated with low survival, high toxicity and a widely divergent individual response. The sponge-gel-supported histoculture model was previously developed to serve as a preclinical model for predicting individual treatment responses. We aimed to optimize the sponge-gel-supported histoculture model and provide more insight in cell specific behaviour by evaluating the tumor and its microenvironment using immunohistochemistry. We collected fresh tumor biopsies from 72 untreated patients and cultured them for 7 days. Biopsies from 57 patients (79%) were successfully cultured and 1451 tumor fragments (95.4%) were evaluated. Fragments were scored for percentage of tumor, tumor viability and proliferation, EGF-receptor expression and presence of T-cells and macrophages. Median tumor percentage increased from 53% at day 0 to 80% at day 7. Viability and proliferation decreased after 7 days, from 90% to 30% and from 30% to 10%, respectively. Addition of EGF, folic acid and hydrocortisone can lead to improved viability and proliferation, however this was not systematically observed. No patient subgroup could be identified with higher culture success rates. Immune cells were still present at day 7, illustrating that the tumor microenvironment is sustained. EGF supplementation did not increase viability and proliferation in patients overexpressing EGF-Receptor.

  3. Abuse Is Abuse: The Influence of Type of Abuse, Victim Age, and Defendant Age on Juror Decision Making.

    PubMed

    Sheahan, Chelsea L; Pica, Emily; Pozzulo, Joanna D

    2017-09-01

    The purpose of the current study was to examine the role of victim age, defendant age, and type of abuse on mock juror decision making. Mock jurors ( N = 556) read a trial transcript in which a soccer coach was accused of sexual abuse or physical abuse against a player. The victim's age (child, adolescent, or young adult), the defendant's age (young, middle age, or older adult), and the type of abuse (sexual or physical) were varied. Mock jurors provided a dichotomous and continuous verdict and rated their perceptions of the victim and the defendant. Although no differences on mock jurors' dichotomous verdict were found due to victim age, defendant age, or type of abuse, mock jurors provided higher guilt ratings when the abuse was sexual and both the victim and defendant were described as young adults. Similarly, mock jurors rated the victim more positively when the victim was described as a young adult (vs. child) for both sexual and physical abuse cases, and rated the defendant more positively when the victim was described as a child compared with young adult in sexual abuse cases. These findings suggest that mock jurors were largely influenced by victim age, particularly when the victim was described as an adult compared with a child.

  4. Saccharin Aza Bioisosteres-Synthesis and Preclinical Property Comparisons.

    PubMed

    Chen, Yantao; Aurell, Carl-Johan; Pettersen, Anna; Lewis, Richard J; Hayes, Martin A; Lepistö, Matti; Jonson, Anna C; Leek, Hanna; Thunberg, Linda

    2017-06-08

    Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B ), and two new types of aza-saccharins (clusters C and D ). We demonstrate a convenient protocol to selectively synthesize products in cluster C or D when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters C and D offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.

  5. The management of abuse: 2. Child abuse.

    PubMed

    Panesear, Jaspel; Sinha, Karen Juggins Sonia; Acharya, Preeti; Jafar, Hima; Bower, Elizabeth J; Harrison, Victoria E; Newton, J Tim

    2006-09-01

    The role of the GDP and the dental team in the recognition and management of child abuse is discussed. Information on the current legislation and protocols for referral are provided. This paper discusses child abuse and offers information and practical advice for the dental team.

  6. Intergenerational Pathways Linking Childhood Sexual Abuse to HIV Risk Among Women

    PubMed Central

    Cavanaugh, Courtenay E.; Classen, Catherine C.

    2009-01-01

    Childhood sexual abuse is prevalent among women and it has been linked to a number of problems affecting women's health and functioning including women's parenting practices. Another body of literature has linked specific maternal parenting practices to daughters’ HIV risk, including mother-daughter sex communication, monitoring/knowledge about daughters’ activities, mother-daughter relationship quality, attitudes towards sex, and modeling of sexual values. This paper reviews and links these two bodies of literature to indicate how maternal histories of childhood sexual abuse may compromise mothers’ parenting practices, which may in turn impact daughters’ HIV risk. We also build upon Malow and colleagues’ model (2006) of the associations between childhood sexual abuse and HIV risk to present a model indicating potential intergenerational pathways between childhood sexual abuse and HIV risk among women. The literature supporting this model and gaps in the literature are described. PMID:19333846

  7. A modified collagen gel enhances healing outcome in a preclinical swine model of excisional wounds.

    PubMed

    Elgharably, Haytham; Roy, Sashwati; Khanna, Savita; Abas, Motaz; Dasghatak, Piya; Das, Amitava; Mohammed, Kareem; Sen, Chandan K

    2013-01-01

    Collagen-based dressings are of great interest in wound care. However, evidence supporting their mechanism of action is scanty. This work provides first results from a preclinical swine model of excisional wounds, elucidating the mechanism of action of a modified collagen gel (MCG) dressing. Following wounding, wound-edge tissue was collected at specific time intervals (3, 7, 14, and 21 days postwounding). On day 7, histological analysis showed significant increase in the length of rete ridges, suggesting improved biomechanical properties of the healing wound tissue. Rapid and transient mounting of inflammation is necessary for efficient healing. MCG significantly accelerated neutrophil and macrophage recruitment to the wound site on day 3 and day 7 with successful resolution of inflammation on day 21. MCG induced monocyte chemotactic protein-1 expression in neutrophil-like human promyelocytic leukemia-60 cells in vitro. In vivo, MCG-treated wound tissue displayed elevated vascular endothelial growth factor expression. Consistently, MCG-treated wounds displayed significantly higher abundance of endothelial cells with increased blood flow to the wound area indicating improved vascularization. This observation was explained by the finding that MCG enhanced proliferation of wound-site endothelial cells. In MCG-treated wound tissue, Masson's trichrome and picrosirius red staining showed higher abundance of collagen and increased collagen type I:III ratio. This work presents first evidence from a preclinical setting explaining how a collagen-based dressing may improve wound closure by targeting multiple key mechanisms. The current findings warrant additional studies to determine whether the responses to the MCG are different from other collagen-based products used in clinical setting. © 2013 by the Wound Healing Society.

  8. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

    PubMed

    Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

    2016-10-01

    Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under

  9. [Child psychiatric assessment and the debate regarding the abuse of abuse].

    PubMed

    Fegert, J M

    1995-03-01

    The current discussion on false allegations in sexual abuse cases has led to a polarization in the views expressed about the credibility of children. Some authors even speak of a "child sexual accuse syndrome" or of a "sexual abuse allegation in divorce" (SAID) syndrome. A phenomenological analysis of the multiple reasons for misinterpretations is presented. Instead of stressing the importance only of false positives in child sexual abuse questions, an attempt is made to describe reasons for false negatives. Based on a retrospective analysis of 50 consecutive child psychiatric experts in connection with court cases, there does not appear to be an increase in false accusations. Rather, only about one third of the cases even involved suspected sexual abuse. Sexual abuse allegations were much more frequent in girls than in boys. Of 20 abuse allegations we judge four to be false allegations. In only one of these cases, that of an adolescent girl who had been abused in childhood, was the false allegation intended.

  10. Biological characterization of preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model: A multi-modality approach

    PubMed Central

    Garimella, Rama; Eskew, Jeff; Bhamidi, Priyanka; Vielhauer, George; Hong, Yan; Anderson, H. Clarke; Tawfik, Ossama; Rowe, Peter

    2013-01-01

    Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60–70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model. PMID:25688332

  11. Alcohol abuse as a risk factor for and consequence of child abuse.

    PubMed

    Widom, C S; Hiller-Sturmhöfel, S

    2001-01-01

    The relationship between child abuse and the use or abuse of alcohol has two aspects. First, some findings have indicated that parental alcohol abuse may be associated with the physical or sexual abuse of children. Research findings in this area remain inconsistent, however. Second, the experience of being abused as a child may increase a person's risk for alcohol-related problems as an adult. This relationship has best been demonstrated in women who had been victims of childhood abuse. Several factors most likely contribute to or influence this relationship, including coping skills; antisocial behavior; and psychological problems, such as posttraumatic stress disorder.

  12. Community Poverty and Child Abuse Fatalities in the United States.

    PubMed

    Farrell, Caitlin A; Fleegler, Eric W; Monuteaux, Michael C; Wilson, Celeste R; Christian, Cindy W; Lee, Lois K

    2017-05-01

    Child maltreatment remains a problem in the United States, and individual poverty is a recognized risk factor for abuse. Children in impoverished communities are at risk for negative health outcomes, but the relationship of community poverty to child abuse fatalities is not known. Our objective was to evaluate the association between county poverty concentration and rates of fatal child abuse. This was a retrospective, cross-sectional analysis of child abuse fatalities in US children 0 to 4 years of age from 1999 to 2014 by using the Centers for Disease Control and Prevention Compressed Mortality Files. Population and poverty statistics were obtained from US Census data. National child abuse fatality rates were calculated for each category of community poverty concentration. Multivariate negative binomial regression modeling assessed the relationship between county poverty concentration and child abuse fatalities. From 1999 to 2014, 11 149 children 0 to 4 years old died of child abuse; 45% (5053) were <1 year old, 56% (6283) were boys, and 58% (6480) were white. The overall rate of fatal child abuse was 3.5 per 100 000 children 0 to 4 years old. In the multivariate model, counties with the highest poverty concentration had >3 times the rate of child abuse fatalities compared with counties with the lowest poverty concentration (adjusted incidence rate ratio, 3.03; 95% confidence interval, 2.4-3.79). Higher county poverty concentration is associated with increased rates of child abuse fatalities. This finding should inform public health officials in targeting high-risk areas for interventions and resources. Copyright © 2017 by the American Academy of Pediatrics.

  13. The effect of learning styles and study behavior on success of preclinical students in pharmacology.

    PubMed

    Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

    2016-01-01

    To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

  14. Child Sexual Abuse

    MedlinePlus

    Sexual abuse is one form of child abuse. It includes a wide range of actions between a child ... to children or pressuring them for sex is sexual abuse. Using a child for pornography is also sexual ...

  15. Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

    PubMed Central

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2015-01-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

  16. PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.

    PubMed

    Winterhoff, Boris; Freyer, Luisa; Hammond, Edward; Giri, Shailendra; Mondal, Susmita; Roy, Debarshi; Teoman, Attila; Mullany, Sally A; Hoffmann, Robert; von Bismarck, Antonia; Chien, Jeremy; Block, Matthew S; Millward, Michael; Bampton, Darryn; Dredge, Keith; Shridhar, Viji

    2015-05-01

    Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Problem-Solving in the Pre-Clinical Curriculum: The Uses of Computer Simulations.

    ERIC Educational Resources Information Center

    Michael, Joel A.; Rovick, Allen A.

    1986-01-01

    Promotes the use of computer-based simulations in the pre-clinical medical curriculum as a means of providing students with opportunities for problem solving. Describes simple simulations of skeletal muscle loads, complex simulations of major organ systems and comprehensive simulation models of the entire human body. (TW)

  18. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    PubMed Central

    Walther, Sebastian; Halpern, Michael

    2010-01-01

    The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. PMID:27713372

  19. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Model Notice of Individuals Receiving Substance Abuse Services Appendix to Part 54a Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... against you on the basis of religion, a religious belief, a refusal to hold a religious belief, or a...

  20. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Model Notice of Individuals Receiving Substance Abuse Services Appendix to Part 54a Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... against you on the basis of religion, a religious belief, a refusal to hold a religious belief, or a...

  1. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Model Notice of Individuals Receiving Substance Abuse Services Appendix to Part 54a Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... against you on the basis of religion, a religious belief, a refusal to hold a religious belief, or a...

  2. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Model Notice of Individuals Receiving Substance Abuse Services Appendix to Part 54a Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... against you on the basis of religion, a religious belief, a refusal to hold a religious belief, or a...

  3. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Model Notice of Individuals Receiving Substance Abuse Services Appendix to Part 54a Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... against you on the basis of religion, a religious belief, a refusal to hold a religious belief, or a...

  4. Why Is Childhood Maltreatment Associated with Adolescent Substance Abuse? A Critical Review of Explanatory Models

    ERIC Educational Resources Information Center

    Hovdestad, Wendy E.; Tonmyr, Lil; Wekerle, Christine; Thornton, Tiffany

    2011-01-01

    Childhood maltreatment and adolescent substance abuse are important health issues that have been linked by research and theory for at least 50 years. Considering the intricacies of child maltreatment research, this paper aims to answer the question: which models show the most promise to explain why child maltreatment is a risk indicator for…

  5. A Theoretical Foundation for Understanding Clergy-Perpetrated Sexual Abuse

    ERIC Educational Resources Information Center

    Fogler, Jason M.; Shipherd, Jillian C.; Rowe, Erin; Jensen, Jennifer; Clarke, Stephanie

    2008-01-01

    Incorporating elements from broadband theories of psychological adaptation to extreme adversity, including Summit's (1983) Child Sexual Abuse Accommodation Syndrome, Finkelhor and Browne's (1986) Traumagenic Dynamics Model of sexual abuse, and Pyszczynski and colleagues' (1997) Terror Management Theory, this paper proposes a unified theoretical…

  6. Improving the quality of preclinical research echocardiography: Observations, training and guidelines for measurement.

    PubMed

    Donner, Daniel G; Kiriazis, Helen; Du, Xiao-Jun; Marwick, Thomas H; McMullen, Julie R

    2018-04-20

    Informal training in preclinical research may be a contributor to the poor reproducibility of preclinical cardiology research and low rates of translation into clinical research and practice. Mouse echocardiography is a widely used technique to assess cardiac structure and function in drug intervention studies using disease models. The inter-observer variability (IOV) of clinical echocardiographic measurements has been shown to improve with formalized training, but preclinical echocardiography lacks similarly critical standardization of training. The aims of this investigation were to assess the IOV of echocardiographic measurements from studies in mice, and address any technical impediments to reproducibility by implementing standardized guidelines through formalized training. In this prospective, single-site, observational cohort study, 13 scientists performing preclinical echocardiographic image analysis were assessed for measurement of short-axis M-mode-derived dimensions and calculated left ventricular mass (LVMass). Ten M-mode images of mouse hearts acquired and analyzed by an expert researcher with a spectrum of LVMass were selected for assessment, and validated by autopsy weight. Following the initial observation, a structured formal training program was introduced, and accuracy and reproducibility were re-evaluated. Mean absolute percentage error (MAPE) for Expert-calculated LVMass was 6{plus minus}4% compared to autopsy LVMass, and 25{plus minus}21% for participants before training. Standardized formal training improved participant MAPE by approximately 30% relative to expert-calculated LVMass (p<0.001). Participants initially categorized with high-range error (25-45%) improved to low-moderate error ranges (<15-25%). This report reveals an example of technical skill training insufficiency likely endemic to preclinical research and provides validated guidelines for echocardiographic measurement for adaptation to formalized in-training programs.

