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

PubMed Central

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

2017-01-01

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

Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review

PubMed Central

Regner, Gabriela G.; Pereira, Patrícia; Leffa, Douglas T.; de Oliveira, Carla; Vercelino, Rafael; Fregni, Felipe; Torres, Iraci L. S.

2018-01-01

Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002–2017) using the keywords “tDCS,” “epilepsy,” “clinical trials,” and “animal models.” Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy. PMID:29623027

Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer’s Disease

PubMed Central

Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Mañanas, Miguel Angel; Lopera, Francisco; Hernández, Alher Mauricio

2016-01-01

Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD. PMID:27792014

Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

PubMed Central

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

2015-01-01

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

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

PubMed

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

In vivo MRI cell tracking using perfluorocarbon probes and fluorine-19 detection

PubMed Central

Ahrens, Eric T.; Zhong, Jia

2013-01-01

This article is a brief survey of preclinical in vivo cell tracking methods and applications using perfluorocarbon (PFC) probes and fluorine-19 (19F) MRI detection. Detection of the 19F signal offers high cell specificity and quantification abilities in spin-density weighted MR images. We discuss the compositions of matter, methods, and applications of PFC-based cell tracking using ex vivo and in situ PFC labeling in preclinical studies of inflammation and cellular therapeutics. We will also address potential applicability of 19F cell tracking to clinical trials. PMID:23606473

Perceptions of Teaching Methods for Preclinical Oral Surgery: A Comparison with Learning Styles

PubMed Central

Omar, Esam

2017-01-01

Purpose: Dental extraction is a routine part of clinical dental practice. For this reason, understanding the way how students’ extraction knowledge and skills development are important. Problem Statement and Objectives: To date, there is no accredited statement about the most effective method for the teaching of exodontia to dental students. Students have different abilities and preferences regarding how they learn and process information. This is defined as learning style. In this study, the effectiveness of active learning in the teaching of preclinical oral surgery was examined. The personality type of the groups involved in this study was determined, and the possible effect of personality type on learning style was investigated. Method: This study was undertaken over five years from 2011 to 2015. The sample consisted of 115 students and eight staff members. Questionnaires were submitted by 68 students and all eight staff members involved. Three measures were used in the study: The Index of Learning Styles (Felder and Soloman, 1991), the Myers-Briggs Type Indicator (MBTI), and the styles of learning typology (Grasha and Hruska-Riechmann). Results and Discussion: Findings indicated that demonstration and minimal clinical exposure give students personal validation. Frequent feedback on their work is strongly indicated to build the cognitive, psychomotor, and interpersonal skills needed from preclinical oral surgery courses. Conclusion: Small group cooperative active learning in the form of demonstration and minimal clinical exposure that gives frequent feedback and students’ personal validation on their work is strongly indicated to build the skills needed for preclinical oral surgery courses. PMID:28357004

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

PubMed Central

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement. Conclusions The study has commenced, but it is too early to provide results or conclusions. PMID:28254733

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

PubMed

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

2009-10-01

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

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium.

PubMed

Knopp, K L; Stenfors, C; Baastrup, C; Bannon, A W; Calvo, M; Caspani, O; Currie, G; Finnerup, N B; Huang, W; Kennedy, J D; Lefevre, I; Machin, I; Macleod, M; Rees, H; Rice, A S C; Rutten, K; Segerdahl, M; Serra, J; Wodarski, R; Berge, O-G; Treedef, R-D

2017-12-29

Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of "negative" data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Tendinopathies and platelet-rich plasma (PRP): from pre-clinical experiments to therapeutic use

PubMed Central

Kaux, Jean-François; Drion, Pierre; Croisier, Jean-Louis; Crielaard, Jean-Michel

2015-01-01

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon’s healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed. PMID:26195890

The Potential of Adaptive Design in Animal Studies.

PubMed

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-10-12

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.

The Potential of Adaptive Design in Animal Studies

PubMed Central

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-01-01

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research. PMID:26473839

Dissolution DNP for in vivo preclinical studies

NASA Astrophysics Data System (ADS)

Comment, Arnaud

2016-03-01

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

SU-C-BRE-01: 3D Conformal Micro Irradiation Results of Four Treatment Sites for Preclinical Small Animal and Clinical Treatment Plans

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

Price, S; Yaddanapudi, S; Rangaraj, D

Purpose: Small animal irradiation can provide preclinical insights necessary for clinical advancement. In order to provide clinically relevant data, these small animal irradiations must be designed such that the treatment methods and results are comparable to clinical protocols, regardless of variations in treatment size and modality. Methods: Small animal treatments for four treatment sites (brain, liver, lung and spine) were investigated, accounting for change in treatment energy and target size. Up to five orthovoltage (300kVp) beams were used in the preclinical treatments, using circular, square, and conformal tungsten apertures, based on the treatment site. Treatments were delivered using the imagemore » guided micro irradiator (microIGRT). The plans were delivered to a mouse sized phantom and dose measurements in axial and coronal planes were performed using radiochromic film. The results of the clinical and preclinical protocols were characterized in terms of conformality number, CTV coverage, dose nonuniformity ratio, and organ at risk sparing. Results: Preclinical small animal treatment conformality was within 1–16% of clinical results for all treatment sites. The volume of the CTV receiving 100% of the prescription dose was typically within 10% of clinical values. The dose non-uniformity was consistently higher for preclinical treatments compared to clinical treatments, indicating hot spots in the target. The ratios of the mean dose in the target to the mean dose in an organ at risk were comparable if not better for preclinical versus clinical treatments. Finally, QUANTEC dose constraints were applied and the recommended morbidity limits were satisfied in each small animal treatment site. Conclusion: We have shown that for four treatment sites, preclinical 3D conformal small animal treatments can be clinically comparable if clinical protocols are followed. Using clinical protocols as the standard, preclinical irradiation methods can be altered and iteratively improved to achieve a clinically relevant irradiation model.« less

Gastroenterology Curriculum in the Canadian Medical School System.

PubMed

Dang, ThucNhi Tran; Wong, Clarence; Bistritz, Lana

2017-01-01

Background and Purpose. Gastroenterology is a diverse subspecialty that covers a wide array of topics. The preclinical gastroenterology curriculum is often the only formal training that medical students receive prior to becoming residents. There is no Canadian consensus on learning objectives or instructional methods and a general lack of awareness of curriculum at other institutions. This results in variable background knowledge for residents and lack of guidance for course development. Objectives. (1) Elucidate gastroenterology topics being taught at the preclinical level. (2) Determine instructional methods employed to teach gastroenterology content. Results . A curriculum map of gastroenterology topics was constructed from 10 of the medical schools that responded. Topics often not taught included pediatric GI diseases, surgery and trauma, food allergies/intolerances, and obesity. Gastroenterology was taught primarily by gastroenterologists and surgeons. Didactic and small group teaching was the most employed teaching method. Conclusion. This study is the first step in examining the Canadian gastroenterology curriculum at a preclinical level. The data can be used to inform curriculum development so that topics generally lacking are better incorporated in the curriculum. The study can also be used as a guide for further curriculum design and alignment across the country.

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

PubMed Central

Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

2014-01-01

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

In Vivo Investigation of Breast Cancer Progression by Use of an Internal Control1

PubMed Central

Baeten, John; Haller, Jodi; Shih, Helen; Ntziachristos, Vasilis

2009-01-01

Optical imaging of breast cancer has been considered for detecting functional and molecular characteristics of diseases in clinical and preclinical settings. Applied to laboratory research, photonic investigations offer a highly versatile tool for preclinical imaging and drug discovery. A particular advantage of the optical method is the availability of multiple spectral bands for performing imaging. Herein, we capitalize on this feature to demonstrate how it is possible to use different wavelengths to offer internal controls and significantly improve the observation accuracy in molecular imaging applications. In particular, we show the independent in vivo detection of cysteine proteases along with tumor permeability and interstitial volume measurements using a dual-wavelength approach. To generate results with a view toward clinically geared studies, a transgenic Her2/neu mouse model that spontaneously developed mammary tumors was used. In vivo findings were validated against conventional ex vivo tests such as histology and Western blot analyses. By correcting for biodistribution parameters, the dual-wavelength method increases the accuracy of molecular observations by separating true molecular target from probe biodistribution. As such, the method is highly appropriate for molecular imaging studies where often probe delivery and target presence are not independently assessed. On the basis of these findings, we propose the dual-wavelength/normalization approach as an essential method for drug discovery and preclinical imaging studies. PMID:19242603

Increasing efficiency of preclinical research by group sequential designs

PubMed Central

Piper, Sophie K.; Rex, Andre; Florez-Vargas, Oscar; Karystianis, George; Schneider, Alice; Wellwood, Ian; Siegerink, Bob; Ioannidis, John P. A.; Kimmelman, Jonathan; Dirnagl, Ulrich

2017-01-01

Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain. PMID:28282371

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

PubMed

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

2015-08-01

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

Investigating the Efficacy of Practical Skill Teaching: A Pilot-Study Comparing Three Educational Methods

ERIC Educational Resources Information Center

Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

2013-01-01

Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a…

Transparency in the reporting of in vivo pre-clinical pain research: The relevance and implications of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.

PubMed

Rice, Andrew S C; Morland, Rosemary; Huang, Wenlong; Currie, Gillian L; Sena, Emily S; Macleod, Malcolm R

2017-12-29

Clear reporting of research is crucial to the scientific process. Poorly designed and reported studies are damaging not only to the efforts of individual researchers, but also to science as a whole. Standardised reporting methods, such as those already established for reporting randomised clinical trials, have led to improved study design and facilitated the processes of clinical systematic review and meta-analysis. Such standards were lacking in the pre-clinical field until the development of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. These were prompted following a survey which highlighted a widespread lack of robust and consistent reporting of pre-clinical in vivo research, with reports frequently omitting basic information required for study replication and quality assessment. The resulting twenty item checklist in ARRIVE covers all aspects of experimental design with particular emphasis on bias reduction and methodological transparency. Influential publishers and research funders have already adopted ARRIVE. Further dissemination and acknowledgement of the importance of these guidelines is vital to their widespread implementation. Conclusions and implications Wide implementation of the ARRIVE guidelines for reporting of in vivo preclinical research, especially pain research, are essential for a much needed increased transparency and quality in publishing such research. ARRIVE will also positively influence improvements in experimental design and quality, assist the conduct of accurate replication studies of important new findings and facilitate meta-analyses of preclinical research.

