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Sample records for abuse preclinical models

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

    Science.gov (United States)

    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.

  2. Preclinical models for obesity research.

    Science.gov (United States)

    Barrett, Perry; Mercer, Julian G; Morgan, Peter J

    2016-11-01

    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.

  3. Preclinical models for obesity research

    Directory of Open Access Journals (Sweden)

    Perry Barrett

    2016-11-01

    Full Text Available 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.

  4. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2009-10-01

    include astrocytoma, malignant peripheral nerve sheath tumor ( MPNST ), pheochromocytoma, and juvenile myelomonocytic leukemia (JMML). NF2 affects 1 in...features of NF1-associated mouse tumor models of MPNST /Triton tumor, astrocytoma, JMML, plexiform neurofibroma, and chemotherapy-induced leukemia...for an effective treatment for these previously untreatable tumors. Malignant Peripheral Nerve Sheath Tumors ( MPNSTs ). The Parada lab previously

  5. Preclinical and human surrogate models of itch

    DEFF Research Database (Denmark)

    Hoeck, Emil August; Marker, Jens Broch; Gazerani, Parisa;

    2016-01-01

    Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch, are lim...... currently applied in animals and humans. This article is protected by copyright. All rights reserved.......Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch......, are limited. Relevant preclinical and human surrogate models of non-histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysesthesiae. While...

  6. Preclinical fluorescent mouse models of pancreatic cancer

    Science.gov (United States)

    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.

  7. Kinetic modeling in pre-clinical positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kuntner, Claudia [AIT Austrian Institute of Technology GmbH, Seibersdorf (Austria). Biomedical Systems, Health and Environment Dept.

    2014-07-01

    Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges of deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data.

  8. Cannabis abuse in adolescence and the risk of psychosis: a brief review of the preclinical evidence.

    Science.gov (United States)

    Rubino, T; Parolaro, D

    2014-07-03

    Epidemiological studies suggest that Cannabis use during adolescence confers an increased risk for developing psychotic symptoms later in life. However, despite their interest, the epidemiological data are not conclusive, due to their heterogeneity; thus modeling the adolescent phase in animals is useful for investigating the impact of Cannabis use on deviations of adolescent brain development that might confer a vulnerability to later psychotic disorders. Although scant, preclinical data seem to support the presence of impaired social behaviors, cognitive and sensorimotor gating deficits as well as psychotic-like signs in adult rodents after adolescent cannabinoid exposure, clearly suggesting that this exposure may trigger a complex behavioral phenotype closely resembling a schizophrenia-like disorder. Similar treatments performed at adulthood were not able to produce such phenotype, thus pointing to a vulnerability of the adolescent brain towards cannabinoid exposure. The neurobiological substrate of the adolescent vulnerability is still largely unknown and experimental studies need to elucidate the cellular and molecular mechanism underlying these effects. However, the few data available seem to suggest that heavy adolescent exposure to cannabinoids is able to modify neuronal connectivity in specific brain areas long after the end of the treatment. This is likely due to disruption of maturational events within the endocannabinoid system during adolescence that in turn impact on the correct neuronal refinement peculiar of the adolescent brain, thus leading to altered adult brain functionality and behavior.

  9. GEMMs as preclinical models for testing pancreatic cancer therapies

    Directory of Open Access Journals (Sweden)

    Aarthi Gopinathan

    2015-10-01

    Full Text Available Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs, the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

  10. Review paper: preclinical models of psoriasis.

    Science.gov (United States)

    Danilenko, D M

    2008-07-01

    Psoriasis is the most common autoimmune disease in man and is characterized by focal to coalescing raised cutaneous plaques with consistent scaling and variable erythema. The specific pathogenesis of psoriasis is not completely understood, but the underlying mechanisms involve a complex interplay between epidermal keratinocytes, T lymphocytes as well as other leukocytes (including dendritic cells and other antigen presenting cells [APCs]), and vascular endothelium. Mirroring the complexity of mechanisms that underlie psoriasis, there are a relatively large number of models of psoriasis. Each model is based on a slightly different pathogenic mechanism, and each has its similarities to psoriasis as well as its limitations. In general, psoriasis models can be very broadly divided on the basis of the pathogenic mechanisms that interplay to cause psoriasis, with the addition of several relatively poorly defined spontaneous murine mutant models. Other than the spontaneous mutant models, murine models of psoriasis can be divided into those that are genetically engineered (transgenic and knockout-with manipulation of either the epidermis, leukocytes, or the endothelium), and those that are induced (either by immune transfer or by xenotransplantation of skin from psoriatic patients). In addition to the murine models, in vitro human epidermal models have recently become more widely utilized. While no one single model of psoriasis is ideal, many have proven to be extremely valuable in investigating and better understanding the molecular mechanisms that underlie the complex interplay between epidermal keratinocytes, the innate and adaptive immune system, and the vascular endothelium in psoriasis.

  11. Preclinical models for neuroblastoma: establishing a baseline for treatment.

    Directory of Open Access Journals (Sweden)

    Tal Teitz

    Full Text Available BACKGROUND: Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. PRINCIPAL FINDINGS: Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. SIGNIFICANCE: The studies suggest that use of both the TH-NMYC model of neuroblastoma and the

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

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    Tremoleda, Jordi L; Khalil, Magdy; Gompels, Luke L; Wylezinska-Arridge, Marzena; Vincent, Tonia; Gsell, Willy

    2011-07-29

    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.

  13. Preclinical Assessment of a Strategy to Minimize the Abuse Liability of Opiate Medications for Pain

    Science.gov (United States)

    2015-07-01

    Prescription opioid overdose causes more deaths than cocaine and heroine combined (5). Furthermore, prescription opioid abuse represents a growing economic...presence of pain and to help in validating mechanisms that can ameliorate it. In our lab, the CPP boxes have three contextually distinct conditioning...Talan A, Steuer, E et al. Cue Induced changes in dopamine are of the same magnitude as cocaine -induced changes in dopamine. Neuropsychopharmacology

  14. Nephrectomized and hepatectomized animal models as tools in preclinical pharmacokinetics.

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    Vestergaard, Bill; Agersø, Henrik; Lykkesfeldt, Jens

    2013-08-01

    Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.

  15. Pre-clinical Orthotopic Murine Model of Human Prostate Cancer.

    Science.gov (United States)

    Shahryari, Varahram; Nip, Hannah; Saini, Sharanjot; Dar, Altaf A; Yamamura, Soichiro; Mitsui, Yozo; Colden, Melissa; Bucay, Nathan; Tabatabai, Laura Z; Greene, Kirsten; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir; Majid, Shahana

    2016-08-29

    To study the multifaceted biology of prostate cancer, pre-clinical in vivo models offer a range of options to uncover critical biological information about this disease. The human orthotopic prostate cancer xenograft mouse model provides a useful alternative approach for understanding the specific interactions between genetically and molecularly altered tumor cells, their organ microenvironment, and for evaluation of efficacy of therapeutic regimens. This is a well characterized model designed to study the molecular events of primary tumor development and it recapitulates the early events in the metastatic cascade prior to embolism and entry of tumor cells into the circulation. Thus it allows elucidation of molecular mechanisms underlying the initial phase of metastatic disease. In addition, this model can annotate drug targets of clinical relevance and is a valuable tool to study prostate cancer progression. In this manuscript we describe a detailed procedure to establish a human orthotopic prostate cancer xenograft mouse model.

  16. Typological and Integrative Models of Sexual Abuse

    Directory of Open Access Journals (Sweden)

    Demidova L.Y.,

    2014-11-01

    Full Text Available We discuss the basic typological and integrative theoretical models that explain the occurrence of child sexual abuse and the differences detected among the perpetrators of crimes against sexual integrity of minors. A comprehensive review of the theoretical concepts of sexual abuse in our country, in fact has not been carried out, and in this paper for the first time we made such an attempt. It is shown that the existing notions of sexual abuse largely overlap each other, but each of the models somehow takes into account the factors not explicitly addressed in other concepts. Systematic consideration of the theoretical models of sexual abuse can generalize and systematize the available data on the mechanisms of pedophile behavior. This review provides an opportunity to develop a new benchmark in the study of sexual abuse, get closer to building the most accurate and comprehensive model. In turn, this may contribute to solving the questions about the factors, dynamics, and the prevention of criminal sexual conduct against children

  17. Preclinical models to investigate retinal ischemia: Advances and drawbacks

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    Gillipsie eMinhas

    2012-05-01

    Full Text Available Retinal ischemia is a frequent source of irreparable visual impairment affecting over a hundred million individuals in the world. It is associated with a wide range of retinal disorders like ischemic optic neuropathies, obstructive retinopathies, carotid occlusive disorders, diabetic retinopathy and glaucoma. Compared to other tissues retina has a higher metabolic rate; any disruption in blood supply can have an effect on the supply of oxygen leading to retinal ischemia. If occlusion is not rescued the outcome is irreversible with ischemic and apoptotic cascades resulting in cell death. In addition to in-vitro models, animal models are necessary to further our understanding of the etiology, pathology, and evolution of retinal ischemia besides the evaluation, development, and improvement of therapeutic strategies. The various existing animal models of retinal ischemia are characterised by obstruction of retinal circulation that allows the study of neurovascular changes. In this review we provide an overview of major models and emerging preclinical therapeutic strategies.

  18. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma

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    Oren J Becher

    2015-07-01

    Full Text Available Diffuse Intrinsic Pontine Glioma (DIPG is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of six and eight. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab, as well as to potentially treat them in the clinic. This review will detail the initial strides towards modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Lastly, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.

  19. Healing from Childhood Sexual Abuse: A Theoretical Model

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    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…

  20. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.

    Directory of Open Access Journals (Sweden)

    Dorothy M French

    Full Text Available The fibroblast growth factor (FGF-FGF receptor (FGFR signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1. LD1 inhibited: 1 FGF1 and FGF19 binding to FGFR4, 2 FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3 tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

  1. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.

    Science.gov (United States)

    French, Dorothy M; Lin, Benjamin C; Wang, Manping; Adams, Camellia; Shek, Theresa; Hötzel, Kathy; Bolon, Brad; Ferrando, Ronald; Blackmore, Craig; Schroeder, Kurt; Rodriguez, Luis A; Hristopoulos, Maria; Venook, Rayna; Ashkenazi, Avi; Desnoyers, Luc R

    2012-01-01

    The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

  2. Abuse

    Science.gov (United States)

    ... basic needs like food, shelter, and love. Family violence can affect anyone. It can happen in any kind of family. Sometimes parents abuse each other, which can be hard for a child to witness. Some parents abuse their kids by using physical or verbal cruelty as a way of discipline. ...

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

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Tianwu [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Geneva Neuroscience Center, Geneva University, Geneva CH-1205 (Switzerland); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen 9700 RB (Netherlands)

    2016-01-15

    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.

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

    Science.gov (United States)

    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.

  5. Abuse

    Science.gov (United States)

    ... indicate neglect. Belittling, threats or other uses of power by spouses, family members or others may indicate verbal or emotional abuse. Strained or tense relationships and frequent arguments between ...

  6. Ex vivo model for pre-clinical evaluation of dialyzers containing new membranes.

    Science.gov (United States)

    Mahiout, A; Meinhold, H; Jörres, A; Krieg, R; Kessel, M; Tretzel, J; Baurmeister, U

    1985-01-01

    The ex vivo model which reflects hemodialysis modulating factors during the first twenty minutes of blood membrane interaction, is applicable as a pre-clinical test for new membranes. The biocompatibility of a new cellulosic membrane (MC) proved to be superior to regenerated cellulose and comparable to synthetic membranes such as PAN regarding complement activation.

  7. Impulsivity in Animal Models for Drug Abuse Disorders

    OpenAIRE

    Jentsch, J. David

    2008-01-01

    Different conceptual frameworks have been generated to explain substance abuse; of relevance to this article, dysfunction of impulse control systems that are required for avoiding or stopping drug-seeking and –taking may play a key role in addiction. This review summarizes work in animal models that explains the pervasive association between impulse control and substance abuse. It further underscores the concept that impulse control may be a critical target for pharmacological intervention in...

  8. The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease.

    Science.gov (United States)

    't Hart, Bert A; Abbott, David H; Nakamura, Katsuki; Fuchs, Eberhard

    2012-11-01

    The development of biologic molecules (monoclonal antibodies, cytokines, soluble receptors) as specific therapeutics for human disease creates a need for animal models in which safety and efficacy can be tested. Models in lower animal species are precluded when the reagents fail to recognize their targets, which is often the case in rats and mice. In this Feature article we will highlight the common marmoset, a small-bodied nonhuman primate (NHP), as a useful model in biomedical and preclinical translational research.

  9. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    Science.gov (United States)

    2010-10-01

    ..., ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES Pt. 54a, App. Appendix to Part 54a—Model Notice of Individuals Receiving Substance Abuse Services Model Notice to Individuals Receiving Substance Abuse Services No provider of substance abuse services receiving Federal funds from the...

  10. Preclinical computational models: predictors of tibial insert damage patterns in total knee arthroplasty: AAOS exhibit selection.

    Science.gov (United States)

    Morra, Edward A; Heim, Christine S; Greenwald, A Seth

    2012-09-19

    Computational models that predict clinical surface damage of the tibial insert during activities of daily living are emerging as powerful tools to assess the safety and efficacy of contemporary total knee arthroplasty designs. These models have the advantage of quickly determining the performance of new designs at low cost, and they allow direct comparison with the performance of classic, clinically successful designs. This study validated finite element and kinematic modeling predictions through comparison with preclinical physical testing results, damage patterns on retrieved tibial inserts, and clinically measured knee motion. There is a mounting body of evidence to support the role of computational modeling as a preclinical tool that enables the optimization of total knee arthroplasty designs and the auditing of component quality control before large-scale manufacturing is undertaken.

  11. RODENT STROKE MODEL GUIDELINES FOR PRECLINICAL STROKE TRIALS (1ST EDITION)

    OpenAIRE

    Liu, Shimin; Zhen, Gehua; Meloni, Bruno P.; Campbell, Kym; Winn, H. Richard

    2009-01-01

    Translational stroke research is a challenging task that needs long term team work of the stroke research community. Highly reproducible stroke models with excellent outcome consistence are essential for obtaining useful data from preclinical stroke trials as well as for improving inter-lab comparability. However, our review of literature shows that the infarct variation coefficient of commonly performed stroke models ranges from 5% to 200%. An overall improvement of the commonly used stroke ...

  12. Preclinical models of Graves' disease and associated secondary complications.

    Science.gov (United States)

    Moshkelgosha, Sajad; So, Po-Wah; Diaz-Cano, Salvador; Banga, J Paul

    2015-01-01

    Autoimmune thyroid disease is the most common organ-specific autoimmune disorder which consists of two opposing clinical syndromes, Hashimoto's thyroiditis and Graves' (hyperthyroidism) disease. Graves' disease is characterized by goiter, hyperthyroidism, and the orbital complication known as Graves' orbitopathy (GO), or thyroid eye disease. The hyperthyroidism in Graves' disease is caused by stimulation of function of thyrotropin hormone receptor (TSHR), resulting from the production of agonist antibodies to the receptor. A variety of induced mouse models of Graves' disease have been developed over the past two decades, with some reproducible models leading to high disease incidence of autoimmune hyperthyroidism. However, none of the models show any signs of the orbital manifestation of GO. We have recently developed an experimental mouse model of GO induced by immunization of the plasmid encoded ligand binding domain of human TSHR cDNA by close field electroporation that recapitulates the orbital pathology in GO. As in human GO patients, immune mice with hyperthyroid or hypothyroid disease induced by anti-TSHR antibodies exhibited orbital pathology and chemosis, characterized by inflammation of orbital muscles and extensive adipogenesis leading to expansion of the orbital retrobulbar space. Magnetic resonance imaging of the head region in immune mice showed a significant expansion of the orbital space, concurrent with proptosis. This review discusses the different strategies for developing mouse models in Graves' disease, with a particular focus on GO. Furthermore, it outlines how this new model will facilitate molecular investigations into pathophysiology of the orbital disease and evaluation of new therapeutic interventions.

  13. Optimizing modelling in iterative image reconstruction for preclinical pinhole PET

    Science.gov (United States)

    Goorden, Marlies C.; van Roosmalen, Jarno; van der Have, Frans; Beekman, Freek J.

    2016-05-01

    The recently developed versatile emission computed tomography (VECTor) technology enables high-energy SPECT and simultaneous SPECT and PET of small animals at sub-mm resolutions. VECTor uses dedicated clustered pinhole collimators mounted in a scanner with three stationary large-area NaI(Tl) gamma detectors. Here, we develop and validate dedicated image reconstruction methods that compensate for image degradation by incorporating accurate models for the transport of high-energy annihilation gamma photons. Ray tracing software was used to calculate photon transport through the collimator structures and into the gamma detector. Input to this code are several geometric parameters estimated from system calibration with a scanning 99mTc point source. Effects on reconstructed images of (i) modelling variable depth-of-interaction (DOI) in the detector, (ii) incorporating photon paths that go through multiple pinholes (‘multiple-pinhole paths’ (MPP)), and (iii) including various amounts of point spread function (PSF) tail were evaluated. Imaging 18F in resolution and uniformity phantoms showed that including large parts of PSFs is essential to obtain good contrast-noise characteristics and that DOI modelling is highly effective in removing deformations of small structures, together leading to 0.75 mm resolution PET images of a hot-rod Derenzo phantom. Moreover, MPP modelling reduced the level of background noise. These improvements were also clearly visible in mouse images. Performance of VECTor can thus be significantly improved by accurately modelling annihilation gamma photon transport.

  14. Recent Trends in Detection of Huntingtin and Preclinical Models of Huntington’s Disease

    OpenAIRE

    2014-01-01

    Huntington’s disease is a genetically inherited neurodegenerative disease that is characterized by neuronal cell death in the brain. Molecular biology techniques to detect and quantify huntingtin protein in biological samples involve fluorescence imaging, western blotting, and PCR. Modified cell lines are widely used as models for Huntington’s disease for preclinical screening of drugs to study their ability to suppress the expression of huntingtin. Although worm and fly species have been exp...

  15. Preclinical mouse models and methods for the discovery of the causes and treatments of atherosclerosis

    Science.gov (United States)

    Hewing, Bernd; Fisher, Edward A

    2013-01-01

    Introduction Atherosclerosis is the leading cause of death in the Western world. Despite huge advances in understanding its pathophysiological mechanisms, current treatment is mostly based on ‘traditional’ risk factors. The introduction of statins more than 20 years ago reduced morbidity and mortality of atherosclerosis by 30%, leaving a residual cardiovascular risk. Therefore, efforts continue toward the development of novel therapies that can be added to established treatments. Besides targeting dyslipidemia, recent focus has been put on preventing or resolving inflammatory processes involved in atherosclerosis. Areas covered The article discusses therapeutic and diagnostic targets in atherosclerosis and how they can be discovered and studied in preclinical animal models. The roles of immune cells, specifically macrophages and monocytes, in plaque inflammation are discussed. The article also describes current preclinical models of atherosclerosis, specifically the mouse, study designs (for progression and regression studies), basic and advanced methods of analysis of atherosclerotic lesions, and discusses the challenges of translating the findings to humans. Expert opinion Advances in genomics, proteomics, lipidomics and the development of high-throughput screening techniques help to improve our understanding of atherosclerosis disease mechanisms immensely and facilitate the discovery of new diagnostic and therapeutic targets. Preclinical studies in animals are still indispensable to uncover pathways involved in atherosclerotic disease and to evaluate novel drug targets. The translation of these targets, however, from animal studies to humans remains challenging. There is a strong need for novel biomarkers that can be used to prove the concept of a new target in humans. PMID:22468952

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

    Science.gov (United States)

    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. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

    Science.gov (United States)

    Pajtler, Kristian W; Sadowski, Natalie; Ackermann, Sandra; Althoff, Kristina; Schönbeck, Kerstin; Batzke, Katharina; Sch, Simonäfers; Odersky, Andrea; Heukamp, Lukas; Astrahantseff, Kathy; Künkele, Annette; Deubzer, Hedwig E; Schramm, Alexander; Spr, Annikaüssel; Thor, Theresa; Lindner, Sven; Eggert, Angelika; Fischer, Matthias; Schulte, Johannes H

    2017-01-01

    Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients. PMID:28036269

  18. Changes in plasma catecholamines levels as preclinical biomarkers in experimental models of Parkinson's disease.

    Science.gov (United States)

    Kim, A R; Ugryumov, M V

    2015-01-01

    The goal of this study was to investigate the changes in the concentrations of blood plasma catecholamines as possible biomarkers of Parkinson's disease (PD) in the mouse experimental model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A significant decrease was detected in the levels of dopamine and L-DOPA in the PD preclinical stage model as a result of the catecholamines systemic metabolism disfunction. In the PD early clinical stage models, the level of L-DOPA and dihydroxyphenylacetic acid decreased, which is consistent with the results of blood tests in untreated patients.

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

    Science.gov (United States)

    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.

  20. Challenging the Paradigms of Experimental TBI Models: From Preclinical to Clinical Practice.

    Science.gov (United States)

    Tortella, Frank C

    2016-01-01

    Despite prodigious advances in TBI neurobiology research and a broad arsenal of animal models mimicking different aspects of human brain injury, this field has repeatedly experienced collective failures to translate from animals to humans, particularly in the area of therapeutics. This lack of success stems from variability and inconsistent standardization across models and laboratories, as well as insufficient objective and quantifiable diagnostic measures (biomarkers, high-resolution imaging), understanding of the vast clinical heterogeneity, and clinically centered conception of the TBI animal models. Significant progress has been made by establishing well-defined standards for reporting animal studies with "preclinical common data elements" (CDE), and for the reliability and reproducibility in preclinical TBI therapeutic research with the Operation Brain Trauma Therapy (OBTT) consortium. However, to break the chain of failures and achieve a therapeutic breakthrough in TBI will probably require the use of higher species models, specific mechanism-based injury models by which to theranostically targeted treatment portfolios are tested, more creative concepts of therapy intervention including combination therapy and regeneration neurobiology strategies, and the adoption of dosing regimens based upon pharmacokinetic-pharmacodynamic (PK-PD) studies and guided by the injury severity and TBI recovery process.

  1. Animal Models of Gastrointestinal and Liver Diseases. The difficulty of animal modeling of pancreatic cancer for preclinical evaluation of therapeutics.

    Science.gov (United States)

    Logsdon, Craig D; Arumugam, Thiruvengadam; Ramachandran, Vijaya

    2015-09-01

    Pancreatic ductal adenocarcinoma (PDAC) is relatively rare but extremely lethal. Standard cytotoxic therapeutics provide little benefit. To date, newer targeted therapeutics have also not been highly successful. Often novel therapeutics that have appeared to perform well in preclinical models have failed in the clinic. Many factors contribute to these failures, but the one most often attributed is the shortcomings of the preclinical models. A plethora of animal models now exist for PDAC, including cell line xenografts, patient-derived xenografts, a wide variety of genetic mouse models, and syngeneic xenografts. These models have generated a tremendous amount of information useful for the understanding of PDAC. Yet none seems to well predict clinical outcomes of new treatments. This review will discuss how genetic instability and cellular heterogeneity make this disease so difficult to model accurately. We will also discuss the strengths and weaknesses of many of the popular models. Ultimately we will argue that there is no perfect model and that the best approach to understanding clinical performance is the use of multiple preclinical models with an understanding of their salient features.

  2. Relationships among Abuse Characteristics, Coping Strategies, and Abused Women's Psychological Health: A Path Model

    Science.gov (United States)

    Parker, Glennys; Lee, Christina

    2007-01-01

    We examined relationships between abuse, coping, and psychological health among 143 women who had experienced abuse in adult relationships. Measures included characteristics of the abuse, problem-focused and emotion-focused coping, Sense of Coherence, and four measures of psychological wellbeing--the SF-36 Mental Component Scale, the General…

  3. Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Cheng eWang

    2012-10-01

    Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

  4. Molecular imaging of neuroinflammation in preclinical rodent models using positron emission tomography.

    Science.gov (United States)

    Gargiulo, Sara; Coda, Anna R; Panico, Mariarosaria; Gramanzini, Matteo; Moresco, Rosa M; Chalon, Sylvie; Pappatà, Sabina

    2017-03-01

    Neuroinflammation (NI) is an adaptive response to different noxious stimuli, involving microglia, astrocytes and peripheral immune cells. NI is a hallmark of several acute and chronic diseases of central nervous system (CNS) and contributes to both damage and repair of CNS tissue. Interventional or genetically modified rodent models mimicking human neuropathologies may provide valuable insights on basic mechanisms of NI, but also for improving the development of new diagnostic and therapeutic strategies. Preclinical positron emission tomography (PET) allows to investigate noninvasively the inflammatory response in CNS of rodent models at a molecular level, validating innovative probes for early diagnosis, and characterizing the time course of neuroinflammatory changes and their relationship with disease progression, as well as the effects of experimental treatments with high translational potential. In particular, recent efforts of preclinical PET field are intended to develop specific and selective radiotracers that target the activation of innate immune system in CNS. Here, we have reviewed the state of art for PET in relevant rodent models of acute and chronic neuropathologies associated with NI, with particular regard on imaging of activated microglia and astrocytes.

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

    Science.gov (United States)

    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.

  6. Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine.

    Science.gov (United States)

    Green, Jennifer L; Dykstra, Linda A; Carelli, Regina M

    2015-06-01

    In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose.

  7. Imaging axonal degeneration and repair in pre-clinical animal models of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Soumya S Yandamuri

    2016-05-01

    Full Text Available Multiple sclerosis (MS is a central nervous system (CNS disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Over time, this neurologic damage manifests clinically as debilitating motor and cognitive symptoms. Existing MS therapies focus on symptom relief and delay of disease progression through reduction of neuroinflammation. However, long-term strategies to remyelinate, protect, or regenerate axons have remained elusive, posing a challenge to treating progressive forms of MS. Preclinical mouse models and techniques such as immunohistochemistry, flow cytometry, and genomic and proteomic analysis have provided advances in our understanding of discrete time-points of pathology following disease induction. More recently, in vivo and in situ two-photon microscopy (2P has made it possible to visualize continuous real-time cellular behavior and structural changes occurring within the CNS during neuropathology. Research utilizing 2P imaging to study axonopathy in neuroinflammatory demyelinating disease has focused on five areas: (1 axonal morphologic changes (2 organelle transport and health, (3 relationship to inflammation, (4 neuronal excitotoxicity, and (5 regenerative therapies. 2P imaging may also be used to identify novel therapeutic targets via identification and clarification of dynamic cellular and molecular mechanisms of axonal regeneration and remyelination. Here, we review tools that have made 2P accessible for imaging neuropathologies and advances in our understanding of axonal degeneration and repair in preclinical models of demyelinating diseases.

  8. From bench to bedside: utility of the rabbit elastase aneurysm model in preclinical studies of intracranial aneurysm treatment.

    Science.gov (United States)

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

    2016-05-01

    Preclinical 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) the 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 preclinical studies using this model are applied in the treatment of intracranial aneurysms in humans. The model has 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 extracranial location of the model 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, but further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms.

  9. High efficacy of intravesical treatment of metformin on bladder cancer in preclinical model.

    Science.gov (United States)

    Peng, Mei; Su, Qiongli; Zeng, Qing; Li, Le; Liu, Zhihong; Xue, Lei; Cheng, Yan; Huang, Yanjun; Tao, Ting; Lv, Hongwei; Li, Xiaohui; Tao, Xiaojun; Guo, Peng; Chen, Alex F; Yang, Xiaoping

    2016-02-23

    Anticancer potential of metformin has been extensively studied. However, its anticancer clinical use remains yet to be approved since sufficient concentration on target organs could not be achieved via conventional administration. To overcome this drawback, we aim to examine the efficiency of novel intravesical treatment of metformin on syngeneic orthotopic preclinical model. Three human and one murine bladder cancer cell lines were tested in vitro for inhibitory sensitivity by MTT and cologenic assays. AMPK pathway including AKT, Erk and S6K was examined by western blot and further explored by regulating activated levels using specific inhibitors. In vivo efficacy was determined by Kaplan-Meier survival curves and measurements of body and bladder weights plus tumor biomarkers. Lactic acid and metformin levels of plasma were measured by standard procedures. The results demonstrated that metformin activated AMPK and decreased phosphorylation of Akt and Erk. Furthermore, combinations of metformin with either Akt or Erk inhibitors synergistically diminished cancer proliferation, suggesting the involvement of Akt- and Erk- related pathways. Intravesical metformin 26 and 104 mg/kg, twice per week demonstrated a rapid elimination of the implanted tumor without any evidence of toxicity. In contrast, oral treatment at a dose of 800mg/kg/d exhibited little efficacy whereas severe toxicity existed if the dosage is higher. Collectively, intravesical metformin displays potent inhibition on bladder cancer in vitro and this preclinical study reveals the profound therapeutic application of metformin with durable tolerance via intravesical administration route.

  10. [Preclinical in vitro and in vivo models for the assessment of biological activity in biosimilarity studies].

    Science.gov (United States)

    Escobedo-Moratilla, Abraham; Barba de la Rosa, Ana Paulina; Pérez-Urizar, José Trinidad

    2015-01-01

    A drug that contains a recombinant protein as an active principle is called a biotechnological drug or biopharmaceutical.There are currently over 300 biopharmaceuticals worldwide. Many of these contains a similar active principle (biosimilar drug) as other previously registered (innovator drug). It has suggested that due to the complex implications in a formulation containing a protein, the manufacturing process is a key factor for efficacy and safety requirements. In fact, certain variability has been detected of the protein properties in different lots (or batches) of the same manufacturer, which produce changes at a clinical level. For this reason, the evaluation of biosimilar drugs has acquired great relevance, being the preclinical level of one of the more important stages of the development due to its lower cost (with respect to the clinical level) and its high capacity to detect formulation-manufacture problems. However, the demonstration of comparability at physicochemical, preclinical, and clinical levels is required in order to achieve market registration. In this review the in vitro and in vivo models used for the assessment of proposed biosimilars will be discussed.

  11. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  12. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

    Directory of Open Access Journals (Sweden)

    Antonio Gonzalez-Bulnes

    2016-03-01

    Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

  13. Photoacoustic tomography of vascular therapy in a preclinical mouse model of colorectal carcinoma

    Science.gov (United States)

    Johnson, S. P.; Ogunlade, O.; Zhang, E.; Laufer, J.; Rajkumar, V.; Pedley, R. B.; Beard, P.

    2014-03-01

    Vascular therapy in oncology exploits the differences between normal blood vessels and abnormal tumour neoangiogenesis to selectively target cancer. For optimal treatment efficacy, and translation of novel compounds, the response of the tumour vasculature needs to be assessed. Photoacoustic tomography (PAT) is capable of this as it provides highly spatially resolved 3D images of vascular networks in biological tissue to cm depths. In preclinical models of cancer this is sufficient to encompass entire subcutaneous tumours, and can therefore be used to evaluate pharmacological intervention directed at the vasculature. In this study the vascular disrupting agent OXi4503 was used to treat subcutaneous tumour mouse models of two human colorectal carcinoma tumour types (SW1222, LS174T) at a range of concentrations (40mg/kg, 10mg/kg, 1mg/kg and sham dose control). The characteristic destruction of tumour vasculature caused by OXi4503 was observed by PAT and confirmed ex vivo via histology. Differences observed between the two tumour types assessed demonstrate the importance of tumour microenvironment and pathophysiology on response to therapy. Differential response to different doses of OXi4503 was observed, with outward tumour growth only seen once entire tumour viability had been re-established; this demonstrates the potential of PAT to act as a biomarker of response for the translation of novel anti-vascular compounds and also within the clinic. This study shows clearly that PAT can accurately assess the time course of drug action and relapse of pharmacodynamic effect in preclinical models of cancer and the important translational prospects for vascular targeted tumour therapies.

  14. Preclinical models of muscle spasticity: valuable tools in the development of novel treatment for neurological diseases and conditions.

    Science.gov (United States)

    Bespalov, Anton; Mus, Liudmila; Zvartau, Edwin

    2016-05-01

    Poor validity of preclinical animal models is one of the most commonly discussed explanations for the failures to develop novel drugs in general and in neuroscience in particular. However, there are several areas of neuroscience such as injury-induced spasticity where etiological factor can be adequately recreated and models can focus on specific pathophysiological mechanisms that likely contribute to spasticity syndrome in humans (such as motoneuron hyperexcitability and spinal hyperreflexia). Methods used to study spasticity in preclinical models are expected to have a high translational value (e.g., electromyogram (EMG)-based electrophysiological tools) and can efficiently assist clinical development programs. However, validation of these models is not complete yet. First, true predictive validity of these models is not established as clinically efficacious drugs have been used to reverse validate preclinical models while newly discovered mechanisms effective in preclinical models are yet to be fully explored in humans (e.g., 5-HT2C receptor inverse agonists, fatty acid amid hydrolase inhibitors). Second, further efforts need to be invested into cross-laboratory validation of study protocols and tools, adherence to the highest quality standards (blinding, randomization, pre-specified study endpoints, etc.), and systematic efforts to replicate key sets of data. These appear to be readily achievable tasks that will enable development not only of symptomatic but also of disease-modifying therapy of spasticity, an area that seems to be currently not in focus of research efforts.

  15. Effective adjunctive therapy by an innate defense regulatory peptide in a preclinical model of severe malaria.

    Science.gov (United States)

    Achtman, Ariel H; Pilat, Sandra; Law, Charity W; Lynn, David J; Janot, Laure; Mayer, Matt L; Ma, Shuhua; Kindrachuk, Jason; Finlay, B Brett; Brinkman, Fiona S L; Smyth, Gordon K; Hancock, Robert E W; Schofield, Louis

    2012-05-23

    Case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. We assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (IDR) peptides, based on host defense peptides. The Plasmodium berghei ANKA model of experimental cerebral malaria was adapted to use as a preclinical screen by combining late-stage intervention in established infections with advanced bioinformatic analysis of early transcriptional changes in co-regulated gene sets. Coadministration of IDR-1018 with standard first-line antimalarials increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. Thus, IDR peptides provided host-directed adjunctive therapy for severe disease in combination with antimalarial treatment.

  16. EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis

    Science.gov (United States)

    Greaves, Erin; Horne, Andrew W.; Jerina, Helen; Mikolajczak, Marta; Hilferty, Lisa; Mitchell, Rory; Fleetwood-Walker, Sue M.; Saunders, Philippa T. K.

    2017-01-01

    Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis. PMID:28281561

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

    Science.gov (United States)

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

    2016-01-01

    Aims 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. Background 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

  18. Mesenchymal stem cell therapy promotes the improvement and recovery of renal function in a preclinical model

    Directory of Open Access Journals (Sweden)

    Antônio Urt Filho

    2016-01-01

    Full Text Available 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.

  19. CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa.

    Science.gov (United States)

    Wu, Wen-Hsuan; Tsai, Yi-Ting; Justus, Sally; Lee, Ting-Ting; Zhang, Lijuan; Lin, Chyuan-Sheng; Bassuk, Alexander G; Mahajan, Vinit B; Tsang, Stephen H

    2016-08-01

    Massive parallel sequencing enables identification of numerous genetic variants in mutant organisms, but determining pathogenicity of any one mutation can be daunting. The most commonly studied preclinical model of retinitis pigmentosa called the "rodless" (rd1) mouse is homozygous for two mutations: a nonsense point mutation (Y347X) and an intronic insertion of a leukemia virus (Xmv-28). Distinguishing which mutation causes retinal degeneration is still under debate nearly a century after the discovery of this model organism. Here, we performed gene editing using the CRISPR/Cas9 system and demonstrated that the Y347X mutation is the causative variant of disease. Genome editing in the first generation produced animals that were mosaic for the corrected allele but still showed neurofunction preservation despite low repair frequencies. Furthermore, second-generation CRISPR-repaired mice showed an even more robust rescue and amelioration of the disease. This predicts excellent outcomes for gene editing in diseased human tissue, as Pde6b, the mutated gene in rd1 mice, has an orthologous intron-exon relationship comparable with the human PDE6B gene. Not only do these findings resolve the debate surrounding the source of neurodegeneration in the rd1 model, but they also provide the first example of homology-directed recombination-mediated gene correction in the visual system.

  20. Can laboratory animals violate behavioural norms? Towards a preclinical model of conduct disorder.

    Science.gov (United States)

    Macrì, Simone; Zoratto, Francesca; Chiarotti, Flavia; Laviola, Giovanni

    2017-02-03

    Conduct disorder (CD), a disturbance characterised by excess rates of aggression - often associated with callousness, lack of empathy and shallow/deficient affect - is extremely prevalent (2-10%) in the juvenile population. CD symptoms are quantitative rather than qualitative in nature whereby, rather than exhibiting abnormal behaviours, CD patients indulge in normal behaviours at abnormal rates. Although genetic and environmental factors contribute to CD aetiology, their precise contribution is yet to be determined. Experimental animal models may aid discriminating genetic vs. environmental effects and designing innovative therapeutic approaches. Here we discuss a theoretical framework potentially favouring the design of experimental models of CD. We suggest that the latter shall recapitulate the "norm violation" typical of the human disorder across the core domains involved in CD: aggression, callousness, empathy and emotionality. We first review how these domains have been operationalised in preclinical models; we then suggest that these experimental paradigms shall be combined with appropriate statistical tools to identify a subset of individuals consistently characterised by abnormal values in CD-relevant phenotypes.

  1. Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor.

    Science.gov (United States)

    Hu, Yafang; Bobb, Daniel; Lu, Yunbiao; He, Jianping; Dome, Jeffrey S

    2014-09-01

    Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.

  2. Cardiorenal syndrome: pathophysiological mechanism, preclinical models, novel contributors and potential therapies

    Institute of Scientific and Technical Information of China (English)

    Fu Qiang; Cao Longxing; Li Huang; Wang Binghui; Li Zhiliang

    2014-01-01

    Objective To review the current knowledge about the pathophysiological mechanisms,preclinical models,novel contributors and potential therapies of cardiorenal syndrome.Data sources The literature concerning cardioranal syndrome in this review was collected from PubMed published in English up to January 2014.Study selection Original articles and critical reviews related to cardiorenal syndrome were selected and carefully analyzed.Results Cardiorenal syndrome is a condition characterized by kidney and heart failure where failure of one organ worsens the function of the other thus further accelerating the progressive failure of both organs.The pathophysiology of cardiorenal syndrome is not fully understood,but may be caused by a complex combination of neurohormonal system activation,endothelial dysfunction,proteinuria,oxidative stress,uremic toxins and other factors.Managing cardiorenal syndrome is still a major therapeutic challenge in clinical practice because many of the drugs used to control heart failure can worsen renal function,and vice versa.Non-dialyzable uremic toxins,such as indoxyl sulfate,causing detrimental effects on the heart and kidney as well as stimulation of inflammatory responses,may be an effective therapeutic target for cardiorenal syndrome.Conclusions Suitable disease models of cardiorenal syndrome are urgently needed to investigate the pathophysiology and effective therapeutic approaches to the condition.Non-dialyzable protein-bound uremic toxins that may have cardiac and renal effects may provide therapeutic benefit to cardiorenal syndrome patients.

  3. A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

    Directory of Open Access Journals (Sweden)

    Jody E. Hooper

    2015-01-01

    Full Text Available Embryonal rhabdomyosarcoma (eRMS is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

  4. Preclinical photoacoustic models: application for ultrasensitive single cell malaria diagnosis in large vein and artery

    Science.gov (United States)

    Menyaev, Yulian A.; Carey, Kai A.; Nedosekin, Dmitry A.; Sarimollaoglu, Mustafa; Galanzha, Ekaterina I.; Stumhofer, Jason S.; Zharov, Vladimir P.

    2016-01-01

    In vivo photoacoustic flow cytometry (PAFC) has demonstrated potential for early diagnosis of deadly diseases through detection of rare circulating tumor cells, pathogens, and clots in nearly the entire blood volume. Before clinical application, this promising diagnostic platform requires verification and optimization using adequate preclinical models. We show here that this can be addressed by examination of large mouse blood vessels which are similar in size, depth and flow velocity to human vessels used in PAFC. Using this model, we verified the capability of PAFC for ultrasensitive, noninvasive, label-free, rapid malaria diagnosis. The time-resolved detection of delayed PA signals from deep vessels provided complete elimination of background from strongly pigmented skin. We discovered that PAFC’s sensitivity is higher during examination of infected cells in arteries compared to veins at similar flow rate. Our advanced PAFC platform integrating a 1060 nm laser with tunable pulse rate and width, a wearable probe with a focused transducer, and linear and nonlinear nanobubble-amplified signal processing demonstrated detection of parasitemia at the unprecedented level of 0.00000001% within 20 seconds and the potential to further improve the sensitivity 100-fold in humans, that is approximately 106 times better than in existing malaria tests. PMID:27699126

  5. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    Science.gov (United States)

    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.

  6. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    CERN Document Server

    Di Clemente, Riccardo; 10.1038/srep00532

    2012-01-01

    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.