  7. Abuse liability assessment of an e-cigarette refill liquid using intracranial self-stimulation and self-administration models in rats

    PubMed Central

    LeSage, MG; Staley, M; Muelken, P; Smethells, JR; Stepanov, I; Vogel, RI; Pentel, PR; Harris, AC

    2016-01-01

    Background The popularity of electronic cigarettes (ECs) has increased dramatically despite their unknown health consequences. Because the abuse liability of ECs is one of the leading concerns of the Food and Drug Administration (FDA), models to assess it are urgently needed to inform FDA regulatory decisions regarding these products. The purpose of this study was to assess the relative abuse liability of an EC liquid compared to nicotine alone in rats. Because this EC liquid contains non-nicotine constituents that may enhance its abuse liability, we hypothesized that it would have greater abuse liability than nicotine alone. Methods Nicotine alone and nicotine dose-equivalent concentrations of EC liquid were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, acquisition of self-administration, reinforcing efficacy (i.e., elasticity of demand), blockade of these behavioral effects by mecamylamine, nicotine pharmacokinetics and nicotinic acetylcholine receptor binding and activation. Results There were no significant differences between formulations on any measure, except that EC liquid produced less of an elevation in ICSS thresholds at high nicotine doses. Conclusions Collectively, these findings suggest that the relative abuse liability of this EC liquid is similar to that of nicotine alone in terms of its reinforcing and reinforcement-enhancing effects, but that it may have less aversive/anhedonic effects at high doses. The present methods may be useful for assessing the abuse liability of other ECs to inform potential FDA regulation of those products. PMID:27627814

  8. Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

    PubMed

    Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

    2016-05-01

    Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

  9. The case for introducing pre-registered confirmatory pharmacological pre-clinical studies.

    PubMed

    Kiwanuka, Olivia; Bellander, Bo-Michael; Hånell, Anders

    2018-05-01

    When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

  10. Child Sexual Abuse

    MedlinePlus

    ... No child is prepared to cope with repeated sexual stimulation. Even a two or three year old, who ... abuse. Some signs can only be detected on physical exam by a physician. Sexual abuse can also include noncontact abuse, such as ...

  11. Determining Possible Professionals and Respective Roles and Responsibilities for a Model Comprehensive Elder Abuse Intervention: A Delphi Consensus Survey.

    PubMed

    Du Mont, Janice; Kosa, Daisy; Macdonald, Sheila; Elliot, Shannon; Yaffe, Mark

    2015-01-01

    We have undertaken a multi-phase, multi-method program of research to develop, implement, and evaluate a comprehensive hospital-based nurse examiner elder abuse intervention that addresses the complex functional, social, forensic, and medical needs of older women and men. In this study, we determined the importance of possible participating professionals and respective roles and responsibilities within the intervention. Using a modified Delphi methodology, recommended professionals and their associated roles and responsibilities were generated from a systematic scoping review of relevant scholarly and grey literatures. These items were reviewed, new items added for review, and rated/re-rated for their importance to the intervention on a 5-point Likert scale by an expert panel during a one day in-person meeting. Items that did not achieve consensus were subsequently re-rated in an online survey. Those items that achieved a mean Likert rating of 4+ (rated important to very important), and an interquartile range<1 in the first or second round, and/or for which 80% of ratings were 4+ in the second round were retained for the model elder abuse intervention. Twenty-two of 31 recommended professionals and 192 of 229 recommended roles and responsibilities rated were retained for our model elder abuse intervention. Retained professionals were: public guardian and trustee (mean rating = 4.88), geriatrician (4.87), police officer (4.87), GEM (geriatric emergency management) nurse (4.80), GEM social worker (4.78), community health worker (4.76), social worker/counsellor (4.74), family physician in community (4.71), paramedic (4.65), financial worker (4.59), lawyer (4.59), pharmacist (4.59), emergency physician (4.57), geriatric psychiatrist (4.33), occupational therapist (4.29), family physician in hospital (4.28), Crown prosecutor (4.24), neuropsychologist (4.24), bioethicist (4.18), caregiver advocate (4.18), victim support worker (4.18), and respite care worker (4.12). A

  12. [Treatment program for dual-diagnosis substance abusers].

    PubMed

    Kandel, Isack

    2007-01-01

    Dual-diagnosis mentally ill patients, i.e. those characterized with substance abuse problems combined with mental health problems, are a challenge both for systems treating substance abusers and for mental health services. These patients are not easily integrated in either of these healthcare systems and/or are treated only for one aspect of their problem by each of these systems. For such patients it is necessary to create a separate treatment model, combining care of the problem of substance abuse and attention to the patient's mental pathology, according to his individual personality traits. For purposes of this programme a treatment setting operating on the model of a therapeutic community is proposed. This setting will open an affiliated treatment programme for dual-diagnosed patients in a separate treatment programme that is not part of the therapeutic community but will be affiliated with it and will accept dual-diagnosis patients.

  13. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    NASA Astrophysics Data System (ADS)

    di Clemente, Riccardo; Pietronero, Luciano

    2012-07-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  14. Assessment of Spectral Doppler in Preclinical Ultrasound Using a Small-Size Rotating Phantom

    PubMed Central

    Yang, Xin; Sun, Chao; Anderson, Tom; Moran, Carmel M.; Hadoke, Patrick W.F.; Gray, Gillian A.; Hoskins, Peter R.

    2013-01-01

    Preclinical ultrasound scanners are used to measure blood flow in small animals, but the potential errors in blood velocity measurements have not been quantified. This investigation rectifies this omission through the design and use of phantoms and evaluation of measurement errors for a preclinical ultrasound system (Vevo 770, Visualsonics, Toronto, ON, Canada). A ray model of geometric spectral broadening was used to predict velocity errors. A small-scale rotating phantom, made from tissue-mimicking material, was developed. True and Doppler-measured maximum velocities of the moving targets were compared over a range of angles from 10° to 80°. Results indicate that the maximum velocity was overestimated by up to 158% by spectral Doppler. There was good agreement (<10%) between theoretical velocity errors and measured errors for beam-target angles of 50°–80°. However, for angles of 10°–40°, the agreement was not as good (>50%). The phantom is capable of validating the performance of blood velocity measurement in preclinical ultrasound. PMID:23711503

  15. The complexities of elder abuse.

    PubMed

    Roberto, Karen A

    2016-01-01

    Elder abuse is a growing societal concern, affecting at least 1 in 10 older Americans. Researchers and practitioners alike consistently assert that a dramatic discrepancy exists between the prevalence rates of elder abuse and the number of elder abuse cases reported. As a field of study, recognition and understanding of elder abuse is still emerging. Comparing findings of a small, but growing, body of literature on perceived and substantiated cases of elder abuse is challenging because there is no uniform term or agreed-upon definition used among state governments, researchers, health care and service providers, and advocates. This article summarizes current understanding of elder abuse, including what constitutes elder abuse, risk factors for elder abuse, perpetrators of elder abuse, and outcomes of elder abuse. Issues associated with the detection of elder abuse and intervention strategies for victims of abuse are addressed. In the final section, potential roles and contributions of psychologists for advancing elder abuse research, professional practice, and policy development are highlighted. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  16. The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

    PubMed

    Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

    2015-12-29

    CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

  17. The effects of MDMA pretreatment on the behavioural effects of other drugs of abuse in the rat elevated plus-maze test.

    PubMed

    Sumnall, H R; O'Shea, E; Marsden, C A; Cole, J C

    2004-04-01

    Few preclinical studies have found long-term behavioural consequences of the serotonergic neurotoxicity produced by 3,4-methylenedioxymethamphetamine (MDMA). This study investigated whether pretreatment with MDMA altered the behavioural effects of other drugs of abuse. Adult male Lister hooded rats (n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle intraperitoneally every 2 h for 6 h. Fourteen days later, the behavioural effects of d-amphetamine (2 mg/kg), cocaine (10 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) were assessed in the elevated plus-maze test. MDMA pretreatment produced approximately 20-25% decrease in hippocampal 5-HT and 5-HIAA concentrations, and [(3)H]paroxetine binding when analysed 2 weeks later. Despite inducing neurotoxicity, this regimen had no effect upon the plus-maze behaviour induced by ethanol, heroin, and MDMA. Acutely, and independent of neurotoxic pretreatment, MDMA produced a clear anxiogenic-like behavioural profile with a reduction of open arm entries and suppression of explorative behaviours. Despite being acutely anxiogenic, pretreatment with a neurotoxic regimen of MDMA has little effect on the anxiety-related effects of other drugs of abuse. It is possible that extended time points would produce significant changes, although the available evidence suggests that the plus-maze may not be a suitable model for detection of behavioural dysfunction after neurotoxic MDMA.

  18. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE

    PubMed Central

    and, Kevin D. Deane; El-Gabalawy, Hani

    2014-01-01

    Established and emerging data demonstrate that a ‘preclinical’ period of disease precedes the onset of clinical rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as other autoimmune rheumatic diseases (ARDs).This preclinical stage of development of disease is characterized by abnormalities in disease-related biomarkers before the onset of the clinically apparent signs and symptoms. Numerous genetic and environmental risk factors for ARDs have also been identified, and many of these factors are likely to act before the clinical appearance of tissue injury to initiate and/or propagate autoimmunity and autoimmune disease. Thus, biomarkers representative of these autoimmune processes could potentially be used in conjunction with other clinical parameters during the preclinical period of ARDs to predict the future development of clinically apparent disease. This Review focuses on the preclinical stages of RA and SLE, as our current understanding of these diseases can be used to present an overall model of the development of ARDs that might ultimately be used to develop screening programmes and preventive strategies. Important considerations for the future development of such approaches, in particular, the issues that require additional research and how they might be addressed, are also discussed. PMID:24514912

  19. Child Abuse and Neglect: A Manual for the Pastoral Counselor.

    DTIC Science & Technology

    This manual was developed to help the pastor identify, evaluate, and counsel families experiencing child abuse situations. Precise data is presented...agencies involved in treating child abuse . The causal factors - parent, child, and environment are discussed. A practical viewpoint and analysis of the legal...ramifications of child abuse are presented. This manual presents a biblical bases for the counseling model which determine intervention strategies

  20. Child physical punishment, injury and abuse (part two).

    PubMed

    Watkins, Dianne; Cousins, Judy

    2005-09-01

    This is the second paper in a series of two that focus on causational factors that contribute to child physical punishment, injury and child physical abuse. Paper one concentrated on the extent of child physical punishment, injuries sustained and the relationship between macrotheoretical factors. It highlighted a continuum between child physical discipline, injuries and child physical abuse. Paper two introduces the reader to microtheoretical factors that contribute to child physical punishment and its relationship with child physical injuries and abuse. The focus is on parental and child influences, lifestyle factors and socialisation of parents. It will integrate macrotheroretical factors highlighted in paper one and microtheroretical factors presented in this paper into a framework for the prevention of child physical injury and abuse based on an ecological model.

  1. Drosophila: An Emergent Model for Delineating Interactions between the Circadian Clock and Drugs of Abuse

    PubMed Central

    De Nobrega, Aliza K.

    2017-01-01

    Endogenous circadian oscillators orchestrate rhythms at the cellular, physiological, and behavioral levels across species to coordinate activity, for example, sleep/wake cycles, metabolism, and learning and memory, with predictable environmental cycles. The 21st century has seen a dramatic rise in the incidence of circadian and sleep disorders with globalization, technological advances, and the use of personal electronics. The circadian clock modulates alcohol- and drug-induced behaviors with circadian misalignment contributing to increased substance use and abuse. Invertebrate models, such as Drosophila melanogaster, have proven invaluable for the identification of genetic and molecular mechanisms underlying highly conserved processes including the circadian clock, drug tolerance, and reward systems. In this review, we highlight the contributions of Drosophila as a model system for understanding the bidirectional interactions between the circadian system and the drugs of abuse, alcohol and cocaine, and illustrate the highly conserved nature of these interactions between Drosophila and mammalian systems. Research in Drosophila provides mechanistic insights into the corresponding behaviors in higher organisms and can be used as a guide for targeted inquiries in mammals. PMID:29391952

  2. Psychological abuse, substance abuse distress, dissatisfaction with friendships, and incident psychiatric problems.

    PubMed

    Sheikh, Mashhood Ahmed

    2018-05-01

    The aim of this study was to assess the mediating role of dissatisfaction with friendships in adulthood in the associations between psychological abuse in childhood, substance abuse distress in childhood, and incident psychiatric problems (IPPs) in adulthood over 13 years of follow-up. We used data collected from 1994 to 2008 within the framework of the Tromsø Study (N = 9502), a representative, longitudinal, prospective cohort study. Poisson regression analysis was used to assess the associations between psychological abuse, substance abuse distress, dissatisfaction with friendships in adulthood, and IPPs in adulthood. Indirect effects and proportion mediated (%) were assessed with the difference-in-coefficients method. Psychological abuse (relative risk [RR] = 1.66, 95% confidence interval [CI]: 1.45-1.89) and substance abuse distress in childhood (RR = 1.38, 95% CI: 1.18-1.62) were associated with an increased risk of dissatisfaction with friendships in adulthood. Dissatisfaction with friendships in adulthood was associated with an increased risk of IPPs in adulthood (RR = 1.71, 95% CI: 1.33-2.20). Moreover, dissatisfaction with friendships in adulthood mediated 9.31% (95% CI: 4.25-14.57) of the association between psychological abuse in childhood and IPPs in adulthood, and 9.17% (95% CI: 4.35-16.33) of the association between substance abuse distress in childhood and IPPs in adulthood. Dissatisfaction with friendships in adulthood mediates a minor proportion of the associations between psychological abuse, substance abuse distress, and IPPs in adulthood. Interventions aimed at decreasing dissatisfaction with friendships may dampen some of the effect of psychological abuse and substance abuse distress in childhood on IPPs in adulthood. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Considering sex as a biological variable in preclinical research.

    PubMed

    Miller, Leah R; Marks, Cheryl; Becker, Jill B; Hurn, Patricia D; Chen, Wei-Jung; Woodruff, Teresa; McCarthy, Margaret M; Sohrabji, Farida; Schiebinger, Londa; Wetherington, Cora Lee; Makris, Susan; Arnold, Arthur P; Einstein, Gillian; Miller, Virginia M; Sandberg, Kathryn; Maier, Susan; Cornelison, Terri L; Clayton, Janine A

    2017-01-01

    In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. © FASEB.

  4. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    PubMed Central

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  5. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

    PubMed Central

    Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

    2016-01-01

    Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

  6. Childhood Risk Factors for Alcohol Abuse and Psychological Distress among Adult Lesbians

    ERIC Educational Resources Information Center

    Hughes, Tonda L.; Johnson, Timothy P.; Wilsnack, Sharon C.; Szalacha, Laura A.