Using standardized patients versus video cases for representing clinical problems in problem-based learning

PubMed Central

2016-01-01

Purpose: The quality of problem representation is critical for developing students’ problem-solving abilities in problem-based learning (PBL). This study investigates preclinical students’ experience with standardized patients (SPs) as a problem representation method compared to using video cases in PBL. Methods: A cohort of 99 second-year preclinical students from Inje University College of Medicine (IUCM) responded to a Likert scale questionnaire on their learning experiences after they had experienced both video cases and SPs in PBL. The questionnaire consisted of 14 items with eight subcategories: problem identification, hypothesis generation, motivation, collaborative learning, reflective thinking, authenticity, patient-doctor communication, and attitude toward patients. Results: The results reveal that using SPs led to the preclinical students having significantly positive experiences in boosting patient-doctor communication skills; the perceived authenticity of their clinical situations; development of proper attitudes toward patients; and motivation, reflective thinking, and collaborative learning when compared to using video cases. The SPs also provided more challenges than the video cases during problem identification and hypotheses generation. Conclusion: SPs are more effective than video cases in delivering higher levels of authenticity in clinical problems for PBL. The interaction with SPs engages preclinical students in deeper thinking and discussion; growth of communication skills; development of proper attitudes toward patients; and motivation. Considering the higher cost of SPs compared with video cases, SPs could be used most advantageously during the preclinical period in the IUCM curriculum. PMID:26923094

Indicators of Preclinical Disability: Women’s Experiences of an Aging Body

PubMed Central

LORENZ, REBECCA ANN

2010-01-01

This paper is derived from a larger multimethod longitudinal study of women’s bodily experiences and coping practices before the onset of disability. Twelve women participated in repeated performance measures, in-depth interviews of daily life and physically challenging events, and observations of daily activities conducted over 18 months. Interpretive phenomenological analysis of textual data showed that women’s bodies provided multiple indicators or symptoms of preclinical disability. These indicators informed the women that their body was out of synch with their environment; conspicuous during social activities; and vulnerable to becoming dependent on others, technology, or assistive devices to accomplish daily activities. Greater attention to bodily indicators or symptoms may offer a practical method for clinicians to identify preclinical disability. PMID:19418344

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

PubMed

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

2016-01-01

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

A psychological approach to providing self-management education for people with type 2 diabetes: the Diabetes Manual

PubMed Central

Sturt, Jackie; Taylor, Hafrun; Docherty, Andrea; Dale, Jeremy; Louise, Taylor

2006-01-01

Background The objectives of this study were twofold (i) to develop the Diabetes Manual, a self-management educational intervention aimed at improving biomedical and psychosocial outcomes (ii) to produce early phase evidence relating to validity and clinical feasibility to inform future research and systematic reviews. Methods Using the UK Medical Research Council's complex intervention framework, the Diabetes Manual and associated self management interventions were developed through pre-clinical, and phase I evaluation phases guided by adult-learning and self-efficacy theories, clinical feasibility and health policy protocols. A qualitative needs assessment and an RCT contributed data to the pre-clinical phase. Phase I incorporated intervention development informed by the pre-clinical phase and a feasibility survey. Results The pre-clinical and phase I studies resulted in the production in the Diabetes Manual programme for trial evaluation as delivered within routine primary care consultations. Conclusion This complex intervention shows early feasibility and face validity for both diabetes health professionals and people with diabetes. Randomised trial will determine effectiveness against clinical and psychological outcomes. Further study of some component parts, delivered in alternative combinations, is recommended. PMID:17129376

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies.

PubMed

Versteegden, Luuk R M; de Jonge, Paul K J D; IntHout, Joanna; van Kuppevelt, Toin H; Oosterwijk, Egbert; Feitz, Wout F J; de Vries, Rob B M; Daamen, Willeke F

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study design is required to improve clinical translation of tissue engineering technologies. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

First impressions: what are preclinical medical students in the US and Canada learning about sexual and reproductive health?

PubMed

Steinauer, Jody; LaRochelle, Flynn; Rowh, Marta; Backus, Lois; Sandahl, Yarrow; Foster, Angel

2009-07-01

This study evaluates the inclusion of sexual and reproductive health (SRH) topics in preclinical US and Canadian medical education. Between 2002 and 2005, we sent surveys to the student coordinators of active Medical Students for Choice chapters at 122 US and Canadian medical schools. Students reported on the preclinical curricular inclusion of 50 specific SRH topics in the broad categories of pregnancy, contraception, infertility, elective abortion, ethical and social issues, and other topics. We received 77 completed surveys, for an overall response rate of 63%. Coverage of pregnancy physiology and STIs/HIV was uniformly high. In contrast, inclusion of contraceptive methods and elective abortion procedures greatly varied by subtopic and geographic region. Thirty-three percent of respondents reported no coverage of elective abortion-related topics. Inclusion of contraception and elective abortion in preclinical medical school courses varies widely. As critical components of women's lives and health, we recommend that medical schools work to integrate comprehensive family planning content into their standard curricula.

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies.

PubMed

Barazzetti, Gaia; Hurst, Samia A; Mauron, Alexandre

2016-08-01

: As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine. ©AlphaMed Press.

The Hamburg Selection Procedure for Dental Students – Introduction of the HAM-Nat as subject-specific test for study aptitude

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2013-01-01

Introduction: The present study examines the question whether the selection of dental students should be based solely on average school-leaving grades (GPA) or whether it could be improved by using a subject-specific aptitude test. Methods: The HAM-Nat Natural Sciences Test was piloted with freshmen during their first study week in 2006 and 2007. In 2009 and 2010 it was used in the dental student selection process. The sample size in the regression models varies between 32 and 55 students. Results: Used as a supplement to the German GPA, the HAM-Nat test explained up to 12% of the variance in preclinical examination performance. We confirmed the prognostic validity of GPA reported in earlier studies in some, but not all of the individual preclinical examination results. Conclusion: The HAM-Nat test is a reliable selection tool for dental students. Use of the HAM-Nat yielded a significant improvement in prediction of preclinical academic success in dentistry. PMID:24282449

Optimized design and analysis of preclinical intervention studies in vivo

PubMed Central

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

2016-01-01

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

Optimized design and analysis of preclinical intervention studies in vivo.

PubMed

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

2016-08-02

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

Choice Impulsivity: Definitions, Measurement Issues, and Clinical Implications

PubMed Central

Hamilton, Kristen R.; Mitchell, Marci R.; Wing, Victoria C.; Balodis, Iris M.; Bickel, Warren K.; Fillmore, Mark; Lane, Scott D.; Lejuez, C. W.; Littlefield, Andrew K.; Luijten, Maartje; Mathias, Charles W.; Mitchell, Suzanne H.; Napier, T. Celeste; Reynolds, Brady; Schütz, Christian G.; Setlow, Barry; Sher, Kenneth J.; Swann, Alan C.; Tedford, Stephanie E.; White, Melanie J.; Winstanley, Catharine A.; Yi, Richard; Potenza, Marc N.; Moeller, F. Gerard

2015-01-01

Background Impulsivity critically relates to many psychiatric disorders. Given the multi-faceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. Method The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Results Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. Conclusions The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures. PMID:25867841

Use of dynamic images in radiology education: Movies of CT and MRI in the anatomy classroom.

PubMed

Jang, Hye Won; Oh, Chang-Seok; Choe, Yeon Hyeon; Jang, Dong Su

2018-04-19

Radiology education is a key component in many preclinical anatomy courses. However, the reported effectiveness of radiology education within such anatomy classrooms has varied. This study was conducted to determine if a novel educational method using dynamic images of movies of computed tomography (CT) and magnetic resonance imaging (MRI) was effective in radiology education during a preclinical anatomy course, aided by clay modeling, specific hand gestures (digit anatomy), and reports from dissection findings uploaded to the anatomy course website (digital reports). Feedback surveys using a five-point Likert scale were administered to better clarify students' opinions regarding their understanding of CT and MRI of anatomical structures, as well as to determine if such preclinical radiology education was helpful in their clinical studies. After completion of the anatomy course taught with dynamic images of CT and MRI, most students demonstrated an adequate understanding of basic CT and MR images. Additionally, students in later clinical years generally believed that their study of radiologic images during the preclinical anatomy course was helpful for their clinical studies and clerkship rotations. Moreover, student scores on imaging anatomy examinations demonstrated meaningful improvements in performance after using dynamic images from movies of CT and MRI. Anat Sci Educ. © 2018 American Association of Anatomists. © 2018 American Association of Anatomists.

CAP—advancing the evaluation of preclinical Alzheimer disease treatments

PubMed Central

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

2016-01-01

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

Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

PubMed Central

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

2015-01-01

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

The Flipped Classroom for pre-clinical dental skills teaching - a reflective commentary.

PubMed

Crothers, A J; Bagg, J; McKerlie, R

2017-05-12

A Flipped Classroom method for teaching of adult practical pre-clinical dental skills was introduced to the BDS curriculum in Glasgow during the 2015/2016 academic session. This report provides a commentary of the first year of employing this method - from the identification of the need to optimise teaching resources, through the planning, implementation and development of the method, with an early indication of performance.

A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies.

PubMed

Navarro-Fontestad, Carmen; González-Álvarez, Isabel; Fernández-Teruel, Carlos; Bermejo, Marival; Casabó, Vicente Germán

2012-01-01

The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confidence interval. In this way, the new proposed method demonstrates to be as useful as WinNonlin® software when it was applicable. Copyright © 2011 John Wiley & Sons, Ltd.

SU-E-T-606: Performance of MR-Based 3D FXG Dosimetry for Preclinical Irradiation

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

Welch, M; Jaffray, D; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MRmore » and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century at CIHR and the Gifford Ontario Student Opportunity Trust Fund.« less

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems.

PubMed

Liu, Zhichao; Delavan, Brian; Roberts, Ruth; Tong, Weida

2018-01-01

Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay? (2) are some biological processes more conservative across different preclinical testing systems than others? and (3) do these preclinical testing systems have the similar resolution in differentiating drugs by their therapeutic uses? For question 1, a high similarity was noted (PRank score = 0.90), indicating the potential utility of shorter term in vivo studies to predict outcome in longer term and more expensive in vivo model systems. There was a moderate similarity between rat primary hepatocytes and in vivo repeat-dose studies (PRank score = 0.71) but a low similarity (PRank score = 0.56) between rat primary hepatocytes and in vivo single dose studies. To address question 2, we limited the analysis to gene sets relevant to specific toxicogenomic pathways and we found that pathways such as lipid metabolism were consistently over-represented in all three assay systems. For question 3, all three preclinical assay systems could distinguish compounds from different therapeutic categories. This suggests that any noted differences in assay systems was biological process-dependent and furthermore that all three systems have utility in assessing drug responses within a certain drug class. In conclusion, this comparison of three commonly used rat TGx systems provides useful information in utility and application of TGx assays.