  7. Effects of spatial and spectral frequencies on wide-field functional imaging (wifi) characterization of preclinical breast cancer models

    Science.gov (United States)

    Moy, Austin; Kim, Jae G.; Lee, Eva Y. H. P.; Choi, Bernard

    2010-02-01

    A common strategy to study breast cancer is the use of the preclinical model. These models provide a physiologically relevant and controlled environment in which to study both response to novel treatments and the biology of the cancer. Preclinical models, including the spontaneous tumor model and mammary window chamber model, are very amenable to optical imaging and to this end, we have developed a wide-field functional imaging (WiFI) instrument that is perfectly suited to studying tumor metabolism in preclinical models. WiFI combines two optical imaging modalities, spatial frequency domain imaging (SFDI) and laser speckle imaging (LSI). Our current WiFI imaging protocol consists of multispectral imaging in the near infrared (650-980 nm) spectrum, over a wide (7 cm x 5 cm) field of view. Using SFDI, the spatially-resolved reflectance of sinusoidal patterns projected onto the tissue is assessed, and optical properties of the tissue are determined, which are then used to extract tissue chromophore concentrations in the form of oxy-, deoxy-, and total hemoglobin concentrations, and percentage of lipid and water. In the current study, we employ Monte Carlo simulations of SFDI light propagation in order to characterize the penetration depth of light in both the spontaneous tumor model and mammary window chamber model. Preliminary results suggest that different spatial frequency and wavelength combinations have different penetration depths, suggesting the potential depth sectioning capability of the SFDI component of WiFI.

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

    Science.gov (United States)

    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.

  9. Preclinical imaging in animal models of radiation therapy; Praeklinische Bildgebung im Tiermodell bei Strahlentherapie

    Energy Technology Data Exchange (ETDEWEB)

    Nikolaou, K.; Cyran, C.C.; Reiser, M.F.; Clevert, D.-A. [Klinikum der Ludwig-Maximilians-Universitaet, Campus Grosshadern, Institut fuer Klinische Radiologie, Muenchen (Germany); Lauber, K. [Klinikum der Ludwig-Maximilians-Universitaet, Klinik und Poliklinik fuer Strahlentherapie, Muenchen (Germany)

    2012-03-15

    Modern radiotherapy benefits from precise and targeted diagnostic and pretherapeutic imaging. Standard imaging modalities, such as computed tomography (CT) offer high morphological detail but only limited functional information on tumors. Novel functional and molecular imaging modalities provide biological information about tumors in addition to detailed morphological information. Perfusion magnetic resonance imaging (MRI) CT or ultrasound-based perfusion imaging as well as hybrid modalities, such as positron emission tomography (PET) CT or MRI-PET have the potential to identify and precisely delineate viable and/or perfused tumor areas, enabling optimization of targeted radiotherapy. Functional information on tissue microcirculation and/or glucose metabolism allow a more precise definition and treatment of tumors while reducing the radiation dose and sparing the surrounding healthy tissue. In the development of new imaging methods for planning individualized radiotherapy, preclinical imaging and research plays a pivotal role, as the value of multimodality imaging can only be assessed, tested and adequately developed in a preclinical setting, i.e. in animal tumor models. New functional imaging modalities will play an increasing role for the surveillance of early treatment response during radiation therapy and in the assessment of the potential value of new combination therapies (e.g. combining anti-angiogenic drugs with radiotherapy). (orig.) [German] Die moderne Strahlentherapie profitiert massgeblich von einer detaillierten wie auch funktionellen praetherapeutischen Bildgebung. Die ueblicherweise praetherapeutisch eingesetzten radiologischen Standardverfahren wie die Computertomographie liefern zwar hochwertige morphologische Details, jedoch keine funktionelle Information. Es ist somit ein zunehmender Bedarf an funktionellen und molekularen Bildgebungsmodalitaeten feststellbar, mit denen ergaenzend zur morphologischen Bildgebung auch biologisch

  10. Multitargeting strategy using lenvatinib and golvatinib: maximizing anti-angiogenesis activity in a preclinical cancer model.

    Science.gov (United States)

    Nakazawa, Youya; Kawano, Satoshi; Matsui, Junji; Funahashi, Yasuhiro; Tohyama, Osamu; Muto, Hiroki; Nakagawa, Takayuki; Matsushima, Tomohiro

    2015-02-01

    Almost all cancers show intrinsic and/or evasive resistance to vascular endothelial growth factor (VEGF) inhibitors by multiple mechanisms. Serum angiopoietin-2 (Ang2) level has been proposed as a potential biomarker of VEGF inhibitor response in several cancers. From these clinical observations, the Ang2 and Tie2 (its receptor) axis has been focused on as a promising target. Here, we show a novel strategy to circumvent the resistance by combining multi-tyrosine kinase inhibitors lenvatinib (VEGF receptor, fibroblast growth factor receptor, and RET inhibitor) and golvatinib (E7050; c-Met, Tie2, and EphB4 inhibitor). Tie2 identifies a highly pro-angiogenic macrophage subset, Tie2-expressing macrophages (TEM). Angi-Tie2 and EphB4-EphrinB2 signaling plays critical roles in pericyte-mediated vessel stabilization. In vitro analyses suggested that golvatinib combined with lenvatinib inhibited pericyte-mediated vessel stabilization and TEM differentiation. In thyroid and endometrial cancer models, golvatinib and lenvatinib inhibited pericyte network development and TEM infiltration, resulting in severe perfusion disorder and massive apoptosis. Body weight loss was tolerable, and no macroscopic change was observed. These preclinical studies suggest that modulation of the tumor microenvironment by a strategic and well-tolerated combination of multi-targeting tyrosine kinase inhibitors may sensitize cancer to VEGF inhibitors.

  11. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    Science.gov (United States)

    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

  12. Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides

    Institute of Scientific and Technical Information of China (English)

    LI Liang-zhu; YANG Yu; YUAN Song-hua; WAN Yan-min; QIU Chao; FENG Yan-ling; XU Jian-qing; ZHANG Xiao-yan

    2010-01-01

    Background 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.Methods 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-Y (IFN-Y), 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.Results 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

  13. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Shuhua Chen

    Full Text Available Previously, we demonstrated that allopregnanolone (APα promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD. In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R, three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing

  14. Preclinical mouse models for assessing axial compression of long bones during exercise.

    Science.gov (United States)

    Stadelmann, Vincent A; Brun, Julia; Bonnet, Nicolas

    2015-01-01

    The aim of this laboratory method is to describe two approaches for the investigation of bone responses to mechanical loading in mice in vivo. The first is running exercise, because it is easily translatable clinically, and the second is axial compression of the tibia, because it is precisely controllable. The effects of running exercise, and in general physical activity, on bone tissue have been shown to be both direct through mechanical loading (ground impact and muscle tension) and indirect through metabolic changes. Therefore, running exercise has been considered the most convenient preclinical model for demonstrating the general idea that exercise is good for bone health, either early in age for increasing peak bone mass or later in age by slowing down bone loss. However, numerous combinations of protocols have been reported, which makes it difficult to formulate a simple take-home message. This laboratory method also provides a detailed description of in vivo direct mechanical axial compression of the mouse tibia. The effects of mechanical loading depend on the force (strain), frequency, waveform and duration of application, and they range from bone anabolism with low bone remodeling, inducing lamellar bone accumulation, to bone catabolism with high bone remodeling, leading to microdamage, woven bone formation and bone loss. Direct in vivo loading models are extensively used to study mechanotransduction pathways, and contribute by this way to the development of new bone anabolism treatments. Although it is particularly difficult to assemble an internationally adopted protocol description, which would give reproducible bone responses, here we have attempted to provide a comprehensive guide for best practice in performing running exercise and direct in vivo mechanical loading in the laboratory.

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

    Science.gov (United States)

    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…

  16. A Process Model for Understanding Adaptation to Sexual Abuse: The Role of Shame in Defining Stigmatization.

    Science.gov (United States)

    Feiring, Candice; And Others

    1996-01-01

    This article presents a theoretical and testable model of psychological processes in child and adolescent victims of sexual abuse. It proposes that sexual abuse leads to shame through mediation of cognitive attributions which leads to poor adjustment. Three factors--social support, gender, and developmental period--are hypothesized to moderate the…

  17. A Multi-Dimensional Model of Groupwork for Adolescent Girls Who Have Been Sexually Abused.

    Science.gov (United States)

    Lindon, Jillian; Nourse, Carol A.

    1994-01-01

    A treatment approach for sexually abused adolescent girls, using a group work model, incorporated three treatment modalities: a skills component, a psychotherapeutic component, and an educative component. Abused girls demonstrated difficulties in many areas of their lives. The six participants showed improvement according to self-statements and…

  18. Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine.

    Science.gov (United States)

    Barbato, Emanuele; Barton, Paul J; Bartunek, Jozef; Huber, Sally; Ibanez, Borja; Judge, Daniel P; Lara-Pezzi, Enrique; Stolen, Craig M; Taylor, Angela; Hall, Jennifer L

    2015-11-01

    The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies.

  19. Benefits of Non-Linear Mixed Effect Modeling and Optimal Design : Pre-Clinical and Clinical Study Applications

    OpenAIRE

    Ernest II, Charles Steven

    2013-01-01

    Despite the growing promise of pharmaceutical research, inferior experimentation or interpretation of data can inhibit breakthrough molecules from finding their way out of research institutions and reaching patients. This thesis provides evidence that better characterization of pre-clinical and clinical data can be accomplished using non-linear mixed effect modeling (NLMEM) and more effective experiments can be conducted using optimal design (OD).  To demonstrate applicability of NLMEM and OD...

  20. Treatment and prevention of elder abuse and neglect: where knowledge and practice meet-a model for intervention to prevent and treat elder abuse in Israel.

    Science.gov (United States)

    Alon, Sara; Berg-Warman, Ayelet

    2014-01-01

    Successful handling of elder abuse and neglect requires various interventions. This article presents findings from an evaluation study of a model for intervention implemented in three municipalities in Israel. Data from 558 older adults, exposed to abuse and treated through the program, and interviews with victims, abusers, and professionals revealed that improvement was achieved in 66% of the cases. In 20% of the cases, the abuse was stopped. The most widespread type of intervention consisted of individual counseling. Legal intervention yielded the highest rate of improvement (82%). Provision of supportive services for victims of neglect was found to be most effective (82% of improvement in the situation).

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

    Science.gov (United States)

    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. Abuse Potential of Pregabalin

    DEFF Research Database (Denmark)

    Schjerning, Ole; Rosenzweig, Mary; Pottegård, Anton

    2016-01-01

    BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers...... for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known. OBJECTIVE: The aim...... of this study was to present a systematic review of the data concerning the abuse potential of pregabalin. METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin. RESULTS: We included preclinical (n = 17...

  3. Labelling and tracking of human mesenchymal stromal cells in preclinical studies and large animal models of degenerative diseases.

    Science.gov (United States)

    Vaegler, Martin; Maerz, Jan K; Amend, Bastian; da Silva, Luis Arenas; Mannheim, Julia G; Fuchs, Kerstin; Will, Susanne; Sievert, Karl D; Stenzl, Arnulf; Hart, Melanie L; Aicher, Wilhelm K

    2014-01-01

    Success of stem cell therapies were reported in different medical disciplines, including haematology, rheumatology, orthopaedic surgery, traumatology, and others. Currently, more than 4000 clinical trials using stem cells have been completed or are underway, among which 378 investigated or are at present investigating mesenchymal stromal cells (MSCs). The majority of clinical trials using stem- or progenitor- cells, including hematopoietic stem cells and MSCs, target the immune system. However, therapies based on MSCs are increasingly implemented to treat symptoms in which failure of the resident stem cells in situ, or malfunction of tissues or structures are not associated with immune cells or inflammation, but instead are associated with mechanical or metabolic stress, ageing, developmental or acquired malformations, and other causes. To proceed further in the development of stem cell therapies as a safe and effective treatment for surgical and other medical specialities, the behaviour of MSCs implanted in preclinical models and their impact on the site of application need to be explored in detail. Depending on the pre-clinical model employed, tracking of labelled stem cells in live animals makes an enormous difference for exploration of the mechanisms and kinetics involved in MSC-mediated tissue regeneration. Here we review (pre-)clinically applicable key methods to label human MSCs for short and long-term observations in small and large animal models.

  4. A Novel Preclinical Model of Moderate Primary Blast-Induced Traumatic Brain Injury.

    Science.gov (United States)

    Divani, Afshin A; Murphy, Amanda J; Meints, Joyce; Sadeghi-Bazargani, Homayoun; Nordberg, Jessica; Monga, Manoj; Low, Walter C; Bhatia, Prerana M; Beilman, Greg J; SantaCruz, Karen S

    2015-07-15

    Blast-induced traumatic brain injury (bTBI) is the "signature" injury of the recent Iraq and Afghanistan wars. Here, we present a novel method to induce bTBI using shock wave (SW) lithotripsy. Using a lithotripsy machine, Wistar rats (N = 70; 408.3 ± 93 g) received five SW pulses to the right side of the frontal cortex at 24 kV and a frequency of 60 Hz. Animals were then randomly divided into three study endpoints: 24 h (n = 25), 72 h (n = 19) and 168 h (n = 26). Neurological and behavioral assessments (Garcia's test, beam walking, Rotarod, and elevated plus maze) were performed at the baseline, and further assessments followed at 3, 6, 24, 72, and 168 h post-injury, if applicable. We performed digital subtraction angiography (DSA) to assess presence of cerebral vasospasm due to induced bTBI. Damage to brain tissue was assessed by an overall histological severity (OHS) score based on depth of injury, area of hemorrhage, and extent of axonal injury. Except for beam walking, OHS was significantly correlated with the other three outcome measures with at least one of their assessments during the first 6 h after the experiment. OHS manifested the highest absolute correlation coefficients with anxiety at the baseline and 6 h post-injury (r(baseline) = -0.75, r(6hrs) = 0.85; p<0.05). Median hemispheric differences for contrast peak values (obtained from DSA studies) for 24, 72, and 168 h endpoints were 3.45%, 3.05% and 0.2%, respectively, with statistically significant differences at 1 versus 7 d (p<0.05) and 3 versus 7 d (p<0.01). In this study, we successfully established a preclinical rat model of bTBI with characteristics similar to those observed in clinical cases. This new method may be useful for future investigations aimed at understanding bTBI pathophysiology.

  5. Women's steps of change and entry into drug abuse treatment. A multidimensional stages of change model.

    Science.gov (United States)

    Brown, V B; Melchior, L A; Panter, A T; Slaughter, R; Huba, G J

    2000-04-01

    The Transtheoretical, or Stages of Change Model, has been applied to the investigation of help-seeking related to a number of addictive behaviors. Overall, the model has shown to be very important in understanding the process of help-seeking. However, substance abuse rarely exists in isolation from other health, mental health, and social problems. The present work extends the original Stages of Change Model by proposing "Steps of Change" as they relate to entry into substance abuse treatment programs for women. Readiness to make life changes in four domains-domestic violence, HIV sexual risk behavior, substance abuse, and mental health-is examined in relation to entry into four substance abuse treatment modalities (12-step, detoxification, outpatient, and residential). The Steps of Change Model hypothesizes that help-seeking behavior of substance-abusing women may reflect a hierarchy of readiness based on the immediacy, or time urgency, of their treatment issues. For example, women in battering relationships may be ready to make changes to reduce their exposure to violence before admitting readiness to seek substance abuse treatment. The Steps of Change Model was examined in a sample of 451 women contacted through a substance abuse treatment-readiness program in Los Angeles, California. A series of logistic regression analyses predict entry into four separate treatment modalities that vary. Results suggest a multidimensional Stages of Change Model that may extend to other populations and to other types of help-seeking behaviors.

  6. SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Hendrikx, Geert [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Voeoe, Stefan [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Bauwens, Matthias [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht (Netherlands); Post, Mark J. [Maastricht University, Department of Physiology, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); University Hospital, RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

    2016-12-15

    The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging. (orig.)

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

    Science.gov (United States)

    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.

  8. Pavlovian sign-tracking model of alcohol abuse.

    Science.gov (United States)

    Tomie, Arthur; Sharma, Nikyta

    2013-09-01

    While poorly controlled alcohol drinking is a prominent symptom of alcohol abuse, its environmental determinants remain poorly understood. The Sign-Tracking Model (STM), developed by Tomie and his associates, postulates that poorly controlled alcohol drinking is due to the development of signal-directed behaviors induced by Pavlovian sign-tracking procedures. In laboratory studies of animal learning, presentation of the lever (conditioned stimulus, CS) followed by the presentation of the food (unconditioned stimulus, US) induces sign-tracking conditioned response (CR) performance, wherein rats approach and contact, then express consummatory-like responses (i.e., licking, gnawing, and chewing) directed at the lever CS. The Pavlovian sign-tracking CR is an involuntary acquired reflexive response. It is poorly controlled and elicited by the presentation of the CS. STM proposes that poorly controlled alcohol drinking in humans may be due to repeated pairings of the alcohol sipper (e.g., cocktail glass) CS with alcohol's rewarding effects US, resulting in sign-tracking CR performance. The cocktail glass CS will elicit Pavlovian sign-tracking CR performance of reflexive and involuntary alcohol intake. This paper reviews evidence in the Pavlovian conditioning literature that in animals the positive contingency between the alcohol sipper CS and alcohol US induces sign-tracking of alcohol drinking. Also reviewed is evidence that in human beings alcohol drinking is a direct function of the positive contingency between a particular alcohol glassware CS and alcohol US. Implications of these findings for the Sign-Tracking Model (STM) are discussed.

  9. Preclinical models of atherosclerosis. The future of Hybrid PET/MR technology for the early detection of vulnerable plaque.

    Science.gov (United States)

    Cuadrado, Irene; Saura, Marta; Castejón, Borja; Martin, Ana María; Herruzo, Irene; Balatsos, Nikolaos; Zamorano, Jose Luis; Zaragoza, Carlos

    2016-04-08

    Cardiovascular diseases are the leading cause of death in developed countries. The aetiology is currently multifactorial, thus making them very difficult to prevent. Preclinical models of atherothrombotic diseases, including vulnerable plaque-associated complications, are now providing significant insights into pathologies like atherosclerosis, and in combination with the most recent advances in new non-invasive imaging technologies, they have become essential tools to evaluate new therapeutic strategies, with which can forecast and prevent plaque rupture. Positron emission tomography (PET)/computed tomography imaging is currently used for plaque visualisation in clinical and pre-clinical cardiovascular research, albeit with significant limitations. However, the combination of PET and magnetic resonance imaging (MRI) technologies is still the best option available today, as combined PET/MRI scans provide simultaneous data acquisition together with high quality anatomical information, sensitivity and lower radiation exposure for the patient. The coming years may represent a new era for the implementation of PET/MRI in clinical practice, but first, clinically efficient attenuation correction algorithms and research towards multimodal reagents and safety issues should be validated at the preclinical level.

  10. Adapting a model of response to child abuse to the conditions in the circumpolar north

    DEFF Research Database (Denmark)

    Søbjerg, Lene Mosegaard; Thams, Alice Fredsgaard

    2016-01-01

    This short communication presents recent changes in the approach to sexually abused children in Greenland. The communication acknowledges the importance of adjusting foreign models of social care to the local circumstances of the Arctic population and geography.......This short communication presents recent changes in the approach to sexually abused children in Greenland. The communication acknowledges the importance of adjusting foreign models of social care to the local circumstances of the Arctic population and geography....

  11. Preclinical imaging and translational animal models of cancer for accelerated clinical implementation of nanotechnologies and macromolecular agents.

    Science.gov (United States)

    De Souza, Raquel; Spence, Tara; Huang, Huang; Allen, Christine

    2015-12-10

    The majority of animal models of cancer have performed poorly in terms of predicting clinical performance of new therapeutics, which are most often first evaluated in patients with advanced, metastatic disease. The development and use of metastatic models of cancer may enhance clinical translatability of preclinical studies focused on the development of nanotechnology-based drug delivery systems and macromolecular therapeutics, potentially accelerating their clinical implementation. It is recognized that the development and use of such models are not without challenge. Preclinical imaging tools offer a solution by allowing temporal and spatial characterization of metastatic lesions. This paper provides a review of imaging methods applicable for evaluation of novel therapeutics in clinically relevant models of advanced cancer. An overview of currently utilized models of oncology in small animals is followed by image-based development and characterization of visceral metastatic cancer models. Examples of imaging tools employed for metastatic lesion detection, evaluation of anti-tumor and anti-metastatic potential and biodistribution of novel therapies, as well as the co-development and/or use of imageable surrogates of response, are also discussed. While the focus is on development of macromolecular and nanotechnology-based therapeutics, examples with small molecules are included in some cases to illustrate concepts and approaches that can be applied in the assessment of nanotechnologies or macromolecules.

  12. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review.

    Directory of Open Access Journals (Sweden)

    Lauralyn A McIntyre

    Full Text Available The Acute Respiratory Distress Syndrome (ARDS is a devastating clinical condition that is associated with a 30-40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI (the pre-clinical correlate of human ARDS on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18-0.34, I2 8%. Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics. Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.

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

    Directory of Open Access Journals (Sweden)

    Amy J. C. Dohmen

    2015-08-01

    Full Text Available 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Dohmen, Amy J. C., E-mail: a.dohmen@nki.nl [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Swartz, Justin E. [Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Van Den Brekel, Michiel W. M. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Willems, Stefan M. [Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Spijker, René [Medical library, Academic Medical Center, Amsterdam 1100 DE (Netherlands); Dutch Cochrane Centre, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Neefjes, Jacques [Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Zuur, Charlotte L. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands)

    2015-08-28

    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.

  15. A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger?

    Science.gov (United States)

    Strolin, Silvia; Bossi, Gianluca; Strigari, Lidia

    2017-01-01

    Background Preclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR). In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects. Methods We reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED). To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells. Results Our results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated. Conclusion Our study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice. PMID:28222111

  16. Childhood Sexual Abuse

    Directory of Open Access Journals (Sweden)

    Evrim Aktepe

    2009-08-01

    behavioral and psychological results by itself, early trauma may also lead to biological effects. Especially traumas during neuron plasticity phase may lead hypersensitivity of neuroendocrine stress response. Early life stresses are shown to lead changes in corticotrophin releasing factor system in preclinical and clinical phase studies. In the treatment of sexual abuse, emotional process related with trauma should be focused on. This process may be conducted with play therapy. Development of higher level defense mechanism, increasing ego capacity, orientation to social activity and personal activity according to skills is aimed. For the elimination of guiltiness related with stigmatization, the child should be told that it is not herhis fault to incorporate into sexual interaction and the culprit is abuser. It is fairly important for medical staff, school and family to have sufficient information about sexual abuse for prevention and early recognition.

  17. Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

    OpenAIRE

    Virginia Rivulgo; Mónica Sparo; Mónica Ceci; Elida Fumuso; Alejandra Confalonieri; Gastón Delpech; Sánchez Bruni, Sergio F.

    2016-01-01

    Azithromycin(AZM)therapeutic failure and relapses of patients treated with generic -35 formulations have been observed in clinical practice.The main goal of this research was 36 to compare in a pre-clinical study the serum exposure and lung tissue concentrationof 37 two commercial formulations AZM-based in murine model. The current study involved 38 264 healthy Balb-C.Mice were divided in two groups (n=44): Animals of Group A 39 (Reference Formulation ?R-) were orally treated with AZM suspens...

  18. Abuse and dependence liability analysis of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder (ADHD): what have we learned?

    Science.gov (United States)

    Dela Peña, Ike; Kim, Bung-Nyun; Han, Doug Hyun; Kim, Yeni; Cheong, Jae Hoon

    2013-04-01

    Methylphenidate is the most prescribed stimulant medication for attention-deficit/hyperactivity disorder (ADHD). Despite the well documented clinical benefits of the drug, several questions remain unanswered concerning the effects of extended methylphenidate use (e.g. can methylphenidate be abused by ADHD patients? does repeated methylphenidate treatment produce addiction?). Preclinical studies can help address the long-term safety of clinical treatments, moreover animal studies provide valuable information on the details of drug actions. The spontaneously hypertensive rat (SHR), bred from normotensive Wistar Kyoto rat strain, is considered as the best validated and the most widely used animal model of ADHD. We reviewed the findings of research reports that investigated the abuse and dependence liability of methylphenidate in SHR. In particular, we surveyed the studies which investigated the effects of methylphenidate pretreatment on subsequent methylphenidate-induced conditioned place preference or self-administration for they may give insights into the abuse or dependence liability of long-term methylphenidate treatment in ADHD.

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

    Science.gov (United States)

    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.

  20. Vaccines for Drug Abuse

    Science.gov (United States)

    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

  1. Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices.

    Science.gov (United States)

    Schomberg, Dominic T; Tellez, Armando; Meudt, Jennifer J; Brady, Dane A; Dillon, Krista N; Arowolo, Folagbayi K; Wicks, Joan; Rousselle, Serge D; Shanmuganayagam, Dhanansayan

    2016-04-01

    Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.

  2. A Model Adolescent Substance-Abuse Treatment Program.

    Science.gov (United States)

    Copans, Stuart

    1993-01-01

    Describes two adolescent substance abuse treatment programs in New England psychiatric center: Osgood Three, which is no longer in existence, and Tyler Three, which replaced it and is struggling to grow. Considers transition from Osgood Three to Tyler Three, process of change, and learning what can be preserved from past and what must be…

  3. Disruption of Learning Processes by Chemotherapeutic Agents in Childhood Survivors of Acute Lymphoblastic Leukemia and Preclinical Models

    Directory of Open Access Journals (Sweden)

    Emily B. Bisen-Hersh, Philip N. Hineline, Ellen A. Walker

    2011-01-01

    Full Text Available Objective: With the survival rate of acute lymphoblastic leukemia (ALL surpassing 90 percent within this decade, new research is emerging in the field of late effects. A review of the research investigating the relationship of treatment regimens for ALL to specific late effect deficits, underlying mechanisms, and possible remediation is warranted to support continued studies.Methods: The clinical literature was briefly surveyed to describe the occurrence and topography of late effects, specifically neurocognitive deficits. Additionally, the preclinical literature was reviewed to uncover potential underlying mechanisms of these deficits. The advantages of using rodent models to answer these questions are outlined, as is an assessment of the limited number of rodent models of childhood cancer treatment.Results: The literature supports that childhood survivors of ALL exhibit academic difficulties and are more likely to be placed in a special education program. Behavioral evidence has highlighted impairments in the areas of attention, working memory, and processing speed, leading to a decrease in full scale IQ. Neurophysiological and preclinical evidence for these deficits has implicated white matter abnormalities and acquired brain damage resulting from specific chemotherapeutic agents commonly used during treatment.Conclusions: The exact role of chemotherapeutic agents in learning deficits remains mostly unknown. Recommendations for an improved rodent model of learning deficits in childhood cancer survivors are proposed, along with suggestions for future directions in this area of research, in hopes that forthcoming treatment regimens will reduce or eliminate these types of impairments.

  4. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  5. VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer.

    Science.gov (United States)

    Zhou, Jianhua; Wang, Huaijun; Zhang, Huiping; Lutz, Amelie M; Tian, Lu; Hristov, Dimitre; Willmann, Jürgen K

    2016-07-15

    Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.

  6. Childhood Sexual Abuse, Disordered Eating, Alexithymia, and General Distress: A Mediation Model

    Science.gov (United States)

    Hund, Anita R.; Espelage, Dorothy L.

    2005-01-01

    Drawing from trauma-related theory (e.g., M. F. Schwartz & P. Gay, 1996), this article presents a model of associations among child sexual abuse (CSA), psychological distress, alexithymia, and disordered eating (DE). Structural equation modeling was used to test this conceptual model with a sample of female college students (N = 589). Results…

  7. Efficacy of EGFR inhibition is modulated by model, sex, genetic background and diet: implications for preclinical cancer prevention and therapy trials.

    Directory of Open Access Journals (Sweden)

    Erica S Rinella

    Full Text Available Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies. The efficacy of the small molecule EGFR inhibitor AG1478 was evaluated using two mouse models, Apc(Min/+ and azoxymethane (AOM, both sexes on three genetic backgrounds, C57BL/6J (B6 and A/J (A inbred strains and AB6F1 hybrids, and two diets, standard chow (STD or Western-style diet (WD. AG1478 has significant anti-tumor activity in the B6-Apc(Min/+ model with STD but only moderately on the WD and in the AOM model on an A background with a WD but not STD. On the F1 hybrid background AG1478 is effective in the Apc(Min/+ model with either STD or WD, but has only moderate efficacy in the AOM model with either diet. Sex differences were also observed. Unexpectedly, the level of liver EGFR phosphorylation inhibition by AG1478 was not positively correlated with inhibition of tumor growth in the AOM model. Model-dependent interactions between genetic background and diet can dramatically impact preclinical results, and indicate that low predictive values of preclinical studies can be attributed to study designs that do not account for the heterogeneous patient population or the diets they consume. Better-designed preclinical studies should lead to more accurate predictions of therapeutic response in the clinic.

  8. Disengaged parenting: Structural equation modeling with child abuse, insecure attachment, and adult symptomatology.

    Science.gov (United States)

    Briere, John; Runtz, Marsha; Eadie, Erin; Bigras, Noémie; Godbout, Natacha

    2017-03-09

    Based on attachment theory, we hypothesized that self-reported childhood experiences of disengaged parenting (DP) would predict adults' psychological symptoms even more than, on average, childhood sexual, physical, or psychological abuse. In a large (N=640) university sample, bootstrapped multiple regression analyses indicated that although various forms of child maltreatment were correlated with symptomatology at the univariate level, DP was the primary multivariate predictor. Structural equation modeling indicated significant direct paths from (a) DP to both nonsexual child maltreatment and sexual abuse, (b) DP and nonsexual child maltreatment to insecure attachment, and (c) sexual abuse and insecure attachment to symptomatology. There were significant indirect effects of DP on psychological symptoms through sexual and nonsexual abuse, as well as through attachment. These results suggest that although child abuse has direct and indirect impacts on psychological symptoms, exposure to DP may be especially detrimental, both by increasing the risk of child abuse and by virtue of its impacts on attachment insecurity. They also support the potential use of attachment-oriented intervention in the treatment of adults maltreated as children.

  9. Childhood physical abuse and midlife physical health: testing a multi-pathway life course model.

    Science.gov (United States)

    Springer, Kristen W

    2009-07-01

    Although prior research has established that childhood abuse adversely affects midlife physical health, it is unclear how abuse continues to harm health decades after the abuse has ended. In this project, I assess four life course pathways (health behaviors, cognition, mental health, and social relation) that plausibly link childhood physical abuse to three midlife physical health outcomes (bronchitis diagnosis, ulcer diagnosis, and general physical health). These three outcomes are etiologically distinct, leading to unique testable hypotheses. Multivariate models controlling for childhood background and early adversity were estimated using data from over 3000 respondents in the Wisconsin Longitudinal Study, USA. The results indicate that midlife social relations and cognition do not function as pathways for any outcome. However, smoking is a crucial pathway connecting childhood abuse with bronchitis; mental health is important for ulcers; and BMI, smoking, and mental health are paramount for general physical health. These findings suggest that abuse survivors' coping mechanisms can lead to an array of midlife health problems. Furthermore, the results validate the use of etiologically distinct outcomes for understanding plausible causal pathways when using cross-sectional data.

  10. In vitro and in vivo evaluation of tubulin inhibitors with non-small cell lung cancer pre-clinical models

    Directory of Open Access Journals (Sweden)

    Lama R

    2015-05-01

    Full Text Available Synthetic small molecule tubulin inhibitors have many advantages as novel anti-cancer agents compared to the current tubulin inhibitors generated from natural products. Our previous studies led to the design and synthesis of a series of novel tubulin inhibitors. Some of these compounds also inhibited heat shock protein 27 (Hsp27, and showed promising in vitro anti-cancer activities in several breast cancer cell lines at sub nano-molar concentrations. However, whether these compounds could suppress tumor growth in animals was not investigated yet. In the current study, to identify the best drug candidates, therapeutic efficacy of the representative compounds from previous analyses was evaluated using non-small cell lung cancer preclinical models. These agents dose-dependently inhibited the growth of lung cancer cells in both monolayer cultures and three-dimensional multicellular spheroids. Several compounds also showed promising tumor growth suppressive activity in nude mice xenograft model

  11. Comparing Reasons for Quitting Substance Abuse with the Constructs of Behavioral Models: A Qualitative Study

    Directory of Open Access Journals (Sweden)

    Hamid Tavakoli Ghouchani

    2015-03-01

    Full Text Available Background and Objectives: The world population has reached over seven billion people. Of these, 230 million individuals abuse substances. Therefore, substance abuse prevention and treatment programs have received increasing attention during the past two decades. Understanding people’s motivations for quitting drug abuse is essential to the success of treatment. This study hence sought to identify major motivations for quitting and to compare them with the constructs of health education models. Materials and Methods: In the present study, qualitative content analysis was used to determine the main motivations for quitting substance abuse. Overall, 22 patients, physicians, and psychotherapists were selected from several addiction treatment clinics in Bojnord (Iran during 2014. Purposeful sampling method was applied and continued until data saturation was achieved. Data were collected through semi-structured, face-to-face interviews and field notes. All interviews were recorded and transcribed. Results: Content analysis revealed 33 sub-categories and nine categories including economic problems, drug-related concerns, individual problems, family and social problems, family expectations, attention to social status, beliefs about drug addiction, and valuing the quitting behavior. Accordingly, four themes, i.e. perceived threat, perceived barriers, attitude toward the behavior, and subjective norms, were extracted. Conclusion: Reasons for quitting substance abuse match the constructs of different behavioral models (e.g. the health belief model and the theory of planned behavior.

  12. The relevance of preclinical research models for the development of antimigraine drugs: Focus on 5-HT1B/1D and CGRP receptors

    DEFF Research Database (Denmark)

    Gupta, S.; Villalon, C.M.

    2010-01-01

    approaches, have significantly contributed to the two antimigraine principles in therapeutics, namely: 5-HT1B/1D receptor agonists (known as triptans) and CGRP receptor antagonists (known as gepants). This review will analyze the preclinical experimental models currently known for the development...... of these therapeutic principles, which are mainly based on the vascular and/or neurogenic theories of migraine pathogenesis. These include models based on the involvement of cranial vasodilatation and/or the trigeminovascular system in migraine. Clearly, the preclinical strategies should involve both approaches, while...

  13. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

    Directory of Open Access Journals (Sweden)

    Katherine M Ku

    Full Text Available The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD, allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD and Long-Evans (LE, between the ages of postnatal day (PND 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii the testing environment may profoundly influence the expression of strain-specific social behavior and (iii simple, automated measures of sociability may not capture the complexities of rat social interactions.

  14. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders

    Science.gov (United States)

    Ku, Katherine M.; Weir, Ruth K.; Silverman, Jill L.; Berman, Robert F.; Bauman, Melissa D.

    2016-01-01

    The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26–56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions. PMID:27351457

  15. Development of an adolescent inpatient sexual abuse group: application of Lewin's model of change.

    Science.gov (United States)

    Riddle, C R

    1994-01-01

    The development and implementation of an adolescent sexual abuse group on an inpatient psychiatric unit is described. Steps of Kurt Lewin's model of change are used as a framework for this planned change. Specific issues concerning group procedure and process are detailed. Recommendations for this group and broader use of the Lewin model are included.

  16. Practice Makes Perfect? The Role of Participant Modeling in Sexual Abuse Prevention Programs.

    Science.gov (United States)

    Wurtele, Sandy K.; And Others

    1987-01-01

    Assigned 26 kindergarten children to either a sexual abuse prevention program which taught self-protective skills through modeling and active rehearsal (PM) or a program which taught the same skills by having children watch skills modeled by experimenter (SM). Results provide support for greater efficacy of PM relative to SM for learning of…

  17. A model of blended learning in a preclinical course in prosthetic dentistry.

    Science.gov (United States)

    Reissmann, Daniel R; Sierwald, Ira; Berger, Florian; Heydecke, Guido

    2015-02-01

    The aim of this study was to evaluate the use of blending learning that added online tools to traditional learning methods in a preclinical course in prosthetic dentistry at one dental school in Germany. The e-learning modules were comprised of three main components: fundamental principles, additional information, and learning objective tests. Video recordings of practical demonstrations were prepared and cut into sequences meant to achieve single learning goals. The films were accompanied by background information and, after digital processing, were made available online. Additionally, learning objective tests and learning contents were integrated. Evaluations of 71 of 89 students (response rate: 80%) in the course with the integrated e-learning content were available for the study. Compared with evaluation results of the previous years, a substantial and statistically significant increase in satisfaction with learning content (from 30% and 34% to 86%, plearning effect (from 65% and 63% to 83%, pblended learning concept. The results showed that the e-learning tool was appreciated by the students and suggest that learning objective tests can be successfully implemented in blended learning.

  18. Hippocampal-dependent neurocognitive impairment following cranial irradiation observed in pre-clinical models: current knowledge and possible future directions.

    Science.gov (United States)

    Tomé, Wolfgang A; Gökhan, Şölen; Gulinello, Maria E; Brodin, N Patrik; Heard, John; Mehler, Mark F; Guha, Chandan

    2016-01-01

    We reviewed the literature for studies pertaining to impaired adult neurogenesis leading to neurocognitive impairment following cranial irradiation in rodent models. This compendium was compared with respect to radiation dose, converted to equivalent dose in 2 Gy fractions (EQD2) to allow for direct comparison between studies. The effects of differences between animal species and the dependence on animal age as well as for time after irradiation were also considered. One of the major sites of de novo adult neurogenesis is the hippocampus, and as such, this review also focuses on assessing evidence related to the expression and potential effects of inflammatory cytokines on neural stem cells in the subgranular zone of the dentate gyrus and whether this correlates with neurocognitive impairment. This review also discusses potential strategies to mitigate the detrimental effects on neurogenesis and neurocognition resulting from cranial irradiation, and how the rationale for these strategies compares with the current outcome of pre-clinical studies.

  19. Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models

    Directory of Open Access Journals (Sweden)

    Antonina Mitrofanova

    2015-09-01

    Full Text Available Although genetically engineered mouse (GEM models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.

  20. Evaluation of experimental and finite element models of synthetic and cadaveric femora for pre-clinical design-analysis.

    Science.gov (United States)

    McNamara, B P; Cristofolini, L; Toni, A; Taylor, D

    1994-01-01

    The aim of this study was to determine the validity with which the finite element method could model synthetic bone and thereby determine the appropriateness of such femur analogues for application in pre-clinical tests. The performance of these synthetic femora was compared with cadaveric bone when employing the same geometric and material definition protocols. A four-point bend loading configuration was selected for this analysis. Four synthetic femurs and an embalmed cadaveric bone were tested experimentally to determine the structural bending stiffness (k) for the diaphysis of these bones. A finite element (FE) model was generated and an analysis performed for each bone type to estimate the Young's modulus (E) required to obtain a model stiffness equivalent to that obtained experimentally. The estimated material elastic modulus in the FE model for the synthetic femur was found to be very similar to available data for this bone analogue. The estimated cadaveric bone modulus however was found to differ significantly from documented values for cortical bone. A theoretical analysis demonstrated the great sensitivity of the estimated modulus value to the accuracy of the geometric definition. The very low variability found in the experimental test on the synthetic bones together with their more regular geometry and the possibility of achieving greater accuracy in geometric definition was shown to enable the production of a valid FE model of this bone for an isotropic homogeneous material description. Conversely, the greater irregularity of geometry, together with the less obvious differentiation between the cortical and cancellous bone in the cadaveric specimen makes accurate geometric description of this bone very difficult. This fact, together with the uncertainty concerning the quality of the cadaveric bone and its viscoelastic response during mechanical testing, makes reproduction of its behaviour in a FE model a much more demanding task. It is suggested that

  1. Stress, depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models.

    Science.gov (United States)

    Grippo, Angela J; Johnson, Alan Kim

    2009-01-01

    Bidirectional associations between mood disorders and cardiovascular diseases are extensively documented. However, the precise physiological and biochemical mechanisms that underlie such relationships are not well understood. This review focuses on the neurobiological processes and mediators that are common to both mood and cardiovascular disorders. The discussion places an emphasis on the role of exogenous stressors in addition to: (a) neuroendocrine and neurohumoral changes involving dysfunction of the hypothalamic-pituitary-adrenal axis and the activation of the renin-angiotensin-aldosterone system, (b) immune alterations including activation of pro-inflammatory cytokines, (c) autonomic and cardiovascular dysregulation including increased sympathetic drive, withdrawal of parasympathetic tone, cardiac rate and rhythm disturbances, and altered baroreceptor reflex function, (d) central neurotransmitter system dysfunction involving the dopamine, norepinephrine and serotonin systems, and (e) behavioral changes including fatigue and physical inactivity. The review also discusses experimental investigations using preclinical disease models to elucidate the neurobiological mechanisms underlying the link between mood disorders and cardiovascular disease. These include: (a) the chronic mild stress model of depression, (b) a model of congestive heart failure, (c) a model of cardiovascular deconditioning, (d) pharmacological manipulations of body fluid and sodium balance, and (e) pharmacological manipulations of the central serotonergic system. In combination with an extensive human research literature, the investigation of mechanisms underlying mood and cardiovascular regulation using animal models will enhance understanding the association between depression and cardiovascular disease. This will ultimately promote the development of better treatments and interventions for individuals with co-morbid psychological and somatic pathologies.

  2. SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Shang, M; Sands, M; Bolch, W [University of Florida, Gainesville, FL (United States)

    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 adult 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.

  3. NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models

    DEFF Research Database (Denmark)

    Bhatt, Deepak K; Gupta, Saurabh; Jansen-Olesen, Inger;

    2013-01-01

    BackgroundNXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5-hydroxytryptamine 1B/1D (5-HT(1B/1D)) receptor agonist. Using preclinical models, we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-...

  4. Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer

    NARCIS (Netherlands)

    Bisht, Savita; Mizuma, Masamichi; Feldmann, Georg; Ottenhof, Niki A.; Hong, Seung-Mo; Pramanik, Dipankar; Chenna, Venugopal; Karikari, Collins; Sharma, Rajni; Goggins, Michael G.; Rudek, Michelle A.; Ravi, Rajani; Maitra, Amarnath; Maitra, Anirban

    2010-01-01

    Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Neve

  5. A Comprehensive Action Model to Combat Drug Abuse in High School

    Science.gov (United States)

    Petrillo, Robert F.