    2007-01-01

    Objective: This study examined the relationships between childhood and family background variables, including sexual and physical abuse, and subsequent alcohol abuse and psychological distress in adult lesbians. Methodology: Structural equation modeling was used to evaluate relationships between childhood sexual and physical abuse and parenting…

  7. A Model Intervention for Elder Abuse and Dementia.

    ERIC Educational Resources Information Center

    Anetzberger, Georgia J.; Palmisano, Barbara R.; Sanders, Margaret; Bass, David; Dayton, Carol; Eckert, Sharen; Schimer, Maria R.

    2000-01-01

    Describes a two-year collaborative project that improved the reporting and management of potential and suspected elder abuse situations involving persons with dementia. The educational curriculum and cross training program as well as the handbook for caregivers are discussed. Project organization, implementation, and evaluation are also discussed…

  8. Alienation and Domestic Abuse: How Abused Women Cope with Loneliness

    ERIC Educational Resources Information Center

    Arokach, Ami

    2006-01-01

    This study explored the manner in which abused women cope with loneliness. Eighty women, victims of domestic abuse, were compared to 84 women from the general population who have had no history of abusive relationships. A 34-item yes/no loneliness questionnaire was utilized in order to compare the "beneficial" ways of coping with loneliness in the…

  9. [Prevalence of sexual abuse in students and its relation with drug abuse].

    PubMed

    Ramos-Lira, L; Saldívar-Hernández, G; Medina-Mora, M E; Rojas-Guiot, E; Villatoro-Velázquez, J

    1998-01-01

    To determine the prevalence of sexual abuse among high school (secondary and preparatory) students, male and female, throughout Mexico, and its relationship with drug abuse. Data were obtained from the National Survey of Drug Use in Schools applied in November and December, 1991. A total of 61,779 students, 51.8% men and 47.1% women, with a mean age of 14.4 years completed the self-applied questionnaire. Sexual abuse was explored from the perspective of the abusers and of the victims. The prevalence of sexual abuse in adolescent victims was 4.3% and no statistically significant differences were found between sexes. The prevalence of sexual aggressors was 2.5%. Men coerced someone else in a higher proportion than women. Adolescent women experienced sexual abuse at a younger age than men and they also reported a higher percentage of intrafamily abuse. Men reported friends as the most frequent aggressors. Victims and aggressors of both sexes reported a significantly higher drug consumption than students without these antecedents. The differences in the experience of sexual abuse between men and women are described. In particular, the fact that sexual abuse in men mainly occurs outside the family sphere, while in women it is mainly within the family and at a younger age than in men. Additionally, the need for further research focusing on the consequences on mental health of infantile and adolescent sexual abuse and drug consumption is emphasized, considering the characteristics of each gender.

  10. Elder Abuse among African Americans

    ERIC Educational Resources Information Center

    Tauriac, Jesse J.; Scruggs, Natoschia

    2006-01-01

    Perceptions of extreme, moderate, and mild forms of elder abuse among African-American women (n=25) and men (n=10) were examined. African-American respondents emphasized physical abuse when giving examples of extremely abusive behavior. Along with physical abuse, verbal abuse was the most frequently identified form of abuse, and was significantly…

  11. Gene-environment interactions and construct validity in preclinical models of psychiatric disorders.

    PubMed

    Burrows, Emma L; McOmish, Caitlin E; Hannan, Anthony J

    2011-08-01

    The contributions of genetic risk factors to susceptibility for brain disorders are often so closely intertwined with environmental factors that studying genes in isolation cannot provide the full picture of pathogenesis. With recent advances in our understanding of psychiatric genetics and environmental modifiers we are now in a position to develop more accurate animal models of psychiatric disorders which exemplify the complex interaction of genes and environment. Here, we consider some of the insights that have emerged from studying the relationship between defined genetic alterations and environmental factors in rodent models. A key issue in such animal models is the optimization of construct validity, at both genetic and environmental levels. Standard housing of laboratory mice and rats generally includes ad libitum food access and limited opportunity for physical exercise, leading to metabolic dysfunction under control conditions, and thus reducing validity of animal models with respect to clinical populations. A related issue, of specific relevance to neuroscientists, is that most standard-housed rodents have limited opportunity for sensory and cognitive stimulation, which in turn provides reduced incentive for complex motor activity. Decades of research using environmental enrichment has demonstrated beneficial effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. One interpretation of such studies is that environmentally enriched animals more closely approximate average human levels of cognitive and sensorimotor stimulation, whereas the standard housing currently used in most laboratories models a more sedentary state of reduced mental and physical activity and abnormal stress levels. The use of such standard housing as a single environmental variable may limit the capacity for preclinical models to translate into successful clinical trials. Therefore, there is a need to

  12. Childhood sexual abuse and substance abuse treatment utilization among substance-dependent incarcerated women.

    PubMed

    Peltan, Jessica R; Cellucci, Tony

    2011-10-01

    Incarcerated women have high rates of substance abuse problems and trauma. A variety of variables may influence whether these women seek help or are referred for substance abuse problems. This study reports an exploratory project on service utilization among incarcerated substance-dependent women (N = 40) in southeastern Idaho. Using self-report and interview tools, most participants reported some substance abuse treatment history, although extent and types of treatment varied. Most of the women also reported some type of childhood abuse. Age, income, and consequences of alcohol and other drug use related positively to substance abuse treatment. However, severity of childhood sexual abuse and current trauma symptoms were negatively correlated with substance abuse treatment episodes. These women may use substances to cope with childhood trauma or may not perceive the substance abuse system as responsive to their co-occurring trauma symptoms. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. The neuropsychology of normal aging and preclinical Alzheimer's disease.

    PubMed

    Caselli, Richard J; Locke, Dona E C; Dueck, Amylou C; Knopman, David S; Woodruff, Bryan K; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S; Reiman, Eric M

    2014-01-01

    A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  14. Predictors of nurses' experience of verbal abuse by nurse colleagues.

    PubMed

    Keller, Ronald; Krainovich-Miller, Barbara; Budin, Wendy; Djukic, Maja

    Between 45% and 94% of registered nurses (RNs) experience verbal abuse, which is associated with physical and psychological harm. Although several studies examined predictors of RNs' verbal abuse, none examined predictors of RNs' experiences of verbal abuse by RN colleagues. To examine individual, workplace, dispositional, contextual, and interpersonal predictors of RNs' reported experiences of verbal abuse from RN colleagues. In this secondary analysis, a cross-sectional design with multiple linear regression analysis was used to examine the effect of 23 predictors on verbal abuse by RN colleagues in a sample of 1,208 early career RNs. Selected variables in the empirical intragroup conflict model explained 23.8% of variance in RNs' experiences of verbal abuse by RN colleagues. A number of previously unstudied factors were identified that organizational leaders can monitor and develop or modify policies to prevent early career RNs' experiences of verbal abuse by RN colleagues. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. An Aftercare Group Model for Adolescent Substance Abusers.

    ERIC Educational Resources Information Center

    Coleman, Sally

    1987-01-01

    Discusses what makes an aftercare group for adolescent substance abusers function productively and describes the format that seems to work best for young adolescents in an aftercare group. Emphasizes importance of group facilitator skills in areas of leadership, safety, and structure in helping adolescents gain re-identification as abstaining…

  16. Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs.

    PubMed

    Köster, Ursula; Nolte, Ingo; Michel, Martin C

    2016-02-01

    Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

  17. Individual differences in the behavioral effects of nicotine: A review of the preclinical animal literature

    PubMed Central

    Falco, Adriana M.; Bevins, Rick A.

    2015-01-01

    Not everyone who tries tobacco or other nicotine-containing products becomes a long-term user. Certain traits or factors that are differentially present in these individuals must be able to help health care providers and researchers determine who is more likely to become chronic users of nicotine-containing products. Some of these factors, particularly sensation-seeking/novelty, impulsivity, and anxiety, lend themselves to the creation of animal models of reactivity to nicotine. These models of reactivity to nicotine can improve the translational aspects of preclinical animal research on nicotine-induced behaviors and treatments in order to help reduce negative outcomes in human populations. The goal of this review is to evaluate the current status of animal models of individual differences that serve to predict the later behavioral effects of nicotine. The limited utility and inconsistency of existing novelty models is considered, as well as the promise of impulsivity and anxiety models in preclinical animal populations. Finally, other models that could be employed to extend the benefit of the current research are examined. PMID:26410616

  18. Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences.

    PubMed

    Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J; Granero, Luis; Polache, Ana; Zornoza, Teodoro

    2017-01-01

    Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism.

  19. Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences

    PubMed Central

    Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J.; Granero, Luis; Polache, Ana; Zornoza, Teodoro

    2017-01-01

    Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism. PMID:28326026

  20. Non-invasive, Contrast-enhanced Spectral Imaging of Breast Cancer Signatures in Preclinical Animal Models In vivo

    PubMed Central

    Ramanujan, V Krishnan; Ren, Songyang; Park, Sangyong; Farkas, Daniel L

    2011-01-01

    We report here a non-invasive multispectral imaging platform for monitoring spectral reflectance and fluorescence images from primary breast carcinoma and metastatic lymph nodes in preclinical rat model in vivo. The system is built around a monochromator light source and an acousto-optic tunable filter (AOTF) for spectral selection. Quantitative analysis of the measured reflectance profiles in the presence of a widely-used lymphazurin dye clearly demonstrates the capability of the proposed imaging platform to detect tumor-associated spectral signatures in the primary tumors as well as metastatic lymphatics. Tumor-associated changes in vascular oxygenation and interstitial fluid pressure are reasoned to be the physiological sources of the measured reflectance profiles. We also discuss the translational potential of our imaging platform in intra-operative clinical setting. PMID:21572915

  1. Exploring the controversy in child abuse pediatrics and false accusations of abuse.

    PubMed

    Gabaeff, Steven C

    2016-01-01

    There is a controversy in child abuse pediatrics between an established corps of child abuse pediatricians aligned with hospital colleagues and law enforcement, and a multi-specialty challenger group of doctors and other medical professionals working with public interest lawyers. The latter group questions the scientific validity of the core beliefs of child abuse pediatricians and believes that there are a substantial number of false accusations of abuse occurring. An unproven primary hypothesis, crafted around 1975 by a small group of pediatricians with an interest in child abuse, lies at the foundation of child abuse pediatrics. With no scientific study, it was hypothesized that subdural hemorrhage (SDH) and retinal hemorrhage (RH) were diagnostic of shaking abuse. That hypothesis became the so-called "shaken baby syndrome." Through the period 1975-1985, in a coordinated manner, these child abuse specialists coalesced under the American Academy of Pediatrics and began working with district attorneys and social workers, informing them of the ways in which their hypothesis could be applied to prosecutions of child abuse and life-altering social service interventions. In a legal context, using then-prevailing evidentiary rules which treated scientific expert testimony as valid if it was "generally accepted" in the field, they represented falsely that there was general acceptance of their hypothesis and therefore it was valid science. As the ability to convict based on this unproven prime hypothesis (SDH and RH equals abuse) increased, some defense attorneys were professionally compelled by their own doubts to reach out to experts from other fields with experience with SDH and RH, trauma, and biomechanics, for second opinions. Medical and legal challenges to the established thinking soon emerged, based on both old and new evidenced-based literature. As the intensity of the controversy increased, the probability of false accusation became more apparent and the need

  2. Elder physical abuse.

    PubMed

    Young, Lisa M

    2014-11-01

    Physical abuse of the elderly is a significant public health concern. The true prevalence of all types is unknown, and under-reporting is known to be significant. The geriatric population is projected to increase dramatically over the next 10 years, and the number of abused individuals is projected to increase also. It is critical that health care providers feel competent in addressing physical elder abuse. This article presents cases illustrating the variety of presenting symptoms that may be attributed to physical elder abuse. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Benefits attained from space flight in pre-clinical evaluation of candidate drugs

    NASA Astrophysics Data System (ADS)

    Stodieck, Louis S.; Bateman, Ted; Ayers, Reed; Ferguson, Virginia; Simske, Steve

    1998-01-01

    Modern medicine has made great strides in recent decades. The promises of biotechnology and advances in gene identification and manipulation offer tremendous potential for treatment of disease. However, developing new drug therapies by biotechnology and pharmaceutical companies is still a very costly and time consuming process. One of the important milestones in drug development is the successful completion of preclinical evaluation. During this phase, drug candidates must be shown to be safe, yet effective as a treatment of the target disease or disorder. Critical for preclinical testing is the availability of biomedical test models that adequately mimic the target disease. A good model will 1) allow confident prediction of a drug's effects before expensive clinical trials are begun, 2) provide convincing data for use in an FDA new drug application and 3) minimize the time required for testing. Space flight may offer a completely unique and new set of biomedical models for use in pharmaceutical testing. This paper highlights some examples of recent experiments done in space to test new compounds for Chiron, (Emmeryville, CA) and discusses the importance of the International Space Station to greatly expand such commercial opportunities.

  4. Associations between mental health, substance use, and sexual abuse experiences among Latinas.

    PubMed

    Ulibarri, Monica D; Ulloa, Emilio C; Salazar, Marissa

    2015-01-01

    This study examined self-reported sexually abusive experiences in childhood and adulthood as correlates of current drug use, alcohol abuse, and depression and posttraumatic stress disorder (PTSD) symptoms. Participants were 204 Latina women 18-34 years old. Results indicated significant relationships between history of sexual abuse (regardless of age of occurrence), depression symptoms, PTSD symptoms, alcohol abuse, and drug use. When examined separately, childhood sexual abuse was associated with symptoms of depression, PTSD, and substance use but not alcohol abuse behaviors. Experiencing sexual abuse in adulthood was associated with symptoms of depression, alcohol abuse behaviors, and substance use but not PTSD symptoms. Structural equation modeling showed that substance use partially mediated the relationship between sexual abuse and mental health outcomes. These findings suggest mental health and substance use services should incorporate treatment for trauma, which may be the root of comorbid mental health and substance use issues.

  5. Preclinical studies of alcohol binge drinking

    PubMed Central

    Crabbe, John C.; Harris, R. Adron; Koob, George F.

    2011-01-01

    Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID:21272009

  6. [Preclinical evaluation of the safety of biotechnology products: specific aspects].

    PubMed

    Descotes, Jacques; Ravel, Guillaume; Vial, Thierry

    2003-01-01

    Biotechnology-derived products represent a class of increasingly numerous drugs. One of their major characteristics is extreme diversity, which requires specific approaches for the preclinical evaluation of their safety. The selection of relevant animal species is not easy, as most of these products are human-specific. Thus, only one species will often be used, i.e. primates. As most of these products are large molecules, they can be directly immunogenic. When they are human-specific, no animal model is available to predict the risk. Many biotechnology-derived products have an expected influence on the immune system. This must be taken into account in the preclinical strategy of immunotoxicity evaluation that is now required for every new drug. As conventional toxicity testing is generally limited, safety pharmacology studies should include more than the core battery of assays required by current guidelines in order to complement missing data as much as possible. Because of these particularities, a comprehensive investigation of metabolism and pharmacokinetics is not usually needed. Some products can cross-react with cellular components not intended as therapeutic targets. It is, therefore, essential to rule out the risk of possible cross-reactions that can result in adverse effects. Finally, viral safety is a crucial component of the preclinical safety evaluation of these products. Overall, biotechnology-derived products raise specific issues because of their innovative and original characteristics, and it is difficult to address all these issues if not by using a case-by-case approach.