Faculty Perceptions of Formative Assessment and Implementation Practices in Preclinical Medical Edcuation: A Q Method Study

ERIC Educational Resources Information Center

Close, Brandy

2017-01-01

This study describes faculty perceptions of formative assessment and the influence their perceptions have on implementation practices. Assessment is often misunderstood and too often becomes an afterthought in the teaching process. Measuring curricular success by overall student outcomes means instructional and assessment methods have a…

Preclinical students’ experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia

PubMed Central

2012-01-01

Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419

Is lecture dead? A preliminary study of medical students' evaluation of teaching methods in the preclinical curriculum.

PubMed

Zinski, Anne; Blackwell, Kristina T C Panizzi Woodley; Belue, F Mike; Brooks, William S

2017-09-22

To investigate medical students' perceptions of lecture and non-lecture-based instructional methods and compare preferences for use and quantity of each during preclinical training. We administered a survey to first- and second-year undergraduate medical students at the University of Alabama School of Medicine in Birmingham, Alabama, USA aimed to evaluate preferred instructional methods.  Using a cross-sectional study design, Likert scale ratings and student rankings were used to determine preferences among lecture, laboratory, team-based learning, simulation, small group case-based learning, large group case-based learning, patient presentation, and peer teaching. We calculated mean ratings for each instructional method and used chi-square tests to compare proportions of first- and second-year cohorts who ranked each in their top 5 preferred methods. Among participating students, lecture (M=3.6, SD=1.0), team based learning (M=4.2, SD=1.0), simulation (M=4.0, SD=1.0), small group case-based learning (M=3.8, SD=1.0), laboratory (M=3.6, SD=1.0), and patient presentation (M=3.8, SD=0.9) received higher scores than other instructional methods. Overall, second-year students ranked lecture lower (χ 2 (1, N=120) =16.33, p<0.0001) and patient presentation higher (χ 2 (1, N=120) =3.75, p=0.05) than first-year students. While clinically-oriented teaching methods were preferred by second-year medical students, lecture-based instruction was popular among first-year students. Results warrant further investigation to determine the ideal balance of didactic methods in undergraduate medical education, specifically curricula that employ patient-oriented instruction during the second preclinical year.

Teaching methods and surgical training in North American graduate periodontics programs: exploring the landscape.

PubMed

Ghiabi, Edmond; Taylor, K Lynn

2010-06-01

This project aimed at documenting the surgical training curricula offered by North American graduate periodontics programs. A survey consisting of questions on teaching methods employed and the content of the surgical training program was mailed to directors of all fifty-eight graduate periodontics programs in Canada and the United States. The chi-square test was used to assess whether the residents' clinical experience was significantly (P<0.05) influenced by having a) a structured preclinical program or b) another dental residency program in the institution. Thirty-four programs (59 percent) responded to the survey. Twenty-six programs (76 percent of respondents) reported offering a structured preclinical component. Traditional teaching methods such as slides, live demonstration, DVD/CD, and animal cadavers were the most common teaching methods used, whereas online courses, computer simulation, and various surgical mannequins were least commonly used. The most commonly performed surgical procedures were conventional flaps, periodontal plastic procedures, hard tissue grafts, and implants. Furthermore, residents in programs offering a structured preclinical component performed significantly more procedures (P=0.012) using lasers than those in programs not offering a structured preclinical program. Devising new and innovative teaching methods is a clear avenue for future development in North American graduate periodontics programs.

Harnessing the potential of noninvasive in vivo preclinical imaging of the immune system: challenges and prospects.

PubMed

Diken, Mustafa; Pektor, Stefanie; Miederer, Matthias

2016-10-01

Preclinical imaging has become a powerful method for investigation of in vivo processes such as pharmacokinetics of therapeutic substances and visualization of physiologic and pathophysiological mechanisms. These are important aspects to understand diseases and develop strategies to modify their progression with pharmacologic interventions. One promising intervention is the application of specifically tailored nanoscale particles that modulate the immune system to generate a tumor targeting immune response. In this complex interaction between immunomodulatory therapies, the immune system and malignant disease, imaging methods are expected to play a key role on the way to generate new therapeutic strategies. Here, we summarize examples which demonstrate the current potential of imaging methods and develop a perspective on the future value of preclinical imaging of the immune system.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2015-03-01

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

The development of the rotigotine transdermal patch: a historical perspective.

PubMed

Waters, Cheryl

2013-08-01

The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. Copyright © 2013 Elsevier Inc. All rights reserved.

Proteomic Data Resources for EDRN Ovary Cancer Researchers within the EDRN — EDRN Public Portal

Cancer.gov

This project will generate a highly valuable data resource and make it available to all EDRN ovarian cancer researchers. The resource will include comprehensive proteomic (tandem mass spectrometry, MS/MS) data generated from plasma samples that have been collected between four months and four years prior to clinical detection of ovarian cancer. These pre-clinical samples, provided from the Beta Carotene and Retinol Efficacy Trial (CARET) prospective study, will be interrogated using IPAS, the proteomic profiling method developed by the Hanash Laboratory and with the quantitative methods developed by the McIntosh laboratory. In addition, we will combine these pre-clinical data with already completed IPAS interrogations of plasma collected at the time of ovarian cancer diagnosis. Thus together we will provide information on both pre-clinical and clinical behavior of a large number of proteins. Based on our preliminary work we are able to quantify over 500 plasma proteins in each of these experiments, many of which are putative ovarian cancer biomarkers, showing the platform is capable of providing useful information regarding biomarker candidates.

The case for introducing pre-registered confirmatory pharmacological pre-clinical studies.

PubMed

Kiwanuka, Olivia; Bellander, Bo-Michael; Hånell, Anders

2018-05-01

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

PubMed

Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

2014-03-01

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

Effectiveness of project ACORDE materials: applied evaluative research in a preclinical technique course.

PubMed

Shugars, D A; Trent, P J; Heymann, H O

1979-08-01

Two instructional strategies, the traditional lecture method and a standardized self-instructional (ACORDE) format, were compared for efficiency and perceived usefulness in a preclinical restorative dentistry technique course through the use of a posttest-only control group research design. Control and experimental groups were compared on (a) technique grades, (b) didactic grades, (c) amount of time spent, (d) student and faculty perceptions, and (e) observation of social dynamics. The results of this study demonstrated the effectiveness of Project ACORDE materials in teaching dental students, provided an example of applied research designed to test contemplated instructional innovations prior to use and used a method which highlighted qualitative, as well as quantitative, techniques for data gathering in applied research.

Evaluating the interaction of a tracheobronchial stent in an ovine in-vivo model.

PubMed

McGrath, Donnacha J; Thiebes, Anja Lena; Cornelissen, Christian G; O'Brien, Barry; Jockenhoevel, Stefan; Bruzzi, Mark; McHugh, Peter E

2018-04-01

Tracheobronchial stents are used to restore patency to stenosed airways. However, these devices are associated with many complications such as stent migration, granulation tissue formation, mucous plugging and stent strut fracture. Of these, granulation tissue formation is the complication that most frequently requires costly secondary interventions. In this study a biomechanical lung modelling framework recently developed by the authors to capture the lung in-vivo stress state under physiological loading is employed in conjunction with ovine pre-clinical stenting results and device experimental data to evaluate the effect of stent interaction on granulation tissue formation. Stenting is simulated using a validated model of a prototype covered laser-cut tracheobronchial stent in a semi-specific biomechanical lung model, and physiological loading is performed. Two computational methods are then used to predict possible granulation tissue formation: the standard method which utilises the increase in maximum principal stress change, and a newly proposed method which compares the change in contact pressure over a respiratory cycle. These computational predictions of granulation tissue formation are then compared to pre-clinical stenting observations after a 6-week implantation period. Experimental results of the pre-clinical stent implantation showed signs of granulation tissue formation both proximally and distally, with a greater proximal reaction. The standard method failed to show a correlation with the experimental results. However, the contact change method showed an apparent correlation with granulation tissue formation. These results suggest that this new method could be used as a tool to improve future device designs.

Regularly incremented phase encoding - MR fingerprinting (RIPE-MRF) for enhanced motion artifact suppression in preclinical cartesian MR fingerprinting.

PubMed

Anderson, Christian E; Wang, Charlie Y; Gu, Yuning; Darrah, Rebecca; Griswold, Mark A; Yu, Xin; Flask, Chris A

2018-04-01

The regularly incremented phase encoding-magnetic resonance fingerprinting (RIPE-MRF) method is introduced to limit the sensitivity of preclinical MRF assessments to pulsatile and respiratory motion artifacts. As compared to previously reported standard Cartesian-MRF methods (SC-MRF), the proposed RIPE-MRF method uses a modified Cartesian trajectory that varies the acquired phase-encoding line within each dynamic MRF dataset. Phantoms and mice were scanned without gating or triggering on a 7T preclinical MRI scanner using the RIPE-MRF and SC-MRF methods. In vitro phantom longitudinal relaxation time (T 1 ) and transverse relaxation time (T 2 ) measurements, as well as in vivo liver assessments of artifact-to-noise ratio (ANR) and MRF-based T 1 and T 2 mean and standard deviation, were compared between the two methods (n = 5). RIPE-MRF showed significant ANR reductions in regions of pulsatility (P < 0.005) and respiratory motion (P < 0.0005). RIPE-MRF also exhibited improved precision in T 1 and T 2 measurements in comparison to the SC-MRF method (P <  0.05). The RIPE-MRF and SC-MRF methods displayed similar mean T 1 and T 2 estimates (difference in mean values < 10%). These results show that the RIPE-MRF method can provide effective motion artifact suppression with minimal impact on T 1 and T 2 accuracy for in vivo small animal MRI studies. Magn Reson Med 79:2176-2182, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

NEMA NU 4-2008 validation and applications of the PET-SORTEO Monte Carlo simulations platform for the geometry of the Inveon PET preclinical scanner

NASA Astrophysics Data System (ADS)

Boisson, F.; Wimberley, C. J.; Lehnert, W.; Zahra, D.; Pham, T.; Perkins, G.; Hamze, H.; Gregoire, M.-C.; Reilhac, A.