    1970-01-01

    Emphasized in the model are: creation and adoption of new Board policies and procedures to deal with the drug abuser, crash Emergency Room" program of drug education for grades 4 through 12, inservice education of staff, lowkey parent education, increased employment of paraprofessional supervisory personnel, and community acceptance of and…

  6. An Alternative Counseling Model for Alcohol Abuse in College: A Case Study

    Science.gov (United States)

    Hayes, B. Grant; Curry, Jennifer; Freeman, Mark S.; Kuch, Tyson H.

    2010-01-01

    Abstinence education remains a prevailing approach for addressing college student alcohol abuse. This case study illustrates an alternative method of intervening that combines motivational interviewing, harm reduction, and a brief solution-focused model. The counseling approach illustrated emphasizes reduction in, rather than abstinence from,…

  7. Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases.

    Directory of Open Access Journals (Sweden)

    Olga Aprelikova

    Full Text Available Triple negative breast cancer (TNBC is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1/SV40-T/t-antigen (C3(1/Tag mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice that carry only one copy of the C3(1/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice, but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1/Tag tumor-derived M6 cell line or individual C3(1/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment

  8. Strategies for preclinical pharmacokinetic investigation in streptozotocin-induced diabetes mellitus (DMIS) and alloxan-induced diabetes mellitus (DMIA) rat models: case studies and perspectives.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2015-03-01

    Preclinical rodent models that manifest type 2 diatetes mellitus using either streptozotocin (DMIS) or alloxan (DMIA) have been well established. Both DMIS and DMIA models have served as key experimental tools to evaluate and understand the pharmacokinetic disposition of scores of drugs and therefore some key questions with respect to absorption, metabolism or elimination of drugs can be answered during the development of full-blown diabetes in the animal models. The choice of the right preclinical rodent model and adaptation of the appropriate experimental design could help to generate data to enable go or no-go decision on the clinical candidate. Also, such models may help to understand the risk potential from a drug-drug interaction perspective. The review provides an overview of the strategies and perspectives of institutionalizing DMIS and/or DMIA rat models using relevant case studies.

  9. 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

    OpenAIRE

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

    2006-01-01

    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 hypothesiz...

  10. The WRAIR projectile concussive impact model of mild traumatic brain injury: re-design, testing and preclinical validation.

    Science.gov (United States)

    Leung, Lai Yee; Larimore, Zachary; Holmes, Larry; Cartagena, Casandra; Mountney, Andrea; Deng-Bryant, Ying; Schmid, Kara; Shear, Deborah; Tortella, Frank

    2014-08-01

    The WRAIR projectile concussive impact (PCI) model was developed for preclinical study of concussion. It represents a truly non-invasive closed-head injury caused by a blunt impact. The original design, however, has several drawbacks that limit the manipulation of injury parameters. The present study describes engineering advancements made to the PCI injury model including helmet material testing, projectile impact energy/head kinematics and impact location. Material testing indicated that among the tested materials, 'fiber-glass/carbon' had the lowest elastic modulus and yield stress for providing an relative high percentage of load transfer from the projectile impact, resulting in significant hippocampal astrocyte activation. Impact energy testing of small projectiles, ranging in shape and size, showed the steel sphere produced the highest impact energy and the most consistent impact characteristics. Additional tests confirmed the steel sphere produced linear and rotational motions on the rat's head while remaining within a range that meets the criteria for mTBI. Finally, impact location testing results showed that PCI targeted at the temporoparietal surface of the rat head produced the most prominent gait abnormalities. Using the parameters defined above, pilot studies were conducted to provide initial validation of the PCI model demonstrating quantifiable and significant increases in righting reflex recovery time, axonal damage and astrocyte activation following single and multiple concussions.

  11. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    Science.gov (United States)

    Peters, Sheila Annie; Jones, Christopher R; Ungell, Anna-Lena; Hatley, Oliver J D

    2016-06-01

    Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.

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

    Science.gov (United States)

    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.

  13. The relevance of preclinical research models for the development of antimigraine drugs: focus on 5-HT(1B/1D) and CGRP receptors.

    Science.gov (United States)

    Gupta, Saurabh; Villalón, Carlos M

    2010-10-01

    Migraine is a complex neurovascular syndrome, causing a unilateral pulsating headache with accompanying symptoms. The past four decades have contributed immensely to our present understanding of migraine pathophysiology and have led to the introduction of specific antimigraine therapies, much to the relief of migraineurs. Pathophysiological factors culminating into migraine headaches have not yet been completely deciphered and, thus, pose an additional challenge for preclinical research in the absence of any direct experimental marker. Migraine provocation experiments in humans use a head-score to evaluate migraine, as articulated by the volunteer, which cannot be applied to laboratory animals. Therefore, basic research focuses on different symptoms and putative mechanisms, one at a time or in combination, to validate the hypotheses. Studies in several species, utilizing different preclinical approaches, have significantly contributed to the two antimigraine principles in therapeutics, namely: 5-HT(1B/1D) receptor agonists (known as triptans) and CGRP receptor antagonists (known as gepants). This review will analyze the preclinical experimental models currently known for the development of these therapeutic principles, which are mainly based on the vascular and/or neurogenic theories of migraine pathogenesis. These include models based on the involvement of cranial vasodilatation and/or the trigeminovascular system in migraine. Clearly, the preclinical strategies should involve both approaches, while incorporating the newer ideas/techniques in order to get better insights into migraine pathophysiology.

  14. Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma

    Science.gov (United States)

    Coni, Sonia; Mancuso, Anna Barbara; Di Magno, Laura; Sdruscia, Giulia; Manni, Simona; Serrao, Silvia Maria; Rotili, Dante; Spiombi, Eleonora; Bufalieri, Francesca; Petroni, Marialaura; Kusio-Kobialka, Monika; De Smaele, Enrico; Ferretti, Elisabetta; Capalbo, Carlo; Mai, Antonello; Niewiadomski, Pawel; Screpanti, Isabella; Di Marcotullio, Lucia; Canettieri, Gianluca

    2017-01-01

    SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB. PMID:28276480

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

    Science.gov (United States)

    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.

  16. Pre-clinical In Vitro and In Vivo Models for Heart Valve Therapies.

    Science.gov (United States)

    Taramasso, Maurizio; Emmert, Maximilian Y; Reser, Diana; Guidotti, Andrea; Cesarovic, Nikola; Campagnol, Marino; Addis, Alessandro; Nietlispach, Fabian; Hoerstrup, Simon P; Maisano, Francesco

    2015-07-01

    Heart valve disease is a frequently encountered pathology, related to high morbidity and mortality rates. Animal models are interesting to investigate the causality but also underlying mechanisms and potential treatments of human heart valve diseases. Strongly believing that both in vivo and ex vivo models are fundamental to support research and development of new technologies, we here report some examples of heart valve disease models, which in our experience have been actively used to support the development of new valve therapies.

  17. A three-dimensional thermal abuse model for lithium-ion cells

    Science.gov (United States)

    Kim, Gi-Heon; Pesaran, Ahmad; Spotnitz, Robert

    To understand further the thermal abuse behavior of large format Li-ion batteries for automotive applications, the one-dimensional modeling approach formulated by Hatchard et al. [T.D. Hatchard, D.D. MacNeil, A. Basu, J.R. Dahn, J. Electrochem. Soc. 148(7) (2001) A755-A761] was reproduced. Then it was extended to three dimensions so we could consider the geometrical features, which are critical in large cells for automotive applications. The three-dimensional model captures the shapes and dimensions of cell components and the spatial distributions of materials and temperatures, and is used to simulate oven tests, and to determine how a local hot spot can propagate through the cell. In simulations of oven abuse testing of cells with cobalt oxide cathode and graphite anode with standard LiPF 6 electrolyte, the three-dimensional model predicts that thermal runaway will occur sooner or later than the lumped model, depending on the size of the cell. The model results showed that smaller cells reject heat faster than larger cells; this may prevent them from going into thermal runaway under identical abuse conditions. In simulations of local hot spots inside a large cylindrical cell, the three-dimensional model predicts that the reactions initially propagate in the azimuthal and longitudinal directions to form a hollow cylinder-shaped reaction zone.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Richter Kimber P

    2006-08-01

    Full Text Available Abstract 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.

  20. Wound Healing Activity of Rubus sanctus Schreber (Rosaceae): Preclinical Study in Animal Models.

    Science.gov (United States)

    Süntar, Ipek; Koca, Ufuk; Keleş, Hikmet; Akkol, Esra Küpeli

    2011-01-01

    Young shoots of Rubus species have been used for healing of wounds, infected insect bites and pimples in folk medicine for ages. In order to evaluate the wound healing activity of Rubus sanctus, four different extracts were prepared from the whole aerial parts of the plant by using n-hexane, chloroform, ethyl acetate and methanol, respectively. Incision wound healing model by using tensiometer on rats and excision model on mice were employed to assess the activity. Remarkable wound healing activity was observed with the ointment formulation of the methanol extract at 1% concentration on the mentioned models. The results of histopathological examination also supported the outcome of both incision and excision wound models. The wound healing effect was comparatively evaluated with a reference ointment Madecassol. The experimental data confirmed the ethnobotanical usage of R. sanctus.

  1. Wound Healing Activity of Rubus sanctus Schreber (Rosaceae: Preclinical Study in Animal Models

    Directory of Open Access Journals (Sweden)

    Ipek Süntar

    2011-01-01

    Full Text Available Young shoots of Rubus species have been used for healing of wounds, infected insect bites and pimples in folk medicine for ages. In order to evaluate the wound healing activity of Rubus sanctus, four different extracts were prepared from the whole aerial parts of the plant by using n-hexane, chloroform, ethyl acetate and methanol, respectively. Incision wound healing model by using tensiometer on rats and excision model on mice were employed to assess the activity. Remarkable wound healing activity was observed with the ointment formulation of the methanol extract at 1% concentration on the mentioned models. The results of histopathological examination also supported the outcome of both incision and excision wound models. The wound healing effect was comparatively evaluated with a reference ointment Madecassol. The experimental data confirmed the ethnobotanical usage of R. sanctus.

  2. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging

    OpenAIRE

    Fecher, David; Hofmann, Elisabeth; Buck, Andreas; BUNDSCHUH, RALPH; Nietzer, Sarah; Dandekar, Gudrun; Walles, Thorsten; Walles, Heike; Lückerath, Katharina; Steinke, Maria

    2016-01-01

    Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. ...

  3. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    Directory of Open Access Journals (Sweden)

    Mi XS

    2014-11-01

    Full Text Available Xue-Song Mi,1,2 Ti-Fei Yuan,3,4 Yong Ding,1 Jing-Xiang Zhong,1 Kwok-Fai So4,5 1Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 3School of Psychology, Nanjing Normal University, Nanjing, People’s Republic of China; 4Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; 5Guangdong-Hongkong-Macau Institute of Central Nervous System, Jinan University, Guangzhou, People’s Republic of China Abstract: Diabetic retinopathy (DR is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. Keywords: animal model, in vitro culture, ex vivo culture, neurovascular dysfunction

  4. Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models

    Directory of Open Access Journals (Sweden)

    Andre Cassell

    2012-11-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is characterized by overexpression of the epidermal growth factor receptor (EGFR where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473, phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

  5. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat.

    Science.gov (United States)

    Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

    2013-05-20

    Previous work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice--the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.

  6. Tracking the extramedullary PML-RARα-positive cell reservoirs in a preclinical model: biomarker of long-term drug efficacy.

    Science.gov (United States)

    Pokorna, Katerina; Le Pogam, Carole; Chopin, Martine; Balitrand, Nicole; Reboul, Murielle; Cassinat, Bruno; Chomienne, Christine; Padua, Rose Ann; Pla, Marika

    2013-02-01

    Using an acute promyelocytic leukemia (APL) preclinical model, we show that oncogene-specific PCR (Polymerase Chain Reaction)-based assays allow to evaluate the efficacy of immunotherapy combining all-trans retinoic acid (ATRA) and a DNA-based vaccine targeting the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) oncogene. Kaplan-Meier survival analysis according to the peripheral blood PML-RARα normalized copy number (NCN) clearly shows that ATRA + DNA-treated mice with an NCN lower than 10 (43%) formed the group with a highly significant (p < 0.0001) survival advantage. Furthermore, a PCR assay was used to assess various tissues and organs for the presence of PML-RARα-positive cells in long-term survivors (n = 15). As expected, the majority of mice (n = 10) had no measurable tissue level of PML-RARα. However, five mice showed a weak positive signal in both the brain and spleen (n = 2), in the brain only (n = 2) and in the spleen only (n = 1). Thus tracking the oncogene-positive cells in long-term survivors reveals for the first time that extramedullary PML-RARα-positive cell reservoirs such as the brain may persist and be involved in relapses.

  7. The impact of hypoxia on the activity of lactate dehydrogenase in two different pre-clinical tumour models

    DEFF Research Database (Denmark)

    Lukacova, Slavka; Sørensen, Brita; Alsner, Jan;

    2008-01-01

    Aim. To investigate the direct relationship between tumour hypoxia and lactate dehydrogenase (Ldh) levels in serum and tumour in two different pre-clinical murine models. Materials and methods. Experiments were performed in CDF1 or C3H/Km mice implanted with a C3H mammary carcinoma and SCCVII...... squamous cell carcinoma, respectively. Low oxygen breathing for 1-72 h was used to increase tumour hypoxia. Ldh activity was measured in the serum and tumour cytosole with a colorimetric method. Tumour Ldha mRNA levels were assessed with RT-PCR. Results. The serum Ldh in non-tumour bearing CDF1 mice and C3......H/km mice was 10.5+/-2 U/ml and 12+/-2 U/ml, respectively. For C3H mammary carcinoma bearing mice, a positive correlation between tumour volume and tumour and serum Ldh was found. Tumour Ldh in SCCVII carcinomas also increased with increasing tumour volume, but no volume dependence of serum Ldh...

  8. The animal models of dementia and Alzheimer's disease for pre-clinical testing and clinical translation.

    Science.gov (United States)

    Anand, Akshay; Banik, Avijit; Thakur, Keshav; Masters, Colin L

    2012-11-01

    Dementia is a clinical syndrome with abnormal degree of memory loss and impaired ability to recall events from the past often characterized by Alzheimer's disease. The various strategies to treat dementia need validation of novel compounds in suitable animal models for testing their safety and efficacy. These may include novel anti-amnesic drugs derived from synthetic chemistry or those derived from traditional herbal sources. Multiple approaches have been adopted to create reliable animal models ranging from rodents to non-human primates, where the animals are exposed to a predetermined injury or causing genetic ablation across specific regions of brain suspected to affect learning functions. In this review various animal models for Alzheimer's disease and treatment strategies in development of anti dementia drugs are discussed and an attempt has been made to provide a comprehensive report of the latest developments in the field.

  9. The pig as a large preclinical model for therapeutic human anti-cancer vaccine development

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr; Frøsig, Thomas Mørch; Welner, Simon

    2016-01-01

    Development of therapeutic cancer vaccines has largely been based on rodent models and the majority failed to establish therapeutic responses in clinical trials. We therefore used pigs as a large animal model for human cancer vaccine development due to the large similarity between the porcine...... and human immunome. We administered peptides derived from porcine IDO, a cancer antigen important in human disease, formulated in Th1-inducing adjuvants to outbred pigs. By in silico prediction 136 candidate IDO-derived peptides were identified and peptide-SLA class I complex stability measurements revealed...

  10. Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: a model for preclinical studies

    DEFF Research Database (Denmark)

    Thim, Troels; Hagensen, Mette; Drouet, L.;

    2010-01-01

    years but then weigh >200 kg making them impractical and costly. We aimed at down-sizing this pig and accelerating coronary plaque development to make the model more useful and affordable. METHODS AND RESULTS: Familial hypercholesterolaemic farm pigs were downsized by crossing them with smaller pigs...

  11. Development of an ex vivo human-porcine respiratory model for preclinical studies.

    Science.gov (United States)

    Perinel, Sophie; Pourchez, Jérémie; Leclerc, Lara; Avet, John; Durand, Marc; Prévôt, Nathalie; Cottier, Michèle; Vergnon, Jean M

    2017-02-24

    Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures "pleural" depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with (81m)Krypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies.

  12. Development of an ex vivo human-porcine respiratory model for preclinical studies

    Science.gov (United States)

    Perinel, Sophie; Pourchez, Jérémie; Leclerc, Lara; Avet, John; Durand, Marc; Prévôt, Nathalie; Cottier, Michèle; Vergnon, Jean M.

    2017-01-01

    Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures “pleural” depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with 81mKrypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies. PMID:28233793

  13. Reverse translation of failed treatments can help improving the validity of preclinical animal models

    NARCIS (Netherlands)

    't Hart, Bert A.

    2015-01-01

    A major challenge in translational research is to reduce the currently high proportion of new candidate treatment agents for neuroinflammatory disease, which fail to reproduce promising effects observed in animal models when tested in patients. This disturbing situation has raised criticism against

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

    NARCIS (Netherlands)

    '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

    2014-01-01

    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 precl

  15. Surgical technique: establishing a pre-clinical large animal model to test aortic valve leaflet substitute

    Science.gov (United States)

    Knirsch, Walter; Cesarovic, Niko; Krüger, Bernard; Schmiady, Martin; Frauenfelder, Thomas; Frese, Laura; Dave, Hitendu; Hoerstrup, Simon Philipp; Hübler, Michael

    2016-01-01

    To overcome current limitations of valve substitutes and tissue substitutes the technology of tissue engineering (TE) continues to offer new perspectives in congenital cardiac surgery. We report our experiences and results implanting a decellularized TE patch in nine sheep in orthotropic position as aortic valve leaflet substitute. Establishing the animal model, feasibility, cardiopulmonary bypass issues and operative technique are highlighted. PMID:28149571

  16. Valproic acid improves second-line regimen of small cell lung carcinoma in preclinical models

    Directory of Open Access Journals (Sweden)

    Roland Hubaux

    2015-10-01

    Full Text Available With 5-year survival rates below 5%, small cell lung carcinoma (SCLC has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve second-line therapy of SCLC. The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression and in mouse models (tumour development. We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide in SCLC cells and in mouse models. Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies.

  17. Stem cell derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model

    Science.gov (United States)

    Donegan, Jennifer J.; Tyson, Jennifer A.; Branch, Sarah Y.; Beckstead, Michael J.; Anderson, Stewart A.; Lodge, Daniel J.

    2016-01-01

    An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol (MAM) rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity, and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia. PMID:27480492

  18. Putative cognitive enhancers in preclinical models related to schizophrenia: the search for an elusive target.

    Science.gov (United States)

    Barak, Segev; Weiner, Ina

    2011-08-01

    Several developments have converged to drive what may be called "the cognitive revolution" in drug discovery in schizophrenia (SCZ), including the emphasis on cognitive deficits as a core disabling aspect of SCZ, the increasing consensus that cognitive deficits are not treated satisfactorily by the available antipsychotic drugs (APDs), and the failure of animal models to predict drug efficacy for cognitive deficits in clinical trials. Consequently, in recent years, a paradigm shift has been encouraged in animal modeling, triggered by the NIMH sponsored Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, and intended to promote the development and use of behavioral measures in animals that can generate valid (clinically relevant) measures of cognition and thus promote the identification of cognition enhancers for SCZ. Here, we provide a non-exhaustive survey of the effects of putative cognition enhancers (PCEs) representing 10 pharmacological targets as well as antipsychotic drugs (APDs), on SCZ-mimetic drugs (NMDA antagonists, muscarinic antagonist scopolamine and dopaminergic agonist amphetamine), in several tasks considered to measure cognitive processes/domains that are disrupted in SCZ (the five choice serial reaction time task, sustain attention task, working and/or recognition memory (delayed (non)matching to sample, delayed alternation task, radial arm maze, novel object recognition), reversal learning, attentional set shifting, latent inhibition and spatial learning and memory). We conclude that most of the available models have no capacity to distinguish between PCEs and APDs and that there is a need to establish models based on tasks whose perturbations lead to performance impairments that are resistant to APDs, and/or to accept APDs as a "weak gold standard". Several directions derived from the surveyed data are suggested.

  19. Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

    Directory of Open Access Journals (Sweden)

    Jinu Abraham

    2011-01-01

    Full Text Available Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma.

  20. Noninvasive evaluation of respiratory muscles in pre-clinical model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Daniela M. Oliveira

    2016-04-01

    Full Text Available Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD, the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD employing ultrasonography (US. A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

  1. Swept-sine noise-induced damage as a hearing loss model for preclinical assays

    Directory of Open Access Journals (Sweden)

    Lorena eSanz

    2015-02-01

    Full Text Available Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz (violet noises to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 inhibitors P17 and P144 on noise-induced hearing loss. CBA mice were exposed to violet swept-sine noise with different frequency ranges (2-20 or 9-13 kHz and levels (105 or 120 dB SPL for 30 minutes. Mice were evaluated by auditory brainstem response and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by violet swept-sine noise depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL, whereas permanent cochlear damage resulted from the exposure to 120 dB SPL. Exposure to 9-13 kHz noise caused an auditory threshold shift in those frequencies that correlated with hair cell loss in the corresponding areas of the cochlea that were spotted on the cytocochleogram. In summary, we present mouse models of noise-induced hearing loss, which depending on the sound properties of the noise, cause different degrees of cochlear damage, and could therefore be used to study molecules which are potential players in hearing loss protection and repair.

  2. Depression as an evolutionary adaptation: implications for the development of preclinical models.

    Science.gov (United States)

    Hendrie, C A; Pickles, A R

    2009-03-01

    Several authors have suggested that rather than being a disease state, depression is an evolutionary adaptation to human social organization. Adaptations are produced in response to selection pressures and similar adaptations may easily have evolved in a range of other species. The current paper seeks to identify the social pressures that may lead to a species developing depression as an adaptation and the potential benefits that this may confer. It also examines whether rats and mice, the species most commonly used to model depression in the laboratory, have social organizations in which selection pressures towards the development of depression as an adaptation are likely to exist. It is proposed that depression is a useful adaptation in group-living animals, where there is competition for a social rank that gives reproductive advantage over others. The cluster of symptoms associated with depression include altered activity patterns, reduced sociability and appetite, and increased submissiveness. This combination strongly suggests that the function of depression is to reduce the likelihood of an individual being subject to further attack once they have lost social status and so increase their chances of survival in the period immediately following this. Successful transition from high to low status may provide further opportunities to reproduce. Hence, animals that become depressed during this critical period gain a reproductive advantage over those that do not, as these are either killed or expelled from the group. Wild mice do not have social hierarchies and are highly territorial. Wild rats do have social hierarchies however these only compete for reproductive advantage at the level of the sperm, and social status does not translate into significantly greater access to mates. Therefore, there are no selection pressures in these species towards the development of depression and so it is most unlikely that rats and mice have this adaptation. It is concluded that

  3. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme.

    Science.gov (United States)

    Bai, Ren-Yuan; Staedtke, Verena; Aprhys, Colette M; Gallia, Gary L; Riggins, Gregory J

    2011-09-01

    Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer, and despite treatment advances, patient prognosis remains poor. During routine animal studies, we serendipitously observed that fenbendazole, a benzimidazole antihelminthic used to treat pinworm infection, inhibited brain tumor engraftment. Subsequent in vitro and in vivo experiments with benzimidazoles identified mebendazole as the more promising drug for GBM therapy. In GBM cell lines, mebendazole displayed cytotoxicity, with half-maximal inhibitory concentrations ranging from 0.1 to 0.3 µM. Mebendazole disrupted microtubule formation in GBM cells, and in vitro activity was correlated with reduced tubulin polymerization. Subsequently, we showed that mebendazole significantly extended mean survival up to 63% in syngeneic and xenograft orthotopic mouse glioma models. Mebendazole has been approved by the US Food and Drug Administration for parasitic infections, has a long track-record of safe human use, and was effective in our animal models with doses documented as safe in humans. Our findings indicate that mebendazole is a possible novel anti-brain tumor therapeutic that could be further tested in clinical trials.

  4. Considerations for the optimization of induced white matter injury preclinical models

    Directory of Open Access Journals (Sweden)

    Abdullah Shafique Ahmad

    2015-08-01

    Full Text Available The white matter injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in the imaging technologies in the field of stroke have confirmed that white matter injury plays an important role in the prognosis of stroke and suggest that white matter protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of white matter injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective white matter injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective white matter ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly the ratio of white matter to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general white matter injury in animal models (stroke and non-stroke related and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury.

  5. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    Directory of Open Access Journals (Sweden)

    Satoshi Kawano

    Full Text Available The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2 methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1 has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.

  6. Towards a better preclinical model of PTSD: characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone.

    Science.gov (United States)

    Reznikov, Roman; Diwan, Mustansir; Nobrega, José N; Hamani, Clement

    2015-02-01

    Most of the available preclinical models of PTSD have focused on isolated behavioural aspects and have not considered individual variations in response to stress. We employed behavioural criteria to identify and characterize a subpopulation of rats that present several features analogous to PTSD-like states after exposure to classical fear conditioning. Outbred Sprague-Dawley rats were segregated into weak- and strong-extinction groups on the basis of behavioural scores during extinction of conditioned fear responses. Animals were subsequently tested for anxiety-like behaviour in the open-field test (OFT), novelty suppressed feeding (NSF) and elevated plus maze (EPM). Baseline plasma corticosterone was measured prior to any behavioural manipulation. In a second experiment, rats underwent OFT, NSF and EPM prior to being subjected to fear conditioning to ascertain whether or not pre-stress levels of anxiety-like behaviours could predict extinction scores. We found that 25% of rats exhibit low extinction rates of conditioned fear, a feature that was associated with increased anxiety-like behaviour across multiple tests in comparison to rats showing strong extinction. In addition, weak-extinction animals showed low levels of corticosterone prior to fear conditioning, a variable that seemed to predict extinction recall scores. In a separate experiment, anxiety measures taken prior to fear conditioning were not predictive of a weak-extinction phenotype, suggesting that weak-extinction animals do not show detectable traits of anxiety in the absence of a stressful experience. These findings suggest that extinction impairment may be used to identify stress-vulnerable rats, thus providing a useful model for elucidating mechanisms and investigating potential treatments for PTSD.

  7. Complement depletion with humanised cobra venom factor: efficacy in preclinical models of vascular diseases.

    Science.gov (United States)

    Vogel, Carl-Wilhelm; Fritzinger, David C; Gorsuch, W Brian; Stahl, Gregory L

    2015-03-01

    The complement system is an intrinsic part of the immune system and has important functions in both innate and adaptive immunity. On the other hand, inadvertent or misdirected complement activation is also involved in the pathogenesis of many diseases, contributing solely or significantly to tissue injury and disease development. Multiple approaches to develop pharmacological agents to inhibit complement are currently being pursued. We have developed a conceptually different approach of not inhibiting but depleting complement, based on the complement-depleting activities of cobra venom factor (CVF), a non-toxic cobra venom component with structural and functional homology to complement component C3. We developed a humanised version of CVF by creating human complement component C3 derivatives with complement-depleting activities of CVF (humanised CVF) as a promising therapeutic agent for diseases with complement pathogenesis. Here we review the beneficial therapeutic effect of humanised CVF in several murine models of vascular diseases such as reperfusion injury.

  8. Preclinical Evaluation Of Photosensitizing Agents

    Science.gov (United States)

    Kessel, David

    1989-06-01

    Methods for the pre-clinical evaluation of new photosensitizing dyes are described. The resulting information can provide useful leads concerning likely modes and sites of localization. But correlations between results obtained in cell culture and in animal tumor models are sufficiently weak to indicate the need for caution in extrapolation of any in vitro result.

  9. Mitochondrial Dynamics and Mitophagy in the 6-Hydroxydopamine Preclinical Model of Parkinson's Disease

    Science.gov (United States)

    Galindo, Maria F.; Solesio, Maria E.; Atienzar-Aroca, Sandra; Zamora, Maria J.; Jordán Bueso, Joaquín

    2012-01-01

    We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson's disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson's disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson's disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson's disease. PMID:22966477

  10. Conditions for NIR fluorescence-guided tumor resectioning in preclinical lung cancer model (Conference Presentation)

    Science.gov (United States)

    Kim, Minji; Quan, Yuhua; Choi, Byeong Hyun; Choi, Yeonho; Kim, Hyun Koo; Kim, Beop-Min

    2016-03-01

    Pulmonary nodule could be identified by intraoperative fluorescence imaging system from systemic injection of indocyanine green (ICG) which achieves enhanced permeability and retention (EPR) effects. This study was performed to evaluate optimal injection time of ICG for detecting cancer during surgery in rabbit lung cancer model. VX2 carcinoma cell was injected in rabbit lung under fluoroscopic computed tomography-guidance. Solitary lung cancer was confirmed on positron emitting tomography with CT (PET/CT) 2 weeks after inoculation. ICG was administered intravenously and fluorescent intensity of lung tumor was measured using the custom-built intraoperative color and fluorescence merged imaging system (ICFIS) for 15 hours. Solitary lung cancer was resected through thoracoscopic version of ICFIS. ICG was observed in all animals. Because Lung has fast blood pulmonary circulation, Fluorescent signal showed maximum intensity earlier than previous studies in other organs. Fluorescent intensity showed maximum intensity within 6-9 hours in rabbit lung cancer. Overall, Fluorescent intensity decreased with increasing time, however, all tumors were detectable using fluorescent images until 12 hours. In conclusion, while there had been studies in other organs showed that optimal injection time was at least 24 hours before operation, this study showed shorter optimal injection time at lung cancer. Since fluorescent signal showed the maximum intensity within 6-9 hours, cancer resection could be performed during this time. This data informed us that optimal injection time of ICG should be evaluated in each different solid organ tumor for fluorescent image guided surgery.

  11. Mitochondrial dynamics and mitophagy in the 6-hydroxydopamine preclinical model of Parkinson's disease.

    Science.gov (United States)

    Galindo, Maria F; Solesio, Maria E; Atienzar-Aroca, Sandra; Zamora, Maria J; Jordán Bueso, Joaquín

    2012-01-01

    We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson's disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson's disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson's disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson's disease.

  12. Characterization of preclinical models of prostate cancer using PET-based molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Belloli, Sara; Moresco, Rosa M.; Picchio, Maria [Scientific Institute H San Raffaele, Department of Nuclear Medicine, Milan (Italy); IBFM, CNR, Milan (Italy); University of Milano-Bicocca, Milan (Italy); Jachetti, Elena [San Raffaele Scientific Institute, Cancer Immunotherapy and Gene Therapy Program, Milan (Italy); University of Vita-Salute, San Raffaele Institute, Fellowship of the Doctorate School of Cellular and Molecular Medicine, Milan (Italy); Lecchi, Michela [University of Milan, Institute of Radiological Sciences, Milan (Italy); Valtorta, Silvia [Scientific Institute H San Raffaele, Department of Nuclear Medicine, Milan (Italy); University of Milan, Fellowship of the Doctorate School of Molecular Medicine, Milan (Italy); Freschi, Massimo [San Raffaele Scientific Institute, Pathological Anatomy Unit, Milan (Italy); Michelini, Rodrigo Hess; Bellone, Matteo [San Raffaele Scientific Institute, Cancer Immunotherapy and Gene Therapy Program, Milan (Italy); Fazio, Ferruccio [Scientific Institute H San Raffaele, Department of Nuclear Medicine, Milan (Italy); University of Milano-Bicocca, Milan (Italy)

    2009-08-15

    Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice spontaneously develop hormone-dependent and hormone-independent prostate cancer (PC) that potentially resembles the human pathological condition. The aim of the study was to validate PET imaging as a reliable tool for in vivo assessment of disease biology and progression in TRAMP mice using radioligands routinely applied in clinical practice: [{sup 18}F]FDG and [{sup 11}C]choline. Six TRAMP mice were longitudinally evaluated starting at week 11 of age to visualize PC development and progression. The time frame and imaging pattern of PC lesions were subsequently confirmed on an additional group of five mice. PET and [{sup 18}F]FDG allowed detection of PC lesions starting from 23 weeks of age. [{sup 11}C]Choline was clearly taken up only by TRAMP mice carrying neuroendocrine lesions, as revealed by post-mortem histological evaluation. PET-based molecular imaging represents a state-of-the-art tool for the in vivo monitoring and metabolic characterization of PC development, progression and differentiation in the TRAMP model. (orig.)

  13. Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation.

    Science.gov (United States)

    Buga, A-M; Di Napoli, Mario; Popa-Wagner, A

    2013-12-01

    Age is the principal nonmodifiable risk factor for stroke. Over the past 10 years, suitable models for stroke in aged rats have been established. At genetic and cellular level there are significant differences in behavioral, cytological and genomics responses to injury in old animals as compared with the young ones. Behaviorally, the aged rats have the capacity to recover after cortical infarcts albeit to a lower extent than the younger counterparts. Similarly, the increased vulnerability of the aged brain to stroke, together with a decreased interhemisphere synchrony after stroke, assessed by different experimental methods (MRI, fMRI, in vivo microscopy, EEG) leads to unfavorable recovery of physical and cognitive functions in aged people and may have a prognostic value for the recovery of stroke patients. Furthermore, in elderly, comorbidities like diabetes or arterial hypertension are associated with higher risk of stroke, increased mortality and disability, and poorer functional status and quality of life. Aging brain reacts strongly to ischemia-reperfusion injury with an early inflammatory response. The process of cellular senescence can be an important additional contributor to chronic post-stroke by creating a "primed" inflammatory environment in the brain. Overall, these pro-inflammatory reactions promote early scar formation associated with tissue fibrosis and reduce functional recovery. A better understanding of molecular factors and signaling pathways underlying the contribution of comorbidities to stroke-induced pathological sequelae, may be translated into successful treatment or prevention therapies for age-associated diseases which would improve lifespan and quality of life.

  14. Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.

    Science.gov (United States)

    Brown, Jordan W; Rueter, Lynne E; Zhang, Min

    2014-03-03

    Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.

  15. Engaging stakeholders in review and recommendations for models of outcome monitoring for substance abuse treatment.

    Science.gov (United States)

    Rush, Brian; Martin, Garth; Corea, Larry; Rotondi, Nooshin Khobzi

    2012-10-01

    We present an example of a collaborative process designed to review models of outcome monitoring for substance abuse services, with a view to assessing the feasibility of different approaches in Ontario, Canada. A conceptual framework that describes the parameters of an outcome monitoring system and four models of outcome monitoring were identified. Consultations were held with stakeholders (managers, directors, researchers, clinicians, and governmental representatives) about the types of information they would like to obtain from an outcome monitoring system. Our process is useful as a model for collaborative research with respect to performance measurement. The study's implications and limitations are noted.

  16. P-glycoprotein Mediated Efflux Limits Substrate and Drug Uptake in a Preclinical Brain Metastases of Breast Cancer Model

    Directory of Open Access Journals (Sweden)

    Chris E Adkins

    2013-11-01

    Full Text Available The blood-brain barrier (BBB is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB. What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-gp in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker (14C-AIB and a tracer subject to P-gp efflux (rhodamine 123 into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p>0.05; n=756-1214 vessels evaluated at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p>0.05 different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.

  17. In vivo models of brain tumors: roles of genetically engineered mouse models in understanding tumor biology and use in preclinical studies.

    Science.gov (United States)

    Simeonova, Iva; Huillard, Emmanuelle

    2014-10-01

    Although our knowledge of the biology of brain tumors has increased tremendously over the past decade, progress in treatment of these deadly diseases remains modest. Developing in vivo models that faithfully mirror human diseases is essential for the validation of new therapeutic approaches. Genetically engineered mouse models (GEMMs) provide elaborate temporally and genetically controlled systems to investigate the cellular origins of brain tumors and gene function in tumorigenesis. Furthermore, they can prove to be valuable tools for testing targeted therapies. In this review, we discuss GEMMs of brain tumors, focusing on gliomas and medulloblastomas. We describe how they provide critical insights into the molecular and cellular events involved in the initiation and maintenance of brain tumors, and illustrate their use in preclinical drug testing.

  18. Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma

    Science.gov (United States)

    Jueliger, Simone; Lyons, John; Cannito, Sara; Pata, Illar; Pata, Pille; Shkolnaya, Marianna; Lo Re, Oriana; Peyrou, Marion; Villarroya, Francesc; Pazienza, Valerio; Rappa, Francesca; Cappello, Francesco; Azab, Mohammad; Taverna, Pietro; Vinciguerra, Manlio

    2016-01-01

    ABSTRACT Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine. Here we found that guadecitabine is an effective demethylating agent and is able to prevent HCC progression in pre-clinical models. In a xenograft HCC HepG2 model, guadecitabine impeded tumor growth and inhibited angiogenesis, while it could not prevent liver fibrosis and inflammation in a mouse model of steatohepatitis. Demethylating efficacy of guadecitabine on LINE-1 elements was found to be the highest 8 d post-infusion in blood samples of mice. Analysis of a panel of human HCC vs. normal tissue revealed a signature of hypermethylated tumor suppressor genes (CDKN1A, CDKN2A, DLEC1, E2F1, GSTP1, OPCML, E2F1, RASSF1, RUNX3, and SOCS1) as detected by methylation-specific PCR. A pronounced demethylating effect of guadecitabine was obtained also in the promoters of a subset of tumor suppressors genes (CDKN2A, DLEC1, and RUNX3) in HepG2 and Huh-7 HCC cells. Finally, we analyzed the role of macroH2A1, a variant of histone H2A, an oncogene upregulated in human cirrhosis/HCC that synergizes with DNA methylation in suppressing tumor suppressor genes, and it prevents the inhibition of cell growth triggered by decitabine in HCC cells. Guadecitabine, in contrast to decitabine, blocked growth in HCC cells overexpressing macroH2A1 histones and with high CDA levels, despite being unable to fully demethylate CDKN2A, RUNX3, and

  19. Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

    Directory of Open Access Journals (Sweden)

    Chiang Po-Chang

    2010-01-01

    Full Text Available Abstract Inhaled corticosteroids (ICS are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF and cytokine (TNFα production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone. Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone, while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone, likely due to overdosing in this model. We conclude that the

  20. Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

    Science.gov (United States)

    Chiang, Po-Chang; Hu, Yiding; Blom, Jason D.; Thompson, David C.

    2010-06-01

    Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03-0.1 mg ciclesonide, 0.01-0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT

  1. Quetiapine: recent developments in preclinical research

    Directory of Open Access Journals (Sweden)

    Marco Orsetti

    2010-03-01

    Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

  2. Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

    Science.gov (United States)

    Stavropoulos, Andreas; Sculean, Anton; Bosshardt, Dieter D; Buser, Daniel; Klinge, Björn

    2015-06-01

    Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice.

  3. Assessment of Substance Abuse Behaviors in Adolescents’: Integration of Self-Control into Extended Parallel Process Model

    Directory of Open Access Journals (Sweden)

    K Witte

    2005-04-01

    Full Text Available Introduction: An effective preventive health education program on drug abuse can be delivered by applying behavior change theories in a complementary fashion. Methods: The aim of this study was to assess the effectiveness of integrating self-control into Extended Parallel Process Model in drug substance abuse behaviors. A sample of 189 governmental high school students participated in this survey. Information was collected individually by completing researcher designed questionnaire and a urinary rapid immuno-chromatography test for opium and marijuana. Results: The results of the study show that 6.9% of students used drugs (especially opium and marijuana and also peer pressure was determinant factor for using drugs. Moreover the EPPM theoretical variables of perceived severity and perceived self-efficacy with self-control are predictive factors to behavior intention against substance abuse. In this manner, self-control had a significant effect on protective motivation and perceived efficacy. Low self- control was a predictive factor of drug abuse and low self-control students had drug abuse experience. Conclusion: The results of this study suggest that an integration of self-control into EPPM can be effective in expressing and designing primary preventive programs against drug abuse, and assessing abused behavior and deviance behaviors among adolescent population, especially risk seekers

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  6. Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis.

    Science.gov (United States)

    Lu, Jui-Yun; Nelvagal, Hemanth R; Wang, Lingling; Birnbaum, Shari G; Cooper, Jonathan D; Hofmann, Sandra L

    2015-01-01

    The neuronal ceroid lipofuscinoses (NCLs) are a group of related hereditary lysosomal storage disorders characterized by progressive loss of neurons in the central nervous system resulting in dementia, loss of motor skills, seizures and blindness. A characteristic intralysosomal accumulation of autofluorescent storage material occurs in the brain and other tissues. Three major forms and nearly a dozen minor forms of NCL are recognized. Infantile-onset NCL (CLN1 disease) is caused by severe deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1) and no therapy beyond supportive care is available. Homozygous Ppt1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death around 8 months. Direct delivery of lysosomal enzymes to the cerebrospinal fluid is an approach that has gained traction in small and large animal models of several other neuropathic lysosomal storage diseases, and has advanced to clinical trials. In the current study, Ppt1 knockout mice were treated with purified recombinant human PPT1 enzyme delivered to the lumbar intrathecal space on each of three consecutive days at 6 weeks of age. Untreated PPT1 knockout mice and wild-type mice served as additional controls. Four enzyme concentration levels (0, 2.6, 5.3 and 10.6 mg/ml of specific activity 20 U/mg) were administered in a volume of 80 μl infused over 8 min. Each group consisted of 16-20 mice. The treatment was well tolerated. Disease-specific survival was 233, 267, 272, and 284days for each of the four treatment groups, respectively, and the effect of treatment was highly significant (p<0.0001). The timing of motor deterioration was also delayed. Neuropathology was improved as evidenced by decreased autofluorescent storage material in the spinal cord and a decrease in CD68 staining in the cortex and spinal cord. The improvements in motor function and survival are similar to results reported for

  7. Heterosexual male perpetrators of childhood sexual abuse: a preliminary neuropsychiatric model.

    Science.gov (United States)

    Cohen, Lisa J; Nikiforov, Konstantin; Gans, Sniezyna; Poznansky, Olga; McGeoch, Pamela; Weaver, Carrie; King, Enid Gertmanian; Cullen, Ken; Galynker, Igor

    2002-01-01

    This paper presents data from a series of preliminary neuropsychiatric studies, including neuropsychological, personality, sexual history, plethysmographic and neuroimaging investigations, on a sample of 22 male, heterosexual, nonexclusive pedophiles and 24 demographically similar healthy controls. A psychobiological model of pedophilia is proposed, positing that early childhood sexual abuse leads to neurodevelopmental abnormalities in the temporal regions mediating sexual arousal and erotic discrimination and the frontal regions mediating the cognitive aspects of sexual desire and behavioral inhibition. In this way, pedophiles develop deviant pedophilic arousal. Subsequently, if there is comorbid personality pathology, specifically sociopathy and cognitive distortions, there will be failure to inhibit pedophilic behavior.