  7. Establishing "abuse-deterrence equivalence" for generic abuse-deterrent opioid formulations: A proposed development framework.

    PubMed

    Setnik, Beatrice; Cone, Edward J

    2016-01-01

    Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

  8. Measuring Economic Abuse in the Lives of Survivors: Revising the Scale of Economic Abuse.

    PubMed

    Postmus, Judy L; Plummer, Sara-Beth; Stylianou, Amanda M

    2016-05-01

    Recent attention has been given by researchers to understanding how abusers use economic abuse strategies. Unfortunately, limited measures are available to accurately understand the prevalence of economic abuse in the lives of survivors. Recently, researchers created the 28-item Scale of Economic Abuse (SEA) but further validation is needed. This article describes the psychometric evaluation of the SEA through confirmatory and exploratory factor analyses using data collected with 120 survivors of abuse. The findings provide evidence for the reliability and validity of the SEA-12 as a shorter instrument to measure economic abuse as a distinct form of abuse. © The Author(s) 2015.

  9. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

    PubMed

    Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

    2010-09-01

    Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

  10. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    PubMed Central

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  11. Parent Abuse: A Review

    ERIC Educational Resources Information Center

    Kennair, Nicola; Mellor, David

    2007-01-01

    A recent focus of research and clinical practice has been on the issue of abuse of parents by their children (parent abuse). This paper reviews the literature on this phenomenon. While parent abuse falls under the umbrella of family violence, it appears to be qualitatively different from other forms of intra-family abuse. Research has primarily…

  12. A Structural Equation Modeling of the Relationships between Depression, Drug Abuse and Social Support with Suicidal Ideation among Soldiers in Iran in 2015.

    PubMed

    Nosratabadi, Mehdi; Halvaiepour, Zohreh

    2016-01-01

    Military service is a crucial period in the lives of young people and during this period soldier facing with multiple psychosocial problems. The present study aimed to explore structural analysis of the relationships between depression, drug abuse, social support and the risk of suicidal ideation among Military Medical University soldiers in Iran. In the present correlational research, a sample of 176 soldiers, from three units, was selected using randomly stratified sampling. Data were collected through the Social Support Questionnaire (SSQ), the Beck Depression Inventory-II (BDI-II), the Beck Scale for Suicide Ideation (BSS) and the Possibility of Drug Abuse Scale (LDAS). Structural equation modeling was used to test the fit of the model, identify direct and indirect effects of the psychosocial correlates. Data were analyzed using the SPSS and AMOS software (Verson22). out of the whole subjects, 28.4% had suicidal ideation and 65.3% had degrees of depression (mild to severe). A significant reverse relationship was observed between social support and suicidal ideation (p<0.05). The strongest relationship was detected between drug abuse and suicidal ideation. The final structural model indicated that 74% of the variance in suicidal ideation was explained by the three examined variables of depression, social support and drug abuse. The overall results showed that the risk of suicidal ideation, depression and drug abuse are relatively significant in Military Medical University soldiers requiring taking serious actions by the authorities and other relevant organizations in order to improve the psychosocial health status of these soldiers.

  13. [A model of the effects of child sexual abuse on post-traumatic stress: the mediating role of attributions of blame and avoidance coping].

    PubMed

    Cantón-Cortés, David; Cantón, José; Justicia, Fernando; Cortés, María Rosario

    2011-02-01

    Employing structural equation modeling, the direct and indirect effects of the severity of Child Sexual Abuse (CSA), attributions of blame for the abuse, and coping strategies on Post-traumatic Stress Disorder (PTSD) symptomatology are analyzed. The effects of other types of child maltreatment on PTSD were also controlled. The sample comprised 163 female college students who were victims of CSA. The results suggested that victims of more severe abuse showed higher levels of avoidant coping, self blame, and family blame. Having suffered other kinds of abuse or neglect was also related to higher family blame attributions. Lastly, both attributions of blame scales were indirectly related to PTSD symptomatology through avoidant coping. The strong relationships between attributions of blame, coping strategies, and PTSD suggest that it might be useful to intervene early with children who have suffered CSA in an effort to modify the attributions they make about the abuse and the way they cope with it.

  14. Drug abuse prevention for high-risk African American children and their families: a review and model program.

    PubMed

    Van Hasselt, V B; Hersen, M; Null, J A; Ammerman, R T; Bukstein, O G; McGillivray, J; Hunter, A

    1993-01-01

    In this article we are specifically concerned with the familial and socioeconomic factors that contribute to the exceedingly high prevalence rates of drug abuse in African-American children. In addition to detailing the impact of drug abuse in African-American children and their families, we consider how this critical health problem can be prevented using existing knowledge and strategies known to mental health professionals. A model program entitled Project for a Substance Abuse-Free Environment (SAFE) is outlined. Its objectives are to implement: (a) a broad-spectrum family intervention to empower disadvantaged and high-risk families in their communities: (b) a competency-based skills intervention to increase resilience and decrease drug use and other maladaptive behaviors in at-risk children; (c) alternative activities that will promote self-efficacy, achievement, and self-esteem; (d) a culturally-relevant evaluation plan that includes both formative (process) and summative (outcome) evaluation; (e) a comprehensive approach for assessing project impact; (e) systematic procedures for enhancing the maintenance and generalization of gains in participating children and families.

  15. Animal models of addiction: fat and sugar.

    PubMed

    Morgan, Drake; Sizemore, Glen M

    2011-01-01

    The concept of "food addiction" is gaining acceptance among the scientific community, and much is known about the influence of various components of food (e.g. high-fat, sugar, carbohydrate, salt) on behavior and physiology. Most of the studies to date have studied these consequences following relatively long-term diet manipulations and/or relatively free access to the food of interest. It is suggested that these types of studies are primarily tapping into the energy regulation and homeostatic processes that govern food intake and consumption. More recently, the overlap between the neurobiology of "reward-related" or hedonic effects of food ingestion and other reinforcers such as drugs of abuse has been highlighted, contributing to the notion that "food addiction" exists and that various components of food may be the substance of abuse. Based on preclinical animal models of drug addiction, a new direction for this field is using self-administration procedures and identifying an addiction-like behavioral phenotype in animals following various environmental, genetic, pharmacological, and neurobiological manipulations. Here we provide examples from this research area, with a focus on fat and sugar self-administration, and how the sophisticated animal models of drug addiction can be used to study the determinants and consequences of food addiction.

  16. Alcohol Detoxification Completion, Acceptance of Referral to Substance Abuse Treatment, and Entry into Substance Abuse Treatment Among Alaska Native People

    PubMed Central

    Bear, Ursula Running; Beals, Janette; Novins, Douglas K.; Manson, Spero M.

    2016-01-01

    Background Little is known about factors associated with detoxification treatment completion and the transition to substance abuse treatment following detoxification among Alaska Native people. This study examined 3 critical points on the substance abuse continuum of care (alcohol detoxification completion, acceptance of referral to substance abuse treatment, entry into substance abuse treatment following detoxification). Methods The retrospective cohort included 383 adult Alaska Native patients admitted to a tribally owned and managed inpatient detoxification unit. Three multiple logistic regression models estimated the adjusted associations of each outcome separately with demographic/psychosocial characteristics, clinical characteristics, use related behaviors, and health care utilization. Results Seventy-five percent completed detoxification treatment. Higher global assessment functioning scores, longer lengths of stay, and older ages of first alcohol use were associated with completing detoxification. A secondary drug diagnosis was associated with not completing detoxification. Thirty-six percent accepted a referral to substance abuse treatment following detoxification. Men, those with legal problems, and those with a longer length of stay were more likely to accept a referral to substance abuse treatment. Fifty-eight percent had a confirmed entry into a substance abuse treatment program at discharge. Length of stay was the only variable associated with substance abuse treatment entry. Conclusions Services like motivational interviewing, counseling, development of therapeutic alliance, monetary incentives, and contingency management are effective in linking patients to services after detoxification. These should be considered, along with the factors associated with each point on the continuum of care when linking patients to follow-up services. PMID:27705843

  17. Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

    PubMed

    Arias, Jalayne J; Cummings, Jeffrey; Grant, Alexander Rae; Ford, Paul J

    2015-01-01

    Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

  18. Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

    PubMed

    Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

    2014-11-01

    Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. The Abuse-Related Beliefs Questionnaire for Survivors of Childhood Sexual Abuse

    ERIC Educational Resources Information Center

    Ginzburg, Karni; Arnow, Bruce; Hart, Stacey; Gardner, William; Koopman, Cheryl; Classen, Catherine C.; Giese-Davis, Janine; Spiegel, David

    2006-01-01

    Objective: To evaluate the psychometric properties of a new measure, the Abuse-Related Beliefs Questionnaire (ARBQ), designed to assess abuse-related beliefs among adult survivors of childhood sexual abuse (CSA). Study 1 examined the structure of the scale, and Study 2 evaluated its reliability and validity. Method: One hundred and seventy female…

  20. Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

    PubMed Central

    Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

    2017-01-01

    Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery

  1. Dissociation in victims of childhood abuse or neglect: a meta-analytic review.

    PubMed

    Vonderlin, Ruben; Kleindienst, Nikolaus; Alpers, Georg W; Bohus, Martin; Lyssenko, Lisa; Schmahl, Christian

    2018-04-10

    Childhood abuse and neglect are associated with dissociative symptoms in adulthood. However, empirical studies show heterogeneous results depending on the type of childhood abuse or neglect and other maltreatment characteristics. In this meta-analysis, we systematically investigated the relationship between childhood interpersonal maltreatment and dissociation in 65 studies with 7352 abused or neglected individuals using the Dissociative Experience Scale (DES). We extracted DES-scores for abused and non-abused populations as well as information about type of abuse/neglect, age of onset, duration of abuse, and relationship to the perpetrator. Random-effects models were used for data synthesis, and meta-regression was used to predict DES-scores in abused populations from maltreatment characteristics. The results revealed higher dissociation in victims of childhood abuse and neglect compared with non-abused or neglected subsamples sharing relevant population features (MAbuse = 23.5, MNeglect = 18.8, MControl = 13.8) with highest scores for sexual and physical abuse. An earlier age of onset, a longer duration of abuse, and parental abuse significantly predicted higher dissociation scores. This meta-analysis underlines the importance of childhood abuse/neglect in the etiology of dissociation. The identified moderators may inform risk assessment and early intervention to prevent the development of dissociative symptoms.

  2. Social Disadvantage, Severe Child Abuse, and Biological Profiles in Adulthood.

    PubMed

    Lee, Chioun; Coe, Christopher L; Ryff, Carol D

    2017-09-01

    Guided by the stress process model and the life course perspective, we hypothesize: (1) that childhood abuse is concentrated, in terms of type and intensity, among socially disadvantaged individuals, and (2) that experiencing serious abuse contributes to poor biological profiles in multiple body systems in adulthood. Data came from the Biomarker subsample of Midlife in the United States (2004-2006). We used latent class analysis to identify distinct profiles of childhood abuse, each reflecting a combination of type and severity. Results indicate that disadvantaged groups, women, and those from disadvantaged families are at greater risk of experiencing more severe and multiple types of abuse. Those with more severe and multifaceted childhood abuse show greater physiological dysregulation. Childhood abuse experiences partially accounted for the social status differences in physiological profiles. Our findings underscore that differential exposure to serious childhood stressors plays a significant role in gender and class inequalities in adult health.

  3. Perceptions of boundary ambiguity in the process of leaving an abusive partner.

    PubMed

    Khaw, Lyndal; Hardesty, Jennifer L

    2015-06-01

    The process of leaving an abusive partner has been theorized using the Stages of Change Model. Although useful, this model does not account for changes in relational boundaries unique to the process of leaving. Using family stress and feminist perspectives, this study sought to integrate boundary ambiguity into the Stages of Change Model. Boundary ambiguity is defined as a perception of uncertainty as to who is in or out of a family system (Boss & Greenberg, 1984). Twenty-five mothers who had temporarily or permanently left their abusers were interviewed. Data were analyzed using constructivist grounded theory methods. Results identify types, indicators of, and mothers' responses to boundary ambiguity throughout the five stages of change. Most mothers and abusers fluctuated between physical and psychological presence and absence over multiple separations. The integration of boundary ambiguity into the Stages of Change Model highlights the process of leaving an abusive partner as systemic, fluid, and nonlinear. © 2014 Family Process Institute.

  4. Neglected child with substance abuse leading to child abuse: a case report.

    PubMed

    Subramanian, E M G; Subhagya, B; Muthu, M S; Sivakumar, N

    2005-06-01

    Child abuse and neglect is any interaction or lack of interaction between a caregiver and a child resulting in nonaccidental harm to the child's physical and developmental state. Substance abuse is ingestion of any drug, which is capable of altering the mental functioning eventually leading to addiction. This paper presents a case report of a 12-year-old neglected girl with substance abuse for which she was physically abused by her mother.

  5. The neuropsychology of normal aging and preclinical Alzheimer’s disease

    PubMed Central

    Caselli, Richard J.; Locke, Dona E.C.; Dueck, Amylou C.; Knopman, David S.; Woodruff, Bryan K.; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S.; Reiman, Eric M.

    2013-01-01

    Background An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Methods 71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups. Results There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups. Conclusions While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design. PMID:23541188

  6. USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

    PubMed Central

    Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

    2014-01-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

  7. Ushering in the study and treatment of preclinical Alzheimer disease.

    PubMed

    Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

    2013-07-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

  8. The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

    PubMed

    Avey, Marc T; Moher, David; Sullivan, Katrina J; Fergusson, Dean; Griffin, Gilly; Grimshaw, Jeremy M; Hutton, Brian; Lalu, Manoj M; Macleod, Malcolm; Marshall, John; Mei, Shirley H J; Rudnicki, Michael; Stewart, Duncan J; Turgeon, Alexis F; McIntyre, Lauralyn

    2016-01-01

    Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs) as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments) reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47%) of all sub-items (median 51 items; range 37-64). Across all studies, the Methods Section reported less than half (45%) and the Results Section reported less than a third (29%). There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

  9. Potential mediators between child abuse and both violence and victimization in juvenile offenders.

    PubMed

    Day, David M; Hart, Trevor A; Wanklyn, Sonya G; McCay, Elizabeth; Macpherson, Alison; Burnier, Nathalie

    2013-02-01

    Juvenile offenders are at risk for involvement in both fighting behavior and peer victimization. Understanding the potential causal mechanisms leading to these outcomes is important to address the needs of this population. The present study tested four mediator models of violent perpetration and peer victimization in a sample of 112 incarcerated youth (68 males and 44 females). In the models, the relationship between child physical and emotional abuse and fighting and victimization was expected to be mediated by impulsiveness, depression, and drug use. Multiple mediator models were tested according to Preacher and Hayes (2008). Depression fully mediated the relation between child emotional abuse and victimization and partially mediated the relation between child physical abuse and victimization. Drug use fully mediated the relation between child emotional abuse and fighting. These results suggest that treatment of depressive symptoms and drug use among juvenile offenders with a history of child physical or emotional abuse may limit violent perpetration and peer victimization in this population.