2013-10-01

Monte Carlo-based simulation of positron emission tomography (PET) data plays a key role in the design and optimization of data correction and processing methods. Our first aim was to adapt and configure the PET-SORTEO Monte Carlo simulation program for the geometry of the widely distributed Inveon PET preclinical scanner manufactured by Siemens Preclinical Solutions. The validation was carried out against actual measurements performed on the Inveon PET scanner at the Australian Nuclear Science and Technology Organisation in Australia and at the Brain & Mind Research Institute and by strictly following the NEMA NU 4-2008 standard. The comparison of simulated and experimental performance measurements included spatial resolution, sensitivity, scatter fraction and count rates, image quality and Derenzo phantom studies. Results showed that PET-SORTEO reliably reproduces the performances of this Inveon preclinical system. In addition, imaging studies showed that the PET-SORTEO simulation program provides raw data for the Inveon scanner that can be fully corrected and reconstructed using the same programs as for the actual data. All correction techniques (attenuation, scatter, randoms, dead-time, and normalization) can be applied on the simulated data leading to fully quantitative reconstructed images. In the second part of the study, we demonstrated its ability to generate fast and realistic biological studies. PET-SORTEO is a workable and reliable tool that can be used, in a classical way, to validate and/or optimize a single PET data processing step such as a reconstruction method. However, we demonstrated that by combining a realistic simulated biological study ([11C]Raclopride here) involving different condition groups, simulation allows one also to assess and optimize the data correction, reconstruction and data processing line flow as a whole, specifically for each biological study, which is our ultimate intent.

Antitumor Efficacy Testing in Rodents

PubMed Central

2008-01-01

The preclinical research and human clinical trials necessary for developing anticancer therapeutics are costly. One contributor to these costs is preclinical rodent efficacy studies, which, in addition to the costs associated with conducting them, often guide the selection of agents for clinical development. If inappropriate or inaccurate recommendations are made on the basis of these preclinical studies, then additional costs are incurred. In this commentary, I discuss the issues associated with preclinical rodent efficacy studies. These include the identification of proper preclinical efficacy models, the selection of appropriate experimental endpoints, and the correct statistical evaluation of the resulting data. I also describe important experimental design considerations, such as selecting the drug vehicle, optimizing the therapeutic treatment plan, properly powering the experiment by defining appropriate numbers of replicates in each treatment arm, and proper randomization. Improved preclinical selection criteria can aid in reducing unnecessary human studies, thus reducing the overall costs of anticancer drug development. PMID:18957675

Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review

PubMed Central

2014-01-01

Background Avascular necrosis (AVN) of the femoral head (FH) is believed to be caused by a multitude of etiologic factors and is associated with significant morbidity in younger populations. Eventually, the disease progresses and results in FH collapse. Thus, a focus on early disease management aimed at joint preservation by preventing or delaying progression is key. The use of stem cells (SC) for the treatment of AVN of the FH has been proposed. We undertook a systematic review of the medical literature examining the use of SC for the treatment of early stage (precollapse) AVN of the FH, in both pre-clinical and clinical studies. Methods Data collected included: Pre-clinical studies – model of AVN, variety and dosage of SC, histologic and imaging analyses. Clinical studies – study design, classification and etiology of AVN, SC dosage and treatment protocol, incidence of disease progression, patient reported outcomes, volume of necrotic lesion and hip survivorship. Results In pre-clinical studies, the use of SC uniformly demonstrated improvements in osteogenesis and angiogenesis, yet source of implanted SC was variable. In clinical studies, groups treated with SC showed significant improvements in patient reported outcomes; however hip survivorship was not affected. Discrepancies regarding dose of SC, AVN etiology and disease severity were present. Conclusions Routine use of this treatment method will first require further research into dose and quality optimization as well as confirmed improvements in hip survivorship. PMID:24886648

Pre-clinical research in small animals using radiotherapy technology--a bidirectional translational approach.

PubMed

Tillner, Falk; Thute, Prasad; Bütof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang

2014-12-01

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. Copyright © 2014. Published by Elsevier GmbH.

Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase?

PubMed

Salem, Raneem O; Al-Mously, Najwa; AlFadil, Sara; Baalash, Amal

2016-01-01

Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). Pre-clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress.

Using standardized patients versus video cases for representing clinical problems in problem-based learning.

PubMed

Yoon, Bo Young; Choi, Ikseon; Choi, Seokjin; Kim, Tae-Hee; Roh, Hyerin; Rhee, Byoung Doo; Lee, Jong-Tae

2016-06-01

The quality of problem representation is critical for developing students' problem-solving abilities in problem-based learning (PBL). This study investigates preclinical students' experience with standardized patients (SPs) as a problem representation method compared to using video cases in PBL. A cohort of 99 second-year preclinical students from Inje University College of Medicine (IUCM) responded to a Likert scale questionnaire on their learning experiences after they had experienced both video cases and SPs in PBL. The questionnaire consisted of 14 items with eight subcategories: problem identification, hypothesis generation, motivation, collaborative learning, reflective thinking, authenticity, patient-doctor communication, and attitude toward patients. The results reveal that using SPs led to the preclinical students having significantly positive experiences in boosting patient-doctor communication skills; the perceived authenticity of their clinical situations; development of proper attitudes toward patients; and motivation, reflective thinking, and collaborative learning when compared to using video cases. The SPs also provided more challenges than the video cases during problem identification and hypotheses generation. SPs are more effective than video cases in delivering higher levels of authenticity in clinical problems for PBL. The interaction with SPs engages preclinical students in deeper thinking and discussion; growth of communication skills; development of proper attitudes toward patients; and motivation. Considering the higher cost of SPs compared with video cases, SPs could be used most advantageously during the preclinical period in the IUCM curriculum.

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

Lee, Y; Fullerton, G; Goins, B

Purpose: In our previous study a preclinical multi-modality quality assurance (QA) phantom that contains five tumor-simulating test objects with 2, 4, 7, 10 and 14 mm diameters was developed for accurate tumor size measurement by researchers during cancer drug development and testing. This study analyzed the errors during tumor volume measurement from preclinical magnetic resonance (MR), micro-computed tomography (micro- CT) and ultrasound (US) images acquired in a rodent tumor model using the preclinical multi-modality QA phantom. Methods: Using preclinical 7-Tesla MR, US and micro-CT scanners, images were acquired of subcutaneous SCC4 tumor xenografts in nude rats (3–4 rats per group;more » 5 groups) along with the QA phantom using the same imaging protocols. After tumors were excised, in-air micro-CT imaging was performed to determine reference tumor volume. Volumes measured for the rat tumors and phantom test objects were calculated using formula V = (π/6)*a*b*c where a, b and c are the maximum diameters in three perpendicular dimensions determined by the three imaging modalities. Then linear regression analysis was performed to compare image-based tumor volumes with the reference tumor volume and known test object volume for the rats and the phantom respectively. Results: The slopes of regression lines for in-vivo tumor volumes measured by three imaging modalities were 1.021, 1.101 and 0.862 for MRI, micro-CT and US respectively. For phantom, the slopes were 0.9485, 0.9971 and 0.9734 for MRI, micro-CT and US respectively. Conclusion: For both animal and phantom studies, random and systematic errors were observed. Random errors were observer-dependent and systematic errors were mainly due to selected imaging protocols and/or measurement method. In the animal study, there were additional systematic errors attributed to ellipsoidal assumption for tumor shape. The systematic errors measured using the QA phantom need to be taken into account to reduce measurement errors during the animal study.« less

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-06-30

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

Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)

PubMed Central

Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

2012-01-01

Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome. PMID:23078651

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

PubMed

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

2011-03-01

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

Body painting to promote self-active learning of hand anatomy for preclinical medical students.

PubMed

Jariyapong, Pitchanee; Punsawad, Chuchard; Bunratsami, Suchirat; Kongthong, Paranyu

2016-01-01

Background The purpose of this study was to use the body painting method to teach hand anatomy to a group of preclinical medical students. Methods Students reviewed hand anatomy using the traditional method and body painting exercise. Feedback and retention of the anatomy-related information were examined by a questionnaire and multiple-choice questions, respectively, immediately and 1 month after the painting exercise. Results Students agreed that the exercise was advantageous and helped facilitate self-active learning after in-class anatomy lessons. While there was no significant difference in knowledge retention between the control and experimental groups, the students appreciated the exercise in which they applied body paint to the human body to learn anatomy. Conclusion The body painting was an efficient tool for aiding the interactive learning of medical students and increasing the understanding of gross anatomy.

Direct Parametric Image Reconstruction in Reduced Parameter Space for Rapid Multi-Tracer PET Imaging.

PubMed

Cheng, Xiaoyin; Li, Zhoulei; Liu, Zhen; Navab, Nassir; Huang, Sung-Cheng; Keller, Ulrich; Ziegler, Sibylle; Shi, Kuangyu

2015-02-12

The separation of multiple PET tracers within an overlapping scan based on intrinsic differences of tracer pharmacokinetics is challenging, due to limited signal-to-noise ratio (SNR) of PET measurements and high complexity of fitting models. In this study, we developed a direct parametric image reconstruction (DPIR) method for estimating kinetic parameters and recovering single tracer information from rapid multi-tracer PET measurements. This is achieved by integrating a multi-tracer model in a reduced parameter space (RPS) into dynamic image reconstruction. This new RPS model is reformulated from an existing multi-tracer model and contains fewer parameters for kinetic fitting. Ordered-subsets expectation-maximization (OSEM) was employed to approximate log-likelihood function with respect to kinetic parameters. To incorporate the multi-tracer model, an iterative weighted nonlinear least square (WNLS) method was employed. The proposed multi-tracer DPIR (MTDPIR) algorithm was evaluated on dual-tracer PET simulations ([18F]FDG and [11C]MET) as well as on preclinical PET measurements ([18F]FLT and [18F]FDG). The performance of the proposed algorithm was compared to the indirect parameter estimation method with the original dual-tracer model. The respective contributions of the RPS technique and the DPIR method to the performance of the new algorithm were analyzed in detail. For the preclinical evaluation, the tracer separation results were compared with single [18F]FDG scans of the same subjects measured 2 days before the dual-tracer scan. The results of the simulation and preclinical studies demonstrate that the proposed MT-DPIR method can improve the separation of multiple tracers for PET image quantification and kinetic parameter estimations.

Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies

PubMed Central

Wever, Kimberley E.; Hooijmans, Carlijn R.; Riksen, Niels P.; Sterenborg, Thomas B.; Sena, Emily S.; Ritskes-Hoitinga, Merel; Warlé, Michiel C.

2015-01-01

Background Ischemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients. Objective To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation. Methods and results Using systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2–3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively. Conclusions Translation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence. PMID:26580958

Challenges for Preclinical Investigations of Human Biofield Modalities

PubMed Central

Gronowicz, Gloria; Bengston, William

2015-01-01

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

Issues related to development of antiepileptogenic therapies.

PubMed

Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R; Dudek, F Edward; Friedman, Daniel; Galanopoulou, Aristea S; Jensen, Frances E; Kaminski, Rafal M; Kapur, Jaideep; Klitgaard, Henrik; Löscher, Wolfgang; Mody, Istvan; Schmidt, Dieter

2013-08-01

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Non-invasive molecular imaging for preclinical cancer therapeutic development

PubMed Central

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

2013-01-01

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

The neuropsychology of normal aging and preclinical Alzheimer’s disease

PubMed Central

Caselli, Richard J.; Locke, Dona E.C.; Dueck, Amylou C.; Knopman, David S.; Woodruff, Bryan K.; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S.; Reiman, Eric M.

2013-01-01

Background An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Methods 71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups. Results There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups. Conclusions While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design. PMID:23541188

How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school

PubMed Central

Świerszcz, Jolanta; Stalmach-Przygoda, Agata; Kuźma, Marcin; Jabłoński, Konrad; Cegielny, Tomasz; Skrzypek, Agnieszka; Wieczorek-Surdacka, Ewa; Kruszelnicka, Olga; Chmura, Kaja; Chyrchel, Bernadeta; Surdacki, Andrzej; Nowakowski, Michał

2017-01-01

Objective As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. Design Analysis of routinely collected data. Setting One Polish medical school. Participants Complete OSCE records for 462 second-year students and 445 third-year students. Outcome measures OSCE scores by matriculation year. Results In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third-year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second-year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG — tasks which had not been included in the second-year preclinical training. Conclusion Our results suggest the importance of preclinical training in a CS laboratory to improve students’ competence in physical examination at the completion of introductory clinical clerkships during the first clinical year. PMID:28864488

How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school.

PubMed

Świerszcz, Jolanta; Stalmach-Przygoda, Agata; Kuźma, Marcin; Jabłoński, Konrad; Cegielny, Tomasz; Skrzypek, Agnieszka; Wieczorek-Surdacka, Ewa; Kruszelnicka, Olga; Chmura, Kaja; Chyrchel, Bernadeta; Surdacki, Andrzej; Nowakowski, Michał

2017-09-01

As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. Analysis of routinely collected data. One Polish medical school. Complete OSCE records for 462 second-year students and 445 third-year students. OSCE scores by matriculation year. In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third-year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second-year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG - tasks which had not been included in the second-year preclinical training. Our results suggest the importance of preclinical training in a CS laboratory to improve students' competence in physical examination at the completion of introductory clinical clerkships during the first clinical year. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Lessons from a pilot project in cognitive task analysis: the potential role of intermediates in preclinical teaching in dental education.

PubMed

Walker, Judith; von Bergmann, HsingChi

2015-03-01

The purpose of this study was to explore the use of cognitive task analysis to inform the teaching of psychomotor skills and cognitive strategies in clinical tasks in dental education. Methods used were observing and videotaping an expert at one dental school thinking aloud while performing a specific preclinical task (in a simulated environment), interviewing the expert to probe deeper into his thinking processes, and applying the same procedures to analyze the performance of three second-year dental students who had recently learned the analyzed task and who represented a spectrum of their cohort's ability to undertake the procedure. The investigators sought to understand how experts (clinical educators) and intermediates (trained students) overlapped and differed at points in the procedure that represented the highest cognitive load, known as "critical incidents." Findings from this study and previous research identified possible limitations of current clinical teaching as a result of expert blind spots. These findings coupled with the growing evidence of the effectiveness of peer teaching suggest the potential role of intermediates in helping novices learn preclinical dentistry tasks.

Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies

PubMed Central

Jahangiri, Arman; Chin, Aaron T.; Flanigan, Patrick M.; Chen, Rebecca; Bankiewicz, Krystof; Aghi, Manish K.

2017-01-01

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail. PMID:27035164

Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

PubMed

Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

2017-11-01

Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Body painting to promote self-active learning of hand anatomy for preclinical medical students.

PubMed

Jariyapong, Pitchanee; Punsawad, Chuchard; Bunratsami, Suchirat; Kongthong, Paranyu

2016-01-01

The purpose of this study was to use the body painting method to teach hand anatomy to a group of preclinical medical students. Students reviewed hand anatomy using the traditional method and body painting exercise. Feedback and retention of the anatomy-related information were examined by a questionnaire and multiple-choice questions, respectively, immediately and 1 month after the painting exercise. Students agreed that the exercise was advantageous and helped facilitate self-active learning after in-class anatomy lessons. While there was no significant difference in knowledge retention between the control and experimental groups, the students appreciated the exercise in which they applied body paint to the human body to learn anatomy. The body painting was an efficient tool for aiding the interactive learning of medical students and increasing the understanding of gross anatomy.

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2015-03-01

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

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking.

PubMed

Chesworth, Rose; Corbit, Laura H

2017-01-01

One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. © 2015 Society for the Study of Addiction.

A student-initiated and student-facilitated international health elective for preclinical medical students

PubMed Central

Vora, Nirali; Chang, Mina; Pandya, Hemang; Hasham, Aliya; Lazarus, Cathy

2010-01-01

Introduction Global health education is becoming more important for developing well-rounded physicians and may encourage students toward a career in primary care. Many medical schools, however, lack adequate and structured opportunities for students beginning the curriculum. Methods Second-year medical students initiated, designed, and facilitated a pass–fail international health elective, providing a curricular framework for preclinical medical students wishing to gain exposure to the clinical and cultural practices of a developing country. Results All course participants (N=30) completed a post-travel questionnaire within one week of sharing their experiences. Screening reflection essays for common themes that fulfill university core competencies yielded specific global health learning outcomes, including analysis of health care determinants. Conclusion Medical students successfully implemented a sustainable global health curriculum for preclinical student peers. Financial constraints, language, and organizational burdens limit student participation. In future, long-term studies should analyze career impact and benefits to the host country. PMID:20186283

Fibrillar amyloid correlates of preclinical cognitive decline.

PubMed

Stonnington, Cynthia M; Chen, Kewei; Lee, Wendy; Locke, Dona E C; Dueck, Amylou C; Liu, Xiaofen; Roontiva, Auttawut; Fleisher, Adam S; Caselli, Richard J; Reiman, Eric M

2014-01-01

It is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status. From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden. At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Utilization of blended learning to teach preclinical endodontics.

PubMed

Maresca, Cristina; Barrero, Carlos; Duggan, Dereck; Platin, Enrique; Rivera, Eric; Hannum, Wallace; Petrola, Frank

2014-08-01

Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level.

Vitamins in Pancreatic Cancer: A Review of Underlying Mechanisms and Future Applications12

PubMed Central

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-01-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. PMID:26567201

Vitamins in pancreatic cancer: a review of underlying mechanisms and future applications.

PubMed

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-11-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. © 2015 American Society for Nutrition.

Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

PubMed

Corbett, Dale; Carmichael, S Thomas; Murphy, Timothy H; Jones, Theresa A; Schwab, Martin E; Jolkkonen, Jukka; Clarkson, Andrew N; Dancause, Numa; Weiloch, Tadeusz; Johansen-Berg, Heidi; Nilsson, Michael; McCullough, Louise D; Joy, Mary T

2017-08-01

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

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

PubMed

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

2017-06-09

Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields. © 2017 The Authors.

Population based MRI and DTI templates of the adult ferret brain and tools for voxelwise analysis.

PubMed

Hutchinson, E B; Schwerin, S C; Radomski, K L; Sadeghi, N; Jenkins, J; Komlosh, M E; Irfanoglu, M O; Juliano, S L; Pierpaoli, C

2017-05-15

Non-invasive imaging has the potential to play a crucial role in the characterization and translation of experimental animal models to investigate human brain development and disorders, especially when employed to study animal models that more accurately represent features of human neuroanatomy. The purpose of this study was to build and make available MRI and DTI templates and analysis tools for the ferret brain as the ferret is a well-suited species for pre-clinical MRI studies with folded cortical surface, relatively high white matter volume and body dimensions that allow imaging with pre-clinical MRI scanners. Four ferret brain templates were built in this study - in-vivo MRI and DTI and ex-vivo MRI and DTI - using brain images across many ferrets and region of interest (ROI) masks corresponding to established ferret neuroanatomy were generated by semi-automatic and manual segmentation. The templates and ROI masks were used to create a web-based ferret brain viewing software for browsing the MRI and DTI volumes with annotations based on the ROI masks. A second objective of this study was to provide a careful description of the imaging methods used for acquisition, processing, registration and template building and to demonstrate several voxelwise analysis methods including Jacobian analysis of morphometry differences between the female and male brain and bias-free identification of DTI abnormalities in an injured ferret brain. The templates, tools and methodological optimization presented in this study are intended to advance non-invasive imaging approaches for human-similar animal species that will enable the use of pre-clinical MRI studies for understanding and treating brain disorders. Published by Elsevier Inc.

Fabricating customized hydrogel contact lens

NASA Astrophysics Data System (ADS)

Childs, Andre; Li, Hao; Lewittes, Daniella M.; Dong, Biqin; Liu, Wenzhong; Shu, Xiao; Sun, Cheng; Zhang, Hao F.

2016-10-01

Contact lenses are increasingly used in laboratories for in vivo animal retinal imaging and pre-clinical studies. The lens shapes often need modification to optimally fit corneas of individual test subjects. However, the choices from commercially available contact lenses are rather limited. Here, we report a flexible method to fabricate customized hydrogel contact lenses. We showed that the fabricated hydrogel is highly transparent, with refractive indices ranging from 1.42 to 1.45 in the spectra range from 400 nm to 800 nm. The Young’s modulus (1.47 MPa) and hydrophobicity (with a sessile drop contact angle of 40.5°) have also been characterized experimentally. Retinal imaging using optical coherence tomography in rats wearing our customized contact lenses has the quality comparable to the control case without the contact lens. Our method could significantly reduce the cost and the lead time for fabricating soft contact lenses with customized shapes, and benefit the laboratorial-used contact lenses in pre-clinical studies.