  8. The right time, the right place: will targeting human cancer-associated mutations to the mouse provide the perfect preclinical model?

    Science.gov (United States)

    Blyth, Karen; Morton, Jennifer P; Sansom, Owen J

    2012-02-01

    Over the past 10 years the realisation that genetic mouse models of cancer may play a key role in preclinical drug development has gained strong momentum. Moreover sequencing studies of human tumours have provided key insights into the mutational complexity of epithelial cancer, unleashing important clues for researchers to generate accurate genetically engineered mouse (GEM) models of cancer. Thus by targeting multiple cancer associated human mutations to the appropriate murine epithelia, mice develop tumours that more closely recapitulate the human disease. As a number of excellent models now exist, the next 5-10 years will ascertain whether these models will predict response of human cancer to intervention. If so they might become the 'gold standard' where all drugs are required to be tested in mouse models of disease before proceeding into the patient. However, although this principle is very attractive, it is relatively untested and here, using examples of prevalent human cancers, we will review the latest data on preclinical GEM studies and comment on what challenges are left to overcome.

  9. An animal model of social instability stress in adolescence and risk for drugs of abuse.

    Science.gov (United States)

    McCormick, Cheryl M

    2010-02-09

    There is increasing evidence that adolescence, like early life, is a sensitive period in which ongoing brain development can be influenced by environmental factors. This review describes our use of social instability as a model of mild adolescent social stress, its effects on social interactions and on hypothalamic-pituitary-adrenal function over the course of the procedure and in response to new stressors. The effects of social instability are sex-specific, with qualitative differences between the sexes on HPA function over the course of the stressor procedure, and with greater effects in males on behaviour observed during the social instability and greater effects in females on behavioural responses to drugs of abuse into adulthood, long after the stress exposure. The results from investigations with this model of adolescent social stress are discussed in relation to those of studies using other stressor procedures. Elevated exposure to glucocorticoids over the course of adolescence confers sex-specific changes in behavioural responses to drugs of abuse, which may be of relevance for understanding risk factors in people.

  10. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.

    Science.gov (United States)

    Herter, Sylvia; Herting, Frank; Mundigl, Olaf; Waldhauer, Inja; Weinzierl, Tina; Fauti, Tanja; Muth, Gunter; Ziegler-Landesberger, Doris; Van Puijenbroek, Erwin; Lang, Sabine; Duong, Minh Ngoc; Reslan, Lina; Gerdes, Christian A; Friess, Thomas; Baer, Ute; Burtscher, Helmut; Weidner, Michael; Dumontet, Charles; Umana, Pablo; Niederfellner, Gerhard; Bacac, Marina; Klein, Christian

    2013-10-01

    We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation.

  11. PREDICTIVE MODEL FOR SURVIVAL AND GROWTH OF SALMONELLA TYPHIMURIUM DT104 ON CHICKEN SKIN DURING TEMPERATURE ABUSE

    Science.gov (United States)

    To better predict risk of Salmonella infection from chicken subjected to temperature abuse, a study was undertaken to develop a predictive model for survival and growth of Salmonella Typhimurium DT104 on chicken skin with native micro flora. For model development, chicken skin portions were inocula...

  12. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

    Directory of Open Access Journals (Sweden)

    Wilkes D

    2012-10-01

    Full Text Available Denise Wilkes,1 Guangwen Li,2 Carmina F Angeles,3 Joel T Patterson,4 Li-Yen Mae Huang21Department of Anesthesiology, 2Department of Neuroscience and Cell Biology, 3Department of Neurosurgery University of Texas Medical Branch, Galveston, TX, USA; 4Neurospine Institute, Eugene, OR, USABackground: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.Results: Peroneal nerve injury (PNI produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50 for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain

  13. Effects of Methadone Maintenance Treatment on Decision-Making Processes in Heroin-Abusers: A Cognitive Modeling Analysis

    Directory of Open Access Journals (Sweden)

    Arash Khodadadi

    2010-05-01

    Full Text Available A B S T R A C TIntroduction: Although decision-making processes have become a principal target of study among addiction researchers, few researches are published according to effects of different treatment methods on the cognitive processes underlying decision making up to now. Utilizing cognitive modeling method, in this paper we examine the effects of Methadone maintenance treatment (MMT on cognitive processes underlying decision-making disorders in heroin-abusers. Methods: For this purpose, for the first time, we use the balloon analog risk task (BART to assess the decision-making ability of heroin-abusers before and after treatment and compare it to the non heroin-dependent subjects. Results: Results demonstrate that heroin-abusers show more risky behavior than other groups. But, there is no difference between the performance of heroin-abusers after 6 months of MMT and control group. Modeling subjects’ behavior in BART reveals that poor performance in heroin-abusers is due to reward-dependency and insensitivity to evaluation. Discussion: Results show that 6 months of MMT decreases reward-dependency and increases sensitivity to evaluation.

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

    Science.gov (United States)

    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.

  15. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

    Science.gov (United States)

    El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

    2015-01-01

    Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.

  16. Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: an overview.

    Science.gov (United States)

    Di Pilato, Pantaleo; Niso, Mauro; Adriani, Walter; Romano, Emilia; Travaglini, Domenica; Berardi, Francesco; Colabufo, Nicola A; Perrone, Roberto; Laviola, Giovanni; Lacivita, Enza; Leopoldo, Marcello

    2014-01-01

    The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.

  17. Optimised and rapid pre-clinical screening in the SOD1(G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS.

    Directory of Open Access Journals (Sweden)

    Richard J Mead

    Full Text Available The human SOD1(G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS. In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6 SOD1(G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  18. Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

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    Ghosh Anamitra

    2012-10-01

    Full Text Available Abstract Background Parkinson’s disease (PD is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of PD. Methods Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1, glial fibrillary acidic protein (GFAP, gp91phox and inducible nitric oxide synthase (iNOS, were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT, 4-hydroxynonenal (4-HNE and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. Results Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN. MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in

  19. Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.

    Directory of Open Access Journals (Sweden)

    Britta Vormoor

    Full Text Available Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG and Rag2(-/-/γc(-/- mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000 injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which

  20. Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

    Science.gov (United States)

    Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

    2009-04-15

    Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

  1. The future of preclinical animal models in pharmaceutical discovery and development: a need to bring in cerebro to the in vivo discussions.

    Science.gov (United States)

    Everitt, Jeffrey I

    2015-01-01

    Animal models have provided an important tool to help make the decision to take potential therapies from preclinical studies to humans. In the past several years, the strong reliance of the pharmaceutical discovery and development process on the use of animal models has come under increasing scrutiny for ethical and scientific reasons. Several prominent and widely publicized articles have reported limited concordance of animal experiments with subsequent human clinical trials. Recent assessments of the quality of animal studies have suggested that this translational failure may be due in part to shortcomings in the planning, conduct, and reporting of in vivo studies. This article will emphasize methods to assure best practice rigor in animal study methods and reporting. It will introduce the so-called scientific 3Rs of relevance, robustness, and reproducibility to the in vivo study approach and will review important new trends in the animal research and pharmaceutical discovery and development communities.

  2. Modeling and short circuit detection of 18650 Li-ion cells under mechanical abuse conditions

    Science.gov (United States)

    Sahraei, Elham; Campbell, John; Wierzbicki, Tomasz

    2012-12-01

    In this research a simple, yet accurate model of a single cell, needed for safety assessment of batteries under mechanical abuse conditions, was developed. Extensive testing was performed on a 18650 lithium ion cell, including indentation by a hemispherical punch, lateral indentation by a cylindrical rod, compression between two flat plates, and three-point bending. The batteries were tested in an environmental chamber at a 10% SOC. A finite element model was developed, composed of shell elements representing outside casing, and solid elements for the active material with a binder lumped together with the current collectors and the separator. The jelly roll is modeled as a homogenized and isotropic material. The homogenous model assumes different properties in tension and compression, but does not account for the effect of structural anisotropy caused by the layered nature of the jelly roll. Very good correlation was obtained between LS Dyna numerical simulation and test results in terms of load-displacement relations, deformed shape of the battery, and initiation and propagation of a crack in the shell casing. The FE model was also capable of predicting the onset of short circuit of the cell.

  3. 76 FR 70463 - National Institute on Drug Abuse; Notice of Closed Meetings

    Science.gov (United States)

    2011-11-14

    ... HUMAN SERVICES National Institutes of Health National Institute on Drug Abuse; Notice of Closed Meetings... Committee: National Institute on Drug Abuse Special Emphasis Panel; Preclinical Medications Discovery and... Specialist, Office of Extramural Affairs, National Institute on Drug Abuse, NIH, DHHS, Room 4227, MSC...

  4. Performance of statistical models to predict mental health and substance abuse cost

    Directory of Open Access Journals (Sweden)

    Ettner Susan L

    2006-10-01

    Full Text Available Abstract Background Providers use risk-adjustment systems to help manage healthcare costs. Typically, ordinary least squares (OLS models on either untransformed or log-transformed cost are used. We examine the predictive ability of several statistical models, demonstrate how model choice depends on the goal for the predictive model, and examine whether building models on samples of the data affects model choice. Methods Our sample consisted of 525,620 Veterans Health Administration patients with mental health (MH or substance abuse (SA diagnoses who incurred costs during fiscal year 1999. We tested two models on a transformation of cost: a Log Normal model and a Square-root Normal model, and three generalized linear models on untransformed cost, defined by distributional assumption and link function: Normal with identity link (OLS; Gamma with log link; and Gamma with square-root link. Risk-adjusters included age, sex, and 12 MH/SA categories. To determine the best model among the entire dataset, predictive ability was evaluated using root mean square error (RMSE, mean absolute prediction error (MAPE, and predictive ratios of predicted to observed cost (PR among deciles of predicted cost, by comparing point estimates and 95% bias-corrected bootstrap confidence intervals. To study the effect of analyzing a random sample of the population on model choice, we re-computed these statistics using random samples beginning with 5,000 patients and ending with the entire sample. Results The Square-root Normal model had the lowest estimates of the RMSE and MAPE, with bootstrap confidence intervals that were always lower than those for the other models. The Gamma with square-root link was best as measured by the PRs. The choice of best model could vary if smaller samples were used and the Gamma with square-root link model had convergence problems with small samples. Conclusion Models with square-root transformation or link fit the data best. This function

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

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    Shellenberger Sylvia

    2010-05-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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

  6. Nanocapsular forms of preparations in preclinical studies

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    Ekaterina Grinevich

    2010-07-01

    Full Text Available The paper examines preclinical study of nanocapsule deliverysystem, particularly the influence of nanocapsule with a vasodilatorin the process of programmed myocardial cells death. Isosorbidedinitrate was loaded in nanocapsules. To investigate the effectnanocapsule isosorbide dinitrate on the process of apoptosis incardiomyocytes, a series of experimental works wereperformed. For this purpose, a model of coronary insufficiency in 4groups of animals were elaborated. The experimental works onlaboratory animals were conducted in accordance withrequirements of the European Convention for the protection ofvertebrate animals. The first preclinical trials showed the presenceof specific activity of obtained drugs. The basis of nanocapsularsystem was phosphatidylinositol, and the active loading substanceswere alprostadil, interferon alpha.

  7. Identifying Life-Threatening Admissions for Drug Dependence or Abuse (ILIADDA): Derivation and Validation of a Model.

    Science.gov (United States)

    Nguyen, Tri-Long; Boudemaghe, Thierry; Leguelinel-Blache, Géraldine; Eiden, Céline; Kinowski, Jean-Marie; Le Manach, Yannick; Peyrière, Hélène; Landais, Paul

    2017-01-01

    Given that drug abuse and dependence are common reasons for hospitalization, we aimed to derive and validate a model allowing early identification of life-threatening hospital admissions for drug dependence or abuse. Using the French National Hospital Discharge Data Base, we extracted 66,101 acute inpatient stays for substance abuse, dependence, mental disorders or poisoning associated with medicines or illicit drugs intake, recorded between January 1st, 2009 and December 31st, 2014. We split our study cohort at the center level to create a derivation cohort and a validation cohort. We developed a multivariate logistic model including patient’s age, sex, entrance mode and diagnosis as predictors of a composite primary outcome of in-hospital death or ICU admission. A total of 2,747 (4.2%) patients died or were admitted to ICU. The risk of death or ICU admission was mainly associated with the consumption of opioids, followed by cocaine and other narcotics. Particularly, methadone poisoning was associated with a substantial risk (OR: 35.70, 95% CI [26.94–47.32], P < 0.001). In the validation cohort, our model achieved good predictive properties in terms of calibration and discrimination (c-statistic: 0.847). This allows an accurate identification of life-threatening admissions in drug users to support an early and appropriate management. PMID:28290530

  8. Preclinical Toxicology of New Drugs.

    Science.gov (United States)

    1986-04-04

    8217 . -. . . . . . 3. . ANNUAL REPORT Contract No. DAMD17-84-C-4088 on PRECLINICAL TOXICOLOGY OF NEW DRUGS Report 8740-86-2 to UNITED STATES ARMY MEDICAL RESEARCH...N RECIPIENTS CATALOG NUMBER 8740-86-2 /1 4. TITLE (mid Subtitle) TYPE OF REPORT & PERIOD COVERED , ; Annual Report PRECLINICAL TOXICOLOGY OF NEW DRUGS March...9 It P V .---, - 77 T ANNUAL REPORT Contract No. DAMD17-84-C-4088 on PRECLINICAL TOXICOLOGY OF NEW DRUGS Report

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

    Science.gov (United States)

    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…

  10. A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs

    NARCIS (Netherlands)

    Stevens, Jasper; Suidgeest, Ernst; van der Graaf, Piet Hein; Danhof, Meindert; de Lange, Elizabeth C M

    2009-01-01

    PURPOSE: To develop a new minimal-stress model for intranasal administration in freely moving rats and to evaluate in this model the brain distribution of acetaminophen following intranasal versus intravenous administration. METHODS: Male Wistar rats received one intranasal cannula, an intra-cerebra

  11. Some theoretical models and constructs generic to substance abuse prevention programs for adolescents: possible relevance and limitations for problem gambling.

    Science.gov (United States)

    Evans, Richard I

    2003-01-01

    For the past several years the author and his colleagues have explored the area of how social psychological constructs and theoretical models can be applied to the prevention of health threatening behaviors in adolescents. In examining the need for the development of gambling prevention programs for adolescents, it might be of value to consider the application of such constructs and theoretical models as a foundation to the development of prevention programs in this emerging problem behavior among adolescents. In order to provide perspective to the reader, the present paper reviews the history of various psychosocial models and constructs generic to programs directed at prevention of substance abuse in adolescents. A brief history of some of these models, possibly most applicable to gambling prevention programs, are presented. Social inoculation, reasoned action, planned behavior, and problem behavior theory, are among those discussed. Some deficits of these models, are also articulated. How such models may have relevance to developing programs for prevention of problem gambling in adolescents is also discussed. However, the inherent differences between gambling and more directly health threatening behaviors such as substance abuse must, of course, be seriously considered in utilizing such models. Most current gambling prevention programs have seldom been guided by theoretical models. Developers of gambling prevention programs should consider theoretical foundations, particularly since such foundations not only provide a guide for programs, but may become critical tools in evaluating their effectiveness.

  12. Alterations of BDNF and trkB mRNA Expression in the 6-Hydroxydopamine-Induced Model of Preclinical Stages of Parkinson’s Disease: An Influence of Chronic Pramipexole in Rats

    OpenAIRE

    Klemencja Berghauzen-Maciejewska; Jadwiga Wardas; Barbara Kosmowska; Urszula Głowacka; Katarzyna Kuter; Krystyna Ossowska

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into...

  13. Delayed minimally invasive injection of allogenic bone marrow stromal cell sheets regenerates large bone defects in an ovine preclinical animal model.

    Science.gov (United States)

    Berner, Arne; Henkel, Jan; Woodruff, Maria A; Steck, Roland; Nerlich, Michael; Schuetz, Michael A; Hutmacher, Dietmar W

    2015-05-01

    Cell-based tissue engineering approaches are promising strategies in the field of regenerative medicine. However, the mode of cell delivery is still a concern and needs to be significantly improved. Scaffolds and/or matrices loaded with cells are often transplanted into a bone defect immediately after the defect has been created. At this point, the nutrient and oxygen supply is low and the inflammatory cascade is incited, thus creating a highly unfavorable microenvironment for transplanted cells to survive and participate in the regeneration process. We therefore developed a unique treatment concept using the delayed injection of allogenic bone marrow stromal cell (BMSC) sheets to regenerate a critical-sized tibial defect in sheep to study the effect of the cells' regeneration potential when introduced at a postinflammatory stage. Minimally invasive percutaneous injection of allogenic BMSCs into biodegradable composite scaffolds 4 weeks after the defect surgery led to significantly improved bone regeneration compared with preseeded scaffold/cell constructs and scaffold-only groups. Biomechanical testing and microcomputed tomography showed comparable results to the clinical reference standard (i.e., an autologous bone graft). To our knowledge, we are the first to show in a validated preclinical large animal model that delayed allogenic cell transplantation can provide applicable clinical treatment alternatives for challenging bone defects in the future.

  14. Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Kuter, Katarzyna; Kolasiewicz, Wacław; Głowacka, Urszula; Dziubina, Anna; Ossowska, Krystyna; Wardas, Jadwiga

    2014-09-01

    Depression is a frequent comorbid disorder in Parkinson's disease and may antedate its motor symptoms. However, mechanisms underlying Parkinson's disease-associated depression are unknown and its current medication is insufficient. The aim of the present study was to compare antidepressant-like effects of imipramine, fluoxetine and pramipexole in a model of preclinical stages of Parkinson's disease in rats. 6-Hydroxydopamine was bilaterally injected into the ventrolateral region of the caudate-putamen in rats. This treatment induced moderate decreases in the levels of dopamine and its metabolites in the caudate-putamen, nucleus accumbens and frontal cortex and reduced the density of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta and ventral tegmental area. The lesion increased immobility measured in the forced swimming test without influencing locomotor activity. Chronic (13 days) administration of pramipexole (1mg/kg sc/twice a day) reversed prolongation of the immobility time in lesioned animals but did not stimulate their locomotion. Chronic pramipexole activated dopaminergic transmission in the brain structures which might contribute to its effectiveness in the forced swimming test. In contrast, the 13-day administration of imipramine (10mg/kg ip/day) and fluoxetine (10mg/kg ip/day) did not shorten the immobility time in lesioned rats but reduced their locomotion. The present study indicates that already a moderate lesion of dopaminergic neurons induces "depressive-like" behaviour in animals which is reversed by chronic administration of the antiparkinsonian drug, pramipexole.

  15. Yessotoxin, a Marine Toxin, Exhibits Anti-Allergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model

    Science.gov (United States)

    Tobío, Araceli; Alfonso, Amparo; Madera-Salcedo, Iris; Botana, Luis M.

    2016-01-01

    Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug. PMID:27973568

  16. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

    Science.gov (United States)

    Nassar, Inthisham; Pasupati, Thanikachalam; Judson, John Paul; Segarra, Ignacio

    2010-06-01

    Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

  17. Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma.

    Science.gov (United States)

    Amengual, Jennifer E; Clark-Garvey, Sean; Kalac, Matko; Scotto, Luigi; Marchi, Enrica; Neylon, Ellen; Johannet, Paul; Wei, Ying; Zain, Jasmine; O'Connor, Owen A

    2013-09-19

    Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor κB. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210.

  18. Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies

    Science.gov (United States)

    Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J.; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S.

    2014-08-01

    Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention-PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time.

  19. Determining Possible Professionals and Respective Roles and Responsibilities for a Model Comprehensive Elder Abuse Intervention: A Delphi Consensus Survey.

    Directory of Open Access Journals (Sweden)

    Janice Du Mont

    Full Text Available 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 large and

  20. Social-Relational Risk Factors for Predicting Elder Physical Abuse: An Ecological Bi-Focal Model

    Science.gov (United States)

    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…

  1. Testing a Model of Participant Retention in Longitudinal Substance Abuse Research

    Science.gov (United States)

    Gilmore, Devin; Kuperminc, Gabriel P.

    2014-01-01

    Longitudinal substance abuse research has often been compromised by high rates of attrition, thought to be the result of the lifestyle that often accompanies addiction. Several studies have used strategies including collection of locator information at the baseline assessment, verification of the information, and interim contacts prior to…

  2. Feasibility of primary tumor culture models and preclinical prediction assays for head and neck cancer : A narrative review

    NARCIS (Netherlands)

    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

  3. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation.

    Science.gov (United States)

    Moshkelgosha, Sajad; So, Po-Wah; Deasy, Neil; Diaz-Cano, Salvador; Banga, J Paul

    2013-09-01

    Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

  4. Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model

    Energy Technology Data Exchange (ETDEWEB)

    Lo Dico, A.; Martelli, C. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); Valtorta, S.; Belloli, S. [National Researches Council (CNR), Institute of Molecular Bioimaging and Physiology (IBFM), Segrate, MI (Italy); IRCCS San Raffaele Scientific Institute, Experimental Imaging Center, Milan (Italy); Raccagni, I.; Moresco, R.M. [IRCCS San Raffaele Scientific Institute, Experimental Imaging Center, Milan (Italy); University of Milano-Bicocca, Department of Health Sciences, Monza (Italy); Diceglie, C. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Doctorate School of Molecular Medicine, Milan (Italy); Gianelli, U.; Bosari, S. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Division of Pathology, Milan (Italy); Vaira, V. [Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Division of Pathology, Milan (Italy); Istituto Nazionale Genetica Molecolare ' ' Romeo ed Enrica Invernizzi' ' (INGM), Milan (Italy); Politi, L.S. [IRCCS San Raffaele Scientific Institute, Neuroradiology Department and Neuroradiology Research Group, Milan (Italy); Lucignani, G. [University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); University of Milan, Department of Health Sciences, Milan (Italy); San Paolo Hospital, Department of Diagnostic Services, Unit of Nuclear Medicine, Milan (Italy); Ottobrini, L. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); National Researches Council (CNR), Institute of Molecular Bioimaging and Physiology (IBFM), Segrate, MI (Italy)

    2015-03-27

    Hypoxia-inducible factor 1α (HIF-1α) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1α modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model. U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1α activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging. This cell model can be used to monitor HIF-1α activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1α activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1α activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action. The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1α activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures. (orig.)

  5. Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model.

    Science.gov (United States)

    Williamson, Tara; Bai, Ren-Yuan; Staedtke, Verena; Huso, David; Riggins, Gregory J

    2016-10-18

    Inheritance of a gene mutation leads to the initiation of 5 to 10% of most cancers, including colon cancer cases. We developed a chemoprevention strategy using a novel combination of the non-steroidal anti-inflammatory (NSAID) sulindac plus the anthelminthic benzimidazole, mebendazole. This oral drug combination was effective in the ApcMin/+ mouse model of Familial Adenomatous Polyposis (FAP). Treatment with 35 mg/kg daily mebendazole reduced the number of intestinal adenomas by 56% (P = 0.0002), 160 ppm sulindac by 74% (P cancer patients using mebendazole either alone or in combination. The findings have implications for populations with moderate and above risk for developing cancer.

  6. Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients

    OpenAIRE

    Shurell, Elizabeth; Tran, Linh M.; Nakashima, Jonathan; Smith, Kathleen B.; Tam, Brenna M.; Li, Yunfeng; Dry, Sarah M.; Federman, Noah; Tap, William D; Wu, Hong; Eilber, Fritz C.

    2014-01-01

    Background Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied. Methods Forty-three mGFAP-Cre+;Pten loxp/+;LSL-K-ras G12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974–2011, n = 113 MPNST patients) a...

  7. The preclinical stage of spinocerebellar ataxias.

    Science.gov (United States)

    Maas, Roderick P P W M; van Gaalen, Judith; Klockgether, Thomas; van de Warrenburg, Bart P C

    2015-07-07

    The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset.

  8. Physical Abuse

    Science.gov (United States)

    ... be acquaintances, sons, daughters, grandchildren, or others. Physical abuse that is perpetrated by spouses or intimate partners in order to gain power and control over the victim is described in ...

  9. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

    Science.gov (United States)

    Kuhn, Deborah J; Berkova, Zuzana; Jones, Richard J; Woessner, Richard; Bjorklund, Chad C; Ma, Wencai; Davis, R Eric; Lin, Pei; Wang, Hua; Madden, Timothy L; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Orlowski, Robert Z

    2012-10-18

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

  10. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

    Directory of Open Access Journals (Sweden)

    Bonnie K Harrington

    Full Text Available Acalabrutinib (ACP-196 is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL. First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR was 25% (5/20 with a median progression free survival (PFS of 22.5 days. Clinical benefit was observed in 30% (6/20 of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL.

  11. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C.; Russell, Duncan S.; Zhang, Xiaoli; Urie, Bridget K.; London, Cheryl A.; Byrd, John C.; Johnson, Amy J.; Kisseberth, William C.

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  12. Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model.

    Science.gov (United States)

    Donegan, J J; Tyson, J A; Branch, S Y; Beckstead, M J; Anderson, S A; Lodge, D J

    2016-08-02

    An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.Molecular Psychiatry advance online publication, 2 August 2016; doi:10.1038/mp.2016.121.

  13. Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis

    Science.gov (United States)

    Xue, Xiaohua; Soroosh, Pejman; De Leon-Tabaldo, Aimee; Luna-Roman, Rosa; Sablad, Marciano; Rozenkrants, Natasha; Yu, Jingxue; Castro, Glenda; Banie, Homayon; Fung-Leung, Wai-Ping; Santamaria-Babi, Luis; Schlueter, Thomas; Albers, Michael; Leonard, Kristi; Budelsky, Alison L.; Fourie, Anne M.

    2016-01-01

    The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases. PMID:27905482

  14. Mouse models for studies of HLA-G functions in basic science and pre-clinical research.

    Science.gov (United States)

    Nguyen-Lefebvre, Anh Thu; Ajith, Ashwin; Portik-Dobos, Vera; Horuzsko, Daniel D; Mulloy, Laura L; Horuzsko, Anatolij

    2016-09-01

    HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

  15. A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models.

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    Hao Zhang

    Full Text Available Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC. Currently approved agents inhibit mechanistic target of rapamycin (mTOR complex 1 (mTORC1. However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794.

  16. A Hamster Model of Diet-Induced Obesity for Preclinical Evaluation of Anti-Obesity, Anti-Diabetic and Lipid Modulating Agents.

    Directory of Open Access Journals (Sweden)

    Louise S Dalbøge

    Full Text Available Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO and hypercholesterolemia Golden Syrian hamster model.Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days, normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4 inhibitor, linagliptin (3.0 mg/kg, PO, QD also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day or neuromedin U (NMU, 1.5 mg/kg/day, continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents.

  17. Personal health records in the preclinical medical curriculum: modeling student responses in a simple educational environment utilizing Google Health

    Directory of Open Access Journals (Sweden)

    Karamanlis Dimokratis A

    2012-09-01

    Full Text Available Abstract Background Various problems concerning the introduction of personal health records in everyday healthcare practice are reported to be associated with physicians’ unfamiliarity with systematic means of electronically collecting health information about their patients (e.g. electronic health records - EHRs. Such barriers may further prevent the role physicians have in their patient encounters and the influence they can have in accelerating and diffusing personal health records (PHRs to the patient community. One way to address these problems is through medical education on PHRs in the context of EHR activities within the undergraduate medical curriculum and the medical informatics courses in specific. In this paper, the development of an educational PHR activity based on Google Health is reported. Moreover, student responses on PHR’s use and utility are collected and presented. The collected responses are then modelled to relate the satisfaction level of students in such a setting to the estimation about their attitude towards PHRs in the future. Methods The study was conducted by designing an educational scenario about PHRs, which consisted of student instruction on Google Health as a model PHR and followed the guidelines of a protocol that was constructed for this purpose. This scenario was applied to a sample of 338 first-year undergraduate medical students. A questionnaire was distributed to each one of them in order to obtain Likert-like scale data on the sample’s response with respect to the PHR that was used; the data were then further analysed descriptively and in terms of a regression analysis to model hypothesised correlations. Results Students displayed, in general, satisfaction about the core PHR functions they used and they were optimistic about using them in the future, as they evaluated quite high up the level of their utility. The aspect they valued most in the PHR was its main role as a record-keeping tool, while

  18. The curry spice curcumin selectively inhibits cancer cells growth in vitro and in preclinical model of glioblastoma.

    Science.gov (United States)

    Zanotto-Filho, Alfeu; Braganhol, Elizandra; Edelweiss, Maria Isabel; Behr, Guilherme A; Zanin, Rafael; Schröder, Rafael; Simões-Pires, André; Battastini, Ana Maria Oliveira; Moreira, José Cláudio Fonseca

    2012-06-01

    Previous studies suggested that curcumin is a potential agent against glioblastomas (GBMs). However, the in vivo efficacy of curcumin in gliomas remains not established. In this work, we examined the mechanisms underlying apoptosis, selectivity, efficacy and safety of curcumin from in vitro (U138MG, U87, U373 and C6 cell lines) and in vivo (C6 implants) models of GBM. In vitro, curcumin markedly inhibited proliferation and migration and induced cell death in liquid and soft agar models of GBM growth. Curcumin effects occurred irrespective of the p53 and PTEN mutational status of the cells. Interestingly, curcumin did not affect viability of primary astrocytes, suggesting that curcumin selectivity targeted transformed cells. In U138MG and C6 cells, curcumin decreased the constitutive activation of PI3K/Akt and NFkappaB survival pathways, down-regulated the antiapoptotic NFkappaB-regulated protein bcl-xl and induced mitochondrial dysfunction as a prelude to apoptosis. Cells developed an early G2/M cell cycle arrest followed by sub-G1 apoptosis and apoptotic bodies formation. Caspase-3 activation occurred in the p53-normal cell type C6, but not in the p53-mutant U138MG. Besides its apoptotic effect, curcumin also synergized with the chemotherapeutics cisplatin and doxorubicin to enhance GBM cells death. In C6-implanted rats, intraperitoneal curcumin (50 mg kg(-1) d(-1)) decreased brain tumors in 9/11 (81.8%) animals against 0/11 (0%) in the vehicle-treated group. Importantly, no evidence of tissue (transaminases, creatinine and alkaline phosphatase), metabolic (cholesterol and glucose), oxidative or hematological toxicity was observed. In summary, data presented here suggest curcumin as a potential agent for therapy of GBMs.

  19. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    Science.gov (United States)

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline.

  20. Everyone's business: developing an integrated model of care to respond to child abuse in a pediatric hospital setting.

    Science.gov (United States)

    Connolly, Sarah

    2012-01-01

    In pediatric hospitals, social work plays a central role in the prevention, identification, and management of child abuse. Children who are suspected of having been abused or neglected require an evaluation of their psychosocial situation. As an integral member of the health care team, the social worker is well placed to undertake comprehensive psychosocial assessments including information on the child's development, parental capacity, family, and community supports. Current practice approaches have seen a shift away from a narrow, "expert" approach to child protection. This article describes the development of an integrated model of social work service delivery to better respond to vulnerable and at-risk children in a pediatric hospital setting. Developing a new model of service required strategic planning, consultation, and endorsement from senior hospital management. The new model aimed to ensure a high quality, responsive social work service to children at risk of physical abuse, neglect, or cumulative harm. The change necessitated understanding of current research evidence, development of best practice guidelines, and effective communication with staff and external stakeholders. Policy development, implementation of practice guidelines, staff training, data collection, and service evaluation are described. The role of social work management and leadership were central in creating change. Visionary leadership is widely regarded as key to successful organizational change. The management approach included consultation with staff, building commitment to the need for change, addressing staff concerns, and providing a vision of enhanced client outcomes as a result of the change process. This article provides a candid overview of challenges and barriers to change. Change strategies described are easily transferable to other social work settings.

  1. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.

    Science.gov (United States)

    Wang, Jian; Svendsen, Agnete; Kmiecik, Justyna; Immervoll, Heike; Skaftnesmo, Kai Ove; Planagumà, Jesús; Reed, Rolf Kåre; Bjerkvig, Rolf; Miletic, Hrvoje; Enger, Per Øyvind; Rygh, Cecilie Brekke; Chekenya, Martha

    2011-01-01

    Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  2. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.

    Directory of Open Access Journals (Sweden)

    Jian Wang

    Full Text Available Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4 or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  3. Chronic renoprotective effect of pulsatile perfusion machine RM3 and IGL-1 solution in a preclinical kidney transplantation model

    Directory of Open Access Journals (Sweden)

    Thuillier Raphael

    2012-11-01

    Full Text Available Abstract Background Machine perfusion (MP of kidney graft provides benefits against preservation injury, however decreased graft quality requires optimization of the method. We examined the chronic benefits of MP on kidney grafts and the potential improvements provided by IGL-1 solution. Method We used an established autotransplantation pig kidney model to study the effects of MP against the deleterious effects of warm ischemia (WI: 60 minutes followed by 22 hours of cold ischemia in MP or static cold storage (CS followed by autotransplantation. MPS and IGL-1 solutions were compared. Results Animal survival was higher in MPS-MP and both IGL groups. Creatinine measurement did not discriminate between the groups, however MPS-MP and both IGL groups showed decreased proteinuria. Chronic fibrosis level was equivalent between the groups. RTqPCR and immunohistofluorescent evaluation showed that MP and IGL-1 provided some protection against epithelial to mesenchymal transition and chronic lesions. IGL-1 was protective with both MP and CS, particularly against chronic inflammation, with only small differences between the groups. Conclusion IGL-1 used in either machine or static preservation offers similar levels of protection than standard MP. The compatibility of IGL-1 with both machine perfusion and static storage could represent an advantage for clinical teams when choosing the correct solution to use for multi-organ collection. The path towards improving machine perfusion, and organ quality, may involve the optimization of the solution and the correct use of colloids.

  4. The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease

    Science.gov (United States)

    Karuppagounder, Senthilkumar S.; Brahmachari, Saurav; Lee, Yunjong; Dawson, Valina L.; Dawson, Ted M.; Ko, Han Seok

    2014-01-01

    c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD. PMID:24786396

  5. NIR fluorescent image-based evaluation of gastric tube perfusion after esophagectomy in preclinical model (Conference Presentation)

    Science.gov (United States)

    Kim, Minji; Quan, Yuhua; Han, Kook Nam; Choi, Byeong Hyun; Choi, Yeonho; Kim, Hyun Koo; Kim, Beop-Min

    2016-03-01

    This study was to evaluate the feasibility of near infrared (NIR) fluorescent images as a tool for evaluating the perfusion of the gastric tube after esophagectomy. In addition, we investigated the time required to acquire enough signal to confirm the presence of ischemia in gastric tube after injection of indocyanine green (ICG) through peripheral versus and central venous route. 4 porcine underwent esophagogastrostomy and their right gastric arteries were ligated to mimic ischemic condition of gastric tube. ICG (0.6mg/kg) was intravenously injected and the fluorescence signal-to-background ratios (SBR) were measured by using the custom-built intraoperative color and fluorescence imaging system (ICFIS). We evaluated perfusion of gastric tubes by comparing their SBR with esophageal SBR. In ischemic models, SBR of esophagus was higher than that of gastric tube (2.8+/-0.54 vs. 1.7+/-0.37, pperfusion in few minutes after releasing the ligation of right gastric artery. In addition, in comparison study according to the injection route of ICG, The time to acquire signal stabilization was faster in central than in peripheral route (119 +/- 65.1 seconds in central route vs. 295+/-130.4 in peripheral route, p<0.05). NIR fluorescent images could provide the real-time information if there was ischemia or not in gastric tube during operation. And, central injection of ICG might give that information faster than peripheral route.

  6. Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: First pre-clinical study on a murine model

    Energy Technology Data Exchange (ETDEWEB)

    Dallaudière, Benjamin, E-mail: bendallau64@hotmail.fr [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Inserm U698, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Lempicki, Marta [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Pesquer, Lionel [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Louedec, Liliane [Inserm U698, Hôpital universitaire Bichat, Paris (France); Preux, Pierre Marie [Laboratoire de Biostatistiques, Faculté de médecine, Limoges (France); Meyer, Philippe [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hess, Agathe [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Durieux, Marie Hèlène Moreau [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hummel, Vincent; Larbi, Ahmed [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Deschamps, Lydia [Service d’ Anatomopathologie, Hôpital universitaire Bichat, Paris (France); and others

    2013-12-01

    Purpose: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. Materials and method: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1{sup ®} (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T−) after injecting AA in 40 (AAT−). Results: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p < 0.004), and less disorganized collagen fibers and neovessels on histology (p < 0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p > 0.05). Comparison between AAT− and T− showed no AA toxicity on tendon (p = 0.18). Conclusion: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity.

  7. A preclinical evaluation of alternative synthetic biomaterials for fascial defect repair using a rat abdominal hernia model.

    Directory of Open Access Journals (Sweden)

    Daniela Ulrich

    Full Text Available INTRODUCTION: Fascial defects are a common problem in the abdominal wall and in the vagina leading to hernia or pelvic organ prolapse that requires mesh enhancement to reduce operation failure. However, the long-term outcome of synthetic mesh surgery may be unsatisfactory due to post-surgical complications. We hypothesized that mesh fabricated from alternative synthetic polymers may evoke a different tissue response, and provide more appropriate mechanical properties for hernia repair. Our aim was to compare the in vivo biocompatibility of new synthetic meshes with a commercial mesh. METHODS: We have fabricated 3 new warp-knitted synthetic meshes from different polymers with different tensile properties polyetheretherketone (PEEK, polyamide (PA and a composite, gelatin coated PA (PA+G. The rat abdominal hernia model was used to implant the meshes (25 × 35 mm, n = 24/ group. After 7, 30, 60, 90 days tissues were explanted for immunohistochemical assessment of foreign body reaction and tissue integration, using CD31, CD45, CD68, alpha-SMA antibodies. The images were analysed using an image analysis software program. Biomechanical properties were uniaxially evaluated using an Instron Tensile® Tester. RESULTS: This study showed that the new meshes induced complex differences in the type of foreign body reaction over the time course of implantation. The PA, and particularly the composite PA+G meshes, evoked a milder early inflammatory response, and macrophages were apparent throughout the time course. Our meshes led to better tissue integration and new collagen deposition, particularly with the PA+G meshes, as well as greater and sustained neovascularisation compared with the PP meshes. CONCLUSION: PA, PA+G and PEEK appear to be well tolerated and are biocompatible, evoking an overlapping and different host tissue response with time that might convey mechanical variations in the healing tissue. These new meshes comprising different polymers may

  8. Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model.

    Science.gov (United States)

    Kaja, Simon; Naumchuk, Yuliya; Grillo, Stephanie L; Borden, Priscilla K; Koulen, Peter

    2014-01-01

    Glaucoma is a multifactorial progressive ocular pathology, clinically presenting with damage to the retina and optic nerve, ultimately leading to blindness. Retinal ganglion cell loss in glaucoma ultimately results in vision loss. Vesl/Homer proteins are scaffolding proteins that are critical for maintaining synaptic integrity by clustering, organizing and functionally regulating synaptic proteins. Current anti-glaucoma therapies target IOP as the sole modifiable clinical parameters. Long-term pharmacotherapy and surgical treatment do not prevent gradual visual field loss as the disease progresses, highlighting the need for new complementary, alternative and comprehensive treatment approaches. Vesl/Homer expression was measured in the retinae of DBA/2J mice, a preclinical genetic glaucoma model with spontaneous mutations resulting in a phenotype reminiscent of chronic human pigmentary glaucoma. Vesl/Homer proteins were differentially expressed in the aged, glaucomatous DBA/2J retina, both at the transcriptional and translational level. Immunoreactivity for the long Vesl-1L/Homer 1c isoform, but not of the immediate early gene product Vesl-1S/Homer 1a was increased in the synaptic layers of the retina. This increased protein level of Vesl-1L/Homer 1c was correlated with phenotypes of increased disease severity and a decrease in visual performance. The increased expression of Vesl-1L/Homer 1c in the glaucomatous retina likely results in increased intracellular Ca(2+) release through enhancement of synaptic coupling. The ensuing Ca(2+) toxicity may thus activate neurodegenerative pathways and lead to the progressive loss of synaptic function in glaucoma. Our data suggest that higher levels of Vesl-1L/Homer 1c generate a more severe disease phenotype and may represent a viable target for therapy development.