  10. An Examination of the Partner Cyber Abuse Questionnaire in a College Student Sample.

    PubMed

    Wolford-Clevenger, Caitlin; Zapor, Heather; Brasfield, Hope; Febres, Jeniimarie; Elmquist, JoAnna; Brem, Meagan; Shorey, Ryan C; Stuart, Gregory L

    2016-01-01

    To examine the factor structure and convergent validity of a newly developed measure of an understudied form of partner abuse, cyber abuse, and to examine the prevalence of, and gender differences in, victimization by cyber abuse. College students in a dating relationship ( N = 502) completed the Partner Cyber Abuse Questionnaire (Hamby, 2013), as well as measures of partner abuse victimization and depression. Using exploratory factor analysis, we determined a one-factor solution was the most statistically and conceptually best fitting model. The cyber abuse victimization factor was correlated with depressive symptoms and physical, psychological, and sexual partner abuse victimization, supporting the convergent validity of the measure. The overall prevalence of victimization by cyber abuse was 40%, with victimization by specific acts ranging from 2-31%. Men and women did not differ in their victimization by cyber abuse. Cyber abuse is prevalent among college students and occurs concurrently with other partner abuse forms and depressive symptoms. Given the interrelated nature of partner abuse forms, prevention and intervention programs should address partner abuse occurring in-person and through technology. Cyber abuse should also be considered in the conceptualization and measurement of partner abuse to more fully understand this social problem.

  11. A mentorship-based preclinical elective increases exposure, confidence, and interest in surgery.

    PubMed

    Drolet, Brian C; Sangisetty, Suma; Mulvaney, Patrick M; Ryder, Beth A; Cioffi, William G

    2014-02-01

    The predicted shortage of surgeons is of growing concern with declining medical student interest in surgical careers. We hypothesized that earlier exposure to operative experiences and the establishment of resident mentors through a preclinical elective would enhance student confidence and interest in surgery. We developed a preclinical elective in surgery, which served as an organized curriculum for junior medical students to experience surgery through a paired resident-mentorship model. We assessed student exposure and confidence with clinical activities before and after the elective (N = 24, 100% response rate). We compared these students with a cohort of peers not enrolled in the elective (N = 147, 67% response rate). We found significantly improved confidence (2.8 vs 4.4) and clinical exposure (2.4 vs 4.3) before versus after the elective, with precourse scores equal to matched peers. This elective incorporates elements that have been shown to positively influence student decision making in surgical career choice. The mentorship model promotes residents as educators, whereas the elective provides a means for early identification of students interested in surgery. Published by Elsevier Inc.

  12. Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

    PubMed

    Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

    2017-11-01

    Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  13. Stress, Burnout and Coping Strategies in Preclinical Medical Students.

    PubMed

    Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

    2016-02-01

    It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

  14. Stress, Burnout and Coping Strategies in Preclinical Medical Students

    PubMed Central

    Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

    2016-01-01

    It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students’ stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted. PMID:27042604

  15. Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells

    PubMed Central

    Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F; Avril, Marie-Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry

    2012-01-01

    Xeroderma pigmentosum (XP) is a devastating disease associated with dramatic skin cancer proneness. XP cells are deficient in nucleotide excision repair (NER) of bulky DNA adducts including ultraviolet (UV)-induced mutagenic lesions. Approaches of corrective gene transfer in NER-deficient keratinocyte stem cells hold great hope for the long-term treatment of XP patients. To face this challenge, we developed a retrovirus-based strategy to safely transduce the wild-type XPC gene into clonogenic human primary XP-C keratinocytes. De novo expression of XPC was maintained in both mass population and derived independent candidate stem cells (holoclones) after more than 130 population doublings (PD) in culture upon serial propagation (>1040 cells). Analyses of retrovirus integration sequences in isolated keratinocyte stem cells suggested the absence of adverse effects such as oncogenic activation or clonal expansion. Furthermore, corrected XP-C keratinocytes exhibited full NER capacity as well as normal features of epidermal differentiation in both organotypic skin cultures and in a preclinical murine model of human skin regeneration in vivo. The achievement of a long-term genetic correction of XP-C epidermal stem cells constitutes the first preclinical model of ex vivo gene therapy for XP-C patients. PMID:22068429

  16. Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents

    PubMed Central

    German-Ponciano, León Jesús; Rosas-Sánchez, Gilberto Uriel; Rivadeneyra-Domínguez, Eduardo

    2018-01-01

    Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, and γ-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans. PMID:29623232

  17. The prevalence and consequences of burnout on a group of preclinical dental students.

    PubMed

    Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

    2015-01-01

    The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment.

  18. See no evil, hear no evil, speak no evil: why do relatively few male victims of childhood sexual abuse receive help for abuse-related issues in adulthood?

    PubMed

    Holmes, G R; Offen, L; Waller, G

    1997-01-01

    This literature review explores the reasons why comparatively few adult males with a history of childhood sexual abuse are seen by professionals for help with difficulties relating to that abuse. Two potential explanations are discounted as myths-that relatively few males are sexually abused, and that abuse has little effect on males. However, it is suggested that society (including professionals and the victims themselves) has given credence to these myths. Male victims are relatively unlikely to disclose their experience of childhood abuse, and (as a coping strategy) they deny the impact of sexual abuse on their lives. Professionals fail to hypothesise that their male clients may have been abused, and do not create the conditions that would enable males to talk about the abuse. Blumer's (1971) model of the social construction of problems is applied to account for these beliefs and behaviours on the part of victims and clinicians. It is argued that the childhood sexual abuse of males has not yet acquired legitimacy as a problem recognised by society, thus lagging behind the abuse of females. In short, the "evil' of childhood sexual abuse in the male population is not being seen or heard by clinicians, and is not being recognised or talked about by victims. Clinical implications are considered.

  19. Global Prevalence of Elder Abuse: A Meta-analysis and Meta-regression.

    PubMed

    Ho, C Sh; Wong, S Y; Chiu, M M; Ho, R Cm

    2017-06-01

    Elder abuse is increasingly recognised as a global public health and social problem. There has been limited inter-study comparison of the prevalence and risk factors for elder abuse. This study aimed to estimate the pooled and subtype prevalence of elder abuse worldwide and identify significant associated risk factors. We conducted a meta-analysis and meta-regression of 34 population-based and 17 non-population-based studies. The pooled prevalences of elder abuse were 10.0% (95% confidence interval, 5.2%-18.6%) and 34.3% (95% confidence interval, 22.9%-47.8%) in population-based studies and third party- or caregiver-reported studies, respectively. Being in a marital relationship was found to be a significant moderator using random-effects model. This meta-analysis revealed that third parties or caregivers were more likely to report abuse than older abused adults. Subgroup analyses showed that females and those resident in non-western countries were more likely to be abused. Emotional abuse was the most prevalent elder abuse subtype and financial abuse was less commonly reported by third parties or caregivers. Heterogeneity in the prevalence was due to the high proportion of married older adults in the sample. Subgroup analysis showed that cultural factors, subtypes of abuse, and gender also contributed to heterogeneity in the pooled prevalence of elder abuse.

  20. Domestic violence and abuse: an exploration and evaluation of a domestic abuse nurse specialist role in acute health care services.

    PubMed

    McGarry, Julie

    2017-08-01

    The aim of this study was to explore the experiences of clinical staff in responding to disclosure of domestic violence and abuse, and to evaluate the effectiveness of training and support provided by a dedicated Domestic Abuse Nurse Specialist across one acute National Health Service Trust in the UK. The impact of domestic violence and abuse is well documented and is far reaching. Health care professionals have a key role to play in the effective identification and management of abuse across a range of settings. However, there is a paucity of evidence regarding the constituents of effective support for practitioners within wider nonemergency hospital-based services. A qualitative approach semi-structured interviews (n = 11) with clinical staff based in one acute care Trust in the UK. Interviews were informed by an interview guide and analysed using the Framework approach. The organisation of the nurse specialist role facilitated a more cohesive approach to management at an organisational level with training and ongoing support identified as key facets of the role by practitioners. Time constraints were apparent in terms of staff training and this raises questions with regard to the status continuing professional development around domestic violence and abuse. Domestic violence and abuse continues to exert a significant and detrimental impact on the lives and health of those who encounter abuse. Health care services in the UK and globally are increasingly on the frontline in terms of identification and management of domestic violence and abuse. This is coupled with the growing recognition of the need for adequate support structures to be in place to facilitate practitioners in providing effective care for survivors of domestic violence and abuse. This study provides an approach to the expansion of existing models and one which has the potential for further exploration and application in similar settings. © 2016 John Wiley & Sons Ltd.

  1. Determining Possible Professionals and Respective Roles and Responsibilities for a Model Comprehensive Elder Abuse Intervention: A Delphi Consensus Survey

    PubMed Central

    Du Mont, Janice; Kosa, Daisy; Macdonald, Sheila; Elliot, Shannon; Yaffe, Mark

    2015-01-01

    Objective We have undertaken a multi-phase, multi-method program of research to develop, implement, and evaluate a comprehensive hospital-based nurse examiner elder abuse intervention that addresses the complex functional, social, forensic, and medical needs of older women and men. In this study, we determined the importance of possible participating professionals and respective roles and responsibilities within the intervention. Methods Using a modified Delphi methodology, recommended professionals and their associated roles and responsibilities were generated from a systematic scoping review of relevant scholarly and grey literatures. These items were reviewed, new items added for review, and rated/re-rated for their importance to the intervention on a 5-point Likert scale by an expert panel during a one day in-person meeting. Items that did not achieve consensus were subsequently re-rated in an online survey. Analysis Those items that achieved a mean Likert rating of 4+ (rated important to very important), and an interquartile range<1 in the first or second round, and/or for which 80% of ratings were 4+ in the second round were retained for the model elder abuse intervention. Results Twenty-two of 31 recommended professionals and 192 of 229 recommended roles and responsibilities rated were retained for our model elder abuse intervention. Retained professionals were: public guardian and trustee (mean rating = 4.88), geriatrician (4.87), police officer (4.87), GEM (geriatric emergency management) nurse (4.80), GEM social worker (4.78), community health worker (4.76), social worker/counsellor (4.74), family physician in community (4.71), paramedic (4.65), financial worker (4.59), lawyer (4.59), pharmacist (4.59), emergency physician (4.57), geriatric psychiatrist (4.33), occupational therapist (4.29), family physician in hospital (4.28), Crown prosecutor (4.24), neuropsychologist (4.24), bioethicist (4.18), caregiver advocate (4.18), victim support worker (4

  2. Childhood abuse, personality traits, and depressive symptoms in adulthood.

    PubMed

    Lee, Min-Ah; Song, Rira

    2017-03-01

    This study examined associations among childhood abuse, personality traits, and depressive symptoms in adulthood, and whether and how the effects of childhood abuse on depressive symptoms are mediated by the Big Five personality traits (i.e., extraversion, conscientiousness, emotional stability, agreeableness, and openness). The data were drawn from the 2012 Korean General Social Survey, a nationally representative survey using a multistage area proportional probability sampling method. Random effects regression and the Sobel test were used. Random effects models showed that physical and emotional abuse in childhood significantly increased depressive symptoms in adulthood, even after controlling for personality traits and socio-demographic factors. The coefficients of childhood abuse slightly decreased when personality traits were controlled, suggesting that personality traits mediated the relationship between childhood abuse and depressive symptoms. Among the personality traits, extraversion and emotional stability were negatively associated with depressive symptoms whereas agreeableness was positively associated with depressive symptoms. The results of the Sobel test showed that only emotional stability significantly mediated the effects of childhood abuse on depressive symptoms. Those who were exposed to childhood abuse had lower levels of emotional stability, which, in turn, led to depressive symptoms in adulthood. The findings suggest that childhood abuse may have a long lasting effect on mental health over the life course by influencing the formation of personality traits through developmental periods. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. 68Ga-DOTATOC and FDG PET Imaging of Preclinical Neuroblastoma Models.

    PubMed

    Provost, Claire; Prignon, Aurélie; Cazes, Alex; Combaret, Valérie; Delattre, Olivier; Janoueix-Lerosey, Isabelle; Montravers, Françoise; Talbot, Jean-Noël

    2016-09-01

    Somatostatine receptors subtype 2 (SSTR2) are regarded as a potential target in neuroblastoma (NB) for imaging and promising therapeutic approaches. The purpose of this study was to evaluate and compare the SSTR2 status by (68)Ga-[tetraxetan-D-Phe1, Tyr3]-octreotide ((68)Ga-DOTATOC) positron-emission tomography (PET) and the tumour metabolic activity by (18)F-fluorodeoxyglucose (FDG) PET in different experimental models of NB. Three cell lines of human NB with different levels of expression of SSTR2 were grafted into nude mice. Animals were imaged with FDG and (68)Ga-DOTATOC and the maximum standardized uptake value (SUVmax) was determined to quantify tracer uptake. Ex vivo biodistribution of (68)Ga-DOTATOC and immunohistochemical analysis of NB xenografts were performed. Compared with FDG, the SUVmax of (68)Ga-DOTATOC uptake by the tumour was lower but the ratio to background was higher; there was a strong positive correlation between SUVmax values observed with the two tracers (r(2)=0.65). Sorting the cell lines according to uptake of FDG or (68)Ga-DOTATOC, injected activity per gram of tissue, Ki67 index or expression of SSTR2 assessed visually led to the same classification. (68)Ga-DOTATOC allows preclinical imaging of NB according to the intensity of the expression of SSTR2. In contrast with what has been reported for neuroendocrine tumours, in this NB model, the (68)Ga-DOTATOC uptake was positively correlated with FDG uptake and with Ki67 index, usual markers of tumour aggressiveness. If confirmed in humans, this result would favour a theranostic application of (68)Ga-DOTATOC in NB, even in advanced stages. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  4. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

    DTIC Science & Technology

    2014-11-01

    LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 39 19b. TELEPHONE...for this mouse cohort was included in Figure 1. Out of 23 GFAP tv- a; p53 floxed mice infected with RCAS-PDGF-B and RCAS-Cre, 18 developed...being used as part of the DIPG preclinical consortium (together with several laboratories that are using human DIPG xenografts ) to help prioritize

  5. Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts

    PubMed Central

    George, Steven Z.; Wallace, Margaret R.; Wu, Samuel S.; Moser, Michael W.; Wright, Thomas W.; Farmer, Kevin W.; Borsa, Paul A.; Parr, Jeffrey J.; Greenfield, Warren H.; Dai, Yunfeng; Li, Hua; Fillingim, Roger B.