Fabricating customized hydrogel contact lens

PubMed Central

Childs, Andre; Li, Hao; Lewittes, Daniella M.; Dong, Biqin; Liu, Wenzhong; Shu, Xiao; Sun, Cheng; Zhang, Hao F.

2016-01-01

Contact lenses are increasingly used in laboratories for in vivo animal retinal imaging and pre-clinical studies. The lens shapes often need modification to optimally fit corneas of individual test subjects. However, the choices from commercially available contact lenses are rather limited. Here, we report a flexible method to fabricate customized hydrogel contact lenses. We showed that the fabricated hydrogel is highly transparent, with refractive indices ranging from 1.42 to 1.45 in the spectra range from 400 nm to 800 nm. The Young’s modulus (1.47 MPa) and hydrophobicity (with a sessile drop contact angle of 40.5°) have also been characterized experimentally. Retinal imaging using optical coherence tomography in rats wearing our customized contact lenses has the quality comparable to the control case without the contact lens. Our method could significantly reduce the cost and the lead time for fabricating soft contact lenses with customized shapes, and benefit the laboratorial-used contact lenses in pre-clinical studies. PMID:27748361

Biopsychosocial influence on shoulder pain: rationale and protocol for a pre-clinical trial

PubMed Central

George, Steven Z.; Staud, Roland; Borsa, Paul A.; Wu, Samuel S.; Wallace, Margaret R.; Greenfield, Warren. H.; Mackie, Lauren N.; Fillingim, Roger B.

2017-01-01

Background Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12 month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Methods Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. Conclusion This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. Trial Registration ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015) PMID:28315479

Utilizing an Orally Dissolving Strip for Pharmacological and Toxicological Studies: A Simple and Humane Alternative to Oral Gavage for Animals

PubMed Central

Lieu, Dustin; Asatryan, Liana; Davies, Daryl L.

2016-01-01

Prior to testing novel therapeutics in humans, short and long term preclinical (i.e., animal), repetitive pharmacological and toxicological testing is required. In most cases, the preferred route of administration is via oral delivery. At the present time, oral delivery is mostly accomplished using an oral gavage procedure, in part, because it can achieve consistent and precise dosing in the animal model. Although this method is well established it does have complications that can result in a high rate of animal attrition. To this end, the procedure introduced here describes an alternative to the oral gavage method in which the desired drug is incorporated into a tastant, orally dissolving strip (ODS) that can simply be presented to the test animal where it is then rapidly taken up with minimal manipulation of the test subject. Herein, we demonstrate that preclinical, oral drug delivery using the ODS method represents a safe, convenient, and humane alternative to oral gavage. PMID:27078261

Evaluation of the appropriateness of the preclinical phase (stage A and stage B) of heart failure Management in Outpatient clinics in Italy rationale and design of the 'VASTISSIMO' study.

PubMed

Mureddu, Gian F; Nistri, Stefano; Faggiano, Pompilio; Fimiani, Biagio; Misuraca, Gianfranco; Maggi, Antonio; Gori, Anna M; Uguccioni, Massimo; Tavazzi, Luigi; Zito, Giovanni B

2016-07-01

Early detection of heart failure, when still preclinical, is fundamental. Therefore, it is important to assess whether preclinical heart failure management by cardiologists is adequate. The VASTISSIMO study ('EValuation of the AppropriateneSs of The preclInical phase (Stage A and Stage B) of heart failure Management in Outpatient clinics in Italy') is a prospective nationwide study aimed to evaluate the appropriateness of diagnosis and management of preclinical heart failure (stages A and B) by cardiologists working in outpatient clinics in Italy. Secondary goals are to verify if an online educational course for cardiologists can improve management of preclinical heart failure, and evaluate how well cardiologists are aware of patients' adherence to medications. The study involves 80 outpatient cardiology clinics distributed throughout Italy, affiliated either to the Hospital Cardiologists Association or to the Regional Association of Outpatient Cardiologists, and is designed with two phases of consecutive outpatient enrolment each lasting 1 month. In phase 1, physicians' awareness of the risk of heart failure and their decision-making process are recorded. Subsequently, half of the cardiologists are randomized to undergo an online educational course aimed to improve preclinical heart failure management through implementation of guideline recommendations. At the end of the course, all cardiologists are evaluated (phase 2) to see whether changes in clinical management have occurred in those who underwent the educational program versus those who did not. Patients' adherence to prescribed medications will be assessed through the Morisky Self-report Questionnaire. This study should provide valuable information about cardiologists' awareness of preclinical heart failure and the appropriateness of clinical practice in outpatient cardiology clinics in Italy.

[Psychiatric Emergencies in the Preclinical Emergency Medicine Service in Ulm, Germany in 2000 and 2010, and Practical Consequences].

PubMed

Schönfeldt-Lecuona, Carlos; Gahr, Maximilian; Schütz, Stefan; Lang, Dirk; Pajonk, Frank Gerald Bernhard; Connemann, Bernhard J; Muth, Claus-Martin; Freudenmann, Roland W

2017-07-01

Background  Psychiatric emergencies (PE) in preclinical emergency medical services are about 5 - 10 % of all emergencies and represent often a source of difficulties in handling for the non-psychiatric professional helpers that deal with them. Studies informing about quantitative and qualitative changes of PEs in preclinical emergency medicine in Germany are scarce. Methods  Therefore, we conducted a retrospective cross-sectional study of PE in a preclinical emergency medical service based on the protocols of the emergency ambulance of the Section for Emergency Medicine at the University Hospital Ulm comparing the years 2000 and 2010. Results  We observed a significant increase of PEs from 8.8 % in the year 2000 (n = 285, from a total of n = 3227) to 10.3 % in 2010 (n = 454, from a total of n = 4425). In both years intoxications were the most common PE [2000: n = 116 (44.4 %); 2010: n = 171 (37.7 %)], followed by suicide-related behavior [2000: n = 59 (22.6 %); 2010: n = 78 (17.2 %)] and acute anxiety disorders [2000: n = 37 (13 %); 2010: n = 105 (23.1 %)]. The mentioned three conditions accounted for about 80 % of all PE. Most frequently PE occurred at the weekend and with the highest density in the evening and at night (18 - 24 h) in both years. Patients with PE were predominantly men, but the rate of women causing PE increased between 2000 and 2010. Discussion/Conclusion  This study provides preliminary data on current trends in PEs in preclinical emergency medicine in Germany and has implications for improving the medical care provided. © Georg Thieme Verlag KG Stuttgart · New York.

Preclinical electrogastrography in experimental pigs

PubMed Central

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

2010-01-01

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

Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

PubMed

Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie

2016-09-21

We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

PubMed

Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

2013-01-01

The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

A De Novo Tool to Measure the Preclinical Learning Climate of Medical Faculties in Turkey

ERIC Educational Resources Information Center

Yilmaz, Nilufer Demiral; Velipasaoglu, Serpil; Sahin, Hatice; Basusta, Bilge Uzun; Midik, Ozlem; Coskun, Ozlem; Budakoglu, Isil Irem; Mamakli, Sumer; Tengiz, Funda Ifakat; Durak, Halil Ibrahim; Ozan, Sema

2015-01-01

Although several scales are used to measure general and clinical learning climates, there are no scales that assess the preclinical learning climate. Therefore, the purpose of this study was to develop an effective measurement tool in order to assess the preclinical learning climate. In this cross-sectional study, data were collected from 3,540…

Exploratory study of factors related to educational scores of first preclinical year medical students.

PubMed

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

2014-03-01

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R(2) = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction.

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

PubMed

Grill, Joshua D; Karlawish, Jason

2017-12-06

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

Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies

PubMed Central

Kühl, Susanne J.; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R.; Kühl, Michael

2017-01-01

Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee “New Media” [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the acquisition of knowledge by MC exams. Results: On a Likert scale from 1 (strongly disagree) to 6 (strongly agree), the students in the IC intervention groups could be seen to be much more motivated (5.53) than students in the control group (4.01). Students in the IC intervention groups also recognised the relevance of the learning content much more clearly (5.44) than students in the control group (4.01). Furthermore, the IC group also observed that additional competencies were trained in addition to the biochemistry content. In addition, the IC intervention group award the event a school grade of 1.53, the traditional control group a grade of 2.96. The teaching videos were rated very positively by both groups with an average school grade of 1.3 in each case. A qualitative analysis showed that the motivation and a positive attitude of the lecturers played a decisive role in the successful implementation of the IC method. Discussion and conclusion: Pre-clinical students display a high acceptance of the e-learning-based IC method. Teaching communication competencies in a biochemistry seminar was also rated very positively by the students. The quality of the teaching video and the motivation of the lecturers were shown to be a critical parameter for the successful performance of the IC method. What’s more, the IC method can contribute to implementing a competence orientation in medical studies. PMID:28890922

Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies.

PubMed

Kühl, Susanne J; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R; Kühl, Michael

2017-01-01

Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee "New Media" [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the acquisition of knowledge by MC exams. Results: On a Likert scale from 1 (strongly disagree) to 6 (strongly agree), the students in the IC intervention groups could be seen to be much more motivated (5.53) than students in the control group (4.01). Students in the IC intervention groups also recognised the relevance of the learning content much more clearly (5.44) than students in the control group (4.01). Furthermore, the IC group also observed that additional competencies were trained in addition to the biochemistry content. In addition, the IC intervention group award the event a school grade of 1.53, the traditional control group a grade of 2.96. The teaching videos were rated very positively by both groups with an average school grade of 1.3 in each case. A qualitative analysis showed that the motivation and a positive attitude of the lecturers played a decisive role in the successful implementation of the IC method. Discussion and conclusion: Pre-clinical students display a high acceptance of the e-learning-based IC method. Teaching communication competencies in a biochemistry seminar was also rated very positively by the students. The quality of the teaching video and the motivation of the lecturers were shown to be a critical parameter for the successful performance of the IC method. What's more, the IC method can contribute to implementing a competence orientation in medical studies.