  9. Model Exploration of the Legal Regulation on Patent Abuse%专利权滥用法律规制模式探讨

    Institute of Scientific and Technical Information of China (English)

    吴广海

    2012-01-01

    The palenl abuse refers to the palenl owner exercising his or her rights against the social purpose or spirit of creating patent rights, improperly doing harm to others or public interests. There are two types of patent abuses, abuse beyond the legitimate scope of patent rights and abuse within the legitimate scope of patent rights. For the models of regulation on patent abuse, a hybrid model of the combination of anti-monopoly law and patent law is adopted in the U.S.A, and competition law regulation model is adopted in the E U. A hybrid regulation model should be adopted in China, when the patent abuse creates illegal monopoly, applying anti-monopoly law. In the other cases of patent abuse, we should apply patent law.%专利权滥用是指专利权人在行使专利权过程中,违背了专利权创制的社会目的或精神,不正当地损害或可能损害他人或社会公共利益的行为.专利权滥用包括超越专利权范围的滥用和在专利权范围内的滥用.美国对专利权滥用采用反垄断法和专利法共同规制的混合规制模式;欧盟对专利权滥用采用竞争法规制模式.我国法律应采用混合规制模式:在专利权的滥用产生非法垄断情形下,适用反垄断法进行规制,而其他滥用情形则应由专利法进行规制.

  10. Childhood abuse, adult interpersonal abuse, and depression in individuals with extreme obesity.

    Science.gov (United States)

    Salwen, Jessica K; Hymowitz, Genna F; Vivian, Dina; O'Leary, K Daniel

    2014-03-01

    This study sought to examine (a) a mediational model of childhood abuse, adult interpersonal abuse, and depressive symptoms and (b) the impact of weight-related teasing on rates and correlates of childhood abuse. Charts of 187 extremely obese individuals seeking psychological clearance for bariatric (weight-loss) surgery were retrospectively examined. Among the participants, 61% reported a history of childhood abuse, 30.5% reported adult interpersonal abuse, and 15% reported clinically significant depressive symptoms. Initially, the relationship between childhood abuse and current depressive symptoms was significant (pinterpersonal abuse as a mediator in the model reduced the magnitude of its significance (Sobel's test p=.01). The associations between childhood abuse and adult interpersonal abuse and between adult interpersonal abuse and depressive symptoms were significant (prelationship between childhood and adult interpersonal abuse. Bariatric surgery patients report elevated rates of childhood abuse that are comparable to rates in psychiatric populations (e.g., eating disorders, depression), and higher than those in community samples and other medical populations. The relationship between child abuse and depressive symptomatology may be partially explained by the presence of adult interpersonal abuse; additionally, the relationship between childhood and adult interpersonal abuse was stronger for those who did not endure weight-related teasing than for those who did.

  11. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2005-11-01

    rapid tumorigenesis through conditional inversion of the tumor sup- pressor gene Snf5. Cancer Cell . 2002;2:415- 425. 31. Gerber HP, Malik AK, Solar GP...Ultrastructurally, normal arachnoid cells are characterized by loosely interdigitating cellular processes connected by junctional complexes; between the cellular...and cell biology of NF1 and NF2-associated tumors, it has proven difficult to translate these advances into new treatments. The development of

  12. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2006-10-01

    differentiation of NCCs: transforming growth factor β (TGFβ ), fibroblast growth factors ( FGF ), and Wnts (31). Cell culture experiments revealed...between Expanded/Merlin and the Hippo signaling pathway identified in Drosophila may not be conserved in mammals . A continued investigation of this

  13. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2007-10-01

    arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes & Development, 2002, 16:1060-1065. Kissil JL, Johnson KC, Eckman MS and...doubly mutant Nf1 and Wv hematopoietic cells. Blood 2003; 101: 1984-1986. Shannon, K.M. 35 Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe M, and... Paul E. McKeever, Shannon, K.M. 38 Megan Lim, Simon J. Conway, Luis F. Parada, Yuan Zhu, and Sean J. Morrison. 2007. The loss of Nf1 transiently

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

    Science.gov (United States)

    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)

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

    Science.gov (United States)

    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.

  16. {sup 18}F-GE-180: a novel TSPO radiotracer compared to {sup 11}C-R-PK11195 in a preclinical model of stroke

    Energy Technology Data Exchange (ETDEWEB)

    Boutin, Herve; Gerhard, Alexander [University of Manchester, Faculty of Medical and Human Sciences, Manchester (United Kingdom); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Murray, Katie [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Pradillo, Jesus [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Universidad Complutense/Politecnica de Madrid, Madrid (Spain); Maroy, Renaud [SHFJ - CEA Orsay, Orsay (France); Smigova, Alison [University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Jones, Paul A.; Trigg, William [GE Healthcare Ltd., Amersham (United Kingdom)

    2014-10-29

    Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer {sup 11}C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer {sup 18}F-GE-180 in a rat model of stroke. Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with {sup 11}C-R-PK11195 and {sup 18}F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). {sup 18}F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of {sup 11}C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BP{sub ND} = 3.5 ± 0.4 and 2.4 ± 0.5 for {sup 18}F-GE-180 and {sup 11}C-R-PK11195, respectively, with R{sub 1} = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180 significantly displaced {sup 18}F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. The in vivo binding characteristics of {sup 18}F-GE-180 demonstrate a better signal to noise ratio than {sup 11}C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in

  17. NOD/scid IL-2Rgnull mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo

    Directory of Open Access Journals (Sweden)

    Spranger Stefani

    2012-02-01

    Full Text Available Abstract Background To date very few systems have been described for preclinical investigations of human cellular therapeutics in vivo. However, the ability to carry out comparisons of new cellular vaccines in vivo would be of substantial interest for design of clinical studies. Here we describe a humanized mouse model to assess the efficacy of various human dendritic cell (DC preparations. Two reconstitution regimes of NOD/scid IL2Rgnull (NSG mice with adult human peripheral blood mononuclear cells (PBMC were evaluated for engraftment using 4-week and 9-week schedules. This led to selection of a simple and rapid protocol for engraftment and vaccine evaluation that encompassed 4 weeks. Methods NSG recipients of human PBMC were engrafted over 14 days and then vaccinated twice with autologous DC via intravenous injection. Three DC vaccine formulations were compared that varied generation time in vitro (3 days versus 7 days and signals for maturation (with or without Toll-like receptor (TLR3 and TLR7/8 agonists using MART-1 as a surrogate antigen, by electroporating mature DC with in vitro transcribed RNA encoding full length protein. After two weekly vaccinations, the splenocyte populations containing human lymphocytes were recovered 7 days later and assessed for MART-1-specific immune responses using MHC-multimer-binding assays and functional assessment of specific killing of melanoma tumor cell lines. Results Human monocyte-derived DC generated in vitro in 3 days induced better MART-1-specific immune responses in the autologous donor T cells present in the humanized NSG mice. Moreover, consistent with our in vitro observations, vaccination using mature DC activated with TLR3 and TLR7/8 agonists resulted in enhanced immune responses in vivo. These findings led to a ranking of the DC vaccine effects in vivo that reflected the hierarchy previously found for these mature DC variations in vitro. Conclusions This humanized mouse model system enables

  18. Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

    Science.gov (United States)

    Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; Wüllner, U; Sherman, S J; Falk, T

    2014-01-31

    Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy

  19. The relevance of preclinical research models for the development of antimigraine drugs: Focus on 5-HT1B/1D and CGRP receptors

    DEFF Research Database (Denmark)

    Gupta, S.; Villalon, C.M.

    2010-01-01

    Migraine is a complex neurovascular syndrome, causing a unilateral pulsating headache with accompanying symptoms. The past four decades have contributed immensely to our present understanding of migraine pathophysiology and have led to the introduction of specific antimigraine therapies, much......-score to evaluate migraine, as articulated by the volunteer, which cannot be applied to laboratory animals. Therefore, basic research focuses on different symptoms and putative mechanisms, one at a time or in combination, to validate the hypotheses. Studies in several species, utilizing different preclinical...... to the relief of migraineurs. Pathophysiological factors culminating into migraine headaches have not yet been completely deciphered and, thus, pose an additional challenge for preclinical research in the absence of any direct experimental marker. Migraine provocation experiments in humans use a head...

  20. Self-attributions of blame in sexually abused adolescents: a mediational model.

    Science.gov (United States)

    Daigneault, Isabelle; Tourigny, Marc; Hébert, Martine

    2006-02-01

    This study evaluates the mediational role of general attributions in explaining the impact of specific attributions regarding sexual abuse (SA) on six posttraumatic symptoms. One hundred three SA female adolescents (13-17 years old) completed the Trauma Symptoms Checklist for Children (TSCC; Briere, 1989), the blame/guilt subscale of the Children's Impact of Traumatic Events Scale (CITES-R; Wolfe, Gentile, Michienzi, Sas, & Wolfe, 1991), and the Personal Attributions for Negative Events subscale of the Children's Attributions and Perceptions Scale (CAPS; Mannarino, Cohen, & Berman, 1994). Results indicate that general attributions act as a mediator between specific attributions and six posttraumatic symptoms (i.e., anxiety, depression, sexual concerns, posttraumatic stress, dissociation, and anger).

  1. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

    Science.gov (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing

    2014-07-01

    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

  2. Coupled mechanical-electrical-thermal modeling for short-circuit prediction in a lithium-ion cell under mechanical abuse

    Science.gov (United States)

    Zhang, Chao; Santhanagopalan, Shriram; Sprague, Michael A.; Pesaran, Ahmad A.

    2015-09-01

    In order to better understand the behavior of lithium-ion batteries under mechanical abuse, a coupled modeling methodology encompassing the mechanical, electrical and thermal response is presented for predicting short-circuit under external crush. The combined mechanical-electrical-thermal response is simulated in a commercial finite element software LS-DYNA® using a representative-sandwich finite-element model, where electrical-thermal modeling is conducted after an instantaneous mechanical crush. The model includes an explicit representation of each individual component such as the active material, current collector, separator, etc., and predicts their mechanical deformation under quasi-static indentation. Model predictions show good agreement with experiments: the fracture of the battery structure under an indentation test is accurately predicted. The electrical-thermal simulation predicts the current density and temperature distribution in a reasonable manner. Whereas previously reported models consider the mechanical response exclusively, we use the electrical contact between active materials following the failure of the separator as a criterion for short-circuit. These results are used to build a lumped representative sandwich model that is computationally efficient and captures behavior at the cell level without resolving the individual layers.

  3. Understanding cycles of abuse: A multimotive approach.

    Science.gov (United States)

    Simon, Lauren S; Hurst, Charlice; Kelley, Ken; Judge, Timothy A

    2015-11-01

    Fundamental to the definition of abusive supervision is the notion that subordinates are often victims of a pattern of mistreatment (Tepper, 2000). However, little research has examined the processes through which such destructive relational patterns emerge. In this study, we draw from and extend the multimotive model of reactions to interpersonal threat (Smart Richman & Leary, 2009) to formulate and test hypotheses about how employees' emotional and behavioral responses may ameliorate or worsen supervisors' abuse. To test this model, we collected 6 waves of data from a sample of 244 employees. Results revealed reciprocal relationships between abusive supervision and both supervisor-directed counterproductive behavior and supervisor-directed avoidance. Whereas the abusive supervision--counterproductive behavior relationship was partially driven by anger, the abusive supervision--avoidance relationship was partially mediated by fear. These findings suggest that some may find themselves in abusive relationships, in part, because their own reactions to mistreatment can, perhaps unknowingly, reinforce abusive behavior.

  4. Impairment and Abuse of Elderly by Staff in Long-Term Care in Michigan: Evidence from Structural Equation Modeling

    Science.gov (United States)

    Conner, Tom; Prokhorov, Artem; Page, Connie; Fang, Yu; Xiao, Yimin; Post, Lori A.

    2011-01-01

    Elder abuse in long-term care has become a very important public health concern. Recent estimates of elder abuse prevalence are in the range of 2% to 10% (Lachs & Pillemer, 2004), and current changes in population structure indicate a potential for an upward trend in prevalence (Malley-Morrison, Nolido, & Chawla, 2006; Post et al., 2006). More…

  5. Challenges for Preclinical Investigations of Human Biofield Modalities.

    Science.gov (United States)

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-11-01

    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.

  6. Challenges for Preclinical Investigations of Human Biofield Modalities

    Science.gov (United States)

    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

  7. Prescription Drug Abuse

    Science.gov (United States)

    ... Whether they're using street drugs or medications, drug abusers often have trouble at school, at home, with ... a short period of time may make a drug abuser aggressive or paranoid. Although stimulant abuse might not ...

  8. Prevent Child Abuse America

    Science.gov (United States)

    ... call the police . Crisis and support contacts For Child Abuse Reporting Numbers in your State please visit: Child ... suspected child abuse and neglect. Parent Resources Prevent Child Abuse America (800) CHILDREN A resource for tips, referrals, ...

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

    OpenAIRE

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

    2014-01-01

    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 a...

  10. Multimodal imaging based on MRI and PET reveals [{sup 18}F]FLT PET as a specific and early indicator of treatment efficacy in a preclinical model of recurrent glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Corroyer-Dulmont, Aurelien; Peres, Elodie A.; Gerault, Aurelie N.; Divoux, Didier; Toutain, Jerome; Ibazizene, Meziane; MacKenzie, Eric T.; Barre, Louisa; Bernaudin, Myriam; Petit, Edwige; Valable, Samuel [CNRS, UMR 6301 ISTCT, CERVOxy and LDM-TEP groups. GIP CYCERON, Caen (France); CEA, DSV/I2BM, UMR 6301 ISTCT, CERVOxy et LDM-TEP Groups, GIP CYCERON, Caen (France); UNICAEN, UMR 6301 ISTCT, CERVOxy et LDM-TEP Groups, GIP CYCERON, Caen (France); Normandie Univ., Caen(France); Savina, Ariel; Bouquet, Fanny [Roche SAS, Boulogne-Billancourt (France)

    2016-04-15

    The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([{sup 18}F]FDG and [{sup 18}F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [{sup 18}F]FLT uptake, cerebral blood volume and oedema. [{sup 18}F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [{sup 18}F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [{sup 18}F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations. (orig.)

  11. The Effect of Severe Child Sexual Abuse and Disclosure on Mental Health during Adulthood

    Science.gov (United States)

    O'Leary, Patrick; Coohey, Carol; Easton, Scott D.

    2010-01-01

    This study examined the relationship among severe child sexual abuse, disclosure, and mental health symptoms during adulthood. The sample consisted of 172 adults who were sexually abused in childhood. The multivariate model showed that respondents in their 30s and 40s who were abused by more than one abuser, who were injured by their abusers, who…

  12. A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model

    Science.gov (United States)

    Ichimura, Kenzo; Matoba, Tetsuya; Nakano, Kaku; Tokutome, Masaki; Honda, Katsuya; Koga, Jun-ichiro; Egashira, Kensuke

    2016-01-01

    Background There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models. Methods and Results Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon. Conclusions NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic

  13. Exploring the longitudinal offending pathways of child sexual abuse victims: A preliminary analysis using latent variable modeling.

    Science.gov (United States)

    Papalia, Nina L; Luebbers, Stefan; Ogloff, James R P; Cutajar, Margaret; Mullen, Paul E

    2017-01-16

    Very little research has been conducted to show the way in which criminal behavior unfolds over the life-course in children who have been sexually abused, and whether it differs from the 'age-crime' patterns consistently documented in the criminology literature. This study investigated the temporal pathways of criminal offending between the ages of 10-25 years among medically confirmed cases of child sexual abuse (CSA), and considered whether abuse variables, offense variables, and the presence of other adverse outcomes, were associated with heterogeneity in offending pathways among CSA survivors. This study utilized data gathered as part of a large-scale study involving the linkage of forensic examinations on 2759 cases of medically ascertained CSA between 1964 and 1995, to criminal justice and public psychiatric databases 13-44 years following abuse, together with a matched comparison sample of 2677 individuals. We used the subsample of 283 offending individuals (191 victims; 92 comparisons) for whom complete offending data were available. We compared the aggregate age-crime curves for CSA victims and comparisons, and applied longitudinal latent class analysis to identify distinct subgroups of offending pathways between ages 10-25 years within the abuse sample. Four latent pathways emerged among sexually abused offenders, labeled: Early-Onset/High-Risk/Adolescence-Limited; Intermediate-Onset/Low-Risk/Adolescence-Limited; Late-Onset/Low-Risk/Slow-Declining; and Early-Onset/High-Risk/Persistent offenders. Age at abuse, the nature and frequency of offending, and mental health problems, were associated with the offending pathway followed by CSA victims. Consistent with criminological literature, findings indicate considerable heterogeneity in the longitudinal offending patterns of offenders exposed to CSA. Implications for clinical practice and directions for research are highlighted.

  14. N-3 polyunsaturated fatty acids modulate B cell activity in pre-clinical models: Implications for the immune response to infections.

    Science.gov (United States)

    Whelan, Jarrett; Gowdy, Kymberly M; Shaikh, Saame Raza

    2016-08-15

    B cell antigen presentation, cytokine production, and antibody production are targets of pharmacological intervention in inflammatory and infectious diseases. Here we review recent pre-clinical evidence demonstrating that pharmacologically relevant levels of n-3 polyunsaturated fatty acids (PUFA) derived from marine fish oils influence key aspects of B cell function through multiple mechanisms. N-3 PUFAs modestly diminish B cell mediated stimulation of classically defined naïve CD4(+) Th1 cells through the major histocompatibility complex (MHC) class II pathway. This is consistent with existing data showing that n-3 PUFAs suppress the activation of Th1/Th17 cells through direct effects on helper T cells and indirect effects on antigen presenting cells. Mechanistically, n-3 PUFAs lower antigen presentation and T cell signaling by disrupting the formation of lipid microdomains within the immunological synapse. We then review data to show that n-3 PUFAs boost B cell activation and antibody production in the absence and presence of antigen stimulation. This has potential benefits for several clinical populations such as the aged and obese that have poor humoral immunity. The mode of action by which n-3 PUFA boost B cell activation and antibody production remains unclear, but may involve Th2 cytokines, enhanced production of specialized proresolving lipid mediators, and targeting of protein lateral organization in lipid microdomains. Finally, we highlight evidence to show that different n-3 PUFAs are not biologically equivalent, which has implications for the development of future interventions to target B cell activity.

  15. Prevalence of abuse and related factors in a Colombian medical school

    Directory of Open Access Journals (Sweden)

    César Augusto Guevara Cuéllar

    2011-11-01

    Full Text Available Introduction: Different forms of abusive practices are very common in medical schools and have serious implications on vocational and professional formation. The aim of this study is to determine the prevalence of perception of abuse in a university in Colombia and to identify associated factors.Methods: A cross-sectional study was conducted from September to December 2008 in a private medical school. A proportional cycle-based stratified sampling technique and randomized sampling per semester was done. Socio demographic, academic, and abuse-related variables were obtained.Results: One hundred twenty-eight students participated in the study. The prevalence of perception of abuse was 40.6%. The most common type of abuse was psychological (98% and unjustified critique (10.9%, ridiculing (10.7%, shouting (10%, and discredit (9.5% were the most frequent manifestations. Professors in preclinical courses were reported as the most prevalent abusers (25.9%, followed by clinical professors (19.8%. The frequency of abusive manifestations was rare (15.8% and 11.5% in preclinical and clinical years, respectively. The abusive manifestations were most frequent in pathology and pediatrics in the preclinical and clinical years,  espectively. Nineteen percent of the victims of abuse reported such to somebody. The main consequences were desire to withdraw from the career (63.2% and change of career (36.8%. Increased perception of abuse (OR: 4.74 95% IC: 1.9-11.4 p=0.001 was associated during the clinical years.Conclusions: Although abusive practices are more frequent during clinical years, they do not constitute a systematic behavior among medical students from a private university in Colombia in comparison with other  tudies.

  16. Opportunities for computer abuse

    DEFF Research Database (Denmark)

    Willison, Robert Andrew; Backhouse, James

    2005-01-01

    Systems risk refers to the likelihood that an IS is inadequately guarded against certain types of damage or loss. While risks are posed by acts of God, hackers and viruses, consideration should also be given to the `insider' threat of dishonest employees, intent on undertaking some form of computer...... for the offender. To achieve this goal a model known as the `Crime Specific Opportunity Structure' is advanced. Focussing on the opportunities for computer abuse, the model addresses the nature of such opportunities with regards to the organisational context and the threats posed by rogue employees. Drawing...

  17. Preclinical evaluation of racotumomab, an anti-idiotype monoclonal antibody to N-glycolyl-containing gangliosides, with or without chemotherapy in a mouse model of non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Valeria I Segatori

    2012-11-01

    Full Text Available N-glycolylneuraminic acid (NeuGc is a sialic acid molecule usually found in mammalian cells as terminal constituents of different membrane glycoconjugates such as gangliosides. The NeuGcGM3 ganglioside has been described as a tumor antigen for non-small cell lung cancer (NSCLC in humans. Racotumomab is an anti-NeuGc-containing gangliosides anti-idiotype monoclonal antibody (formerly known as 1E10 that has received attention as a potential active immunotherapy for advanced lung cancer in clinical trials. In this work, we have examined the antitumor activity of racotumomab in combination or not with chemotherapy, using the 3LL Lewis lung carcinoma as a preclinical model of NSCLC in C57BL/6 mice. Vaccination with biweekly doses of racotumomab at 50-200 μg/dose formulated in aluminum hydroxide (racotumomab-alum vaccine demonstrated a significant antitumor effect against the progression of lung tumor nodules. Racotumomab-alum vaccination exerted a comparable effect on lung disease to that of pemetrexed-based chemotherapy (100 mg/kg weekly. Interestingly, chemo-immunotherapy was highly effective against lung nodules and well tolerated, although no significant synergistic effect was observed as compared to each treatment alone in the present model. We also obtained evidence on the role of the exogenous incorporation of NeuGc in the metastatic potential of 3LL cells. Our preclinical data provide support for the combination of chemotherapy with the anti-idiotype monoclonal antibody racotumomab, and also reinforce the biological significance of NeuGc in lung cancer.

  18. The matrix model of outpatient stimulant abuse treatment: history and description.

    Science.gov (United States)

    Obert, J L; McCann, M J; Marinelli-Casey, P; Weiner, A; Minsky, S; Brethen, P; Rawson, R

    2000-01-01

    The Matrix model was originally developed in response to the cocaine epidemic of the 1980s. The program consists of relapse prevention groups, education groups, social support groups, individual counseling, and urine and breath testing delivered in a structured manner over a 16-week period. The treatment is a directive, nonconfrontational approach which focuses on current issues and behavior change. Several evaluations of the model have supported its usefulness and efficacy with methamphetamine (MA) users. Methamphetamine users appear to respond to treatment similarly to cocaine users and many continue to show improvements at follow-up.

  19. Preclinical Performance Evaluation of Percutaneous Glucose Biosensors

    Science.gov (United States)

    Soto, Robert J.; Schoenfisch, Mark H.

    2015-01-01

    The utility of continuous glucose monitoring devices remains limited by an obstinate foreign body response (FBR) that degrades the analytical performance of the in vivo sensor. A number of novel materials that resist or delay the FBR have been proposed as outer, tissue-contacting glucose sensor membranes as a strategy to improve sensor accuracy. Traditionally, researchers have examined the ability of a material to minimize the host response by assessing adsorbed cell morphology and tissue histology. However, these techniques do not adequately predict in vivo glucose sensor function, necessitating sensor performance evaluation in a relevant animal model prior to human testing. Herein, the effects of critical experimental parameters, including the animal model and data processing methods, on the reliability and usefulness of preclinical sensor performance data are considered. PMID:26085566

  20. Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model

    Science.gov (United States)

    Lefever, Timothy W.; Marusich, Julie A.; Antonazzo, Kateland R.; Wiley, Jenny L.

    2014-01-01

    Because Δ9-tetrahydrocannabinol (THC) has been a false negative in rat intravenous self-administration procedures, evaluation of the abuse potential of candidate cannabinoid medications has proved difficult. One lab group has successfully trained self-administration of the aminoalkylindole WIN55,212-2 in rats; however, their results have not been independently replicated. The purpose of this study was to extend their model by using a within-subjects design, with the goal of establishing a robust method suitable for substitution testing of other cannabinoids. Male Long-Evans rats were trained to self-administer WIN55,212-2 (0.01 mg/kg/infusion) on a fixed ratio 3 schedule. Dose-effect curves for WIN55,212-2 were determined, followed by vehicle substitution and a dose-effect curve with THC. WIN55,212-2 self-administration was acquired; however, substitution with THC did not maintain responding above vehicle levels. Dose-dependent attenuation by rimonabant confirmed CB1 receptor mediation of WIN55,212-2’s reinforcing effects. Vehicle substitution resulted in a session-dependent decrease in responding (i.e., extinction). While this study provides systematic replication of previous studies, lack of substitution with THC is problematic and suggests that WIN55,212-2 self-administration may be of limited usefulness as a screening tool for detection of the reinforcing effects of potential cannabinoid medications. Clarification of underlying factors responsible for failure of THC to maintain self-administration in cannabinoid-trained rats is needed. PMID:24412835

  1. Methamphetamine decreases CD4 T cell frequency and alters pro-inflammatory cytokine production in a model of drug abuse.

    Science.gov (United States)

    Mata, Mariana M; Napier, T Celeste; Graves, Steven M; Mahmood, Fareeha; Raeisi, Shohreh; Baum, Linda L

    2015-04-01

    The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of methamphetamine on the systemic immune system to better understand the co-morbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n=18) or be given saline (control; n=16) for 14 days. One day after the last operant session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γ and TNF-α, and frequencies of CD4(+), CD8(+), CD200(+) and CD11b/c(+) lymphocytes in the spleen. Rats that self-administered methamphetamine had a lower frequency of CD4(+) T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4(+) T cells. Methamphetamine using rats had a higher frequency of CD8(+) T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Our data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection.

  2. Active Surveillance of Child Abuse Fatalities.

    Science.gov (United States)

    Schloesser, Patricia; And Others

    1992-01-01

    Birth and death certificates were correlated with information in the state Child Abuse and Neglect Registry on 104 abuse-related fatalities. Significant findings included young age of parents at first pregnancy; high rate of single parenthood; and lower educational achievement among mothers. A model for data collection is discussed. (Author/BRM)

  3. An enhanced positive reinforcement model for the severely impaired cocaine abuser.

    Science.gov (United States)

    Foote, J; Seligman, M; Magura, S; Handelsman, L; Rosenblum, A; Lovejoy, M; Arrington, K; Stimmel, B

    1994-01-01

    This article describes a cognitive-behavioral treatment approach that has been extensively modified to work with inner-city methadone-maintained cocaine users. Modifications were deemed essential to address the problems of engagement and retention in treatment that are typically encountered with this population. While this approach relies on such basic tenets of treatment as relapse prevention, cognitive restructuring, and psychoeducation, an understanding of the particular psychological vulnerabilities of this population has been incorporated into the model. The modified approach utilizes positive reinforcement extensively. This includes use of concrete reinforcers to facilitate initial engagement, and use of interpersonal reinforcers (therapist positive regard, attention, and respect) to increase program retention and sustain posttreatment change. Preliminary results indicate that 63% of patients can complete this intensive 6-month program, with considerable reductions in cocaine use and significant change in drug injection behavior.

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

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract 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

  5. Model Child Care Standards Act--Guidance to States to Prevent Child Abuse in Day Care Facilities.

    Science.gov (United States)

    Department of Health and Human Services, Washington, DC.

    The document offers guidelines to states regarding review and revision of child care statutes, standards, and policies to address the prevention of child sexual abuse in day care facilities. General information is also provided on changes in state standards in recent years. Each of six sections examines findings of the 1981 Comparative Licensing…

  6. Bridging Translation by Improving Preclinical Study Design in AKI.

    Science.gov (United States)

    de Caestecker, Mark; Humphreys, Ben D; Liu, Kathleen D; Fissell, William H; Cerda, Jorge; Nolin, Thomas D; Askenazi, David; Mour, Girish; Harrell, Frank E; Pullen, Nick; Okusa, Mark D; Faubel, Sarah

    2015-12-01

    Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

  7. Alcoholism and Alcohol Abuse

    Science.gov (United States)

    ... their drinking causes distress and harm. It includes alcoholism and alcohol abuse. Alcoholism, or alcohol dependence, is a disease that causes ... groups. NIH: National Institute on Alcohol Abuse and Alcoholism

  8. Prescription Drug Abuse

    Science.gov (United States)

    ... what the doctor prescribed, it is called prescription drug abuse. It could be Taking a medicine that ... purpose, such as getting high Abusing some prescription drugs can lead to addiction. These include opioids, sedatives, ...

  9. What is Elder Abuse?

    Science.gov (United States)

    ... Strategic Plan Federal Initiatives Career Opportunities Contact Us Administration on Aging (AoA) What is Elder Abuse? What ... Elder Justice & Adult Protective Services Elder Justice Coordinating Council Prevention of Elder Abuse, Neglect and Exploitation (Title ...

  10. Child abuse - physical

    Science.gov (United States)

    ... way Uses harsh discipline Was abused as a child Alcohol or drug problems Emotional problems or mental illness ... Physical abuse - children References Berkowitz CD, Stewart ST. Child maltreatment. In: Marx JA, Hockberger RS, Walls RM, eds. ...

  11. Cough & Cold Medicine Abuse

    Science.gov (United States)

    ... A Week of Healthy Breakfasts Shyness Cough & Cold Medicine Abuse KidsHealth > For Teens > Cough & Cold Medicine Abuse ... DXM Why Do People Use Cough and Cold Medicines to Get High? There's an ingredient in many ...

  12. Substance abuse as a precipitant of wife abuse victimizations.

    Science.gov (United States)

    Kantor, G K; Straus, M A

    1989-01-01

    This study examines the question of whether drug and alcohol use by victims constitutes a risk factor increasing the chances of their being assaulted by their partners. Data from a subsample of the 1985 National Family Violence Survey consisting of the 2,033 female respondents who were currently married or living in a male-female couple relationship are used as the basis of the analysis. The logistic analysis revealed that, of the ten variables in the model, the most important for distinguishing abused from nonabused women are husband's drug use, a history of paternal violence in womens' family or origin, husband's drunkenness, low income, and wife's drunkenness. Women who abuse alcohol are more likely to be victims of minor marital violence, but female substance abuse of any type is not a significant factor in severe violence.

  13. Reform in teaching preclinical pathophysiology.

    Science.gov (United States)

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-12-01

    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 in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools.

  14. Preclinical assessment of infant formula.

    Science.gov (United States)

    Lönnerdal, Bo

    2012-01-01

    Infant formulas are the sole or predominant source of nutrition for many infants and are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. Preclinical safety assessment therefore needs to include both short-term and long-term studies in animals. It is recommended that procedures are instituted by which experts may serve as independent scientists for companies developing novel products, without having their integrity compromised, and later serve the legislative institutions. A two-level assessment approach to determine the potential toxicity of a novel ingredient, its metabolites, and their effects in the matrix on developing organ systems has been suggested by IOM. This appears reasonable, as novel ingredients can be of different levels of concern. The use of modern methods in genomics and proteomics should be considered in these evaluation processes as well as novel methods to evaluate outcomes, including metabolomics and molecular techniques to assess the microbiome.

  15. Inhalant Abuse and Dextromethorphan.

    Science.gov (United States)

    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.

  16. Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication.

    Directory of Open Access Journals (Sweden)

    Ekaterina Dadachova

    Full Text Available BACKGROUND: Any strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development. METHODOLOGY/PRINCIPAL FINDINGS: Among the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213-Bismuth ((213Bi - (213Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs. The number of binding sites for (213Bi-2556 on the surface of the infected cells was >10(6. The in vivo experiments were performed in two HIV-1 mouse models--splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 µCi (213Bi-2556 group (P = 0.01. Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for (213Bi-2556. CONCLUSIONS/SIGNIFICANCE: We describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from "self" human antigens - this approach promises high selectivity, increased efficacy and low

  17. A neurocognitive model of borderline personality disorder: effects of childhood sexual abuse and relationship to adult social attachment disturbance.

    Science.gov (United States)

    Minzenberg, Michael J; Poole, John H; Vinogradov, Sophia

    2008-01-01

    Borderline personality disorder (BPD) is a paradigmatic disorder of adult attachment, with high rates of antecedent childhood maltreatment. The neurocognitive correlates of both attachment disturbance and maltreatment are both presently unknown in BPD. This study evaluated whether dimensional adult attachment disturbance in BPD is related to specific neurocognitive deficits, and whether childhood maltreatment is related to these dysfunctions. An outpatient BPD group (n=43) performed nearly 1 SD below a control group (n=26) on short-term recall, executive, and intelligence functions. These deficits were not affected by emotionally charged stimuli. In the BPD group, impaired recall was related to attachment-anxiety, whereas executive dysfunction was related to attachment-avoidance. Abuse history was correlated significantly with executive dysfunction and at a trend level with impaired recall. Neurocognitive deficits and abuse history exhibited both independent and interactive effects on adult attachment disturbance. These results suggest that (a) BPD patients' reactivity in attachment relationships is related to temporal-limbic dysfunction, irrespective of the emotional content of stimuli, (b) BPD patients' avoidance within attachment relationships may be a relational strategy to compensate for the emotional consequences of frontal-executive dysregulation, and (c) childhood abuse may contribute to these neurocognitive deficits but may also exert effects on adult attachment disturbance that is both independent and interacting with neurocognitive dysfunction.

  18. Acupuncture does not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage of dopaminergic neurons in a preclinical mouse model of Parkinson's disease.

    Science.gov (United States)

    Yang, Hui-Jun; Gao, Yu; Yun, Ji Young; Kim, Young Eun; Ehm, Gwanhee; Lee, Ji Yeon; Yoon, Min-Yung; Lee, Young-Shin; Kim, Han-Joon; Jeon, Beomseok

    2017-01-01

    Acupuncture treatment, a complementary and alternative medicine, is associated with a suggested neuroprotective effect in previous preclinical studies of Parkinson's disease (PD); however, results from human clinical trials have been mixed or unsuccessful. Recent systematic reviews of translational neuroprotective studies showed that the supposed efficacy is confounded by low methodological quality, particularly by a lack of randomization and concealed allocation. We sought to replicate previous experimental findings with a study design that mitigates the introduction of bias, including randomization, blinded outcome measures, sham acupuncture application, and allocation concealment by blinded neurotoxin administration. We performed 12 sessions of manual acupuncture at acupoint GB34 (yanglingquan) in mice that were administered the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxin for five consecutive days. In this animal model of PD, acupuncture treatment did not attenuate tyrosine hydroxylase-immunoreactive neuronal death, depletion of striatal dopamine levels, or reduced striatal tyrosine hydroxylase expression. Our results indicate that acupuncture is not neuroprotective against nigrostriatal loss in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD.

  19. Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140.

    Science.gov (United States)

    Miller, Chris P; Shomali, Maysoun; Lyttle, C Richard; O'Dea, Louis St L; Herendeen, Hillary; Gallacher, Kyla; Paquin, Dottie; Compton, Dennis R; Sahoo, Bishwabhusan; Kerrigan, Sean A; Burge, Matthew S; Nickels, Michael; Green, Jennifer L; Katzenellenbogen, John A; Tchesnokov, Alexei; Hattersley, Gary

    2011-02-10

    This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.

  20. Transgenic mouse models generated by hydrodynamic transfection for genetic studies of liver cancer and preclinical testing of anti-cancer therapy.

    Science.gov (United States)

    Ju, Hye-Lim; Han, Kwang-Hyub; Lee, Jong Doo; Ro, Simon Weonsang

    2016-04-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide; however, the genetic mechanisms underlying its pathogenesis are incompletely understood. Genetically engineered mouse (GEM) models of HCC have been developed to elucidate the role of individual cancer-related genes in hepatocarcinogenesis. However, the expensive and time-consuming processes related to generating a GEM model discourage the development of diverse genotype models. Recently, a simple and inexpensive liver-specific transgenic approach was developed, in which a hydrodynamics-based transfection (HT) method was coupled with the Sleeping Beauty transposase system. Various HT models in which different oncogenic pathways are activated and/or tumor-suppressing pathways inactivated have been developed in recent years. The applicability of HT models in liver cancer research is expected to broaden and ultimately elucidate the cooperation between oncogenic signaling pathways and aid in designing molecular therapy to target altered pathways.

  1. The validity of sheep mandible model used in the simulation-based preclinical practice training of periodontal surgery%羊下颌模型在牙周手术教学中的应用研究

    Institute of Scientific and Technical Information of China (English)

    许杰; 杨俊; 吴天明; 冀虎圣; 聂晨阳; 张伟; 曹敏; 陈发明

    2016-01-01

    Sheep mandible model was used in periodontal surgery simulation operation.The array of experi-ments proved that the sheep mandible model can imitate human oral and periodontal condition.Differential parts of the model were suitable for implementation of periodontal flap surgery,gingivoectomy,apically repositioned flap surgery and other common periodontal surgery.Using of sheep mandible model in the simulation -based preclinical practice training of periodontal surgery,can improve students'operation skills,strengthen the study effect.The sheep model is feasible in the teaching of periodontal surgery for undergraduates and advanced trainees.%选用羊下颌模型探索牙周手术模拟操作的可行性。实验证明羊下颌模型能够较真实的模拟人类口腔牙周情况,可利用不同部位的解剖特点,选择进行牙周翻瓣术、龈切术、根向复位瓣术等多种常见牙周手术。采用羊下颌模型进行牙周手术模拟操作的临床前教学,可以提高学生操作技能,强化学习效果,值得在牙周病学本科生教学和各层次牙周病学继续教育学习班操作课程中进一步推广。

  2. A Comparative Study of the Hypoxia PET Tracers [{sup 18}F]HX4, [{sup 18}F]FAZA, and [{sup 18}F]FMISO in a Preclinical Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Peeters, Sarah G.J.A., E-mail: sarah.peeters@maastrichtuniversity.nl [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands); Zegers, Catharina M.L.; Lieuwes, Natasja G.; Elmpt, Wouter van [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands); Eriksson, Jonas; Dongen, Guus A.M.S. van [Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam (Netherlands); Dubois, Ludwig; Lambin, Philippe [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands)

    2015-02-01

    Purpose: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [{sup 18}F]FMISO, [{sup 18}F]FAZA, and [{sup 18}F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification. Methods and Materials: PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing. Results: TBR was stabilized and maximal at 2 hours p.i. for [{sup 18}F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [{sup 18}F]HX4 (7.2 ± 0.7), whereas [{sup 18}F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [{sup 18}F]FMISO (R = 0.86; Dice coefficient = 0.76) and [{sup 18}F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [{sup 18}F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [{sup 18}F]HX4 and [{sup 18}F]FAZA upon 7% oxygen breathing. Only [{sup 18}F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen. Conclusions: This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put

  3. A Preclinical Model of Inflammatory Breast Cancer to Study the Involvement of CXCR4 and ACKR3 in the Metastatic Process

    OpenAIRE

    2015-01-01

    Inflammatory breast cancer (IBC) is an aggressive and invasive tumor, accounting for 2.5% of all breast cancer cases, and characterized by rapid progression, regional and distant metastases, younger age of onset, and lower overall survival. Presently, there are no effective therapies against IBC and a paucity of model systems. Our aim was to develop a clinically relevant IBC model that would allow investigations on the role of chemokine receptors in IBC metastasis. Primary cultures of tumor c...

  4. Escalating morphine exposures followed by withdrawal in feline immunodeficiency virus-infected cats: a model for HIV infection in chronic opiate abusers.

    Science.gov (United States)

    Barr, Margaret C; Huitron-Resendiz, Salvador; Sanchez-Alavez, Manuel; Henriksen, Steven J; Phillips, Tom R

    2003-11-24

    Opiate abuse is a risk factor for human immunodeficiency virus (HIV) infection. Because the direct effects of opiates on HIV infection are difficult to determine epidemiologically, animal models of lentivirus infection are relied upon to study the effects of opiates in the absence of confounding factors. Morphine, the predominant metabolite of heroin, is used in most experimental systems examining heroin abuse. In this study, morphine treatment of feline immunodeficiency virus (FIV)-infected cats modeled a typical pattern of escalating drug use interspersed with withdrawals. Plasma cortisol levels were measured for evidence of stress associated with morphine withdrawal. In the morphine-treated cats, cortisol levels peaked at time points corresponding to morphine withdrawal and returned to baseline levels during treatment and several weeks after the final withdrawal. Morphine-treated cats displayed clear behavioral and physical signs of opiate exposure and evidence of withdrawal when the drug was stopped. Morphine-exposed cats did not experience enhanced severity of FIV-related disease; in fact, morphine demonstrated a protective effect on FIV-associated changes in brainstem auditory evoked potentials. Our research suggests that opiate exposure is unlikely to adversely affect the progression of acute lentivirus infection and might be beneficial in controlling associated neurological disease.

  5. Preclinical evaluation of collagen type I scaffolds, including gelatin-collagen microparticles and loaded with a hydroglycolic Calendula officinalis extract in a lagomorph model of full-thickness skin wound.

    Science.gov (United States)

    Millán, D; Jiménez, R A; Nieto, L E; Linero, I; Laverde, M; Fontanilla, M R

    2016-02-01

    Previously, we have developed collagen type I scaffolds including microparticles of gelatin-collagen type I (SGC) that are able to control the release of a hydroglycolic extract of the Calendula officinalis flower. The main goal of the present work was to carry out the preclinical evaluation of SGC alone or loaded with the C. officinalis extract (SGC-E) in a lagomorph model of full-thickness skin wound. A total of 39 rabbits were distributed in three groups, of 13 animals each. The first group was used to compare wound healing by secondary intention (control) with wound healing observed when wounds were grafted with SGC alone. Comparison of control wounds with wounds grafted with SGC-E was performed in the second group, and comparison of wounds grafted with SGC with wounds grafted with SGC-E was performed in the third group. Clinical follow-ups were carried in all animals after surgery, and histological and histomorphometric analyses were performed on tissues taken from the healed area and healthy surrounding tissue. Histological and histomorphometric results indicate that grafting of SGC alone favors wound healing and brings a better clinical outcome than grafting SGC-E. In vitro collagenase digestion data suggested that the association of the C. officinalis extract to SGC increased the SGC-E cross-linking, making it difficult to degrade and affecting its biocompatibility.