    2016-01-01

    Tailored treatment based on individual risk factors is an area with promise to improve options for pain relief. Musculoskeletal pain has a biopsychosocial nature, and multiple factors should be considered when determining risk for chronic pain. This study investigated whether subgroups comprised genetic and psychological factors predicted outcomes in preclinical and clinical models of shoulder pain. Classification and regression tree analysis was performed for an exercise-induced shoulder injury cohort (n = 190) to identify high-risk subgroups, and a surgical pain cohort (n = 150) was used for risk validation. Questionnaires for fear of pain and pain catastrophizing were administered before injury and preoperatively. DNA collected from saliva was genotyped for a priori selected genes involved with pain modulation (COMT and AVPR1A) and inflammation (IL1B and TNF/LTA). Recovery was operationalized as a brief pain inventory rating of 0/10 for current pain intensity and <2/10 for worst pain intensity. Follow-up for the preclinical cohort was in daily increments, whereas follow-up for the clinical cohort was at 3, 6, and 12 months postoperatively. Risk subgroups comprised the COMT high pain sensitivity variant and either pain catastrophizing or fear of pain were predictive of heightened shoulder pain responses in the preclinical model. Further analysis in the clinical model identified the COMT high pain sensitivity variant and pain catastrophizing subgroup as the better predictor. Future studies will determine whether these findings can be replicated in other anatomical regions and whether personalized medicine strategies can be developed for this risk subgroup. PMID:25599310

  6. Contextual Effects on Kindergarten Teachers' Intention to Report Child Abuse

    ERIC Educational Resources Information Center

    Feng, Jui-Ying; Wu, Yow-Wu B.; Fetzer, Susan; Chang, Hsin-Yi

    2012-01-01

    Child abuse is underreported for children with socioeconomic inequalities. The impact of geographic location combined with sociocultural characteristics on teachers' reports of child abuse remains unclear. A national survey of 572 kindergarten teachers from 79 schools in Taiwan used hierarchical linear modeling to investigate the contribution of…

  7. Characterization of novel preclinical dose distributions for micro irradiator

    NASA Astrophysics Data System (ADS)

    Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

    2017-05-01

    This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

  8. Deterred drug abuse using superabsorbent polymers.

    PubMed

    Mastropietro, David J; Muppalaneni, Srinath; Omidian, Hossein

    2016-11-01

    This study aimed to determine whether selected superabsorbent polymers (SAPs) could be used as a suitable alternative to thwart extraction, filtration, and syringeability attempts for abuse. Many abuse-deterrent formulations (ADFs) rely on high molecular weight polymers such as poly(ethylene oxide) to provide crush and extraction resistance. However, these polymers suffer from slow dissolution kinetics, and are susceptible to a variety of abuse conditions. Several commercially available SAPs were evaluated for swelling behavior in extraction solvents, and tableting properties. Post-compaction abuse properties were evaluated by recoverable volume and syringeability after solvent extraction. Drug release and percent drug extraction were conducted using tramadol HCl as a model drug. Certain SAPs had the ability to rapidly imbibe solvent and effectively stop extraction processes in a variety of solvents, including water and water/alcohol mixtures. Tablets containing SAP and drug showed no effect on drug release in vitro. SAPs possess adequate properties for tableting, and maintain their high and fast swelling properties after compaction. The fast and extensive interactions of SAPs with aqueous medium are a major advantage over non-crosslinked high molecular weight viscosifying agents such as poly(ethylene oxide).

  9. Beyond the individual victim: multilevel consequences of abusive supervision in teams.

    PubMed

    Farh, Crystal I C; Chen, Zhijun

    2014-11-01

    We conceptualize a multilevel framework that examines the manifestation of abusive supervision in team settings and its implications for the team and individual members. Drawing on Hackman's (1992) typology of ambient and discretionary team stimuli, our model features team-level abusive supervision (the average level of abuse reported by team members) and individual-level abusive supervision as simultaneous and interacting forces. We further draw on team-relevant theories of social influence to delineate two proximal outcomes of abuse-members' organization-based self-esteem (OBSE) at the individual level and relationship conflict at the team level-that channel the independent and interactive effects of individual- and team-level abuse onto team members' voice, team-role performance, and turnover intentions. Results from a field study and a scenario study provided support for these multilevel pathways. We conclude that abusive supervision in team settings holds toxic consequences for the team and individual, and offer practical implications as well as suggestions for future research on abusive supervision as a multilevel phenomenon. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  10. Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.

    PubMed

    Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; Deweese, Theodore L; Herman, Joseph M

    2012-04-01

    We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.

  11. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

    PubMed Central

    Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

    2017-01-01

    Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana”) in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance. PMID:28469427

  12. Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

    PubMed

    Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

    2017-01-01

    Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

  13. Pathways to PTSD, Part II: Sexually Abused Children

    PubMed Central

    Kaplow, Julie B.; Dodge, Kenneth A.; Amaya-Jackson, Lisa; Saxe, Glenn N.

    2009-01-01

    Objective The goal of this research was to develop and test a prospective model of posttraumatic stress symptoms in sexually abused children that includes pretrauma, trauma, and disclosure-related pathways. Method At time 1, several measures were used to assess pretrauma variables, trauma variables, and stress reactions upon disclosure for 156 sexually abused children ages 8 to 13 years. At the time 2 follow-up (7 to 36 months following the initial interview), the children were assessed for posttraumatic stress disorder (PTSD) symptoms. Results A path analysis involving a series of hierarchically nested ordinary least squares multiple regression analyses indicated three direct paths to PTSD symptoms: avoidant coping, anxiety/arousal, and dissociation, all measured during or immediately after disclosure of sexual abuse. Additionally, age and gender predicted avoidant coping, while life stress and age at abuse onset predicted symptoms of anxiety/arousal. Taken together, these pathways accounted for approximately 57% of the variance in PTSD symptoms. Conclusions Symptoms measured at the time of disclosure constitute direct, independent pathways by which sexually abused children are likely to develop later PTSD symptoms. These findings speak to the importance of assessing children during the disclosure of abuse in order to identify those at greatest risk for later PTSD symptoms. PMID:15994713

  14. Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

    PubMed Central

    Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

    2014-01-01

    Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 108, 2 × 109 and 2 × 1010 colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 109 CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 1010 CFU). The challenge dose, 2 × 1010 CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. PMID:24028276

  15. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis.

    PubMed

    Norman, Rosana E; Byambaa, Munkhtsetseg; De, Rumna; Butchart, Alexander; Scott, James; Vos, Theo

    2012-01-01

    Child sexual abuse is considered a modifiable risk factor for mental disorders across the life course. However the long-term consequences of other forms of child maltreatment have not yet been systematically examined. The aim of this study was to summarise the evidence relating to the possible relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes. A systematic review was conducted using the Medline, EMBASE, and PsycINFO electronic databases up to 26 June 2012. Published cohort, cross-sectional, and case-control studies that examined non-sexual child maltreatment as a risk factor for loss of health were included. All meta-analyses were based on quality-effects models. Out of 285 articles assessed for eligibility, 124 studies satisfied the pre-determined inclusion criteria for meta-analysis. Statistically significant associations were observed between physical abuse, emotional abuse, and neglect and depressive disorders (physical abuse [odds ratio (OR) = 1.54; 95% CI 1.16-2.04], emotional abuse [OR = 3.06; 95% CI 2.43-3.85], and neglect [OR = 2.11; 95% CI 1.61-2.77]); drug use (physical abuse [OR = 1.92; 95% CI 1.67-2.20], emotional abuse [OR = 1.41; 95% CI 1.11-1.79], and neglect [OR = 1.36; 95% CI 1.21-1.54]); suicide attempts (physical abuse [OR = 3.40; 95% CI 2.17-5.32], emotional abuse [OR = 3.37; 95% CI 2.44-4.67], and neglect [OR = 1.95; 95% CI 1.13-3.37]); and sexually transmitted infections and risky sexual behaviour (physical abuse [OR = 1.78; 95% CI 1.50-2.10], emotional abuse [OR = 1.75; 95% CI 1.49-2.04], and neglect [OR = 1.57; 95% CI 1.39-1.78]). Evidence for causality was assessed using Bradford Hill criteria. While suggestive evidence exists for a relationship between maltreatment and chronic diseases and lifestyle risk factors, more research is required to confirm these relationships. This overview of the evidence suggests a causal relationship between non-sexual child

  16. A Model Linking Diverse Women's Child Sexual Abuse History with Sexual Risk Taking

    ERIC Educational Resources Information Center

    Watson, Laurel B.; Matheny, Kenneth B.; Gagne, Phill; Brack, Greg; Ancis, Julie R.

    2013-01-01

    The purpose of our study was to examine the role that child sexual abuse may play in body surveillance and sexual risk behaviors among undergraduate women. First, a measured variable path analysis was conducted, which assessed the relations among a history of child sexual abuse, body surveillance, and sexual risk behaviors. Furthermore, body…

  17. Fetal Abuse.

    ERIC Educational Resources Information Center

    Kent, Lindsey; And Others

    1997-01-01

    Five cases of fetal abuse by mothers suffering from depression are discussed. Four of the women had unplanned pregnancies and had considered termination of the pregnancy. Other factors associated with fetal abuse include pregnancy denial, pregnancy ambivalence, previous postpartum depression, and difficulties in relationships. Vigilance for…

  18. Dextromethorphan Abuse in Adolescence

    PubMed Central

    Bryner, Jodi K.; Wang, Uerica K.; Hui, Jenny W.; Bedodo, Merilin; MacDougall, Conan; Anderson, Ilene B.

    2008-01-01

    Objectives To analyze the trend of dextromethorphan abuse in California and to compare these findings with national trends. Design A 6-year retrospective review. Setting California Poison Control System (CPCS), American Association of Poison Control Centers (AAPCC), and Drug Abuse Warning Network (DAWN) databases from January 1, 1999, to December 31, 2004. Participants All dextromethorphan abuse cases reported to the CPCS, AAPCC, and DAWN. The main exposures of dextromethorphan abuse cases included date of exposure, age, acute vs long-term use, coingestants, product formulation, and clinical outcome. Main Outcome Measure The annual proportion of dextromethorphan abuse cases among all exposures reported to the CPCS, AAPCC, and DAWN databases. Results A total of 1382 CPCS cases were included in the study. A 10-fold increase in CPCS dextromethorphan abuse cases from 1999 (0.23 cases per 1000 calls) to 2004 (2.15 cases per 1000 calls) (odds ratio, 1.48; 95% confidence interval, 1.43–1.54) was identified. Of all CPCS dextromethorphan abuse cases, 74.5% were aged 9 to 17 years; the frequency of cases among this age group increased more than 15-fold during the study (from 0.11 to 1.68 cases per 1000 calls). Similar trends were seen in the AAPCC and DAWN databases. The highest frequency of dextromethorphan abuse occurred among adolescents aged 15 and 16 years. The most commonly abused product was Coricidin HBP Cough & Cold Tablets. Conclusions Our study revealed an increasing trend of dextromethorphan abuse cases reported to the CPCS that is paralleled nationally as reported to the AAPCC and DAWN. This increase was most evident in the adolescent population. PMID:17146018

  19. Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

    PubMed

    Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie

    2016-09-21

    We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

  20. Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics.

    PubMed

    Schaeffer, Tammi

    2012-12-01

    The increased use of opioid pain medication has been mirrored by the increased misuse and abuse of these drugs. As part of a multidisciplinary approach to this epidemic, pharmaceutical companies, with the encouragement of the Food and Drug Administration, have increased the development of abuse-deterrent formulations. While all have the goal of treating pain while mitigating misuse and abuse, there are different technologies utilized to impart the abuse-deterrent properties. The goal of this paper is to review the basis of abuse-deterrent formulations, the different types and approaches of some of the abuse-deterrent products, and their current regulatory status in the USA.

  1. Are fashion models a group at risk for eating disorders and substance abuse?

    PubMed

    Santonastaso, Paolo; Mondini, Silvia; Favaro, Angela

    2002-01-01

    Few studies to date have investigated whether in fact the prevalence of eating disorders (ED) and/or use of illicit drugs is higher among models than among other groups of females. A group of 63 professional fashion models of various nationalities were studied by means of self-reported questionnaires. They were compared with a control group of 126 female subjects recruited from the general population. Fashion models weigh significantly less than controls, but only a small percentage of them uses unhealthy methods to control their weight. The current frequency of full-syndrome ED did not differ between the groups, but partial-syndrome ED were significantly more common among fashion models than among controls. Current substance use or alcohol abuse was reported by 35% of fashion models and 12% of controls. Our findings suggest that fashion models are more at risk for partial ED and use of illicit drugs than females in the general population. Copyright 2002 S. Karger AG, Basel

  2. Growing up with Parental Alcohol Abuse: Exposure to Childhood Abuse, Neglect, and Household Dysfunction.

    ERIC Educational Resources Information Center

    Dube, Shanta R.; Anda, Robert F.; Felitti, Vincent J.; Croft, Janet B.; Edwards, Valerie J.; Giles, Wayne H.

    2001-01-01

    A study involving 8,629 adults examined the association between parental alcohol abuse and child abuse, neglect, and other household dysfunction. Compared to households without alcohol abuse, the adjusted odds ratio for each category of adverse childhood experience was 2 to 13 times higher if parents abused alcohol. (Contains references.) (CR)

  3. Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.

    PubMed

    Xu, Chunxiao; Zhang, Yanping; Rolfe, P Alexander; Hernández, Vivian M; Guzman, Wilson; Kradjian, Giorgio; Marelli, Bo; Qin, Guozhong; Qi, Jin; Wang, Hong; Yu, Huakui; Tighe, Robert; Lo, Kin-Ming; English, Jessie M; Radvanyi, Laszlo; Lan, Yan

    2017-10-01

    Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies. Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt - mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8 + T cells was evaluated by ELISpot assay. Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8 + T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8 + T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy. Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. Childhood Sexual Abuse and Age at Initiation of Injection Drug Use

    PubMed Central

    Ompad, Danielle C.; Ikeda, Robin M.; Shah, Nina; Fuller, Crystal M.; Bailey, Susan; Morse, Edward; Kerndt, Peter; Maslow, Carey; Wu, Yingfeng; Vlahov, David; Garfein, Richard; Strathdee, Steffanie A.