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

PubMed Central

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

2016-01-01

Background The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself, have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. Methods We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. MEDLINE, EMBASE AND COCHRANE databases were searched. Results The literature search yielded 1314 unique articles. Fifteen pre-clinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g. ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps and prostaglandins. High dose ASA may be the drug of choice. A meta-analysis of 3 clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36–0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. Conclusion This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models is being evaluated to guide optimal timing and dose, before prospective randomized trials. PMID:27984533

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

PubMed

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

2017-01-01

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

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

PubMed

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

2018-03-30

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from academic institutions, funding agencies, and animal ethics authorities. © 2018 American Heart Association, Inc.

Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review.

PubMed

Park, Angela; Barrera-Ramirez, Juliana; Ranasinghe, Indee; Pilon, Sophie; Sy, Richmond; Fergusson, Dean; Allan, David S

2016-06-01

Mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) are used in cell-based regenerative therapy. HMG CoA reductase inhibitors (statins) appear promising in blocking apoptosis, prolonging progenitor cell survival and improving their capacity to repair organ function. We performed a systematic review of preclinical and clinical studies to clarify whether statins can improve cell-based repair of organ injury. MEDLINE, EMBASE, and PUBMED databases were searched (1947 to June 25, 2013). Controlled clinical and pre-clinical studies were included that evaluated statin therapy used alone or in combination with MSCs or EPCs in patients or animals with organ injury. After screening 771 citations, 100 records underwent full eligibility screening of which 38 studies met eligibility and were included in the review: Studies were grouped into pre-clinical studies that involved statin treatment in combination with cell therapy (18 studies), preclinical studies of statin therapy alone (13 studies) and clinical studies of statin therapy (7 studies). Studies addressed cardiac injury (14 studies), vascular disorders (15 studies), neurologic conditions (8 studies) and bone fractures (1 study). Pre-clinical studies of statins in combination with MSC infusion (15 studies) or EPC therapy (3 studies) were described and despite marked heterogeneity in reporting outcomes of cellular analysis and organ function, all of these cell-based pre-clinical studies reported improved organ recovery with the addition of statin therapy. Moreover, 13 pre-clinical studies involved the administration of a statin drug alone to animals. An increase in EPC number and/or function (no studies of MSCs) was reported in 11 of these studies (85 %) and improved organ function in 12 studies (92 %). We also identified 7 clinical studies and none involved the administration of cells but described an increased number and/or function of EPCs (no studies of MSCs) and improved organ function with statin therapy (1.2-fold to 35-fold improvement over controls) in all 7 studies. Our systematic review provides a foundation of encouraging results that support further study of statins in regenerative therapy to augment the number and/or function of MSCs used in cell-based repair and to augment the number and function of EPCs in vivo to repair damaged tissues. Larger studies are needed to ensure safety and confirm clinical benefits.

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

PubMed

Fiorentino, Marco; Kellum, John A

2018-05-23

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

The effect of learning styles and study behavior on success of preclinical students in pharmacology.

PubMed

Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

2016-01-01

To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

Terminal-decline effects for select cognitive tasks after controlling for preclinical dementia.

PubMed

Laukka, Erika J; MacDonald, Stuart W S; Bäckman, Lars

2008-05-01

In a previous study, the authors found no accelerated decline in close proximity to death for a measure of global cognitive functioning, after excluding persons in a preclinical phase of dementia. However, specific cognitive tasks might be more sensitive to terminal-decline effects. The purpose of this study was to explore possible terminal-decline effects for a range of cognitive tasks after controlling for preclinical dementia. Community-based cohort study. The Kungsholmen district of Stockholm. A total of 585 persons (75+ years) were repeatedly assessed over an 11-year period. Level and change in cognitive performance were compared for three groups: persons in close proximity to death, persons in a preclinical phase of dementia, and persons who remained alive and nondemented throughout the study. Tasks assessing primary and episodic memory, verbal ability, and visuospatial skill. Compared with an analysis where all dead subjects were included in the impending-death group, removing the preclinical dementia cases resulted in markedly attenuated mortality-related effects. However, the impending-death group still declined at a faster rate relative to the comparison group on Digit Span-forward, word recognition, and category fluency. Notably, these were tasks for which the comparison group showed no significant decline. A considerable proportion of the terminal-decline effect is accounted for by the impact of preclinical dementia. However, for tasks that are relatively resistant to age-related change, such effects might be detected independently of preclinical dementia.

Available Resources | Division of Cancer Prevention

Cancer.gov

Preclinical pharmacology and efficacy studies Identification and evaluation of intermediate biomarkers Formulation optimization for enhanced bioavailability and clinical usefulness Analytical method development for investigational agents in bulk form and in biological fluids and tissues PK and PK-PD modeling to optimize dosing regimen Scale-up non-cGMP and cGMP production of

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

PubMed

Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D; Mitra, Ashim K

2017-02-28

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2015-01-01

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

Do Stages of Dentistry Training Affect Anxiety Provoking Situations?

PubMed Central

Obarisiagbon, A; Azodo, CC; Omoaregba, JO; James, BO

2014-01-01

Background: Undetected and unaddressed anxiety negatively affects performance in clinical learning environments. Aim: The aim was to investigate the anxiety provoking situations in clinical dental care delivery among students of preclinical and clinical years and house officers. Subjects and Methods: A 38-item modified Moss and McManus clinical anxiety questionnaire, general health questionnaire-12 (GHQ-12) and the Zung self-rating anxiety scale were the data collection tools. Results: Of the 84 recruited, 79 completed the study giving 94.0% (79/84) response rate. The median age of the participants was 25 years with 50.6% (40/79) being 20-25 years. Gender distribution revealed that males constituted 60.8% (48/79) of the participants. House officers constituted 29.1% (23/79), clinical students 36.7% (29/79), and preclinical students 34.2 (27/79) of the participants. The top anxiety provoking situations using the modified Moss and McManus clinical anxiety questionnaire were extracting wrong tooth 3.24 (1.06), inability to pass examination 3.32 (1.01), achieving examination requirement 3.19 (1.01), fracturing a tooth 3.08 (0.98) and accidental pulp exposure 2.96 (1.04). Getting diagnosis wrong, help in faint episode, not developing radiograph properly and coping with children were the anxiety provoking situations that showed statistically significant difference in the 3 studied training stages of dentistry. Bonferroni post-hoc analysis significant difference was in the preclinical and clinical students’ pair for getting diagnosis wrong, not developing radiograph properly and coping with children while house officers/clinical students and house officers/preclinical students’ pairs were for help in faint episode. Overall, 2.5% (2/79) had severe, 69.6% (55/79) moderate, 26.6% (21/79) mild clinical anxiety while 1 (1.3%) of the participants expressed no clinical anxiety. Conclusion: Data from this study revealed that the clinical anxiety of moderate severity was prevalent among the studied dental healthcare students. The anxiety-provoking situations were also found to be majorly similar in preclinical, clinical and post-graduation clinical stages of dental training stages in Nigeria. PMID:25506478

Reproducibility of preclinical animal research improves with heterogeneity of study samples

PubMed Central

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

2018-01-01

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

From Theory to Application: A Study of Knowledge Transfer in Dental Education

ERIC Educational Resources Information Center

Peltz, Ivy D.

2014-01-01

Traditionally, dental education is divided into two phases: pre-clinical and clinical education. The pre-clinical phase of dental education includes the assimilation of theoretical topical knowledge in addition to the completion of simulated exercises. Upon completion of and demonstration of competency in their pre-clinical courses, students begin…

Physiological remodeling of bifurcation aneurysms: preclinical results of the eCLIPs device.

PubMed

Marotta, Thomas R; Riina, Howard A; McDougall, Ian; Ricci, Donald R; Killer-Oberpfalzer, Monika

2018-02-01

OBJECTIVE Intracranial bifurcation aneurysms are complex lesions for which current therapy, including simple coiling, balloon- or stent-assisted coiling, coil retention, or intrasaccular devices, is inadequate. Thromboembolic complications due to a large burden of intraluminal metal, impedance of access to side branches, and a high recurrence rate, due largely to the unmitigated high-pressure flow into the aneurysm (water hammer effect), are among the limitations imposed by current therapy. The authors describe herein a novel device, eCLIPs, and its use in a preclinical laboratory study that suggests the device's design and functional features may overcome many of these limitations. METHODS A preclinical model of wide-necked bifurcation aneurysms in rabbits was used to assess functional features and efficacy of aneurysm occlusion by the eCLIPs device. RESULTS The eCLIPs device, in bridging the aneurysm neck, allows coil retention, disrupts flow away from the aneurysm, leaves the main vessel and side branches unencumbered by intraluminal metal, and serves as a platform for endothelial growth across the neck, excluding the aneurysm from the circulation. CONCLUSIONS The eCLIPs device permits physiological remodeling of the bifurcation.

The Roles of Cigarette Smoking and the Lung in the Transitions between Phases of Preclinical Rheumatoid Arthritis

PubMed Central

Sparks, Jeffrey A.; Karlson, Elizabeth W.

2016-01-01

While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis. PMID:26951253

Mechanisms of Neurodegeneration and Regeneration in Alcoholism

PubMed Central

Crews, Fulton T.; Nixon, Kim

2009-01-01

Aims: This is a review of preclinical studies covering alcohol-induced brain neuronal death and loss of neurogenesis as well as abstinence-induced brain cell genesis, e.g. brain regeneration. Efforts are made to relate preclinical studies to human studies. Methods: The studies described are preclinical rat experiments using a 4-day binge ethanol treatment known to induce physical dependence to ethanol. Neurodegeneration and cognitive deficits following binge treatment mimic the mild degeneration and cognitive deficits found in humans. Various histological methods are used to follow brain regional degeneration and regeneration. Results: Alcohol-induced degeneration occurs due to neuronal death during alcohol intoxication. Neuronal death is related to increases in oxidative stress in brain that coincide with the induction of proinflammatory cytokines and oxidative enzymes that insult brain. Degeneration is associated with increased NF-κB proinflammatory transcription and decreased CREB transcription. Corticolimbic brain regions are most sensitive to binge-induced degeneration and induce relearning deficits. Drugs that block oxidative stress and NF-κB transcription or increase CREB transcription block binge-induced neurodegeneration, inhibition of neurogenesis and proinflammatory enzyme induction. Regeneration of brain occurs during abstinence following binge ethanol treatment. Bursts of proliferating cells occur across multiple brain regions, with many new microglia across brain after months of abstinence and many new neurons in neurogenic hippocampal dentate gyrus. Brain regeneration may be important to sustain abstinence in humans. Conclusions: Alcohol-induced neurodegeneration occurs primarily during intoxication and is related to increased oxidative stress and proinflammatory proteins that are neurotoxic. Abstinence after binge ethanol intoxication results in brain cell genesis that could contribute to the return of brain function and structure found in abstinent humans. PMID:18940959

Lacking quality in research: Is behavioral neuroscience affected more than other areas of biomedical science?