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

    Science.gov (United States)

    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.

  7. New cast for a new era: preclinical cancer drug development revisited

    Science.gov (United States)

    Herter-Sprie, Grit S.; Kung, Andrew L.; Wong, Kwok-Kin

    2013-01-01

    Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes. PMID:23999436

  8. Multimodal imaging of bone metastases: From preclinical to clinical applications

    Directory of Open Access Journals (Sweden)

    Stephan Ellmann

    2015-10-01

    Full Text Available Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

  9. Pharmacokinetic analysis of [11C]PBR28 in the rat model of herpes encephalitis: comparison with (R)-[11C]PK11195 for pre-clinical imaging

    NARCIS (Netherlands)

    Kopschina Feltes, Paula; Parente, Andrea; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina; Dierckx, Rudi; de Vries, Erik; Doorduin, Janine

    2015-01-01

    Aim: [11C]PBR28 is a second generation translocator protein (TSPO) ligand with supposedly better imaging characteristics than the most commonly used tracer [11C]PK11195. Surprisingly, only limited studies have evaluated the pharmacokinetic and binding profile of [11C]PBR28 in neuroinflammatory model

  10. Solvent abuse: a review.

    Science.gov (United States)

    Barnes, G E

    1979-01-01

    The literature on solvent abuse is reviewed. Methods of use, symptoms of use, and effects of long-term solvent abuse are discussed. Several surveys on solvent use are summarized. The highest prevalence of solvent abuse seems to occur in native peoples undergoing periods of cultural change. Environmental conditions which are postulated as leading to psychological vulnerability and solvent abuse include: low social assets, parental drug use, peer and sibling influence, and acculturative stress. Solvent abuse seems to provide a pharmacological way out of a stressful environment for people who feel helpless to improve their situation in other ways. Methods of intervention that have been proposed for dealing with solvent abuse are discussed. Methods of intervention thus far employed generally have not been evaluated in any systematic fashion. Suggestions for future research are provided.

  11. Radiolabeled bombesin derivatives for preclinical oncological imaging

    Science.gov (United States)

    de Aguiar Ferreira, Carolina; Fuscaldi, Leonardo Lima; Townsend, Danyelle M.; Rubello, Domenico; de Barros, André Luís Branco

    2017-01-01

    Despite efforts, cancer is still one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths each year, according to the World Health Organization. Among the strategies to reduce cancer progression and improving its management, implementing early detection technologies is crucial. Based on the fact that several types of cancer cells overexpress surface receptors, small molecule ligands, such as peptides, have been developed to allow tumor identification at earlier stages. Allied with imaging techniques such as PET and SPECT, radiolabeled peptides play a pivotal role in nuclear medicine. Bombesin, a peptide of 14 amino acids, is an amphibian homolog to the mammalian gastrin-releasing peptide (GRP), that has been extensively studied as a targeting ligand for diagnosis and therapy of GRP positive tumors, such as breast, pancreas, lungs and prostate cancers. In this context, herein we provide a review of reported bombesin derivatives radiolabeled with a multitude of radioactive isotopes for diagnostic purposes in the preclinical setting. Moreover, since animal models are highly relevant for assessing the potential of clinical translation of this radiopeptides, a brief report of the currently used GRP-positive tumor-bearing animal models is described. PMID:28040598

  12. Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.

    Science.gov (United States)

    Vande Velde, Greetje; Poelmans, Jennifer; De Langhe, Ellen; Hillen, Amy; Vanoirbeek, Jeroen; Himmelreich, Uwe; Lories, Rik J

    2016-01-01

    In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung

  13. Spatial Navigation in Preclinical Alzheimer's Disease

    Science.gov (United States)

    Allison, Samantha L.; Fagan, Anne M.; Morris, John C.; Head, Denise

    2016-01-01

    Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID:26967209

  14. cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas

    DEFF Research Database (Denmark)

    Manfè, Valentina; Biskup, Edyta; Willumsgaard, Ayalah;

    2013-01-01

    improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc...... and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where...

  15. The effectiveness of nano chemotherapeutic particles combined with mifepristone depends on the PR isoform ratio in preclinical models of breast cancer

    OpenAIRE

    Sequeira, Gonzalo Ricardo; Vanzulli, Silvia I; Rojas, Paola Andrea; Lamb, Caroline Ana; Colombo, Lucas Luis; May, Maria; Molinolo, Alfredo; Lanari, Claudia Lee Malvina

    2014-01-01

    There is clinical and experimental evidence suggesting that antiprogestins might be used for the treatment of selected breast cancer patients. Our aim was to evaluate the effect of albumin-bound paclitaxel (Nab-paclitaxel) and pegylated doxorubicin liposomes (PEG-LD) in combination with mifepristone (MFP) in experimental breast cancer models expressing different ratios of progesterone receptor (PR) isoforms A and B. We used two antiprogestin-responsive (PRA>PRB) and two resistant (PRA

  16. The utility of rhesus monkey (Macaca mulatta and other non-human primate models for preclinical testing of Leishmania candidate vaccines

    Directory of Open Access Journals (Sweden)

    Gabriel Grimaldi Jr

    2008-11-01

    Full Text Available Leishmaniasis causes significant morbidity and mortality, constituting an important global health problem for which there are few effective drugs. Given the urgent need to identify a safe and effective Leishmania vaccine to help prevent the two million new cases of human leishmaniasis worldwide each year, all reasonable efforts to achieve this goal should be made. This includes the use of animal models that are as close to leishmanial infection in humans as is practical and feasible. Old world monkey species (macaques, baboons, mandrills etc. have the closest evolutionary relatedness to humans among the approachable animal models. The Asian rhesus macaques (Macaca mulatta are quite susceptible to leishmanial infection, develop a human-like disease, exhibit antibodies to Leishmania and parasite-specific T-cell mediated immune responses both in vivo and in vitro, and can be protected effectively by vaccination. Results from macaque vaccine studies could also prove useful in guiding the design of human vaccine trials. This review summarizes our current knowledge on this topic and proposes potential approaches that may result in the more effective use of the macaque model to maximize its potential to help the development of an effective vaccine for human leishmaniasis.

  17. Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model

    Directory of Open Access Journals (Sweden)

    Alvaro Plaza Reyes

    2016-01-01

    Full Text Available Human embryonic stem cell (hESC-derived retinal pigment epithelial (RPE cells could replace lost tissue in geographic atrophy (GA but efficacy has yet to be demonstrated in a large-eyed model. Also, production of hESC-RPE has not yet been achieved in a xeno-free and defined manner, which is critical for clinical compliance and reduced immunogenicity. Here we describe an effective differentiation methodology using human laminin-521 matrix with xeno-free and defined medium. Differentiated cells exhibited characteristics of native RPE including morphology, pigmentation, marker expression, monolayer integrity, and polarization together with phagocytic activity. Furthermore, we established a large-eyed GA model that allowed in vivo imaging of hESC-RPE and host retina. Cells transplanted in suspension showed long-term integration and formed polarized monolayers exhibiting phagocytic and photoreceptor rescue capacity. We have developed a xeno-free and defined hESC-RPE differentiation method and present evidence of functional integration of clinically compliant hESC-RPE in a large-eyed disease model.

  18. Pre-clinical evaluation of soybean-based wound dressings and dermal substitute formulations in pig healing and non-healing in vivo models

    Directory of Open Access Journals (Sweden)

    Rostislav V Shevchenko

    2014-10-01

    Full Text Available In the last decade, a new class of natural biomaterials derived from de-fatted soybean flour processed by either thermoset or extraction procedures has been developed. These biomaterials uniquely combine adaptability to various clinical applications to proven tissue regeneration properties. In the present work, the biomaterials were formulated either as hydrogel or as paste formulation and their potential as wound dressing material or as dermal substitute was assessed by two in vivo models in pig skin: The healing full-thickness punch biopsy model and the non-healing full-thickness polytetrafluoroethylene (PTFE chamber model. The results clearly show that collagen deposition is induced by the presence of these biomaterials. A unique pattern of early inflammatory response, eliciting neutrophils and controlling macrophage infiltration, is followed by tissue cell colonization of the wound bed with a significant deposition of collagen fibers. The study also highlighted the importance in the use of optimal formulations and appropriate handling upon implantation. In large size, non-healing wounds, wound dermis was best obtained with the paste formulation as hydrogels appeared to be too loose to ensure lasting scaffolding properties. On the contrary, packing of the granules during the application of paste reduced biomaterial degradation rate and prevent the penetration of newly vascularized tissue, thus impeding grafting of split-thickness autologous skin grafts on the dermal substitute base.

  19. Pre-clinical evaluation of soybean-based wound dressings and dermal substitute formulations in pig healing and non-healing in vivo models.

    Science.gov (United States)

    Shevchenko, Rostislav V; Santin, Matteo

    2014-01-01

    In the last decade, a new class of natural biomaterials derived from de-fatted soybean flour processed by either thermoset or extraction procedures has been developed. These biomaterials uniquely combine adaptability to various clinical applications to proven tissue regeneration properties. In the present work, the biomaterials were formulated either as hydrogel or as paste formulation and their potential as wound dressing material or as dermal substitute was assessed by two in vivo models in pig skin: The healing full-thickness punch biopsy model and the non-healing full-thickness polytetrafluoroethylene (PTFE) chamber model. The results clearly show that collagen deposition is induced by the presence of these biomaterials. A unique pattern of early inflammatory response, eliciting neutrophils and controlling macrophage infiltration, is followed by tissue cell colonization of the wound bed with a significant deposition of collagen fibers. The study also highlighted the importance in the use of optimal formulations and appropriate handling upon implantation. In large size, non-healing wounds, wound dermis was best obtained with the paste formulation as hydrogels appeared to be too loose to ensure lasting scaffolding properties. On the contrary, packing of the granules during the application of paste reduced biomaterial degradation rate and prevent the penetration of newly vascularized tissue, thus impeding grafting of split-thickness autologous skin grafts on the dermal substitute base.

  20. SUBSTANCE ABUSE IN INDIA

    Directory of Open Access Journals (Sweden)

    Bano Rubeena

    2009-12-01

    Full Text Available The epidemic of substance abuse in young generation has assumed alarming dimensions in India. Changing cultural values, increasing economic stress and dwindling supportive bonds are leading to initiation into substance use. Cannabis, heroin, and Indian-produced pharmaceutical drugs are the most frequently abused drugs in India. Drug use, misuse or abuse is also primarily due to the nature of the drug abused, the personality of the individual and the addict’s immediate environment. The processes of industrialization, urbanization and migration have led to loosening of the traditional methods of social control rendering an individual vulnerable to the stresses and strains of modern life.

  1. Elder Abuse and Neglect

    Directory of Open Access Journals (Sweden)

    Muge Gulen

    2013-06-01

    Full Text Available Abuse and neglect are preventable societal problems that influence elderly individuals physically, spiritually and socially. Elder abuse is neglected for many years and is a growing problem all over the world. The aim of this article is to review the evaluation of elderly individuals who are exposed to abuse and neglect with systematic detailed history and physical examination and to describe individual, familial, and social measures that should be taken to prevent these abuses. [Archives Medical Review Journal 2013; 22(3.000: 393-407

  2. Cough & Cold Medicine Abuse

    Science.gov (United States)

    ... Know Getting Rid of Old Medicines Dealing With Addiction Understanding Medications and What They Do Prescription Drug Abuse Bath Salts Depressants Ketamine MDMA (Ecstasy) Contact Us Print Resources ...

  3. Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination.

    Science.gov (United States)

    Jones, Christopher R; Hatley, Oliver J D; Ungell, Anna-Lena; Hilgendorf, Constanze; Peters, Sheila Annie; Rostami-Hodjegan, Amin

    2016-05-01

    Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5'-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.

  4. cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas.

    Directory of Open Access Journals (Sweden)

    Valentina Manfè

    Full Text Available Successful/effective cancer therapy in low grade lymphoma is often hampered by cell resistance to anti-neoplastic agents. The crucial mechanisms responsible for this phenomenon are poorly understood. Overcoming resistance of tumor cells to anticancer agents, such as proteasome inhibitors, could improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where xenotransplantation of human CTCL cells overexpressing miR-125b-5p resulted in enhanced tumor growth and a shorter median survival. Our findings describe a novel mechanism through which miR-125b-5p not only regulates tumor growth in vivo, but also increases cellular resistance to proteasome inhibitors via modulation of MAD4.

  5. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.

    Science.gov (United States)

    Patwardhan, Parag P; Ivy, Kathryn S; Musi, Elgilda; de Stanchina, Elisa; Schwartz, Gary K

    2016-01-26

    Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10-18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma.

  6. Interleukin 16- (IL-16- Targeted Ultrasound Imaging Agent Improves Detection of Ovarian Tumors in Laying Hens, a Preclinical Model of Spontaneous Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Animesh Barua

    2015-01-01

    Full Text Available Limited resolution of transvaginal ultrasound (TVUS scanning is a significant barrier to early detection of ovarian cancer (OVCA. Contrast agents have been suggested to improve the resolution of TVUS scanning. Emerging evidence suggests that expression of interleukin 16 (IL-16 by the tumor epithelium and microvessels increases in association with OVCA development and offers a potential target for early OVCA detection. The goal of this study was to examine the feasibility of IL-16-targeted contrast agents in enhancing the intensity of ultrasound imaging from ovarian tumors in hens, a model of spontaneous OVCA. Contrast agents were developed by conjugating biotinylated anti-IL-16 antibodies with streptavidin coated microbubbles. Enhancement of ultrasound signal intensity was determined before and after injection of contrast agents. Following scanning, ovarian tissues were processed for the detection of IL-16 expressing cells and microvessels. Compared with precontrast, contrast imaging enhanced ultrasound signal intensity significantly in OVCA hens at early (P<0.05 and late stages (P<0.001. Higher intensities of ultrasound signals in OVCA hens were associated with increased frequencies of IL-16 expressing cells and microvessels. These results suggest that IL-16-targeted contrast agents improve the visualization of ovarian tumors. The laying hen may be a suitable model to test new imaging agents and develop targeted anti-OVCA therapeutics.

  7. Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

    Science.gov (United States)

    Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

    2016-05-01

    Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

  8. Child Abuse: The Hidden Bruises

    Science.gov (United States)

    ... 5; Updated November 2014 The statistics on physical child abuse are alarming. It is estimated hundreds of thousands ... Physical abuse is not the only kind of child abuse. Many children are also victims of neglect, or ...

  9. Dual-energy computed tomography for the assessment of early treatment effects of regorafenib in a preclinical tumor model: comparison with dynamic contrast-enhanced CT and conventional contrast-enhanced single-energy CT

    Energy Technology Data Exchange (ETDEWEB)

    Knobloch, Gesine; Hamm, Bernd [Charite - Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany); Jost, Gregor; Pietsch, Hubertus [Bayer Healthcare, MR and CT Contrast Media Research, Berlin (Germany); Huppertz, Alexander [Imaging Science Institute Charite - Siemens, Berlin (Germany)

    2014-08-15

    The potential diagnostic value of dual-energy computed tomography (DE-CT) compared to dynamic contrast-enhanced CT (DCE-CT) and conventional contrast-enhanced CT (CE-CT) in the assessment of early regorafenib treatment effects was evaluated in a preclinical setting. A rat GS9L glioma model was examined with contrast-enhanced dynamic DE-CT measurements (80 kV/140 kV) for 4 min before and on days 1 and 4 after the start of daily regorafenib or placebo treatment. Tumour time-density curves (0-240 s, 80 kV), DE-CT (60 s) derived iodine maps and the DCE-CT (0-30 s, 80 kV) based parameters blood flow (BF), blood volume (BV) and permeability (PMB) were calculated and compared to conventional CE-CT (60 s, 80 kV). The regorafenib group showed a marked decrease in the tumour time-density curve, a significantly lower iodine concentration and a significantly lower PMB on day 1 and 4 compared to baseline, which was not observed for the placebo group. CE-CT showed a significant decrease in tumour density on day 4 but not on day 1. The DE-CT-derived iodine concentrations correlated with PMB and BV but not with BF. DE-CT allows early treatment monitoring, which correlates with DCE-CT. Superior performance was observed compared to single-energy CE-CT. circle Regorafenib treatment response was evaluated by CT in a rat tumour model. (orig.)

  10. Collaborative pre-competitive preclinical drug discovery with academics and pharma/biotech partners at Sanford|Burnham: infrastructure, capabilities & operational models.

    Science.gov (United States)

    Chung, Thomas D Y

    2014-03-01

    There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> $1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core

  11. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Directory of Open Access Journals (Sweden)

    Michael Halpern

    2010-08-01

    Full Text Available 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.

  12. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model.

    Science.gov (United States)

    Ferreira, Adilson Kleber; Tavares, Maurício Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-Sá-Junior, Paulo Luiz; Barbuto, José Alexandre Marzagão; Figueiredo, Carlos Rogério; Cury, Yara; Damião, Mariana Celestina Frojuello Costa Bernstorff; Parise-Filho, Roberto

    2015-09-01

    Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analogue of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthetized, and molecular modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis, by flow cytometry, and Western blot analysis of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The production of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico analysis corroborated the biological findings, showing that RPF151 has physicochemical improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy.

  13. Pro- and anti-tumour effects of B cells and antibodies in cancer: a comparison of clinical studies and preclinical models.

    Science.gov (United States)

    Guy, Thomas V; Terry, Alexandra M; Bolton, Holly A; Hancock, David G; Shklovskaya, Elena; Fazekas de St. Groth, Barbara

    2016-08-01

    The primary immune role of B cells is to produce antibodies, but they can also influence T cell function via antigen presentation and, in some contexts, immune regulation. Whether their roles in tumour immunity are similar to those in other chronic immune responses such as autoimmunity and chronic infection, where both pro- and anti-inflammatory roles have been described, remains controversial. Many studies have aimed to define the role of B cells in antitumor immune responses, but despite this considerable body of work, it is not yet possible to predict how they will affect immunity to any given tumour. In many human cancers, the presence of tumour-infiltrating B cells and tumour-reactive antibodies correlates with extended patient survival, and this clinical observation is supported by data from some animal models. On the other hand, T cell responses can be adversely affected by B cell production of immunoregulatory cytokines, a phenomenon that has been demonstrated in humans and in animal models. The isotype and concentration of tumour-reactive antibodies may also influence tumour progression. Recruitment of B cells into tumours may directly reflect the subtype and strength of the anti-tumour T cell response. As the response becomes chronic, B cells may attenuate T cell responses in an attempt to decrease host damage, similar to their described role in chronic infection and autoimmunity. Understanding how B cell responses in cancer are related to the effectiveness of the overall anti-tumour response is likely to aid in the development of new therapeutic interventions against cancer.

  14. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer.

    Science.gov (United States)

    Steenbrugge, Jonas; Breyne, Koen; Denies, Sofie; Dekimpe, Melissa; Demeyere, Kristel; De Wever, Olivier; Vermeulen, Peter; Van Laere, Steven; Sanders, Niek N; Meyer, Evelyne

    2016-12-01

    Breast tumorigenesis is classically studied in mice by inoculating tumor cells in the fat pad, the adipose compartment of the mammary gland. Alternatively, the mammary ducts, which constitute the luminal mammary gland compartment, also provide a suitable inoculation site to induce breast cancer in murine models. The microenvironments in these compartments influence tumor cell progression, yet this effect has not been investigated in an immunocompetent context. Here, we compared both mammary gland compartments as distinct inoculation sites, taking into account the immunological aspect by inoculating 4T1 tumor cells in immunocompetent mice. Following tumor cell inoculation in the adipose compartment of non-pretreated/naive, hormonally pretreated/naive and non-pretreated/lactating mice, the primary tumors developed similarly. However, a slower onset of primary tumor growth was found after inoculations in the luminal compartment of non-pretreated/lactating mice. Despite this difference in tumor development rate, metastasis to the liver and lungs was equally observed and was accompanied by lymphatic spreading of tumor cells and progressive splenomegaly with both inoculation types. Chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) served as innovative biomarkers for disease progression showing increased levels in primary tumors and sera of the non-pretreated/lactating inoculation groups. A slower increase in circulating CHI3L1 but not LCN2 levels, was observed after inoculations in the luminal compartment which corroborated the slower tumor development at this inoculation site. Our results highlight the critical impact of different mammary gland compartments on tumor development in syngeneic murine models and support the use of novel tumor progression biomarkers in an immune-competent environment.

  15. Neuroimaging in Alzheimer's disease: preclinical challenges toward clinical efficacy.

    Science.gov (United States)

    Dustin, Derek; Hall, Benjamin M; Annapragada, Ananth; Pautler, Robia G

    2016-09-01

    The scope of this review focuses on recent applications in preclinical and clinical magnetic resonance imaging (MRI) toward accomplishing the goals of early detection and responses to therapy in animal models of Alzheimer's disease (AD). Driven by the outstanding efforts of the Alzheimer's Disease Neuroimaging Initiative (ADNI), a truly invaluable resource, the initial use of MRI in AD imaging has been to assess changes in brain anatomy, specifically assessing brain shrinkage and regional changes in white matter tractography using diffusion tensor imaging. However, advances in MRI have led to multiple efforts toward imaging amyloid beta plaques first without and then with the use of MRI contrast agents. These technological advancements have met with limited success and are not yet appropriate for the clinic. Recent developments in molecular imaging inclusive of high-power liposomal-based MRI contrast agents as well as fluorine 19 ((19)F) MRI and manganese enhanced MRI have begun to propel promising advances toward not only plaque imaging but also using MRI to detect perturbations in subcellular processes occurring within the neuron. This review concludes with a discussion about the necessity for the development of novel preclinical models of AD that better recapitulate human AD for the imaging to truly be meaningful and for substantive progress to be made toward understanding and effectively treating AD. Furthermore, the continued support of outstanding programs such as ADNI as well as the development of novel molecular imaging agents and MRI fast scanning sequences will also be requisite to effectively translate preclinical findings to the clinic.

  16. Animal models of social contact and drug self-administration.

    Science.gov (United States)

    Strickland, Justin C; Smith, Mark A

    2015-09-01

    Social learning theories of drug abuse propose that individuals imitate drug use behaviors modeled by social peers, and that these behaviors are selectively reinforced and/or punished depending on group norms. Historically, animal models of social influence have focused on distal factors (i.e., those factors outside the drug-taking context) in drug self-administration studies. Recently, several investigators have developed novel models, or significantly modified existing models, to examine the role of proximal factors (i.e., those factors that are immediately present at the time of drug taking) on measures of drug self-administration. Studies using these newer models have revealed several important conclusions regarding the effects of social learning on drug abuse: 1) the presence of a social partner influences drug self-administration, 2) the behavior of a social partner determines whether social contact will increase or decrease drug intake, and 3) social partners can model and imitate specific patterns of drug self-administration. These findings are congruent with those obtained in the human laboratory, providing support for the cross-species generality and validity of these preclinical models. This mini-review describes in detail some of the preclinical animal models used to study social contact and drug self-administration to guide future research on social learning and drug abuse.

  17. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Directory of Open Access Journals (Sweden)

    Nibedita Chattopadhyay

    Full Text Available In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  18. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Science.gov (United States)

    Chattopadhyay, Nibedita; Berger, Allison J; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  19. The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer

    Directory of Open Access Journals (Sweden)

    Ball Richard Y

    2010-07-01

    Full Text Available Abstract Background Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue. Results We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing. Conclusion To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.

  20. Molecular characterization of murine models of squamous carcinomas of preclinical application; Caracterización molecular de modelos múridos de carcinomas escamosos de aplicación preclínica

    Energy Technology Data Exchange (ETDEWEB)

    Bornachea Gomez, O.; Berdugo Zamora, A.

    2015-07-01

    The epidermis is a stratified epithelium affected by numerous pathologies, including cancer, being the tumors originated in this tissue more than half of the epithelial tumors diagnosed every year. Animal models are an essential tool for cancer research, as they provide information to understand how a homologous gene may cause or contribute to the disease in humans. The p53 CE and Rb CE; p53 CE murine models develop undifferentiated epidermal tumors with high metastatic potential that show a strong transcriptional similarity to many human tumors with poor prognosis. Numerous studies have associated the p53 tumor suppressor with deregulation of microRNAs involved in the epithelial-mesenchymal transition (EMT) and metastasis processes. Furthermore, tumors in p53 EC models show an early repression of p63 whose predominant isoform in keratinocytes of the basal layer is Np63. Our results indicate that miR21 helps to provide metastatic capacity to p53-deficient mouse skin tumors. The increased expression of miR21 correlates with active signaling pathways that can be inhibited pharmacologically. Moreover, miR21 expression is elevated in human metastatic lung tumors with poor prognosis. Besides, we also show that ?Np63? expression in p53-deficient cells partially reduces the metastatic behavior, most probably through the modulation microRNAs and transcription factors involved in the EMT process. These facts point to p53-deficient epidermal animal models as excellent candidates for preclinical analysis of human metastatic tumors characterized by TP53 alterations. Finally we developed a model in which the three members of the retinoblastoma family are ablated in the basal cells of stratified epithelia in a tamoxifen inducible manner: Rb1F/F ; Rbl2F/F;Rbl1-/-;K14CreErT2 (TKO). Previously our laboratory had shown that, in the absence of pRb, malignant conversion occurred when p53 is lost. At high doses of tamoxifen these animals show early lethality. When we adjust the dose

  1. Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

    Science.gov (United States)

    Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

    2016-01-01

    Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

  2. Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model.

    Science.gov (United States)

    Bousserouel, Souad; Le Grandois, Julie; Gossé, Francine; Werner, Dalal; Barth, Stephan W; Marchioni, Eric; Marescaux, Jacques; Raul, Francis

    2013-08-01

    Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 µg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 µg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death‑receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis.

  3. Vitamin D for combination photodynamic therapy of skin cancer in individuals with vitamin D deficiency: Insights from a preclinical study in a mouse model of squamous cell carcinoma

    Science.gov (United States)

    Anand, Sanjay; Thomas, Erik; Hasan, Tayyaba; Maytin, Edward V.

    2016-03-01

    Combination photodynamic therapy (cPDT) in which vitamin D (VD) is given prior to aminolevulinate, a precursor (pro-drug) for protoporphyrin IX (PpIX), is an approach developed in our laboratory. We previously showed that 1α,25- dihydroxyvitamin D3 (calcitriol), given prior to PDT, enhances accumulation of PpIX and improves cell death post-PDT in a mouse skin cancer model. However, since calcitriol poses a risk for hypercalcemia, we replaced systemic calcitriol with oral cholecalciferol (D3), administered as a high (tenfold, "10K") diet over a ten-day period. Here, we ask whether VD deficiency might alter the response to cPDT. Nude mice were fed a VD-deficient diet for at least 4 weeks ("deficient"); controls were fed a normal 1,000 IU/kg diet ("1K"). Human A431 cells were implanted subcutaneously and mice were switched to the 10K diet or continued on their baseline diets (controls). In other experiments, mice received a human equivalent dose of 50,000 IU D3 by oral gavage, to simulate administration of a single, high-dose VD pill. At various times, tumors were harvested and serum was collected to measure levels of VD metabolic intermediates. A significant increase in PpIX levels and in the expression of differentiation and proliferation markers in tumor tissue was observed after VD supplementation of both the deficient and 1K mice. Further results describing mechanistic details of PpIX enhancement through alteration of heme- and VD-metabolic enzyme levels will be presented. Based on these results, a clinical study using oral vitamin D prior to PDT for human skin cancer should be performed.

  4. Modifications to the Trauma Recovery and Empowerment Model (TREM) for Substance-Abusing Women with Histories of Violence: Outcomes and Lessons Learned at a Colorado Substance Abuse Treatment Center

    Science.gov (United States)

    Toussaint, Danielle W.; VanDeMark, Nancy R.; Bornemann, Angela; Graeber, Carla J.

    2007-01-01

    A growing body of literature demonstrates the co-occurrence of posttraumatic stress disorder and substance use disorder for females seeking substance abuse treatment. Nonetheless, relatively few trauma-specific treatments have been implemented or evaluated with this population. In this quasi-experimental study (N = 170), the Trauma Recovery and…

  5. The Idealized Cultural Identities Model on Help-Seeking and Child Sexual Abuse: A Conceptual Model for Contextualizing Perceptions and Experiences of South Asian Americans

    Science.gov (United States)

    Kanukollu, Shanta N.; Mahalingam, Ramaswami

    2011-01-01

    In this paper, we propose an interdisciplinary framework to study perceptions of child sexual abuse and help-seeking among South Asians living in the United States. We integrate research on social marginality, intersectionality, and cultural psychology to understand how marginalized social experience accentuates South Asian immigrants' desire to…

  6. Child sexual abuse.

    Science.gov (United States)

    Hymel, K P; Jenny, C

    1997-08-01

    Multiple obstacles can hinder the medical evaluation of suspected child sexual abuse in pediatric primary care. The need for diagnostic accuracy is high. Knowledge of sexual abuse risk factors, an understanding of the victimization process, and awareness of the varied clinical presentations of sexual abuse can be of assistance. Open-ended questioning of the suspected victim is the most critical component of the evaluation. Skillful medical interviewing requires time, training, patience, and practice. Pediatricians lacking any of these four requirements should defer interviewing in sexual abuse cases to other professionals. Abnormal physical findings from sexual abuse are uncommon. Colposcopy has assisted pediatricians greatly in reaching consensus regarding diagnostic physical findings. Cases of acute sexual assault require familiarity with the forensic rape examination, STD screening and prophylaxis, and pregnancy prevention. Victimization from sexual abuse continues long after the abusive acts end, often requiring long-term therapeutic intervention. An emerging standard of care for medical evaluations of suspected child sexual abuse recognizes the requirement for patience and compassion while retaining objectivity. The pediatrician's primary concern must be for the child's physical and emotional well-being.

  7. Adolescent Substance Abuse.

    Science.gov (United States)

    Thorne, Craig R.; DeBlassie, Richard R.

    1985-01-01

    Cummings (1979), citing evidence from the National Institute of Drug Abuse, reports that one of every eleven adult Americans suffers from a severe addictive problem. Drug addiction is epidemic among teenagers; one of every six teenagers suffers from a severe addictive problem. This paper focuses on adolescent drug/substance abuse. (Author)

  8. Multi-disciplinary data organization and visualization models for clinical and pre-clinical studies: A case study in the application of proton beam radiosurgery for treating spinal cord injury related pain

    Science.gov (United States)

    Verma, Sneha K.; Liu, Brent J.

    2016-03-01

    An increasing adoption of electronic medical records has made information more accessible to clinicians and researchers through dedicated systems such as HIS, RIS and PACS. The speed and the amount at which information are generated in a multi-institutional clinical study make the problem complicated compared to day-to-day hospital workflow. Often, increased access to the information does not translate into the efficient use of that information. Therefore, it becomes crucial to establish models which can be used to organize and visualize multi-disciplinary data. Good visualization in turn makes it easy for clinical decision-makers to reach a conclusion within a small span of time. In a clinical study involving multi-disciplinary data and multiple user groups who need access to the same data and presentation states based on the stage of the clinical trial or the task are crucial within the workflow. Therefore, in order to demonstrate the conceptual system design and system workflow, we will be presenting a clinical trial based on application of proton beam for radiosurgery which will utilize our proposed system. For demonstrating user role and visualization design purposes, we will be focusing on three different user groups which are researchers involved in patient enrollment and recruitment, clinicians involved in treatment and imaging review and lastly the principle investigators involved in monitoring progress of clinical study. Also datasets for each phase of the clinical study including preclinical and clinical data as it related to subject enrollment, subject recruitment (classifier), treatment (DICOM), imaging, and pathological analysis (protein staining) of outcomes.

  9. Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model.

    Science.gov (United States)

    Mony, Jyothi Thyagabhavan; Zhang, Lixin; Ma, Tianzhou; Grabosch, Shannon; Tirodkar, Tejas S; Brozick, Joan; Tseng, George; Elishaev, Esther; Edwards, Robert P; Huang, Xin; Vlad, Anda M

    2015-09-01

    Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 × 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 μg/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer.

  10. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

    Directory of Open Access Journals (Sweden)

    Ferrari Stefano

    2009-12-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

  11. Dextromethorphan Abuse in Adolescence

    Science.gov (United States)

    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

  12. Preclinical Models in Vascularized Composite Allotransplantation

    Science.gov (United States)

    2015-06-28

    mechanism [31]. Small animal research is typically less resource intensive enabling a larger study population, and re- sults can be realised faster. They...functional recovery of vital structures is one predic- tor of the value of vascularized composite allografts. For ex- ample, facial nerve regeneration...Nonetheless, measuring functional recovery is a chal- lenge and various strategies have been attempted. Clinical measurements of function include the use

  13. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents.

    Science.gov (United States)

    Williams, Robert J; Goodale, Leslie A; Shay-Fiddler, Michele A; Gloster, Susan P; Chang, Samuel Y

    2004-01-01

    The prevalence of methylphenidate and dextroamphetamine misuse and abuse was examined in 450 adolescents referred for substance abuse treatment. Twenty three percent reported nonmedical use of these substances and six percent were diagnosed as methylphenidate or dextroamphetamine abusers. Abuse was more common in individuals who were out of school and had an eating disorder. Methylphenidate and dextroamphetamine abuse appears to be much less common than abuse of most other substances. It does occur, however, and parents and schools need to exert greater control over the dispensing of these medications. Physicians are advised to prescribe non-stimulant medications (eg, bupropion) when treating attention deficit hyperactivity disorder in substance-abusing individuals.

  14. The Economics of Reproducibility in Preclinical Research.

    Directory of Open Access Journals (Sweden)

    Leonard P Freedman

    2015-06-01

    Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

  15. Anabolic steroid abuse and dependence.

    Science.gov (United States)

    Brower, Kirk J

    2002-10-01

    Anabolic-androgenic steroids (AAS) are mainly used to treat androgen deficiency syndromes and, more recently, catabolic states such as AIDS-associated wasting. There is no evidence in the reviewed literature that AAS abuse or dependence develops from the therapeutic use of AAS. Conversely, 165 instances of AAS dependence have been reported among weightlifters and bodybuilders who, as part of their weight training regimens, chronically administered supraphysiologic doses, often including combinations of injected and oral AAS as well as other drugs of abuse. A new model is proposed in which both the "myoactive" and psychoactive effects of AAS contribute to the development of AAS dependence. The adverse consequences of AAS are reviewed, as well as their assessment by means of a history and physical, mental status examination, and laboratory testing. When patients with AAS use disorders are compared with patients with other substance use disorders, both similarities and differences become apparent and have implications for treatment.

  16. Encountering Child Abuse at Camp.

    Science.gov (United States)

    Durall, John K.

    1997-01-01

    Defines child abuse, including the three categories: physical, sexual, and psychological. Presents characteristics and behaviors of each type of abuse, and long-term effects. Discusses how to handle abuse that occurs at camp, and the effects on the camp. Sidebars present abuse statistics, 15 activities that promote psychological wellness, and 8…

  17. Child Abuse and Mandated Reporting

    Science.gov (United States)

    Woika, Shirley; Bowersox, Carissa

    2013-01-01

    Teachers and teachers-in-training are mandated reporters; they are legally required to report any suspected child abuse or neglect. This article describes: (1) How to file a report; (2) How prevalent child abuse is; (3) What abuse is; (4) What it means to be a mandated reporter; (5) When the report should be made; and (6) What to do if abuse is…

  18. Genetic and biological markers in drug abuse and alcoholism

    Energy Technology Data Exchange (ETDEWEB)

    Braude, M.C.; Chao, H.M.

    1986-01-01

    This book contains 11 selections. Some of the titles are: Polymorphic Gene Marker Studies; Pharmacogenetic Approaches to the Prediction of Drug Response; Genetic Markers of Drug Abuse in Mouse Models; Genetics as a Tool for Identifying Biological Markers of Drug Abuse; and Studies of an Animal Model of Alcoholism.

  19. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  20. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Directory of Open Access Journals (Sweden)

    Klemencja Berghauzen-Maciejewska

    Full Text Available Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day and imipramine (10 mg/kg ip once a day were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG] and amygdala (basolateral/lateral as well as the BDNF mRNA content in the habenula (medial/lateral. The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core and ventral tegmental area (VTA. Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  1. Feminist-cognitive-behavioral and process-psychodynamic treatments for men who batter: interaction of abuser traits and treatment models.

    Science.gov (United States)

    Saunders, D G

    1996-01-01

    At a community-based domestic violence program, 218 men with a history of partner abuse were randomly assigned to either feminist-cognitive-behavioral or process-psychodynamic group treatments. The treatments were not hypothesized to differ in outcome. However, men with particular characteristics were expected to have lower recidivism rates depending on the type of treatment received. Treatment integrity was verified through audio-taped codings of each session. The partners of 79% of the 136 treatment completers gave reports of the men's behavior an average of 2 years post-treatment. These reports were supplemented with arrest records and self-reports. Rates of violence did not differ significantly between the two types of treatment nor did reports from the women of their fear level, general changes perceived in the men, and conflict resolution methods. However, interaction effects were found between some offender traits and the two treatments. As predicted, men with dependent personalities had better outcomes in the process-psychodynamic groups and those with antisocial traits had better outcomes in the cognitive-behavioral groups. The results suggest that more effective treatment may occur if it is tailored to specific characteristics of offenders.

  2. An integral approach to substance abuse.

    Science.gov (United States)

    Amodia, Diana S; Cano, Carol; Eliason, Michele J

    2005-12-01

    There is a pressing need in the substance abuse field for more comprehensive models of etiology and treatment that address the complex issues of addiction, including the biological, social, cultural, spiritual and developmental needs of individuals and groups. This article presents a theoretical framework for an integral approach to substance abuse that expands on the existing biopsychosocial model. One contribution of the model is an integrated approach to spirituality from a cross-cultural perspective. This integral approach examines substance abuse etiology and treatment from a four-quadrant perspective adapted from the work of Ken Wilber, and incorporates concepts from integrative medicine and transpersonal psychology/psychiatry. Implications of the model are explored.

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

    Science.gov (United States)

    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.

  4. Child Sexual Abuse

    Science.gov (United States)

    ... sense of self-esteem, cope with feelings of guilt about the abuse, and begin the process of overcoming the trauma. Such treatment can help reduce the ... Child and Adolescent Psychiatrists Teen Suicide ...

  5. Counselor Trainees' Self-Statement Responses to Sexually and Physically Abused Clients, and Client Role Conflict.

    Science.gov (United States)

    Parisien, Lynne S.; Long, Bonita C.

    1994-01-01

    Assessed 63 female counselor trainees after viewing videotape of client reporting sexual abuse, physical abuse, or role conflict. Results indicated that trainees who expected to counsel sexually abused client increased their positive self-statements. Applied Schwartz's States-of-Mind model to self-statement ratios, and, according to model,…

  6. Opioid Abuse after TBI

    Science.gov (United States)

    2014-07-01

    AD_________________ Award Number: W81XWH-11-1-0373 TITLE: " Opioid Abuse after TBI...2014 2. REPORT TYPE Annual 3. DATES COVERED 1 July 2013 - 30 June 2014 4. TITLE AND SUBTITLE " Opioid Abuse after TBI" 5a. CONTRACT NUMBER 5b...the brain’s reward circuitry which may make an injured brain more susceptible to the rewarding effects of opioids . We are currently conducting

  7. Toxic Knowledge: Self-Alteration Through Child Abuse Work.

    Science.gov (United States)

    Sigad, Laura I; Davidov, Jonathan; Lev-Wiesel, Rachel; Eisikovits, Zvi

    2016-02-01

    The purpose of the present article is to examine the multiple ways in which the private lives of professionals are affected by involvement with child abuse intervention and prevention. Using a descriptive-phenomenological perspective and 40 in-depth interviews with professionals to present a model based on qualitative data, we studied the ways in which child abuse professionals conceptualize, understand, and integrate their experiences into their personal and family lives. We find that the process of internalizing child abuse knowledge occurs in two domains: One affirms or denies the existence of the phenomenon; the other concerns the strategies used to contend with the effects of working in abuse. Knowledge of child abuse is toxic, in the sense that it serves as a catalyst leading to the alteration of one's self-perception and parental identity. We present a typology of self-alteration resulting from child abuse knowledge and describe the mechanism of this change.

  8. 1H magnetic resonance spectroscopy in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, Joost C. H.; Sijens, Paul E.; Roos, Raymund A. C.; Leenders, Klaus L.

    2007-01-01

    Huntington disease (HD) is a hereditary brain disease, causing progressive deterioration after a preclinical phase. The pathophysiology of early brain abnormalities around disease onset is largely unknown. Some preclinical mutation carriers (PMC) show structural or metabolic changes on brain imaging

  9. Associations between mental health, substance use, and sexual abuse experiences among Latinas.

    Science.gov (United States)

    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.

  10. Linking child maltreatment history with child abuse potential: Relative roles of maltreatment types

    Directory of Open Access Journals (Sweden)

    Mitkovic-Voncina Marija

    2014-01-01

    Full Text Available The independent roles of each childhood maltreatment type on child abuse potential in adults have been insufficiently explored and are inconsistent, with dissociation as one of the possible suggested mediators of intergenerational child abuse. We investigated these effects among 164 non-clinical adult parents, who filled in general questionnaires: Childhood Trauma Questionnaire (CTQ, Child Abuse Potential Inventory (CAPI and Dissociative Experience Scale (DES. Among all maltreatment types (emotional, physical and sexual abuse, emotional and physical neglect, emotional abuse was the only independent predictor in the regression model of child abuse potential. The relationship between emotional abuse history and child abuse potential was partially mediated by dissociation. The findings could speak in favor of the potentially unique detrimental role of emotional abuse in intergenerational maltreatment, with dissociation as one of the possible mechanisms.