    2005-01-01

    Objectives. We examined the relation between childhood sexual abuse and injection drug use initiation among young adult injection drug users. Methods. We used mixed effect linear models to compare age at first injection among 2143 young injection drug users by first sexual abuse age categories. Results. The participants were predominantly male (63.3%) and White (52.8%). Mean age and age at first injection were 23.7 and 19.6 years, respectively; 307 participants (14.3%) reported childhood sexual abuse. After adjustment for gender, race/ethnicity, noninjection drug use before first injection drug use, and recruitment site, childhood sexual abuse was independently associated with younger age at first injection. Conclusions. Childhood sexual abuse was associated with earlier initiation of injection drug use. These data emphasize the need to integrate substance abuse prevention with postvictimization services for children and adolescents. PMID:15798133

  5. An Examination of the Partner Cyber Abuse Questionnaire in a College Student Sample

    PubMed Central

    Wolford-Clevenger, Caitlin; Zapor, Heather; Brasfield, Hope; Febres, Jeniimarie; Elmquist, JoAnna; Brem, Meagan; Shorey, Ryan C.; Stuart, Gregory L.

    2015-01-01

    Objective To examine the factor structure and convergent validity of a newly developed measure of an understudied form of partner abuse, cyber abuse, and to examine the prevalence of, and gender differences in, victimization by cyber abuse. Method College students in a dating relationship (N = 502) completed the Partner Cyber Abuse Questionnaire (Hamby, 2013), as well as measures of partner abuse victimization and depression. Results Using exploratory factor analysis, we determined a one-factor solution was the most statistically and conceptually best fitting model. The cyber abuse victimization factor was correlated with depressive symptoms and physical, psychological, and sexual partner abuse victimization, supporting the convergent validity of the measure. The overall prevalence of victimization by cyber abuse was 40%, with victimization by specific acts ranging from 2–31%. Men and women did not differ in their victimization by cyber abuse. Conclusions Cyber abuse is prevalent among college students and occurs concurrently with other partner abuse forms and depressive symptoms. Given the interrelated nature of partner abuse forms, prevention and intervention programs should address partner abuse occurring in-person and through technology. Cyber abuse should also be considered in the conceptualization and measurement of partner abuse to more fully understand this social problem. PMID:27014498

  6. Inhalant Abuse and Dextromethorphan.

    PubMed

    Storck, Michael; Black, Laura; Liddell, Morgan

    2016-07-01

    Inhalant abuse is the intentional inhalation of a volatile substance for the purpose of achieving an altered mental state. As an important, yet underrecognized form of substance abuse, inhalant abuse crosses all demographic, ethnic, and socioeconomic boundaries, causing significant morbidity and mortality in school-aged and older children. This review presents current perspectives on epidemiology, detection, and clinical challenges of inhalant abuse and offers advice regarding the medical and mental health providers' roles in the prevention and management of this substance abuse problem. Also discussed is the misuse of a specific "over-the-counter" dissociative, dextromethorphan. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Parent abuse by adolescents with first-episode psychosis in Egypt.

    PubMed

    Fawzi, Mounir H; Fawzi, Mohab M; Fouad, Amira A

    2013-12-01

    To determine the rate of parent abuse in a sample of Egyptian adolescents with first-episode psychosis (FEP) and to identify the association between parent abuse and a number of sociodemographic and clinical factors of interest in these patients. As yet, the abuse of parents by their children, especially mentally ill children, in contrast to child abuse, has remained a research taboo. In a cross-sectional study in Zagazig (Egypt), a sample of 150 adolescent outpatients (82 boys; 68 girls), presenting with FEP, was assessed for the occurrence of parent abuse using both interview and questionnaire methods (Abused Parent Questionnaire, APQ). Univariate analyses were used to compare parent abusers and nonabusers along a number of sociodemographic and clinical variables. Variables that were associated with parent abuse were entered into a multivariate logistic regression analysis model. We found that 61 patients (40.7%) perpetrated abuse against parents, mostly mothers (55/61; 90.2%). Five significant risk factors for parent abuse were identified by multivariate analysis. These were parent's female gender (95% CI = 7.82-45.56), patient's male gender (95% CI = 3.15-37.14), Childhood Trauma Questionnaire - Short Form total score (95% CI = 1.48-14.91), Positive and Negative Syndrome Scale positive subscale score (95% CI = 1.26-9.59), and duration of untreated psychosis (95% CI = 1.01-4.72). The study indicates that parent abuse, particularly mother abuse, in untreated adolescents with FEP is an issue calling for increased awareness of the problem. The findings may have important implications for parental psychoeducation and support, and earlier access to treatment. Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  8. Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

    PubMed Central

    Xiong, Jianghui; Liu, Juan; Rayner, Simon; Tian, Ze; Li, Yinghui; Chen, Shanguang

    2010-01-01

    The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies. PMID:21085674

  9. Estimating Local Child Abuse.

    ERIC Educational Resources Information Center

    Ards, Sheila

    1989-01-01

    Three conceptual approaches to estimating local child abuse rates using the National Incidence Study of Child Abuse and Neglect data set are evaluated. All three approaches yield estimates of actual abuse cases that exceed the number of reported cases. (SLD)

  10. State of the science on prevention of elder abuse and lessons learned from child abuse and domestic violence prevention: Toward a conceptual framework for research.

    PubMed

    Teresi, Jeanne A; Burnes, David; Skowron, Elizabeth A; Dutton, Mary Ann; Mosqueda, Laura; Lachs, Mark S; Pillemer, Karl

    2016-01-01

    The goal of this review is to discuss the state of the science in elder abuse prevention. Findings from evidence-based programs to reduce elder abuse are discussed, drawing from findings and insights from evidence-based programs for child maltreatment and domestic/intimate partner violence. A conceptual measurement model for the study of elder abuse is presented and linked to possible measures of risk factors and outcomes. Advances in neuroscience in child maltreatment and novel measurement strategies for outcome assessment are presented.

  11. The evaluation of the abuse liability of drugs.

    PubMed

    Johanson, C E

    1990-01-01

    In order to place appropriate restrictions upon the availability of certain therapeutic agents to limit their abuse, it is important to assess abuse liability, an important aspect of drug safety evaluation. However, the negative consequences of restriction must also be considered. Drugs most likely to be tested are psychoactive compounds with therapeutic indications similar to known drugs of abuse. Methods include assays of pharmacological profile, drug discrimination procedures, self-administration procedures, and measures of drug-induced toxicity including evaluations of tolerance and physical dependence. Furthermore, the evaluation of toxicity using behavioural end-points is an important component of the assessment, and it is generally believed that the most valid procedure in this evaluation is the measurement of drug self-administration. However, even this method rarely predicts the extent of abuse of a specific drug. Although methods are available which appear to measure relative abuse liability, these procedures are not validated for all drug classes. Thus, additional strategies, including abuse liability studies in humans, modelled after those used with animals, must be used in order to make a more informed prediction. Although there is pressure to place restrictions on new drugs at the time of marketing, in light of the difficulty of predicting relative abuse potential, a better strategy might be to market a drug without restrictions, but require postmarketing surveillance in order to obtain more accurate information on which to base a final decision.

  12. A discrete choice model of drug abuse treatment location.

    PubMed Central

    Goodman, A C; Nishiura, E; Hankin, J R

    1998-01-01

    OBJECTIVE: To identify short-term drug abuse treatment location risk factors for ten large, self-insured firms starting January 1, 1989 and ending December 31, 1991. DATA SOURCES/STUDY SETTING: Study population selected from a large database of health insurance claims for all treatment events starting January 1, 1989 and ending December 31, 1991. STUDY DESIGN: A nested binomial logit method is used to estimate firm-specific patterns of treatment location. The differences in treatment location patterns among firms are then decomposed into firm effects (holding explanatory variables constant among firms) and variable effects (holding firm-specific parameters constant). PRINCIPAL FINDINGS: Probability of inpatient drug treatment is directly related to the type of drug diagnosis. The most important factors are diagnoses of drug dependence (versus drug abuse) and/or a cocaine dependence. Firm-specific factors also make a substantive difference. Controlling for patient risk factors, firm-specific probabilities of inpatient treatment vary by as much as 87 percent. Controlling for practices of firms and their insurance carriers, differing patient risk profiles cause probabilities of inpatient treatment to vary by as much as 69 percent among firms. Use of the outpatient setting increased over the three-year period. CONCLUSIONS: There are two plausible explanations for the findings. First, people beginning treatment later in the three-year period had less severe conditions than earlier cases and therefore had less need of inpatient treatment. Second, drug abuse treatment experienced the same trend toward the increased use of outpatient care that characterized treatment for other illnesses in the 1980s and early 1990s. PMID:9566181

  13. Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

    PubMed

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

    2016-01-01

    The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

  14. Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

    PubMed

    Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

    2013-03-01

    Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted

  15. Substance abuse and child maltreatment.

    PubMed

    Wells, Kathryn

    2009-04-01

    Pediatricians and other medical providers caring for children need to be aware of the dynamics in the significant relationship between substance abuse and child maltreatment. A caregiver's use and abuse of alcohol, marijuana, heroin, cocaine, methamphetamine, and other drugs place the child at risk in multiple ways. Members of the medical community need to understand these risks because the medical community plays a unique and important role in identifying and caring for these children. Substance abuse includes the abuse of legal drugs as well as the use of illegal drugs. The abuse of legal substances may be just as detrimental to parental functioning as abuse of illicit substances. Many substance abusers are also polysubstance users and the compounded effect of the abuse of multiple substances may be difficult to measure. Often other interrelated social features, such as untreated mental illness, trauma history, and domestic violence, affect these families.

  16. Assessing Risk/Benefit for Trials Using Preclinical Evidence: A Proposal

    PubMed Central

    Kimmelman, Jonathan; Henderson, Valerie C.

    2015-01-01

    Abstract Moral evaluation of risk/benefit in early phase studies requires assessing the clinical promise of a candidate intervention using preclinical evidence. Yet there is little to guide ethics committees, investigators, sponsors or other stakeholders morally charged with making these assessments (“evaluators”). In what follows, we draw on published guidelines for preclinical study design to develop a structured process for assessing the clinical promise of new interventions. In the first step, evaluators gather all relevant preclinical studies, assess the magnitude of treatment effects, and determine clinical promise in light of various threats to valid clinical inference. In the second step, evaluators adjust assessments of clinical promise from preclinical studies by examining how other agents in the same reference class-and supported by similar evidence- have fared in clinical development. Assessments of clinical promise can then be fed into moral evaluation of risk and benefit in early phase trials. Though our approach has limitations, it offers a systematic and transparent method for assessing risk/benefit in early phase trials of novel interventions. PMID:26463620

  17. Performance Evaluation of a Dedicated Preclinical PET/CT System for the Assessment of Mineralization Process in a Mouse Model of Atherosclerosis.

    PubMed

    Rucher, Guillaume; Cameliere, Lucie; Fendri, Jihene; Abbas, Ahmed; Dupont, Kevin; Kamel, Said; Delcroix, Nicolas; Dupont, Axel; Berger, Ludovic; Manrique, Alain

    2018-04-30

    The purpose of this study was to assess the impact of positron emission tomography/X-ray computed tomography (PET/CT) acquisition and reconstruction parameters on the assessment of mineralization process in a mouse model of atherosclerosis. All experiments were performed on a dedicated preclinical PET/CT system. CT was evaluated using five acquisition configurations using both a tungsten wire phantom for in-plane resolution assessment and a bar pattern phantom for cross-plane resolution. Furthermore, the radiation dose of these acquisition configurations was calculated. The PET system was assessed using longitudinal line sources to determine the optimal reconstruction parameters by measuring central resolution and its coefficient of variation. An in vivo PET study was performed using uremic ApoE -/- , non-uremic ApoE -/- , and control mice to evaluate optimal PET reconstruction parameters for the detection of sodium [ 18 F]fluoride (Na[ 18 F]F) aortic uptake and for quantitative measurement of Na[ 18 F]F bone influx (Ki) with a Patlak analysis. For CT, the use of 1 × 1 and 2 × 2 binning detector mode increased both in-plane and cross-plane resolution. However, resolution improvement (163 to 62 μm for in-plane resolution) was associated with an important radiation dose increase (1.67 to 32.78 Gy). With PET, 3D-ordered subset expectation maximization (3D-OSEM) algorithm increased the central resolution compared to filtered back projection (1.42 ± 0.35 mm vs. 1.91 ± 0.08, p < 0.001). The use of 3D-OSEM with eight iterations and a zoom factor 2 yielded optimal PET resolution for preclinical study (FWHM = 0.98 mm). These PET reconstruction parameters allowed the detection of Na[ 18 F]F aortic uptake in 3/14 ApoE -/- mice and demonstrated a decreased Ki in uremic ApoE -/- compared to non-uremic ApoE -/- and control mice (p < 0.006). Optimizing reconstruction parameters significantly impacted on the assessment of mineralization process

  18. Psychometric modeling of abuse and dependence symptoms across six illicit substances indicates novel dimensions of misuse

    PubMed Central

    Clark, Shaunna L.; Gillespie, Nathan A.; Adkins, Daniel E.; Kendler, Kenneth S.; Neale, Michael C.

    2015-01-01

    Aims This study explored the factor structure of DSM III-R/IV symptoms for substance abuse and dependence across six illicit substance categories in a population-based sample of males. Method DSM III-R/IV drug abuse and dependence symptoms for cannabis, sedatives, stimulants, cocaine, opioids and hallucinogens from 4179 males born 1940-1970 from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders were analyzed. Confirmatory factor analyses tested specific hypotheses regarding the latent structure of substance misuse for a comprehensive battery of 13 misuse symptoms measured across six illicit substance categories (78 items). Results Among the models fit, the latent structure of substance misuse was best represented by a combination of substance-specific factors and misuse symptom-specific factors. We found no support for a general liability factor to illicit substance misuse. Conclusions Results indicate that liability to misuse illicit substances is drug class specific, with little evidence for a general liability factor. Additionally, unique dimensions capturing propensity toward specific misuse symptoms (e.g., tolerance, withdrawal) across substances were identified. While this finding requires independent replication, the possibility of symptom-specific misuse factors, present in multiple substances, raises the prospect of genetic, neurobiological and behavioral predispositions toward distinct, narrowly defined features of drug abuse and dependence. PMID:26517709

  19. Child sexual abuse, attachment style, and depression: the role of the characteristics of abuse.

    PubMed

    Cantón-Cortés, David; Cortés, María Rosario; Cantón, José

    2015-02-01

    The aim of the current study was to examine the effects of secure, avoidant, and anxious attachment styles on depressive symptomatology in child sexual abuse (CSA) among young female adult victims. The role of attachment style was studied by considering possible interactive effects with the type of abuse, the relationship with the perpetrator, and the continuity of abuse. Participants were 168 female victims of CSA. Information about the abuse was obtained from a self-reported questionnaire. Attachment style was assessed with the Attachment Style Measure (ASM), and the Beck Depression Inventory (BDI) was used to assess depressive symptomatology. Secure and anxious attachment styles were correlated with low and high depression scores respectively. The effects of attachment style were stronger in cases where the abuse consisted of oral sex/penetration, a non-family member as perpetrator, and in isolated, compared with continued, abuse. These results confirm that characteristics of CSA (type of abuse, relationship with the perpetrator, and continuity of abuse) can affect the impact of attachment style on depressive symptomatology. © The Author(s) 2014.