  11. Development and preliminary validation of the Opioid Abuse Risk Screener.

    Science.gov (United States)

    Henrie-Barrus, Patricia; Averill, Lynnette A; Sudweeks, Richard R; Averill, Christopher L; Mota, Natalie

    2016-01-01

    Prescription opioid drug abuse has reached epidemic proportions. Individuals with chronic pain represent a large population at considerable risk of abusing opioids. The Opioid Abuse Risk Screener was developed as a comprehensive self-administered measure of potential risk that includes a wide range of critical elements noted in the literature to be relevant to opioid risk. The creation, refinement, and preliminary modeling of the item pool, establishment of preliminary concurrent validity, and the determination of the factor structure are presented. The initial development and validation of the Opioid Abuse Risk Screener shows promise for effective risk stratification.

  12. Development and preliminary validation of the Opioid Abuse Risk Screener

    Directory of Open Access Journals (Sweden)

    Patricia Henrie-Barrus

    2016-05-01

    Full Text Available Prescription opioid drug abuse has reached epidemic proportions. Individuals with chronic pain represent a large population at considerable risk of abusing opioids. The Opioid Abuse Risk Screener was developed as a comprehensive self-administered measure of potential risk that includes a wide range of critical elements noted in the literature to be relevant to opioid risk. The creation, refinement, and preliminary modeling of the item pool, establishment of preliminary concurrent validity, and the determination of the factor structure are presented. The initial development and validation of the Opioid Abuse Risk Screener shows promise for effective risk stratification.

  13. Artificial Neural Network Analysis in Preclinical Breast Cancer

    Directory of Open Access Journals (Sweden)

    Gholamreza Motalleb

    2013-01-01

    Full Text Available Objective: In this study, artificial neural network (ANN analysis of virotherapy in preclinical breast cancer was investigated.Materials and Methods: In this research article, a multilayer feed-forward neural network trained with an error back-propagation algorithm was incorporated in order to develop a predictive model. The input parameters of the model were virus dose, week and tamoxifen citrate, while tumor weight was included in the output parameter. Two different training algorithms, namely quick propagation (QP and Levenberg-Marquardt (LM, were used to train ANN.Results: The results showed that the LM algorithm, with 3-9-1 arrangement is more efficient compared to QP. Using LM algorithm, the coefficient of determination (R2 between the actual and predicted values was determined as 0.897118 for all data.Conclusion: It can be concluded that this ANN model may provide good ability to predict the biometry information of tumor in preclinical breast cancer virotherapy. The results showed that the LM algorithm employed by Neural Power software gave the better performance compared with the QP and virus dose, and it is more important factor compared to tamoxifen and time (week.

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

    Science.gov (United States)

    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

  15. Substance Abuse: Implications for Counseling African American Men.

    Science.gov (United States)

    Wade, Jay C.

    1994-01-01

    Examines factors--such as unemployment, economic deprivation, racism, issues pertaining to gender roles--and their contribution to substance abuse in African American men. Specifically reviews the use of alcohol, opiates, crack, and cocaine. Argues that a biopsychosocial model offers the best framework in conceptualizing substance abuse and…

  16. A Theoretical Foundation for Understanding Clergy-Perpetrated Sexual Abuse

    Science.gov (United States)

    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…

  17. Contextual Effects on Kindergarten Teachers' Intention to Report Child Abuse

    Science.gov (United States)

    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…

  18. A Multilevel Evaluation of a Comprehensive Child Abuse Prevention Program

    Science.gov (United States)

    Lawson, Michael A.; Alameda-Lawson, Tania; Byrnes, Edward C.

    2012-01-01

    Objectives: The purpose of this study is to examine the extent to which participation in a county-wide prevention program leads to improvements in protective factors associated with child abuse prevention (CAP) and whether improvements in measured protective factors relate to decreased odds of child abuse. Method: Using multilevel growth modeling,…

  19. Orexin-A level elevation in recently abstinent male methamphetamine abusers.

    Science.gov (United States)

    Chen, Wen-Yin; Kao, Chung-Feng; Chen, Po-Yu; Lin, Shih-Ku; Huang, Ming-Chyi

    2016-05-30

    Research has suggested that methamphetamine (METH) use influences orexin regulation. We examined the difference in orexin-A levels between METH abusers and healthy controls. Fasting serum orexin-A levels were measured in 35 participants who used METH in the preceding 3 weeks and 36 healthy controls. We found METH abusers had significantly higher orexin-A levels. No association was observed between orexin-A levels and METH use variables. Our results, consistent with prior preclinical evidence, showed that recent METH exposure is associated with increased orexin-A expression. Further investigation is required to determine whether orexin-A levels normalize after a longer term of abstinence.

  20. Animal models of alcohol and drug dependence

    Directory of Open Access Journals (Sweden)

    Cleopatra S. Planeta

    2013-01-01

    Full Text Available Drug addiction has serious health and social consequences. In the last 50 years, a wide range of techniques have been developed to model specific aspects of drug-taking behaviors and have greatly contributed to the understanding of the neurobiological basis of drug abuse and addiction. In the last two decades, new models have been proposed in an attempt to capture the more genuine aspects of addiction-like behaviors in laboratory animals. The goal of the present review is to provide an overview of the preclinical procedures used to study drug abuse and dependence and describe recent progress that has been made in studying more specific aspects of addictive behavior in animals.

  1. The complexities of elder abuse.

    Science.gov (United States)

    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

  2. Pain and depression comorbidity: a preclinical perspective

    OpenAIRE

    Li, Jun-Xu

    2014-01-01

    Pain and depression are two highly prevalent and deleterious disorders with significant socioeconomic impact to society. Clinical observations have long recognized the co-existence and interactions of pain and depression. However, the underlying mechanisms of pain-depression comorbidity and their dynamic interactions remain largely unknown. Preclinical animal studies may provide critical information for the understanding of this important comorbidity. This review analyzed the current preclini...

  3. The impact of child sexual abuse on addiction severity: an analysis of trauma processing.

    Science.gov (United States)

    Walker, G C; Scott, P S; Koppersmith, G

    1998-03-01

    The Information of Processing Trauma Model provides a framework for understanding the dynamics and responses of childhood sexual abuse. Chemical dependency plays a role in both the cause and effect of childhood sexual abuse. Survivors of childhood sexual abuse with chemical dependency require treatment of both disorders. This treatment should emphasize the key role of the encapsulation phase in symptom formation and recovery.

  4. Changing the Culture of Alcohol Abuse on Campus: Lessons Learned from Secondhand Smoke

    Science.gov (United States)

    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…

  5. Childhood Risk Factors for Alcohol Abuse and Psychological Distress among Adult Lesbians

    Science.gov (United States)

    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…

  6. The pre-clinical discovery of Amyotrophic Lateral Sclerosis Drugs

    Science.gov (United States)

    Glicksman, Marcie A.

    2012-01-01

    Introduction Amyotrophic Lateral Sclerosis, also referred to as Lou Gehrig’s disease is characterized by the progressive loss of cells in the brain and spinal cord that leads to debilitation and death in 3–5 years. Only one therapeutic drug, Riluzole, has been approved for ALS and that drug improves survival by 2–3 months. The need for new therapeutics, either that can postpone or slow the progression of the motor deficits and prolong survival, is still a strong unmet medical need. Areas Covered Although there are a number of drugs currently in clinical trials for ALS, this review provides an overview of the most promising biological targets and preclinical strategies that are currently being developed and deployed. The list of targets for ALS was compiled from a variety of websites including: individual companies that have ALS programs, and the author’s experience. Expert Opinion Progress is being made in the identification of possible new therapeutics for ALS with recent efforts in: understanding the genetic causes of the disease, susceptibility factors, and the development of additional preclinical animal models. However, many challenges remain in the identification of new ALS therapeutics including: the use of relevant biomarkers, the need for earlier diagnosis of the disease, and additional animal models. Multiple strategies need to be tested, in the clinic, in order to determine what will be effective in patients. PMID:22646982

  7. The Child Abuse

    Directory of Open Access Journals (Sweden)

    Hossein abbasnezhadriyabi

    2016-03-01

    Full Text Available While a large number of children are losing their lives due to poverty, malnutrition, contagious diseases and war, we are witnessing hundreds of children death by reason of misbehaving. Today, "child abuse" as a social-cultural phenomenon which shows crisis in a society, has a growing process in our country. The goal of this research was to investigate the base factors of child abuse that according to the results are consist as follows, poverty, unemployment, addiction, large families, single-parent, Considering the increase of factors such as poverty, addiction, unemployment, divorce, temporary marriage, street children and other effective factors, the hypothesis based on growth of child abuse was proved in Iran.

  8. Substance Abuse Treatment Facilities Locator

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Substance Abuse and Mental Health Services Administration (SAMHSA) provides on-line resource for locating drug and alcohol abuse treatment programs. The...

  9. Child Abuse or Osteogenesis Imperfecta?

    Science.gov (United States)

    Child Abuse or Osteogenesis Imperfecta? 804 W. Diamond Ave., Ste. 210 Gaithersburg, MD 20878 (800) 981-2663 (301) ... welfare services to report a suspected case of child abuse. The child is taken away from the parents ...

  10. Adolescent Relationship Abuse (ARA) Toolkit

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Adolescent Relationship Abuse (ARA) Toolkit provides information and strategies on how to: incorporate abuse prevention into programming; conduct staff training;...

  11. Child neglect and psychological abuse

    Science.gov (United States)

    ... or neglect, call 911. Call the Childhelp National Child Abuse Hotline (1-800-4-A-CHILD). Know that ... can/identifying/. Accessed November 21, 2014. Read More Child abuse - physical Review Date 11/20/2014 Updated by: ...

  12. Substance abuse and child maltreatment.

    Science.gov (United States)

    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.

  13. Synthetic cathinone abuse

    Directory of Open Access Journals (Sweden)

    Capriola M

    2013-07-01

    Full Text Available Michael Capriola Thomasville Medical Center, Thomasville, NC, USA Abstract: The abuse of synthetic cathinones, widely known as bath salts, has been increasing since the mid-2000s. These substances are derivatives of the naturally occurring compound cathinone, which is the primary psychoactive component of khat. The toxicity of synthetic cathinones includes significant sympathomimetic effects, as well as psychosis, agitation, aggression, and sometimes violent and bizarre behavior. Mephedrone and methylenedioxypyrovalerone are currently the predominantly abused synthetic cathinones. Keywords: designer drugs/chemistry, street drugs/pharmacology, substance-related disorders/epidemiology, alkaloids/poisoning

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

    Science.gov (United States)

    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

  15. Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research.

    Science.gov (United States)

    Leiser, Steven C; Dunlop, John; Bowlby, Mark R; Devilbiss, David M

    2011-06-15

    Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs.

  16. The Drug-Abuse Questionnaire.

    Science.gov (United States)

    Ferneau, E.; Mueller, S.

    The drug-abuse questionnaire used to survey college student attitudes on the subject is provided. It is identical to the alcoholism questionnaire except for word changes appropriate to the subject matter. The questionnaire consists of 40 statements about drug abuse and drug abusers, with 7 possible responses: (1) completely disagree; (2) mostly…

  17. Recognizing the adolescent drug abuser.

    Science.gov (United States)

    MacKenzie, R G; Jacobs, E A

    1987-03-01

    Adolescents are at high risk for using and abusing illicit drugs. Guidelines for recognizing drug abusers are presented as well as a staging process for progression of drug use. The family physician is in an ideal position to identify young users/abusers and to assist them and their families in obtaining much needed assistance.

  18. Drug Abuse in Southeast Asia.

    Science.gov (United States)

    Scorzelli, James F.

    This report examines the incidence of drug abuse and the methods of treatment and prevention of drug abuse used in Southeast Asia. Countries studied include Malaysia, Singapore, Thailand, Indonesia, and the Philippines. Because of Malaysia's intensive effort to eliminate its drug abuse problem, emphasis is placed on this country's treatment and…

  19. Geriatric Alcoholism and Drug Abuse

    Science.gov (United States)

    Schuckit, Marc A.

    1977-01-01

    This paper reviews the literature and presents new data on alcohol and drug problems in older individuals. Drug abusers include users of opiates, inadvertent misusers, and deliberate abusers of nonopiates. Two to 10 percent of the elderly are alcoholic, and these are usually individuals beginning alcohol abuse after age 40. (Author)

  20. Substance abuse and criminal behavior.

    Science.gov (United States)

    Bradford, J M; Greenberg, D M; Motayne, G G

    1992-09-01

    As forensic psychiatry develops as a clinical subspecialty, clinical skill in understanding, treating, and predicting violent behavior will become more important. This article addresses the importance of understanding the relationship between substance abuse and violent behavior. This article also discusses morbidity and mortality in substance abuse, the demographics of substance abuse and criminality, and the clinical aspects of the forensic psychiatric evaluation.

  1. Interpersonal types among alcohol abusers: a comparison with drug abusers.

    Science.gov (United States)

    Turner, J A; Mayr, S

    1990-07-01

    Interpersonal types among alcohol abusers were examined with Calsyn, Roszell, and Anderson's (1988) nine-type system for classifying FIRO-B profiles. The frequencies of the nine FIRO-B types among a sample of 135 male veteran alcohol abusers were compared with Calsyn et al.'s (1988) previously published data for a sample of male veteran drug abusers, a normative veteran sample, and a general population sample. The alcohol abusers, like Calsyn et al.'s sample of drug abusers, were more likely to be categorized as "loners," "rebels," and "pessimists" than was the general population sample. While exhibiting preferences for interpersonal types that emphasized social withdrawal, avoidance of responsibility, and mistrust of others, both the alcohol abusers and the drug abusers were heterogeneous groups whose members demonstrated a variety of interpersonal types.

  2. The effect of learning styles and study behavior on success of preclinical students in pharmacology

    Science.gov (United States)

    Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F. Nihan; Cicek, Ekrem

    2016-01-01

    Objectives: To evaluate the effect of learning styles and study behaviors on preclinical medical students’ pharmacology exam scores in a non-Western setting. Materials and Methods: 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. Results: 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. Conclusions: Preclinical medical students’ study behaviors are independent predictive factors for short-term pharmacology success. PMID:26997716

  3. Preventing and Treating Substance Abuse among Adolescents

    Science.gov (United States)

    Sussman, Steve

    2011-01-01

    Substance misuse is one of the most prevalent causes of adolescent injury and death. Additionally, 5-8% of adolescents in the U.S. qualify for a diagnosis of substance abuse disorder. This article discusses formal prevention and treatment program models, focusing on a continuum of care which extends from prevention to treatment alternatives.…

  4. Iowa Case Management for Rural Drug Abuse

    Science.gov (United States)

    Hall, James A.; Vaughan Sarrazin, Mary S.; Huber, Diane L.; Vaughn, Thomas; Block, Robert I.; Reedy, Amanda R.; Jang, MiJin

    2009-01-01

    Objective: The purpose of this research was to evaluate the effectiveness of a comprehensive, strengths-based model of case management for clients in drug abuse treatment. Method: 503 volunteers from residential or intensive outpatient treatment were randomly assigned to one of three conditions of Iowa Case Management (ICM) plus treatment as usual…

  5. Predicting Resilience in Sexually Abused Adolescents

    Science.gov (United States)

    Williams, Javonda; Nelson-Gardell, Debra

    2012-01-01

    This research examined factors that predicted resilience in sexually abused adolescents. Using Bronfenbrenner's Process-Person-Context-Time (PPCT) ecological model, this study considered the proximal and distal factors that would contribute to adolescents' reactions to sexual victimization. This correlational study used hierarchical regression…

  6. 锂离子电池热滥用模型及实验校核%Thermal abuse model of lithium ion cells and experimental validation

    Institute of Scientific and Technical Information of China (English)

    赖彭飞; 叶强; 渠冰; 陈国营

    2012-01-01

    Three dimensional thermal model of Li-ion cells (BYD: LiCoO2-EC/EMC/DEC/DMC-Graphite, 18650) was developed to investigate the thermal abuse behavior during oven test. The model was validated by comparing the simulation results with measured curve for cells under different states, which included cells without filling electrolyte, uncharged cells, and fully charged cells. Base on the correlation between the critical environment temperature and the critical state of charge of cell's before thermal runaway, the criterion curves was proposed in determining the safety of cells.%建立了锂离子电池(BYD:LiCoO2-EC/EMC/DEC/DMC-Graphite,18650)的三维非稳态热滥用模型.根据离线测量的电池材料物性参数进行了炉箱测试的数值模拟,并利用三种不同状态(未注电解液、注液但未充电及充满电)电池的炉箱测试结果对模型进行了校核.在此基础上,研究了锂离子电池在热滥用情况下的放热与温升规律.基于影响电池热失控的两个主要因素(温度和充电状态),提出判别电池热安全性的临界曲线分析法.

  7. Treatment for Child Abusers

    Science.gov (United States)

    Tracy, James J.; Clark, Elizabeth H.

    1974-01-01

    Staff of a child abuse program in a Philadelphia hospital worked with parents in their own homes to help them develop greater competence as adults and as parents. This article describes the use of social learning theory, with some techniques of behavior therapy, as the basis for treatment. (Author)

  8. Other Drugs of Abuse

    Science.gov (United States)

    ... OtherDrugsofAbuse_012017.pdf Previous Index Español English Español PDF Version Download Treatment & Recovery Information Treatment and Recovery ... the U.S. Department of Health and Human Services . PDF documents require the free Adobe Reader . Microsoft Word ...

  9. Drug abuse in athletes

    Directory of Open Access Journals (Sweden)

    Reardon CL

    2014-08-01

    Full Text Available Claudia L Reardon, Shane Creado Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Drug abuse occurs in all sports and at most levels of competition. Athletic life may lead to drug abuse for a number of reasons, including for performance enhancement, to self-treat otherwise untreated mental illness, and to deal with stressors, such as pressure to perform, injuries, physical pain, and retirement from sport. This review examines the history of doping in athletes, the effects of different classes of substances used for doping, side effects of doping, the role of anti-doping organizations, and treatment of affected athletes. Doping goes back to ancient times, prior to the development of organized sports. Performance-enhancing drugs have continued to evolve, with “advances” in doping strategies driven by improved drug testing detection methods and advances in scientific research that can lead to the discovery and use of substances that may later be banned. Many sports organizations have come to ban the use of performance-enhancing drugs and have very strict consequences for people caught using them. There is variable evidence for the performance-enhancing effects and side effects of the various substances that are used for doping. Drug abuse in athletes should be addressed with preventive measures, education, motivational interviewing, and, when indicated, pharmacologic interventions. Keywords: doping, athletes, steroids, drug abuse, mental illness

  10. Prescription Drug Abuse

    Science.gov (United States)

    ... an opportunity to confront the person about the consequences of addiction and ask him or her to accept treatment. Think of an intervention as giving your loved one a clear opportunity to make changes before things get really bad. Prescription drug abuse may occur in people who ...

  11. Infant crying and abuse

    NARCIS (Netherlands)

    Reijneveld, S.A.; van der Wal, M.F.; Brugman, E.; Hira Sing, R.A.; Verloove-Vanhorick, S.P.

    2004-01-01

    Child abuse and neglect are important causes of child morbidity and death. We assessed potentially detrimental parental actions induced by infant crying in 3259 infants aged 1-6 months, in the Netherlands. In infants aged 6 months, 5.6% (95% CI 4.2-7.0) of parents reported having smothered, slapped,

  12. New drugs of abuse.

    Science.gov (United States)

    Rech, Megan A; Donahey, Elisabeth; Cappiello Dziedzic, Jacqueline M; Oh, Laura; Greenhalgh, Elizabeth

    2015-02-01

    Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases.

  13. Drugs and Drug Abuse.

    Science.gov (United States)

    Anastas, Robert, Comp.; And Others.

    GRADES OR AGES: Secondary grades. SUBJECT MATTER: Drugs and drug abuse. ORGANIZATION AND PHYSICAL APPEARANCE: The guide is divided into several sections, each of which is in outline or list form. It is xeroxed and spiral-bound with a paper cover. OBJECTIVES AND ACTIVITIES: No objectives are mentioned. The major portion of the guide contains a…

  14. Abuse behavior of high-power, lithium-ion cells

    Science.gov (United States)

    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.

  15. Cytokine-based Preclinical Approaches to the Therapy of Renal Cancar

    Institute of Scientific and Technical Information of China (English)

    RobertH.Wiltrout

    1995-01-01

    Antigen-nonspecific approaches to the use of BRMs for cancer treatment have resulted inonly limited success to date. Recent demonstrations of T-Iymphocyte-mediated antigen-specific responses against some human tumors, and the more pronounced effects of these cells in preclinical models have refocusedmuch of responses,

  16. Childhood abuse, personality traits, and depressive symptoms in adulthood.

    Science.gov (United States)

    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.

  17. CONCEPTUAL AND METHODOLOGICAL MISTAKES IN PSYCHOLOGY AND HEALTH: A CASE STUDY ON THE USE AND ABUSE OF STRUCTURAL EQUATION MODELLING

    Directory of Open Access Journals (Sweden)

    Julio Alfonso Piña López

    2016-09-01

    Full Text Available In this article, a research paper is analysed, which was justified based on the theory of developmental psychopathology, the protective factors, self-regulation, resilience, and quality of life among individuals who lived with type 2 diabetes and hypertension. Structural equation modelling (SEM was used for the data analysis. Although the authors conclude that the data are adequate to the theory tested, they commit errors of logic, concept, methodology and interpretation which, taken together, demonstrate a flagrant rupture between the theory and the data.

  18. Ramucirumab: preclinical research and clinical development

    Directory of Open Access Journals (Sweden)

    Aprile G

    2014-10-01

    Full Text Available Giuseppe Aprile,1 Erika Rijavec,2 Caterina Fontanella,1 Karim Rihawi,1 Francesco Grossi21Department of Oncology, University Hospital of Udine, Udine, Italy; 2Lung Cancer Unit, National Cancer Institut “San Martino”, Genoa, ItalyAbstract: Ramucirumab (IMC-1121B, LY3009806, a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2, is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer. Keywords: ramucirumab, gastric cancer, lung cancer, breast cancer, antiangiogenic

  19. Ramucirumab: preclinical research and clinical development.

    Science.gov (United States)

    Aprile, Giuseppe; Rijavec, Erika; Fontanella, Caterina; Rihawi, Karim; Grossi, Francesco

    2014-01-01

    Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer.

  20. Thermal conductivity of zirconia based inert matrix fuel: use and abuse of the formal models for testing new experimental data

    Science.gov (United States)

    Degueldre, C.; Arima, T.; Lee, Y. W.

    2003-06-01

    An inert matrix fuel material based on yttria-stabilized cubic zirconia: Er xY yPu zZr 1- x- y- zO 2-( x + y)/2 ( x+ y=0.15, z: [0.05-0.15]) was proposed for burning excess plutonium in light water reactors. The studied inert matrix fuel is made of cubic stabilized zirconia. The limited number of experimental thermal conductivity data justifies this formal and intensive study. Approaches derived from Klemens theory were revisited and the derived conductivity model applied for zirconia, accounting the effects of phononic scattering centers. The hyperbolic thermal conductivity trend with temperature known for pure zirconia, is reduced by isotopes, impurities, dopants and oxygen vacancies, which act as scattering centers and contribute to conductivity reduction to a flat plot with temperature for stabilized zirconia. It is experimentally observed that the thermal conductivity derived from laser flash measurements for Er xY yM zZr 1- x- y- zO 2-( x + y)/2 (with M=Ce or Pu, z=0 or ˜0.1 and x+ y=0.15) is rather constant as a function of temperature in the range 300-1000 K. The thermal conductivity was observed to depend on the concentration of dopants such as YO 1.5 and/or ErO 1.5, CeO 2 (analogous of PuO 2) or PuO 2. The bulk material conductivity of Er 0.05Y 0.10Pu 0.10Zr 0.75O 1.925 is about 2 W m -1 K -1. In this study, the thermal conductivity data of both monoclinic and stabilized cubic zirconia based IMF are tested with the model approach in order to understand the experimental data in a semi-quantitative way.

  1. Abuse Tolerance Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Orendorff, Christopher J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nagasubramanian, Ganesan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Fenton, Kyle R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Allcorn, Eric [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improve lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.

  2. PTSD and Substance Abuse

    Science.gov (United States)

    2014-10-01

    Psychological Association’s addiction syndrome handbook. Washington, DC: American Psychological Association. 35. Najavits, L.M., Highley, J., Dolan, S., Fee...Version (total and criterion D); and the Trauma Symptom Checklist-40 (sexual abuse trauma index and anxiety subscale); functioning on the Sheehan ...months (scaled 0-4). Functioning. The Sheehan Disability Scale [15] has 5 items assessing functioning in work/school, social life, and family life

  3. Child Abuse and Mental Disorders in Iranian Adolescents

    Directory of Open Access Journals (Sweden)

    Azar Pirdehghan

    2016-01-01

    Full Text Available Background Child abuse is a serious social health problem all over the world with important adverse effects. Objectives The aim of this study was to extend our understanding of the relation between mental disorders and child abuse. Materials and Methods The study was designed as a cross-sectional survey on 700 students in secondary schools using multiple cluster sampling in Yazd, Iran in 2013. We applied 2 self reported questionnaires: DASS (depression anxiety stress scales-42 for assessing mental disorders (anxiety, stress and depression and a standard self-reported valid and reliable questionnaire for recording child abuse information in neglect, psychological, physical and sexual domains. The collected data was analyzed using SPSS software. P-values < 0.05 were considered as significant. Results There was a statically significant correlation between mental disorder and child abuse score (Spearman rho: 0.2; P-value < 0.001. The highest correlations between mental disorders and child abuse were found in psychological domain, Spearman’s rho coefficients were 0.46, 0.41 and 0.36 for depression, anxiety and stress respectively (P-value < 0.001. Based on the results of logistic regression for mental disorder, females, last born adolescents and subjects with drug or alcohol abuser parents had mental disorder odds of 3, 0.4 and 1.9 times compared to others; and severe psychological abuse, being severely neglected and having sexual abuse had odds 90, 1.6 and 1.5 respectively in another model. Conclusions Programming for mandatory reporting of child abuse by physicians and all health care givers e.g. those attending schools or health centers, in order to prevent or reduce its detrimental effects is useful and success in preventing child abuse could lead to reductions in the prevalence of mental disorders.

  4. Distinguishing between exploratory and confirmatory preclinical research will improve translation.

    Science.gov (United States)

    Kimmelman, Jonathan; Mogil, Jeffrey S; Dirnagl, Ulrich

    2014-05-01

    Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.

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

    Science.gov (United States)

    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; Allan, Stuart M

    2016-03-01

    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.

  6. Substance abusers' personality disorders and staff members' emotional reactions

    DEFF Research Database (Denmark)

    Thylstrup, Birgitte; Hesse, Morten

    2008-01-01

    workshops completed a self-report inventory of emotional reactions to patients, the Feeling Word Checklist-58, and substance abusers completed a self-report of DSM-IV personality disorder, the DSM-IV and ICD-10 Personality Disorder Questionnaire. Correlational analysis and multiple regression analysis...... impact on emotional reactions. Conclusion The findings confirm clinical experiences that personality disorder features in patients with substance abuse have an impact on staff members reactions to them. These reactions should be considered in supervision of staff, and in treatment models for patients...... with co-morbid personality disorders and substance abuse....

  7. Preclinical and clinical safety studies on DNA vaccines.

    NARCIS (Netherlands)

    Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

    2007-01-01

    DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and clini

  8. Evidence of the Construct Validity of the Scale of Economic Abuse.

    Science.gov (United States)

    Adams, Adrienne E; Beeble, Marisa L; Gregory, Katie A

    2015-01-01

    This study investigated the construct validity of the Scale of Economic Abuse (SEA). Evidence of construct validity was assessed by examining the relationship between the SEA and an economic outcome, financial resources, as perceived by participants. A sample of 93 women with abusive partners were recruited from a domestic violence organization and interviewed 3 times over a period of 4 months. Hierarchical linear modeling was used to examine the relationship between economic abuse and financial resources over time, controlling for the effects of physical and psychological abuse. The findings indicate that baseline economic abuse was significantly related to baseline financial resources, and within-woman change in economic abuse was significantly predicted change in financial resources over time. The findings suggest that the SEA measures what it is intended to measure: an economic dimension of intimate partner abuse that has damaging economic consequences.

  9. Abusive Head Trauma (Shaken Baby Syndrome)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Abusive Head Trauma (Shaken Baby Syndrome) KidsHealth > For Parents > Abusive Head ... babies tend to cry the most. How These Injuries Happen Abusive head trauma results from injuries caused ...

  10. Attraction to sexual violence towards women, sexual abuse of children, and non-sexual criminal behavior: testing the specialist vs. generalist models in male college students.

    Science.gov (United States)

    Voller, Emily K; Long, Patricia J; Aosved, Allison C

    2009-04-01

    A sample of 492 college men anonymously completed an expanded version of the Sexual Experiences Survey, the revised Attraction to Sexual Aggression Scale, and the Marlowe-Crowne Social Desirability Scale Short Form to investigate the relations among perpetration of sexual violence (including rape and sexual assault), attraction to sexual violence, attraction to childhood sexual abuse, and attraction towards other crimes while controlling for the impact of social desirability. Analyses indicated that attractions towards sexual violence, general criminality, and childhood sexual abuse were all significantly interrelated. In addition, sexual assault perpetrators reported higher levels of all three types of attraction as compared to nonperpetrators whereas rape perpetrators reported higher levels of attraction to sexual aggression and criminality. Clinical and research implications are discussed.

  11. Elder abuse in residential long-term care: an update to the 2003 National Research Council report.

    Science.gov (United States)

    Castle, Nicholas; Ferguson-Rome, Jamie C; Teresi, Jeanne A

    2015-06-01

    A synthesis of the last decade of literature on elder abuse in residential long-term care (i.e., Nursing Homes and Assisted Living) is discussed. Presented are definitions of abuse, theoretical and conceptual models, prevalence rates of abuse, outcomes and costs, and sources of abuse. The synthesis represents an update to the literature in the influential 2003 National Research Council report. We identify many of the same issues and concerns exist that were surfaced in this prior report. Many theoretical and conceptual models need further elaboration. Conflicting definitions of abuse are pervasive. Rates of abuse are generally inaccurate, and probably under-reported. However, we also identify progress in many areas. An increase in empirical studies that exist in this area (although very few in Assisted Living). Other forms and types of abuse have also been identified as important, such as resident-to-resident abuse. These areas are discussed, along with potential suggestions for additional research.

  12. Character of abuse towards the elderly through history.

    Science.gov (United States)

    Pruszyński, Jacek J; Gebska-Kuczerowska, Anita; Cicha-Mikołajczyk, Alicja; Gromulska, Lucyna

    2011-01-01

    Abuse, neglect and other forms of discrimination towards the elderly have always been present in history. There has been a model of "old person" in every culture, according to which older people are treated. The more idealized the model is, the less tolerant and more demanding society is towards the elderly. Presented results lead to the conclusion that significant number of older people feel mistreated because of their age in many aspects of daily life. Various forms of abuse may be difficult to thoroughly analyze, for they are so persistent in our collective consciousness. Unfortunately, material civilization progress is not sufficient to eliminate abuse. Thus, monitoring and relevant assistance to people exposed to abuse and violence, particularly those with compromised defense abilities, is crucial.

  13. Children and animal abuse: Criminological, victimological and criminal justice aspects

    Directory of Open Access Journals (Sweden)

    Batrićević Ana

    2011-01-01

    Full Text Available Animal abuse represents a complex social, psychological, criminological, victimological and legal phenomenon whose gravity is increased if a child appears either as the perpetrator or as the observer of violence against animals. Etiology and phenomenology of animal abuse suggest that it tends to overlap with various deviant, delinquent and criminal activities, including physical, emotional and sexual abuse of family or other community members, alcohol and drug abuse, illegal gambling and betting and membership of children and adolescents in street gangs. The author discusses fundamental reasons, causes and motives for animal abuse committed by children as well as the devastating impact of children’s exposure to the scenes of animal abuse on their future delinquent behavior. She emphasizes the link between animal abuse and family violence and analyzes the position of a child as a direct or indirect victim in such situations. In addition, the author estimates the efficiency of existing mechanisms of prevention and state reaction to such behaviours and suggests solutions, which are accepted in comparative law, as potential role models.

  14. Child physical abuse and adult mental health: a national study.

    Science.gov (United States)

    Sugaya, Luisa; Hasin, Deborah S; Olfson, Mark; Lin, Keng-Han; Grant, Bridget F; Blanco, Carlos

    2012-08-01

    This study characterizes adults who report being physically abused during childhood, and examines associations of reported type and frequency of abuse with adult mental health. Data were derived from the 2000-2001 and 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions, a large cross-sectional survey of a representative sample (N = 43,093) of the U.S. population. Weighted means, frequencies, and odds ratios of sociodemographic correlates and prevalence of psychiatric disorders were computed. Logistic regression models were used to examine the strength of associations between child physical abuse and adult psychiatric disorders adjusted for sociodemographic characteristics, other childhood adversities, and comorbid psychiatric disorders. Child physical abuse was reported by 8% of the sample and was frequently accompanied by other childhood adversities. Child physical abuse was associated with significantly increased adjusted odds ratios (AORs) of a broad range of DSM-IV psychiatric disorders (AOR = 1.16-2.28), especially attention-deficit hyperactivity disorder, posttraumatic stress disorder, and bipolar disorder. A dose-response relationship was observed between frequency of abuse and several adult psychiatric disorder groups; higher frequencies of assault were significantly associated with increasing adjusted odds. The long-lasting deleterious effects of child physical abuse underscore the urgency of developing public health policies aimed at early recognition and prevention.

  15. A review of targeted therapies evaluated by the Pediatric Preclinical Testing Program for osteosarcoma

    Directory of Open Access Journals (Sweden)

    Valerie eSampson

    2013-05-01

    Full Text Available Osteosarcoma, the most common malignant bone tumor of childhood, is a high grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical end points for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

  16. Ongoing incestuous abuse during adulthood.

    Science.gov (United States)

    Middleton, Warwick

    2013-01-01

    Individual cases of adult incestuous abuse have surfaced repeatedly in the lay and professional literature of the past 1.5 centuries without it occasioning systematic investigation, such as the reporting of a case series of individuals subjected to such extreme abuse. Yet substantial numbers of patients with dissociative identity disorder at the time of presentation report incestuous abuse continuing into the adult years, and for many the abuse is ongoing. Data relating to a series of 10 such incestuously abused women are presented. These patients were sexually abused from a very early age (typically from before age 3), with the manipulation of their sexual response a key component in conditioning an enduring sexualized attachment. Shame and fear were also used to ensure compliance and silence. The women, when able to speak of it, describe the induction by their paternal abuser of orgasm at an early age, typically around the age of 6. The women have high indices of self-harm and suicidality and are prone to placing themselves in dangerous reenactment scenarios. The average duration of incestuous abuse for this group of women was 31 years, and the average estimate of total episodes of sexual abuse was 3,320. Most women do not feel that they own their body and experience being "fused" to their father. Their mother was reported as an active participant in the sexual abuse or as having done nothing to protect their daughter despite seeing obvious evidence of incest. The fathers, despite a propensity to use or threaten violence, were generally outwardly productively employed, financially comfortable, and stably married and half had close church involvement. However, suicide and murder occurred within the 1st- or 2nd-degree relatives of these women at a high frequency. All 10 had been sexually abused by various groupings of individuals connected to their fathers.

  17. Loperamide dependence and abuse.

    Science.gov (United States)

    MacDonald, Ryan; Heiner, Jason; Villarreal, Joshua; Strote, Jared

    2015-05-02

    Loperamide is a common over-the-counter antidiarrheal considered safe in a broad range of dosages and thought devoid of abuse potential. We describe the first case of a patient with loperamide dependence due to misuse of its opiate-like effects achieved by chronic massive oral ingestions. A 26-year-old man who was taking 800 mg of loperamide per day presented requesting detoxification referral. Loperamide has potential for euphoric effects and information on how to facilitate such effects is easily available. It is important for physicians to be aware of the potential for misuse of and dependence on loperamide, with symptoms mimicking opiate use.

  18. Abusing National Privilege

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    As U.S. mortgage finance giants-Fannie Mae and Freddie Mac-try to sell their huge backlog of foreclosed homes, they face foreclosures themselves as the U.S. Government contemplates cutting their government-backed support as indicated by a white paper issued by the Obama administration in February. Zhang Monan, an associate research fellow with the State Information Center, said the downfall of Fannie Mae and Freddie Mac is the result of abuses of privileges the two companies have enjoyed since their inception.

  19. Hitting without a License: Testing Explanations for Differences in Partner Abuse between Young Adult Daters and Cohabitors.

    Science.gov (United States)

    Magdol, Lynn; Moffitt, Terrie E.; Caspi, Avshalom; Silva, Phil A.

    1998-01-01

    Partner abuse among 21-year olds was compared between cohabitors and daters. Individual, relationship, and social control factors were studied. Cohabitors were more abusive than daters. Factors that differentiate cohabitors from daters were identified, and models were tested for prediction of abuse. Findings are discussed in terms of age and…

  20. Non-pharmacological factors in drug abuse.

    Science.gov (United States)

    Hartnoll, R.

    1990-01-01

    This paper examines the relevance of laboratory models of drug abuse to drug taking in human societies, and discusses their significance relative to other explanatory frameworks. It argues that self-administration models are poor predictors of the prevalence of drug taking, and offer an inadequate basis for both explanation and intervention. Non-pharmacological factors that may be of greater importance derive from social perspectives (notably economic and market factors, socio-economic conditions, and cultural and subcultural processes) and psychological approaches (individual, social learning, cognitive and developmental). It is concluded that drug abuse should be understood within the same framework of explanation as other human behaviour and sentiment, having major cultural, social and cognitive dimensions as well as the strictly behavioural and pharmacological.

  1. Suicide Attempts among Drug Abusers.

    Science.gov (United States)

    Harrsi, Rachel; And Others

    1979-01-01

    The relationship between substance abuse and suicide is indicated by high rate of attempted suicide among alcoholics and drug abusers, as well as increased likelihood of repeated attempts in these populations. This study reports on psychological characteristics of male drug suicide attempters who are in treatment for their addiction problem.…

  2. Counseling with the Drug Abuser.

    Science.gov (United States)

    Demos, George D.

    Counselors, in the past few years, have had to work with a great many drug abusers. While successes are difficult to evaluate, the failures are glaringly evident. In a search for a more effective method of working with drug abusers, 12 questions were devised. These are self-evaluative and directed at the counselor. If a counselor can openly and…

  3. Child Abuse: The Educator's Responsibilities.

    Science.gov (United States)

    California State Office of the Attorney General, Sacramento. School Safety Center.

    Addressing educators and citing the California Penal Code, this booklet discusses the legal responsibilities of persons in child care situations regarding incidents of suspected child abuse. Included are: (1) a definition of child abuse and neglect; (2) reporting procedures including liability of failure to report and immunity of the reporting…

  4. Elder abuse in the Netherlands

    NARCIS (Netherlands)

    Inger Plaisier; Mirjam de Klerk

    2015-01-01

    Original title: Ouderenmishandeling in Nederland It is twenty years since the last study was carried out on the number of older persons in the Netherlands who are deliberate or accidental victims of abuse in the form of verbal, physical or sexual violence, financial abuse and/or neglect by those o

  5. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Science.gov (United States)

    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

  6. Current and future development of extended-release, abuse-deterrent opioid formulations in the United States.

    Science.gov (United States)

    Webster, Lynn R; Markman, John; Cone, Edward J; Niebler, Gwendolyn

    2017-01-01

    Prescription opioid misuse and abuse in the United States (US) is epidemic and is a major burden on health-care resources and costs to society. The need to significantly reduce the risks of prescription opioid misuse and abuse must be balanced with the important needs of patients with chronic pain who may benefit from treatment with opioids. The use of abuse-deterrent formulations (ADFs) of prescription opioids is one approach that could reduce the risk of prescription opioid abuse and misuse while maintaining access to opioids. ADF opioids have properties that make their abuse more difficult, less attractive, or less rewarding. In 2015, the US Food and Drug Administration issued final guidance to industry for the development of ADF opioids that recommended specific studies be conducted to demonstrate the abuse-deterrent properties of new opioid formulations. The technologies and the preclinical and clinical development of ADF opioids are rapidly evolving. This review provides an overview of the required testing for product labeling that includes language about the abuse-deterrent features of an ADF opioid. The objective of this review is to inform and help health-care providers understand the unique development of extended-release ADF opioids and their place in the treatment of patients with pain.

  7. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    Directory of Open Access Journals (Sweden)

    Abbas Yavari

    2009-09-01

    Full Text Available According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports andwidespread use. It remains as an unsolved public-health problem.Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, because most of athletes or students, due to their prohibition or ethical aspects do not admit to AASS abuse. Often they are aware of the risks of their choice and yet, are eager to put themselves at risk without deeper consideration. The abusers use them to improve their physical fitness and appearance.Present article has been collected to elucidate the risks and adverse effects of AASS and explanation of mechanisms of these events.