  20. A Modified Collagen Gel Enhances Healing Outcome in a Pre-Clinical Swine Model of Excisional Wounds

    PubMed Central

    Elgharably, Haytham; Roy, Sashwati; Khanna, Savita; Abas, Motaz; DasGhatak, Piya; Das, Amitava; Mohammed, Kareem; Sen, Chandan K.

    2013-01-01

    Collagen-based dressings are of great interest in wound care. However, evidence supporting their mechanism of action in a wound setting in vivo is scanty. This work providesfirst results from a pre-clinical swine model of excisional wounds elucidating the mechanism of action of a modified collagen gel (MCG) dressing. Following wounding, wound-edge tissue was collected at specific time intervals (3, 7, 14, and 21 days post-wounding). On day 7, histological analysis showed significant increase in the length of rete ridges suggesting improved biomechanical properties of the healing wound tissue. Rapid and transient mounting of inflammation is necessary for efficient healing. MCG significantly accelerated neutrophil and macrophages recruitment to the wound site on day 3 and day 7 with successful resolution of inflammation on day 21. MCG induced MCP-1 expression in neutrophil-like HL-60 cells in vitro. In vivo, MCG treated wound tissue displayed elevated VEGF expression. Consistently, MCG-treated wounds displayed significantly higher abundance of endothelial cells with increased blood flow to the wound area indicating improved vascularization. This observation was explained by the finding that MCG enhanced proliferation of wound-site endothelial cells. In MCG-treated wound tissue, Masson’s Trichrome and Picrosirius red staining showed higher abundance of collagen and increased collagen type I:III ratio. This work presents first evidence from a pre-clinical experimental setting explaining how a collagen-based dressing may improve wound closure by targeting multiple key mechanisms as compared to standard of care i.e., Tegadem treated wounds. The current findings warrant additional studies to determine whether the responses to the MCG are different from other modified or unmodified collagen based products used in clinical setting. PMID:23607796

  1. Childhood attachment, childhood sexual abuse, and onset of masturbation among adult sexual offenders.

    PubMed

    Smallbone, Stephen W; McCabe, Billee-Anne

    2003-01-01

    Written autobiographies of 48 incarcerated adult male sexual offenders (22 rapists, 13 intrafamilial child molesters, and 13 extrafamilial child molesters) were used to generate retrospective self-report measures of their childhood maternal and paternal attachment, childhood sexual abuse experiences, and onset of masturbation. Contrary to expectation, the offenders as a combined group more often reported secure than they did insecure childhood maternal and paternal attachment. There were no differences between the three offender subgroups with respect to maternal attachment; however the rapists and the intrafamilial child molesters were more likely to report insecure paternal attachment than were the extrafamilial child molesters. There were no differences between these offender subgroups in the frequency with which childhood sexual abuse was reported. However, offenders with insecure paternal attachment were more likely to report having been sexually abused than were those with secure paternal attachment. Sexually abused offenders in turn reported earlier onset of masturbation than did those who were not sexually abused. These results are consistent with contemporary attachment models linking insecure childhood attachment to childhood sexual abuse, and with traditional conditioning models linking childhood sexual abuse, early masturbation, and sexual offending.

  2. Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides.

    PubMed

    Li, Liang-Zhu; Yang, Yu; Yuan, Song-Hua; Wan, Yan-Min; Qiu, Chao; Feng, Yan-Ling; Xu, Jian-Qing; Zhang, Xiao-Yan

    2010-12-01

    To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction. A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis. All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8

  3. Increasing efficiency of preclinical research by group sequential designs

    PubMed Central

    Piper, Sophie K.; Rex, Andre; Florez-Vargas, Oscar; Karystianis, George; Schneider, Alice; Wellwood, Ian; Siegerink, Bob; Ioannidis, John P. A.; Kimmelman, Jonathan; Dirnagl, Ulrich

    2017-01-01

    Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain. PMID:28282371

  4. Abusive supervision and subordinates' organization deviance.

    PubMed

    Tepper, Bennett J; Henle, Christine A; Lambert, Lisa Schurer; Giacalone, Robert A; Duffy, Michelle K

    2008-07-01

    The authors developed an integrated model of the relationships among abusive supervision, affective organizational commitment, norms toward organization deviance, and organization deviance and tested the framework in 2 studies: a 2-wave investigation of 243 supervised employees and a cross-sectional study of 247 employees organized into 68 work groups. Path analytic tests of mediated moderation provide support for the prediction that the mediated effect of abusive supervision on organization deviance (through affective commitment) is stronger when employees perceive that their coworkers are more approving of organization deviance (Study 1) and when coworkers perform more acts of organization deviance (Study 2).

  5. Domestic abuse awareness and recognition among primary healthcare professionals and abused women: a qualitative investigation.

    PubMed

    Bradbury-Jones, Caroline; Taylor, Julie; Kroll, Thilo; Duncan, Fiona

    2014-11-01

    To investigate the dynamics of domestic abuse awareness and recognition among primary healthcare professionals and abused women. Domestic abuse is a serious, public health issue that crosses geographical and demographic boundaries. Health professionals are well placed to recognise and respond to domestic abuse, but empirical evidence suggests that they are reluctant to broach the issue. Moreover, research has shown that women are reluctant to disclose abuse. A two-phase, qualitative study was conducted in Scotland. Twenty-nine primary health professionals (midwives, health visitors and general practitioners) participated in the first phase of the study, and 14 abused women took part in phase two. Data were collected in 2011. Semi-structured, individual interviews were conducted with the health professionals, and three focus groups were facilitated with the abused women. Data were analysed using a framework analysis approach. Differing levels of awareness of the nature and existence of abuse are held by abused women and primary healthcare professionals. Specifically, many women do not identify their experiences as abusive. A conceptual representation of domestic abuse - the "abused women, awareness, recognition and empowerment' framework - arising from the study - presents a new way of capturing the complexity of the disclosure process. Further research is necessary to test and empirically validate the framework, but it has potential pedagogical use for the training and education of health professionals and clinical use with abused women. The framework may be used in clinical practice by nurses and other health professionals to facilitate open discussion between professionals and women. In turn, this may empower women to make choices regarding disclosure and safety planning. © 2014 John Wiley & Sons Ltd.

  6. A laboratory silicone for preclinical training in ear prosthesis.

    PubMed

    Anand, Vijay; Haribabu; Vimala; Gnanasamband, Vimala

    2013-07-01

    This article describes an industrial elastic silicone as a material for the laboratory fabrication of ear prosthesis. It has been tested for toxicity in lab animals by the SGS India Pvt. Ltd and approved as a material to pass the parameter of abnormal toxicity. This material therefore can be safely recommended for laboratory exercise to fabricate facial prosthesis. The high cost of the maxillo facial silicone materials prohibits their use for facial prosthesis in pre-clinical training of post-graduate students in maxillofacial prosthodontics. For this reason, pre-clinical laboratory exercise in facial prosthesis is inadequate. A few institutions use polymethyl methacrylate resins which are rigid and do not have elastic characteristics of silicone, which is used for facial defects. This cost-effective industrial silicone material which mimics the elastic and color characteristics of the conventional silicones can be recommended for preclinical exercises.

  7. Relationships between parental alcohol abuse and social support, peer substance abuse risk and social support, and substance abuse risk among South Korean adolescents.

    PubMed

    Park, Sookyung; Kim, Haeryun; Kim, Haesung

    2009-01-01

    This study examined the roles played by parental alcohol abuse and social support, peer substance abuse risk and social support, and substance abuse risk among adolescents in South Korea. Participants were adolescents between the ages of 15 and 22 years (mean, 18), residing in Seoul city and in surrounding Kyung-gi Province. Of 259 participants, 41.3% scored 2 or more on the POSIT scale, which suggested they met the problematic criteria for substance abuse risk. Logistic regression results suggested that the influence of social support on substance abuse risk among adolescents depended on the source of support--parents or peers. These findings need to be considered in the development of intervention programs for adolescents at risk for substance abuse.

  8. Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia

    PubMed Central

    Chitta, K; Paulus, A; Caulfield, T R; Akhtar, S; Blake, M-KK; Ailawadhi, S; Knight, J; Heckman, M G; Pinkerton, A; Chanan-Khan, A

    2014-01-01

    Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target–ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2Ser70-Ala) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity. PMID:25382610

  9. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-01-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

  10. Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

    PubMed

    Corbett, Dale; Carmichael, S Thomas; Murphy, Timothy H; Jones, Theresa A; Schwab, Martin E; Jolkkonen, Jukka; Clarkson, Andrew N; Dancause, Numa; Weiloch, Tadeusz; Johansen-Berg, Heidi; Nilsson, Michael; McCullough, Louise D; Joy, Mary T

    2017-08-01

    Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

  11. Abusive supervision, psychosomatic symptoms, and deviance: Can job autonomy make a difference?

    PubMed

    Velez, Maria João; Neves, Pedro

    2016-07-01

    Recently, interest in abusive supervision has grown (Tepper, 2000). However, little is still known about organizational factors that can reduce its adverse effects on employee behavior. Based on the Job Demands-Resources Model (Demerouti, Bakker, Nachreiner, & Schaufeli, 2001), we predict that job autonomy acts as a buffer of the positive relationship between abusive supervision, psychosomatic symptoms and deviance. Therefore, when job autonomy is low, a higher level of abusive supervision should be accompanied by increased psychosomatic symptoms and thus lead to higher production deviance. When job autonomy is high, abusive supervision should fail to produce increased psychosomatic symptoms and thus should not lead to higher production deviance. Our model was explored among a sample of 170 supervisor-subordinate dyads from 4 organizations. The results of the moderated mediation analysis supported our hypotheses. That is, abusive supervision was significantly related to production deviance via psychosomatic symptoms when job autonomy was low, but not when job autonomy was high. These findings suggest that job autonomy buffers the impact of abusive supervision perceptions on psychosomatic symptoms, with consequences for production deviance. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  12. Drug Use, the Drug Environment, and Child Physical Abuse and Neglect.

    PubMed

    Freisthler, Bridget; Wolf, Jennifer Price; Wiegmann, Wendy; Kepple, Nancy J

    2017-08-01

    Although drug use is considered a risk factor for child maltreatment, very little work has examined how the drug environment may affect physical abuse and neglect by parents. Utilizing information from a telephone survey with 2,597 respondents from 43 cities with valid police data on narcotics incidents, we analyzed the relationship between drug use, drug availability, and child maltreatment using multilevel models. City-level rates of drug abuse and dependence were related to more frequent physical abuse. Parents who use drugs in areas with greater availability of drugs reported more physical abuse and physical neglect. Emotional support was protective of all types of maltreatment. While most child welfare interventions focus on reducing parental drug use in order to reduce child abuse, these findings suggest environmental prevention or neighborhood strengthening approaches designed to reduce the supply of illicit drugs may also reduce child abuse through multiple mechanisms.

  13. The Development of a Sexual Abuse Severity Score: Characteristics of Childhood Sexual Abuse Associated with Trauma Symptomatology, Somatization, and Alcohol Abuse

    ERIC Educational Resources Information Center

    Zink, Therese; Klesges, Lisa; Stevens, Susanna; Decker, Paul

    2009-01-01

    Childhood sexual abuse (CSA) is common and is associated with both mental and physical health problems in adulthood. Using data from an age- and sex-stratified population survey of 600 Olmsted County, Minnesota, residents, a Sexual Abuse Severity Score was developed. The abuse characteristics of 156 CSA respondents were associated with…

  14. Child-Visiting and Domestic Abuse.

    ERIC Educational Resources Information Center

    Shepard, Melanie

    1992-01-01

    Explains problems with child visiting in cases of domestic abuse. Data on domestic abuse, child care concerns, and child adjustment problems were collected from 25 mothers and 22 fathers at a child visiting program serving separated and abusive families. Psychological abuse of mothers correlated with child adjustment problems. (BB)

  15. State-of-the-science on prevention of elder abuse and lessons learned from child abuse and domestic violence prevention: Toward a conceptual framework for research

    PubMed Central

    Teresi, Jeanne A.; Burnes, David; Skowron, Elizabeth A.; Dutton, Mary Ann; Mosqueda, Laura; Lachs, Mark S.; Pillemer, Karl

    2017-01-01

    The goal of this review is to discuss the state-of-the-science in elder abuse prevention. Findings from evidence-based programs to reduce elder abuse are discussed, drawing from findings and insights from evidence-based programs for child maltreatment and domestic/ intimate partner violence. A conceptual measurement model for the study of elder abuse is presented, and linked to possible measures of risk factors and outcomes. Advances in neuroscience in child maltreatment and novel measurement strategies for outcome assessment are presented. PMID:27676289

  16. Preclinical Alzheimer disease and risk of falls.

    PubMed

    Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

    2013-07-30

    We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

  17. Preclinical Alzheimer disease and risk of falls

    PubMed Central

    Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.

    2013-01-01

    Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

  18. Elder Abuse Awareness Project.

    ERIC Educational Resources Information Center

    Doyle, Kathleen; Morrow, Marilyn J.

    1985-01-01

    The Elder Abuse Awareness Project was undertaken: (1) to determine the incidence of abuse and neglect in seven Illinois counties; and (2) to develop, produce, and distribute educational materials on elder abuse for the service provider and for senior citizens. Results are presented and discussed. (MT)

  19. Changing the Culture of Alcohol Abuse on Campus: Lessons Learned from Secondhand Smoke

    ERIC Educational Resources Information Center

    Misch, Donald A.

    2010-01-01

    Alcohol abuse is the single greatest public health hazard on American college and university campuses, but the culture of abusive alcohol consumption continues to be highly resistant to change. The author argues that secondhand smoke campaigns can be used as models to change the culture of alcohol abuse on campus. He proposes the implementation of…

  20. Mimics of child abuse: Can choking explain abusive head trauma?

    PubMed

    Edwards, George A

    2015-10-01

    Choking is one of the alternative explanations of abusive head trauma in children that have been offered in courtroom testimony and in the media. Most of these explanations - including choking - are not scientifically supported. This article highlights four points. (1) The origins of choking as an explanation for intracranial and retinal hemorrhages are speculative. (2) Choking has been used in high profile court testimony as an explanation for the death of a child thought to have been abused. (3) A case report that proposes choking as an alternative explanation for the death of a child diagnosed with abusive head trauma includes omissions and misrepresentations of facts. (4) There was a decision by the editor of the journal that published the case report that it was not necessary to include all the facts of the case; moreover, the editor indicated that facts are not required when presenting an alternative explanation. The use of scientifically unsupported alternative explanations for abusive head trauma based on inaccurate and biased information constitutes further victimization of the abused child and represents a travesty of justice. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.