  8. Child abuse by drowning.

    Science.gov (United States)

    Griest, K J; Zumwalt, R E

    1989-01-01

    Drowning as a form of subtle fatal child abuse is difficult to distinguish from accidental immersion or from sudden unexpected natural death when the circumstances of immersion are concealed. Homicidal drownings are unwitnessed, usually occurring in the home, and the victims are young, either infants or toddlers. Accidental drownings are more likely to involve toddlers or older children in public areas such as swimming pools, drainage ditches, lakes, and rivers. This is especially true in rural areas. In cities, bathtubs remain a major site of accidental childhood drownings. Perpetrators of deliberate drownings often fit the sociopathologic profile of a child abuser. Because there is often a survival interval between immersion and death, pathologic findings consistent with postimmersion syndrome suggest the cause of death. Foreign material in the lungs, if immersion was other than in clear tap water, and injuries of the face are other positive correlating factors. A thorough investigation of the circumstances and cooperation between the investigating agency and the pathologist are essential to determine the correct manner of death in these cases.

  9. Drug abuse among the students

    Directory of Open Access Journals (Sweden)

    Muhammad Zaman

    2015-01-01

    Full Text Available ABSTRACT:Drug abuse is the willful misuse of either licit or illicit drugs for the purpose of recreation, perceived necessity or convenience. Drug abuse is a more intense and often willful misuse of drugs often to the point of addiction. In the eastern world the incidence shows a decline or a static pattern but the number of drug addicts is still enormous.. The major drug of abuse are heroin and marijuana but designer drugs are shown to be on the increase. The aim of the study is to determine the ratio of the drug abuse in student. For this purpose we selected different institutions including “the university of Lahore”, “Forman Christian college”(private sector and Punjab university(Govt sector and conducted survey in 500 student. High proportion of students was found abusing drugs. From this study, we came across multiple factors which are the main cause of drug abuse in medical student including depression, anxiety, schizophrenia, as well as personality disorder like antisocial personality disorder. The most commonly abused drugs include stimulants, opioids, and benzodiazepines, antihistamines. Although survey have indicated high rate of illicit and prescription drugs misuse among college students, few have assessed the negative consequences, personel concerns, or interest in intervention for drugs use. Drug abuse although regarded as a personality disorder, may also be seen as worldwide epidemic with evolutionary genetic, physiology and environmental influences Controlling and affecting human behavior. Globally, the use has reached all time high. The study showed males are more drug abusers as compared to females. The drug abuse ratio in students of private sector is more as compared to Govt sector.

  10. Emotional abuse in childhood and suicidality: The mediating roles of re-victimization and depressive symptoms in adulthood.

    Science.gov (United States)

    Lee, Min-Ah

    2015-06-01

    This study examined the effects of emotional abuse in childhood, along with physical and sexual abuse, on suicidality in adulthood, and whether and how emotional abuse and depressive symptoms in adulthood mediate the association between the childhood emotional abuse and suicidality. The data were drawn from the 2012 Korean General Social Survey, a nationally representative survey with a multistage area proportional probability sampling method. Random effects regression and the Sobel test were used to analyze the relationships between childhood emotional abuse and suicidality and the mediating effects. Random effects models showed that emotional abuse in childhood was positively associated with suicidality in adulthood, even after controlling for physical and sexual abuse in childhood. Emotional abuse and depressive symptoms in adulthood mediated the association between emotional abuse in childhood and suicidality. Depressive symptoms also mediated between emotional abuse in adulthood and suicidality. These findings suggest that emotional abuse in childhood has indirect harmful effects on suicidality in adulthood. It increases suicidality through higher occurrences of re-victimization and depressive symptoms in adulthood. Practitioners and policy makers should recognize that experiences of emotional abuse in childhood may result in re-victimization in adulthood, which, in turn, lead to suicidality. Early intervention programs to reduce the likelihood of experiencing re-victimization may be critical for people exposed to emotional abuse in childhood.

  11. Abuse, support, and depression among homeless and runaway adolescents.

    Science.gov (United States)

    Bao, W N; Whitbeck, L B; Hoyt, D R

    2000-12-01

    This study examines the effectiveness of social support networks on psychological well-being among 602 homeless and runaway adolescents. The respondents were interviewed in shelters, drop-in centers, and on the streets in cities of four Midwestern states (Missouri, Iowa, Nebraska, and Kansas). The path model was used to test the direct effect of family abuse and precocious independence on adolescent depressive symptoms and indirect effects through social support networks. Results indicate that although abusive family origins contribute directly to depressive symptoms there are indirect effects of family abuse and early independence through social support networks. Family abuse and early independence drive homeless adolescents to rely on peers for social support. While support from friends on the street reduces depression, association with deviant peers increases depression.

  12. Time management for preclinical safety professionals.

    Science.gov (United States)

    Wells, Monique Y

    2010-08-01

    A survey about time management in the workplace was distributed to obtain a sense of the level of job satisfaction among preclinical safety professionals in the current economic climate, and to encourage reflection upon how we manage time in our work environment. Roughly equal numbers of respondents (approximately 32%) identified themselves as management or staff, and approximately 27% indicated that they are consultants. Though 45.2% of respondents indicated that time management is very challenging for the profession in general, only 36.7% find it very challenging for themselves. Ten percent of respondents view time management to be exceedingly challenging for themselves. Approximately 34% of respondents indicated that prioritization of tasks was the most challenging aspect of time management for them. Focusing on an individual task was the second most challenging aspect (26%), followed equally by procrastination and delegation of tasks (12.4%). Almost equal numbers of respondents said that they would (35.2%) or might (33.3%) undertake training to improve their time management skills. Almost equal numbers of participants responded "perhaps" (44.6%) or "yes" (44.2%) to the question of whether management personnel should be trained in time management.

  13. [Child abuse in the family].

    Science.gov (United States)

    De Almeida, Helena Nunes; André, Isabel Margarida; De Almeida, Ana Nunes

    2002-01-01

    The objective of this study is to carry out a current survey of the situation of child abuse in the family. It is based on a national survey conducted in 1996, which was addressed to childcare professionals (in the areas of health, education and social services). This survey was based, on the one hand, on a wide-ranging definition of child abuse, including within it not just active forms of physical and psychic violence against the child, but also forms of (both material and affective) privation, omission or negligence which affect the child's growth and development. On the other hand, this study also favoured a contextual approach to child abuse. 1,126 institutions in Portugal were contacted and 755 valid survey responses were received. This report outlines some of the results obtained, namely by providing a description of the sample of the 755 child abuse victims, the respective social and family contexts to which they and the aggressors belong, as well as the types of abuse which have been committed against them; and a typology of forms of abuse and negligence, describing not just the internal aspects that make up child abuse directly, but also its relationship to the child's social and family contexts of belonging. The typology was derived from the statistical handling of the data gathered (factorial analysis of multiple matches, followed by a hierarchical analysis into clusters). A number of key concepts are summarised in the conclusion. Children of all age groups and of both sexes, and from all types of families and social backgrounds, regardless of their place in the phratry, are subject to abuse in Portugal. But different types of abuse and negligence are associated with the contexts to which the children and their families belong. Healthcare professionals are irreplaceable when it comes to detecting the wide variety of types of child abuse, and are an essential look-out post for two types of abuse which often slip through the net of other professionals

  14. Visual Evoked Potential Response Among Drug Abusers- A Cross Sectional Study

    Science.gov (United States)

    Sharma, Rajeev; Thapar, Satish; Mittal, Shilekh

    2016-01-01

    Introduction There is important preclinical evidence that substance abuse may produce neurophysiological disturbances particularly in relation to altered neural synchronization in Visual Evoked Potentials (VEP). Aim The purpose of current study was to compare the latencies and amplitudes of different waveforms of VEP among different drug abusers and controls and also to identify early neurological damage so that proper counseling and timely intervention can be undertaken. Materials and Methods VEP was assessed by Data Acquisition and Analysis system in a sample of 58 drug abusers, all males, within age group of 15-45 years as well as in age matched 30 healthy controls. The peak latencies and peak to peak amplitudes of different waveforms were measured by applying one-way Anova test and unpaired t-test using SPSS version 16. Results In between drug abusers and controls, the difference in the duration of N75 and P100 waveform of VEP was found to be statistically highly significant (pdrug abusers in both eyes. Conclusion Chronic intoxication by different drugs has been extensively associated with amplitude reduction of P100 and prolonged latency of N75 and P100 reflecting an adverse effects of drug dependence on neural transmission within primary visual areas of brain. PMID:27042456

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

    Science.gov (United States)

    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 separation process were significant (Model chi2 = 35.00, df= 7, p < .001).

  16. Coupling of Mechanical Behavior of Cell Components to Electrochemical-Thermal Models for Computer-Aided Engineering of Batteries under Abuse (Presentation)

    Energy Technology Data Exchange (ETDEWEB)

    Pesaran, A.; Wierzbicki, T.; Sahraei, E.; Li, G.; Collins, L.; Sprague, M.; Kim, G. H.; Santhangopalan, S.

    2014-06-01

    The EV Everywhere Grand Challenge aims to produce plug-in electric vehicles as affordable and convenient for the American family as gasoline-powered vehicles by 2022. Among the requirements set by the challenge, electric vehicles must be as safe as conventional vehicles, and EV batteries must not lead to unsafe situations under abuse conditions. NREL's project started in October 2013, based on a proposal in response to the January 2013 DOE VTO FOA, with the goal of developing computer aided engineering tools to accelerate the development of safer lithium ion batteries.

  17. Designing Opioids That Deter Abuse

    Directory of Open Access Journals (Sweden)

    Robert B. Raffa

    2012-01-01

    Full Text Available Prescription opioid formulations designed to resist or deter abuse are an important step in reducing opioid abuse. In creating these new formulations, the paradigm of drug development target should be introduced. Biological targets relating to the nature of addiction may pose insurmountable hurdles based on our current knowledge and technology, but products that use behavioral targets seem logical and feasible. The population of opioid abusers is large and diverse so behavioral targets are more challenging than they appear at first glance. Furthermore, we need to find ways to correlate behavioral observations of drug liking to actual use and abuse patterns. This may involve revisiting some pharmacodynamic concepts in light of drug effect rather than peak concentration. In this paper we present several new opioid analgesic agents designed to resist or deter abuse using physical barriers, the inclusion of an opioid agonist or antagonist, an aversive agent, and a prodrug formulation. Further, this paper also provides insight into the challenges facing drug discovery in this field. Designing and screening for opioids intended to resist or deter abuse is an important step to meet the public health challenge of burgeoning prescription opioid abuse.

  18. Child abuse, a case report

    Directory of Open Access Journals (Sweden)

    Andri M.T. Lubis

    2004-03-01

    Full Text Available Child abuse is a pervasive social and medical problem that remains a major cause of disability and death among children. The annual incidence of abuse is estimated to be 15 to 42 cases per 1,000 children and appears to be increasing. Fractures are the second most common presentation of physical abuse after skin lesions, and approximately one third of abused children will eventually be seen by an orthopedic surgeon. We report a 7-month-old boy who was suspected to be abused. Our diagnosis was based on findings of multiple fractures, delay in seeking medical treatment and discrepancy between the history of illness and the clinical findings. He sustained multiple fractures in variety of healing, namely fractures on left supracondylar humeri, left radius and ulna, right radius and ulna, both femora, right tibia, and left tibia and fibula. Radiological examination was an important modality in revealing the possibility of abuse on this child. He had received medical treatment, protection, consultation team for the parents and an underway police investigation. (Med J Indones 2004; 13: 59-65 Keywords: child, abuse

  19. Occupational turnover intentions among substance abuse counselors.

    Science.gov (United States)

    Rothrauff, Tanja C; Abraham, Amanda J; Bride, Brian E; Roman, Paul M

    2011-01-01

    This study examined predictor, moderator, and mediator variables of occupational turnover intention (OcTI) among substance abuse counselors. Data were obtained via questionnaires from 929 counselors working in 225 private substance abuse treatment (SAT) programs across the United States. Hierarchical multiple regression models were conducted to assess predictor, moderator, and mediator variables of OcTI. OcTI scores were relatively low on a 7-point scale, indicating that very few counselors definitely intended to leave the SAT field. Age, certification, positive perceptions of procedural and distributive justice, and hospital-based status negatively predicted OcTI. Counselors' substance use disorder-impacted history moderated the association between organizational commitment and OcTI. Organizational turnover intention partially mediated the link between organizational commitment and OcTI. Workforce stability might be achieved by promoting perceptions of advantages to working in a particular treatment program, having organizational commitment, showing appreciation for counselors' work, and valuing employees from diverse backgrounds.

  20. Family of Origin Violence and Courtship Abuse.

    Science.gov (United States)

    Marshall, Linda L.; Rose, Patricia

    1988-01-01

    Responses from 336 undergraduates revealed 75 percent of respondents had expressed threats or actual violence and 64 percent had received abuse in intimate relationship. In the sample, 30 percent had parents who abused each other; less often the mother or father had been sole abuser. Multiple regression indicated being abused as child predicted…

  1. Sexual abuse in children -- what to know

    Science.gov (United States)

    ... Sexual abuse - children Signs of sexual abuse in children Suspect sexual abuse when children: Tell you that they are being ... A.M. Editorial team. Related MedlinePlus Health Topics Child Sexual Abuse Browse the Encyclopedia A.D.A.M., Inc. ...

  2. Elder Abuse: The Status of Current Knowledge.

    Science.gov (United States)

    Pedrick-Cornell, Claire; Gelles, Richard J.

    1982-01-01

    Discusses problems of definition of elderly abuse. Examines data and research on the rates of elderly abuse and factors found related to elderly abuse. Critiques theories developed to explain the abuse of the elderly. Presents recommendations for research and practice. (RC)

  3. Women and Drugs: The Heroin Abuser and the Prescription Drug Abuser.

    Science.gov (United States)

    Gutierres, Sara E.; And Others

    1984-01-01

    Reviewed the literature on female drug use/abuse and derived descriptions of the female heroin abuser and the female prescription drug abuser. Researchers suggest that problems of female drug abusers should be viewed in terms of the feminine role as well as the role of drug abuser. (BH)

  4. Self-Esteem and Attitudes toward Love in Abused and Non-Abused Women.

    Science.gov (United States)

    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,…

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

    OpenAIRE

    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 d...

  6. Meth abuse and oral health

    Directory of Open Access Journals (Sweden)

    Deviprasad Makonahally

    2015-01-01

    Full Text Available Methamphetamine abuse is spreading its roots in India due to its widespread appeal, ease of manufacture and low cost compared with other stimulant drugs. Methamphetamine-induced caries is a characteristic finding among methamphetamine abusers. Thus, it is important to understand the typical clinical manifestations inclusive of cervical and proximal caries, elicit proper case history and develop a comprehensive treatment plan to help patients in a complete rehabilitation. We present a series of cases of "meth" abuser for dental professionals to help ensure successful treatment and prevention of disease progression.

  7. Drug abuse among the students

    OpenAIRE

    2015-01-01

    ABSTRACT:Drug abuse is the willful misuse of either licit or illicit drugs for the purpose of recreation, perceived necessity or convenience. Drug abuse is a more intense and often willful misuse of drugs often to the point of addiction. In the eastern world the incidence shows a decline or a static pattern but the number of drug addicts is still enormous.. The major drug of abuse are heroin and marijuana but designer drugs are shown to be on the increase. The aim of the study is to determine...

  8. Abused Sexuality- Experience of Sexuality Post Experiences of Sexual Abuse

    OpenAIRE

    Sunanda Jalote

    2016-01-01

    Sexual abuse has been happening from times immemorial and is that brutal aspect of society which also talk about spirituality, peace and harmony in the same breath. Youth gets irrevocably scarred by such childhood traumas which linger on in their adult life too. In the present study, an effort was made to study and understand how heterosexual and queer youth in contemporary middle class in Delhi explore the relationship sexual abuse survivors have with their own sexuality and how their negoti...

  9. TU-F-12A-01: Quantitative Non-Linear Compartment Modeling of 89Zr- and 124I- Labeled J591 Monoclonal Antibody Kinetics Using Serial Non-Invasive Positron Emission Tomography Imaging in a Pre-Clinical Human Prostate Cancer Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Fung, EK; Cheal, SM; Chalasani, S; Fareedy, SB; Punzalan, B; Humm, JL; Osborne, JR; Larson, SM; Zanzonico, PB [Memorial Sloan Kettering Cancer Center, New York, NY (United States); Otto, B; Bander, NH [Weill Cornell Medical College, New York, NY (United States)

    2014-06-15

    Purpose: To examine the binding kinetics of human IgG monoclonal antibody J591 which targets prostate-specific membrane antigen (PSMA) in a pre-clinical mouse cancer model using quantitative PET compartmental analysis of two radiolabeled variants. Methods: PSMA is expressed in normal human prostate, and becomes highly upregulated in prostate cancer, making it a promising therapeutic target. Two forms of J591, radiolabeled with either {sup 89}Zr or {sup 124}I, were prepared. {sup 89}Zr is a radiometal that becomes trapped in the cell upon internalization by the antigen-antibody complex, while radioiodine leaves the cell. Mice with prostate cancer xenografts underwent non-invasive serial imaging on a Focus 120 microPET up to 144 hours post-injection of J591. A non-linear compartmental model describing the binding and internalization of antibody in tumor xenograft was developed and applied to the PET-derived time-activity curves. The antibody-antigen association rate constant (ka), total amount of antigen per gram tumor (Ag-total), internalization rate of antibody-antigen complex, and efflux rate of radioisotope from tumor were fitted using the model. The surface-bound and the internalized activity were also estimated. Results: Values for ka, Ag-total, and internalization rate were found to be similar regardless of radiolabel payload used. The efflux rate, however, was ∼ 9-fold higher for {sup 124}I-J591 than for {sup 89}Zr-J591. Time-dependent surface-bound and internalized radiotracer activity were similar for both radiolabels at early times post-injection, but clearly differed beyond 24 hours. Conclusion: Binding and internalization of J591 to PSMA-expressing tumor xenografts were similar when radiolabeled with either {sup 89}Zr or {sup 124}I payload. The difference in efflux of radioactivity from tumor may be attributable to differential biological fate intracellularly of the radioisotopes. This has great significance for radioimmunotherapy and antibody

  10. Challenges in linking preclinical anti-microbial research strategies with clinical outcomes for device-associated infections

    Directory of Open Access Journals (Sweden)

    TF Moriarty

    2014-09-01

    Full Text Available Infections related to implanted medical devices have become a significant health care issue in recent decades. Increasing numbers of medical devices are in use, often in an aging population, and these devices are implanted against a background of increasing antibiotic-resistant bacterial populations. Progressively more antibiotic resistant infections, requiring ever more refined treatment options, are therefore predicted to emerge with greater frequency in the coming decades. Improvements in the prevention, diagnosis and treatment of these device-associated infections will remain priority targets both for clinicians and the translational research community charged with addressing these challenges. Preclinical strategies, predictive of ultimate clinical efficacy, should serve as a control point for effective translation of new technologies to clinical applications. The development of new anti-infective medical devices requires a validated preclinical testing protocol; however, reliable validation of experimental and preclinical antimicrobial methodologies currently suffers from a variety of technical limitations. These include the lack of agreement or standardisation of experimental protocols, a general lack of correlation between in vitro and in vivo preclinicalresults and lack of validation between in vivo preclinical implant infection models and clinical (human results. Device-associated infections pose additional challenges to practicing clinicians concerning diagnosis and treatment, both of which are complicated by the biofilms formed on the medical device. The critical challenges facing both preclinical research and clinical laboratories in improving both diagnosis and treatment of medical device-associated infections are the focus of this review.

  11. Cough and Cold Medicine Abuse

    Science.gov (United States)

    ... and Over-the-Counter Medications Stimulant ADHD Medications: Methylphenidate and Amphetamines Synthetic Cannabinoids Synthetic Cathinones ("Bath Salts") Effects of Drug Abuse Comorbidity: Addiction and Other Mental Disorders Drug Use ...

  12. Alcohol abuse and postoperative morbidity

    DEFF Research Database (Denmark)

    Tønnesen, Hanne

    2003-01-01

    precise identification of alcohol abuse. However, the inability of the questionnaires to detect short-term changes in intake and abuse without dependence, the inconsistent predictive values of the biological markers, and the lack of evidence of an association to postoperative morbidity reduces......Patients who drink too much have more complications after surgery. The aim of this thesis was to evaluate the evidence, possible mechanisms, and prevention of the increased postoperative morbidity in alcohol abusers, defined by a consumption of at least five drinks per day. The literature could...... be criticised for several methodological flaws. Nevertheless, the results are in agreement showing moderate to strong evidence of increased postoperative morbidity after surgical procedures on alcohol abusers. There is weak to moderate evidence of increased postoperative mortality, hospital stay, and re...

  13. The Abuse of Drug Information

    Science.gov (United States)

    Hammond, Peter G.

    1973-01-01

    Today's drug information programs may be responsible for increasing drug abuse. A large percentage of existing materials are inaccurate, moralistic and ineffective. This article discusses these points and recommends materials that avoid them. (40 references) (DH)

  14. Childhood Deaths from Physical Abuse.

    Science.gov (United States)

    Kasim, Mohd. Sham; and Others

    1995-01-01

    This paper describes 30 cases of childhood deaths caused by physical abuse in Kuala Lumpur, Malaysia. Data presented include ethnic origins, age, causes of death, identity of perpetrators, and marital situation of parents. (DB)

  15. Meth abuse and oral health

    OpenAIRE

    Deviprasad Makonahally; Vaibhav Gupta; Pushpanjali Krishnappa

    2015-01-01

    Methamphetamine abuse is spreading its roots in India due to its widespread appeal, ease of manufacture and low cost compared with other stimulant drugs. Methamphetamine-induced caries is a characteristic finding among methamphetamine abusers. Thus, it is important to understand the typical clinical manifestations inclusive of cervical and proximal caries, elicit proper case history and develop a comprehensive treatment plan to help patients in a complete rehabilitation. We present a series o...

  16. Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically.

    Science.gov (United States)

    Sena, Emily S; Currie, Gillian L; McCann, Sarah K; Macleod, Malcolm R; Howells, David W

    2014-05-01

    The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal.

  17. Next generation dengue vaccines: A review of the preclinical development pipeline.

    Science.gov (United States)

    Vannice, Kirsten S; Roehrig, John T; Hombach, Joachim

    2015-12-10

    Dengue represents a significant and growing public health problem across the globe, with approximately half of the world's population at risk. The increasing and expanding burden of dengue has highlighted the need for new tools to prevent dengue, including development of dengue vaccines. Recently, the first dengue vaccine candidate was evaluated in Phase 3 clinical trials, and other vaccine candidates are under clinical evaluation. There are also a number of candidates in preclinical development, based on diverse technologies, with promising results in animal models and likely to move into clinical trials and could eventually be next-generation dengue vaccines. This review provides an overview of the various technological approaches to dengue vaccine development with specific focus on candidates in preclinical development and with evaluation in non-human primates.

  18. Pre-clinical research in small animals using radiotherapy technology. A bidirectional translational approach

    Energy Technology Data Exchange (ETDEWEB)

    Tillner, Falk; Buetof, Rebecca [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Thute, Prasad [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Krause, Mechthild [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; German Cancer Consortium (DKTK), Dresden (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); Enghardt, Wolfgang [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany). Inst. of Radiooncology

    2014-07-01

    For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

  19. Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

    Directory of Open Access Journals (Sweden)

    Bruno Vincenzi

    2011-12-01

    Full Text Available Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

  20. Surviving an abusive supervisor: the joint roles of conscientiousness and coping strategies.

    Science.gov (United States)

    Nandkeolyar, Amit K; Shaffer, Jonathan A; Li, Andrew; Ekkirala, Srinivas; Bagger, Jessica

    2014-01-01

    The present study examines a mediated moderation model of the effects of conscientiousness and coping strategies on the relationship between abusive supervision and employees' job performance. Across 2 studies conducted in India, we found evidence that the relationship between abusive supervision and job performance was weaker when employees were high in conscientiousness. In addition, we found that the use of an avoidance coping strategy facilitated a negative relationship between abusive supervision and performance. Finally, we found that the moderating effects of conscientiousness were mediated by the use of avoidance coping strategies. Our findings contribute to theories of abusive supervision, personality, coping strategies, and job performance.

  1. Beneficial health effects of lupeol triterpene: a review of preclinical studies.

    Science.gov (United States)

    Siddique, Hifzur Rahman; Saleem, Mohammad

    2011-02-14

    Since ancient times, natural products have been used as remedies to treat human diseases. Lupeol, a phytosterol and triterpene, is widely found in edible fruits, and vegetables. Extensive research over the last three decades has revealed several important pharmacological activities of lupeol. Various in vitro and preclinical animal studies suggest that lupeol has a potential to act as an anti-inflammatory, anti-microbial, anti-protozoal, anti-proliferative, anti-invasive, anti-angiogenic and cholesterol lowering agent. Employing various in vitro and in vivo models, lupeol has also been tested for its therapeutic efficiency against conditions including wound healing, diabetes, cardiovascular disease, kidney disease, and arthritis. Lupeol has been found to be pharmacologically effective in treating various diseases under preclinical settings (in animal models) irrespective of varying routes of administration viz; topical, oral, intra-peritoneal and intravenous. It is noteworthy that lupeol has been reported to selectively target diseased and unhealthy human cells, while sparing normal and healthy cells. Published studies provide evidence that lupeol modulates the expression or activity of several molecules such as cytokines IL-2, IL4, IL5, ILβ, proteases, α-glucosidase, cFLIP, Bcl-2 and NFκB. This minireview discusses in detail the preclinical studies conducted with lupeol and provides an insight into its mechanisms of action.

  2. Preclinical development of HIvax: Human survivin highly immunogenic vaccines.

    Science.gov (United States)

    Hoffmann, Peter R; Panigada, Maddalena; Soprana, Elisa; Terry, Frances; Bandar, Ivo Sah; Napolitano, Andrea; Rose, Aaron H; Hoffmann, Fukun W; Ndhlovu, Lishomwa C; Belcaid, Mahdi; Moise, Lenny; De Groot, Anne S; Carbone, Michele; Gaudino, Giovanni; Matsui, Takashi; Siccardi, Antonio; Bertino, Pietro

    2015-01-01

    Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP-surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8(+) and CD4(+) T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-γ and granzyme B secretion. In these experiments, both antigen specific CD4(+) and CD8(+) T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers.

  3. Preclinical and clinical development of DNA vaccines for prostate cancer.

    Science.gov (United States)

    Colluru, V T; Johnson, Laura E; Olson, Brian M; McNeel, Douglas G

    2016-04-01

    Prostate cancer is the most commonly diagnosed cancer in the United States. It is also the second leading cause of cancer-related death in men, making it one of the largest public health concerns today. Prostate cancer is an ideal disease for immunotherapies because of the generally slow progression, the dispensability of the target organ in the patient population, and the availability of several tissue-specific antigens. As such, several therapeutic vaccines have entered clinical trials, with one autologous cellular vaccine (sipuleucel-T) recently gaining Food and Drug Administration approval after demonstrating overall survival benefit in randomized phase III clinical trials. DNA-based vaccines are safe, economical, alternative "off-the-shelf" approaches that have undergone extensive evaluation in preclinical models. In fact, the first vaccine approved in the United States for the treatment of cancer was a DNA vaccine for canine melanoma. Several prostate cancer-specific DNA vaccines have been developed in the last decade and have shown promising results in early phase clinical trials. This review summarizes anticancer human DNA vaccine trials, with a focus on those conducted for prostate cancer. We conclude with an outline of special considerations important for the development and successful translation of DNA vaccines from the laboratory to the clinic.

  4. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

    Directory of Open Access Journals (Sweden)

    Andrea Gogos

    2015-01-01

    Full Text Available Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol’s underlying protective mechanisms is also substantially discussed, with particular focus on estradiol’s impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems.

  5. Wireless Handheld Computers in the Preclinical Undergraduate Curriculum

    Directory of Open Access Journals (Sweden)

    Matt Jackson

    2003-02-01

    Full Text Available This report presents the results of a pilot project using wireless PDAs as teaching tools in an undergraduate medical curriculum. This technology was used to foster a transition from a passive to an interactive learning environment in the classroom and provided a solution for the implementation of computer-based exams for a large class. Wayne State Medical School recently provided model e570 Toshiba PocketPCs® (personal digital assistants or PDAs, network interface cards, and application software developed by CampusMobility® to 20 sophomore medical students. The pilot group of preclinical students used the PDAs to access web-based course content, for communication, scheduling, to participate in interactive teaching sessions, and to complete course evaluations. Another part of this pilot has been to utilize the PDAs for computer-based exams in a wireless environment. Server authentication that restricted access during the exams and a proctoring console to monitor and record the PDA screens will be described in this report. Results of a student satisfaction survey will be presented.

  6. Preclinical dosimetry of magnetic fluid hyperthermia for bladder cancer

    Science.gov (United States)

    Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.

    2013-02-01

    Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in 1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

  7. Decellularized myocardial matrix hydrogels: In basic research and preclinical studies.

    Science.gov (United States)

    Wang, Raymond M; Christman, Karen L

    2016-01-15

    A variety of decellularized materials have been developed that have demonstrated potential for treating cardiovascular diseases and improving our understanding of cardiac development. Of these biomaterials, decellularized myocardial matrix hydrogels have shown great promise for creating cellular microenvironments representative of the native cardiac tissue and treating the heart after a myocardial infarction. Decellularized myocardial matrix hydrogels derived from porcine cardiac tissue form a nanofibrous hydrogel once thermally induced at physiological temperatures. Use of isolated cardiac extracellular matrix in 2D and 3D in vitro platforms has demonstrated the capability to provide tissue specific cues for cardiac cell growth and differentiation. Testing of the myocardial matrix hydrogel as a therapy after myocardial infarction in both small and large animal models has demonstrated improved left ventricular function, increased cardiac muscle, and cellular recruitment into the treated infarct. Based on these results, steps are currently being taken to translate these hydrogels into a clinically used injectable biomaterial therapy. In this review, we will focus on the basic science and preclinical studies that have accelerated the development of decellularized myocardial matrix hydrogels into an emerging novel therapy for treating the heart after a myocardial infarction.

  8. Preclinical Evidences for an Antimanic Effect of Carvedilol

    Directory of Open Access Journals (Sweden)

    Greicy Coelho de Souza

    2015-01-01

    Full Text Available Oxidative imbalance, alterations in brain-derived neurotrophic factor (BDNF, and mitochondrial dysfunction are implicated in bipolar disorder (BD pathophysiology and comorbidities, for example, cardiovascular conditions. Carvedilol (CVD, a nonselective beta-blocker widely used for the treatment of hypertension, presents antioxidant and mitochondrial stabilizing properties. Thus, we hypothesized that CVD would prevent and/or reverse mania-like behavioral and neurochemical alterations induced by lisdexamfetamine dimesylate (LDX. To do this, male Wistar rats were submitted to two different protocols, namely, prevention and reversal. In the prevention treatment the rats received daily oral administration (mg/kg of CVD (2.5, 5 or 7.5, saline, valproate (VAL200, or the combination of CVD5 + VAL100 for 7 days. From the 8th to 14th day LDX was added. In the reversal protocol LDX was administered for 7 days with the drugs being added from the 8th to 14th day of treatment. Two hours after the last administration the behavioral (open field and social interaction and neurochemical (reduced glutathione, lipid peroxidation, and BDNF determinations were performed. The results showed that CVD prevented and reversed the behavioral and neurochemical alterations induced by LDX. The administration of CVD5 + VAL100 potentiated the effect of VAL200 alone. Taken together these results demonstrate a possible antimanic effect of CVD in this preclinical model.

  9. Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design.

    Science.gov (United States)

    Simonato, Michele; Löscher, Wolfgang; Cole, Andrew J; Dudek, F Edward; Engel, Jerome; Kaminski, Rafal M; Loeb, Jeffrey A; Scharfman, Helen; Staley, Kevin J; Velíšek, Libor; Klitgaard, Henrik

    2012-11-01

    The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past.

  10. Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies.

    Science.gov (United States)

    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

  11. Immunotherapy for Drug Abuse

    Science.gov (United States)

    Shen, Xiaoyun; Kosten, Thomas R.

    2013-01-01

    Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID:22229313

  12. Fighting Child Sexual Abuse

    Directory of Open Access Journals (Sweden)

    Pesanayi Gwirayi

    2013-01-01

    Full Text Available This study investigated secondary school pupils’ views on strategies that can be used to prevent child sexual abuse (CSA. A survey design was adopted as the operational framework for data gathering. Data were collected from three secondary schools, all in the Gweru district of Zimbabwe. The sample comprised 268 secondary pupils (50% female; M age = 15.42, SD = 1.376. Each participant was asked to write down three main strategies that can be used to fight CSA on a given questionnaire. The responses were then analyzed using the thematic content analysis technique. The study revealed that most pupils believed that CSA can be prevented through teaching them about it and also reporting to the police. Another significant finding was that pupils’ responses tended to vary with gender and level of education. Whereas female respondents suggested that CSA can be fought by avoiding strangers, saying no to sexual advances, and having reliable friends, their male counterparts suggested teaching the community about CSA, forming new clubs, and enacting life imprisonment for perpetrators, among other suggestions. In terms of level of education, Form 2 participants suggested avoiding strangers, staying home at night, whereas their Form 4 counterparts suggested lessons for Guidance and Counseling, saying no to sexual advances, and having reliable friends. These findings unequivocally demonstrate the need to vigorously engage secondary school pupils in activities aimed at fighting CSA to safeguard their inalienable human rights.

  13. Erythropoietin use and abuse

    Directory of Open Access Journals (Sweden)

    M Joseph John

    2012-01-01

    Full Text Available Recombinant human erythropoietin (rhEPO is arguably the most successful therapeutic application of recombinant DNA technology till date. It was isolated in 1977 and the gene decoded in 1985. Since then, it has found varied applications, especially in stimulating erythropoiesis in anemia due to chronic conditions like renal failure, myelodysplasia, infections like HIV, in prematurity, and in reducing peri-operative blood transfusions. The discovery of erythropoietin receptor (EPO-R and its presence in non-erythroid cells has led to several areas of research. Various types of rhEPO are commercially available today with different dosage schedules and modes of delivery. Their efficacy in stimulating erythropoiesis is dose dependent and differs according to the patient′s disease and nutritional status. EPO should be used carefully according to guidelines as unsolicited use can result in serious adverse effects. Because of its capacity to improve oxygenation, it has been abused by athletes participating in endurance sports and detecting this has proved to be a challenge.

  14. In vivo preclinical low field MRI monitoring of tumor growth following a suicide gene therapy in an ortho-topic mice model of human glioblastoma;Controle par IRM bas champ in vivo de l'efficacite d'une therapie genique par gene suicide dans un modele murin de glioblastome orthotopique

    Energy Technology Data Exchange (ETDEWEB)

    Breton, E.; Goetz, Ch.; Aubertin, G.; Constantinesco, A.; Choquet, Ph. [Service de biophysique et medecine nucleaire, hopital de Hautepierre, CHRU de Strasbourg, 67 - Strasbourg (France); Institut de mecanique des fluides et des solides, CNRS, universite de Strasbourg, 67 - Strasbourg (France); Kintz, J.; Accart, N.; Grellier, B.; Erbs, Ph.; Rooke, R. [Transgene SA, parc d' innovation, 67 - Illkirch Graffenstaden (France)

    2010-03-15

    Purpose The aim of this study was to monitor in vivo with low field MRI growth of a murine ortho-topic glioma model following a suicide gene therapy. Methods The gene therapy consisted in the stereotactic injection in the mice brain of a modified vaccinia virus Ankara (M.V.A.) vector encoding for a suicide gene (FCU1) that transforms a non toxic pro-drug 5-fluoro-cytosine (5-F.C.) to its highly cytotoxic derivatives 5-fluorouracil (5-F.U.) and 5-fluoro-uridine-5 monophosphate (5-F.U.M.P.). Using a warmed-up imaging cell, sequential 3D T1 and T2 0.1T MRI brain examinations were performed on 16 Swiss female nu/nu mice bearing ortho-topic human glioblastoma (U 87-MG cells). The 6-week in vivo MRI follow-up consisted in a weekly measurement of the intracerebral tumor volume leading to a total of 65 examinations. Mice were divided in four groups: sham group (n = 4), sham group treated with 5-F.C. only (n = 4), sham group with injection of M.V.A.-FCU1 vector only (n = 4), therapy group administered with M.V.A.-FCU1 vector and 5-F.C. (n = 4). Measurements of tumor volumes were obtained after manual segmentation of T1- and T2-weighted images. Results Intra-observer and inter-observer tumor volume measurements show no significant differences. No differences were found between T1 and T2 volume tumor doubling times between the three sham groups. A significant statistical difference (p < 0.05) in T1 and T2 volume tumor doubling times between the three sham groups and the animals treated with the intratumoral injection of M.V.A.-FCU1 vector in combination with 2 weeks per os 5-F.C. administration was demonstrated. Conclusion Preclinical low field MRI was able to monitor efficacy of suicide gene therapy in delaying the tumor growth in an in vivo mouse model of ortho-topic glioblastoma. (authors)

  15. Psychologic aspects of sexual abuse in adolescence.

    Science.gov (United States)

    Jeffrey, T B; Jeffrey, L K

    1991-12-01

    This paper reviews psychologic aspects of sexual abuse in female adolescents. It documents that sexual abuse is widespread, occurring at an alarming rate at all socioeconomic levels of society. It is perpetrated principally by adult men in the victim's family. Often its effects are tragic. Adolescent female sexual abuse victims are at high risk for subsequent acting out behavior, sexual promiscuity, physical and sexual abuse, anxiety, depression, low self-esteem, alcohol and drug abuse or dependence, chronic sleep disturbance, dissociative disorders, eating disorders, emotional numbing, dissociation, guilt, shame, hyperalertness, suicidal ideation, and multiple associated psychiatric disorders. Although it may appear at a surface level that sexual abuse victims recover from such abuse, follow-up studies suggest that many remain disabled long after the abuse has ended. Health care professionals should be especially cognizant of the magnitude of the impact of sexual abuse on adolescent girls and recognize the need of these patients for psychologic and medical services.

  16. An examination of the relationship between childhood emotional abuse and borderline personality disorder features: the role of difficulties with emotion regulation.

    Science.gov (United States)

    Kuo, Janice R; Khoury, Jennifer E; Metcalfe, Rebecca; Fitzpatrick, Skye; Goodwill, Alasdair

    2015-01-01

    Childhood abuse has been consistently linked with borderline personality disorder (BPD) and recent studies suggest that some forms of childhood abuse might be uniquely related to both BPD and BPD features. In addition, difficulties with emotion regulation have been found to be associated with childhood abuse, BPD, as well as BPD features. The present study examined (1) whether frequency of childhood emotional abuse is uniquely associated with BPD feature severity when controlling for other forms of childhood abuse and (2) whether difficulties with emotion regulation accounts for the relationship between childhood emotional abuse and BPD feature severity. A sample of undergraduates (n=243) completed the Childhood Trauma Questionnaire - Short Form, Difficulties in Emotion Regulation Scale, and Borderline Symptom List-23. Multiple regression analyses and Structural Equation Modeling were conducted. Results indicated that frequency of childhood emotional abuse (and not sexual or physical abuse) was uniquely associated with BPD feature severity. In addition, while there was no direct path between childhood emotional abuse, childhood physical abuse, or childhood sexual abuse and BPD features, there was an indirect relationship between childhood emotional abuse and BPD features through difficulties with emotion regulation. These findings suggest that, of the different forms of childhood abuse, emotional abuse specifically, may have a developmental role in BPD pathology. Prevention and treatment of BPD pathology might benefit from the provision of emotion regulation strategies.

  17. Bridging the gap between basic and applied biology: towards preclinical translation

    Directory of Open Access Journals (Sweden)

    Ross L. Cagan

    2013-05-01

    To better translate basic research findings into the clinic, we are moving away from the traditional one-gene–one-phenotype model towards the discovery of complex mechanisms. In this Editorial, the new Editor-in-Chief and Senior Editors of Disease Models & Mechanisms (DMM discuss the role that the journal will play in this transition. DMM will continue to provide a platform for studies that bridge basic and applied science, and, by demanding the rigorous assessment of animal models of disease, will help drive the establishment of robust standards of preclinical testing for drug development.

  18. Adjuvants for vaccines to drugs of abuse and addiction.

    Science.gov (United States)

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

    2014-09-22

    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.

  19. Is Substance Abuse an Issue for Creative People?

    Science.gov (United States)

    Mabee, Bev

    1985-01-01

    The author proposes a model for lessons on substance abuse that gives children alternative ways to satisfy the natural desire for altered states of consciousness. The model incorporates stages of progressive relaxation, visualization/guided fantasy, sensory experiences, information, and experimentation. (CL)

  20. Predicting Performance in Technical Preclinical Dental Courses Using Advanced Simulation.

    Science.gov (United States)

    Gottlieb, Riki; Baechle, Mary A; Janus, Charles; Lanning, Sharon K

    2017-01-01

    The aim of this study was to investigate whether advanced simulation parameters, such as simulation exam scores, number of student self-evaluations, time to complete the simulation, and time to complete self-evaluations, served as predictors of dental students' preclinical performance. Students from three consecutive classes (n=282) at one U.S. dental school completed advanced simulation training and exams within the first four months of their dental curriculum. The students then completed conventional preclinical instruction and exams in operative dentistry (OD) and fixed prosthodontics (FP) courses, taken during the first and second years of dental school, respectively. Two advanced simulation exam scores (ASES1 and ASES2) were tested as predictors of performance in the two preclinical courses based on final course grades. ASES1 and ASES2 were found to be predictors of OD and FP preclinical course grades. Other advanced simulation parameters were not significantly related to grades in the preclinical courses. These results highlight the value of an early psychomotor skills assessment in dentistry. Advanced simulation scores may allow early intervention in students' learning process and assist in efficient allocation of resources such as faculty coverage and tutor assignment.