PubMed

Bespalov, Anton; Steckler, Thomas

2018-04-15

There are many reasons why novel therapeutics fail in clinical trials but these failures are often attributed to lacking quality of preclinical data. These problems are not limited to any specific therapeutic area, academic or industrial research and are due in large part to several generic factors influencing research quality (e.g., related to definition of pre-specified endpoints, principles of study design and analysis, biased reporting, and lack of proper training). Yet, neuroscience drug discovery is often said to be affected more than the other fields. Within neuroscience, behavioral studies are the most blamed for being poorly designed, underpowered and mis-reported and there are indeed several factors that may be rather unique for behavioral research, such as a multitude of environmental conditions that are difficult to control and that are often not reported, ethical concerns about in vivo research and the pressure to reduce animal numbers, contributing to under-powered studies, and the complexity of study design and analysis, creating too much room for post hoc data massaging and selective reporting. Also, the blood-brain barrier as a frequently neglected complicating factor has to be considered in CNS research. The importance of these factors is increasingly recognized and urgent efforts are needed to demonstrate that behavioral methods of preclinical neuroscience research deliver results that can be as robust as with the non-behavioral methods Until this goal is achieved, behavioral neuroscience and neuroscience in general may be losing young talent, CNS drug discovery may lack the needed investment and this field may indeed be amongst the most affected by the current preclinical data quality crisis. Copyright © 2017 Elsevier B.V. All rights reserved.

Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy.

PubMed

Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison; Kass, David A; McNally, Elizabeth M; Metzger, Joseph M; Spurney, Christopher F; Kinnett, Kathi

2016-02-01

A recent working group meeting focused on contemporary cardiac issues in Duchenne muscular dystrophy (DMD) was hosted by the National Heart, Lung, and Blood Institute in collaboration with the Parent Project Muscular Dystrophy. An outcome of this meeting was to provide freely available detailed protocols for preclinical animal studies. The goal of these protocols is to improve the quality and reproducibility of cardiac preclinical studies aimed at developing new therapeutics for the prevention and treatment of DMD cardiomyopathy.

Regulatory considerations on new adjuvants and delivery systems.

PubMed

Sesardic, D

2006-04-12

New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

The prevalence and consequences of burnout on a group of preclinical dental students

PubMed Central

Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

2015-01-01

Objective: The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Materials and Methods: Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. Results: About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Conclusions: Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment. PMID:26430363

Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer’s Disease: A 7-Year Follow-Up Study

PubMed Central

Waragai, Masaaki; Moriya, Masaru; Nojo, Takeshi

2017-01-01

Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice. PMID:28968236

Magnetic resonance imaging with hyperpolarized agents: methods and applications

NASA Astrophysics Data System (ADS)

Adamson, Erin B.; Ludwig, Kai D.; Mummy, David G.; Fain, Sean B.

2017-07-01

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

PubMed Central

Lalu, Manoj M; Sullivan, Katrina J; Mei, Shirley HJ; Moher, David; Straus, Alexander; Fergusson, Dean A; Stewart, Duncan J; Jazi, Mazen; MacLeod, Malcolm; Winston, Brent; Marshall, John; Hutton, Brian; Walley, Keith R; McIntyre, Lauralyn

2016-01-01

Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18–0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies. DOI: http://dx.doi.org/10.7554/eLife.17850.001 PMID:27870924

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study

PubMed Central

Aschenbrenner, Andrew J.; Balota, David A.; Fagan, Anne M.; Duchek, Janet M.; Benzinger, Tammie L.S.; Morris, John C.

2015-01-01

Objective Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed in order to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. Method All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within two years of the initial assessment to collect cerebrospinal fluid (CSF) and a PET-PIB scan for amyloid imaging. Results Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. Conclusion These results indicate that measures of attentional control and episodic memory can be utilized to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change. PMID:26416094

Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed?

PubMed Central

Nicotra, Lauren; Tuke, Jonathan; Grace, Peter M.; Rolan, Paul E.; Hutchinson, Mark R.

2014-01-01

Translating promising preclinical drug discoveries to successful clinical trials remains a significant hurdle in pain research. Although animal models have significantly contributed to understanding chronic pain pathophysiology, the majority of research has focused on male rodents using testing procedures that produce sex difference data that do not align well with comparable clinical experiences. Additionally, the use of animal pain models presents ongoing ethical challenges demanding continuing refinement of preclinical methods. To this end, this study sought to test a quantitative allodynia assessment technique and associated statistical analysis in a modified graded nerve injury pain model with the aim to further examine sex differences in allodynia. Graded allodynia was established in male and female Sprague Dawley rats by altering the number of sutures placed around the sciatic nerve and quantified by the von Frey test. Linear mixed effects modeling regressed response on each fixed effect (sex, oestrus cycle, pain treatment). On comparison with other common von Frey assessment techniques, utilizing lower threshold filaments than those ordinarily tested, at 1 s intervals, appropriately and successfully investigated female mechanical allodynia, revealing significant sex and oestrus cycle difference across the graded allodynia that other common behavioral methods were unable to detect. Utilizing this different von Frey approach and graded allodynia model, a single suture inflicting less allodynia was sufficient to demonstrate exaggerated female mechanical allodynia throughout the phases of dioestrus and pro-oestrus. Refining the von Frey testing method, statistical analysis technique and the use of a graded model of chronic pain, allowed for examination of the influences on female mechanical nociception that other von Frey methods cannot provide. PMID:24592221

A Flexible, Preclinical, Medical School Curriculum Increases Student Academic Productivity and the Desire to Conduct Future Research

ERIC Educational Resources Information Center

Peacock, Justin G.; Grande, Joseph P.

2015-01-01

In 2006, small blocks of flexible curriculum time, termed selectives, were implemented in the Mayo Medical School preclinical curriculum. Selectives permitted students to pursue professional endeavors, such as research, service, and career exploration, in the preclinical years. The purpose of this study was to survey current and former Mayo…

Should applicants to Nottingham University Medical School study a non-science A-level? A cohort study

PubMed Central

Yates, Janet; Smith, Jennifer; James, David; Ferguson, Eamonn

2009-01-01

Background It has been suggested that studying non-science subjects at A-level should be compulsory for medical students. Our admissions criteria specify only Biology, Chemistry and one or more additional subjects. This study aimed to determine whether studying a non-science subject for A-level is an independent predictor of achievement on the undergraduate medical course. Methods The subjects of this retrospective cohort study were 164 students from one entry-year group (October 2000), who progressed normally on the 5-year undergraduate medical course at Nottingham. Pre-admission academic and socio-demographic data and undergraduate course marks were obtained. T-test and hierarchical multiple linear regression analyses were undertaken to identify independent predictors of five course outcomes at different stages throughout the course. Results There was no evidence that the choice of science or non-science as the third or fourth A-level subject had any influence on course performance. Demographic variables (age group, sex, and fee status) had some predictive value but ethnicity did not. Pre-clinical course performance was the strongest predictor in the clinical phases (pre-clinical Themes A&B (knowledge) predicted Clinical Knowledge, p < 0.001, and pre-clinical Themes C&D (skills) predicted Clinical Skills, p = < 0.01). Conclusion This study of one year group at Nottingham Medical School provided no evidence that the admissions policy on A-level requirements should specify the choice of third or fourth subject. PMID:19159444

The Impact of Supervision on Internal Medicine Residents' Attitudes and Management of Depression in Primary Care: A Pilot Study

ERIC Educational Resources Information Center

Milone, Jennifer M.; Gottumukkala, Aruna; Ward, Christopher P.; York, Kaki M.

2013-01-01

Objective: The authors examined the effect of supervision on internal medicine residents' attitudes toward and management of depression. Method: Internal medicine residents completed a survey during preclinical conferences. The survey included a published, validated questionnaire, the Depression Attitude Questionnaire, and items developed by the…

Preclinical evaluation of posterior spine stabilization devices: can the current standards represent basic everyday life activities?

PubMed

La Barbera, Luigi; Galbusera, Fabio; Wilke, Hans-Joachim; Villa, Tomaso

2016-09-01

To discuss whether the available standard methods for preclinical evaluation of posterior spine stabilization devices can represent basic everyday life activities and how to compare the results obtained with different procedures. A comparative finite element study compared ASTM F1717 and ISO 12189 standards to validated instrumented L2-L4 segments undergoing standing, upper body flexion and extension. The internal loads on the spinal rod and the maximum stress on the implant are analysed. ISO recommended anterior support stiffness and force allow for reproducing bending moments measured in vivo on an instrumented physiological segment during upper body flexion. Despite the significance of ASTM model from an engineering point of view, the overly conservative vertebrectomy model represents an unrealistic worst case scenario. A method is proposed to determine the load to apply on assemblies with different anterior support stiffnesses to guarantee a comparable bending moment and reproduce specific everyday life activities. The study increases our awareness on the use of the current standards to achieve meaningful results easy to compare and interpret.

Extracurricular activities associated with stress and burnout in preclinical medical students.

PubMed

Fares, Jawad; Saadeddin, Zein; Al Tabosh, Hayat; Aridi, Hussam; El Mouhayyar, Christopher; Koleilat, Mohamad Karim; Chaaya, Monique; El Asmar, Khalil

2016-09-01

This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Development and validation of an LC-MS method for determination of Karanjin in rat plasma: application to preclinical pharmacokinetics.

PubMed

Yi, Deliang; Wang, Zhihua; Yi, Longzhi

2015-04-01

A selective and sensitive liquid chromatography-mass spectrometry (MS) method was developed and validated for the determination of karanjin in rat plasma. The target analyte, together with the internal standard (warfarin), was extracted from rat plasma by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a ZORBAX SB-C18 column using a mixture of acetonitrile and 0.1% aqueous formic acid as the mobile phase with linear gradient elution. MS detection was performed on a single quadrupole MS by selected ion monitoring mode via a positive electrospray ionization source. The assay exhibited a linear dynamic range of 2.50-3,000 ng/mL for karanjin. The intra- and inter-day precision was <10.8%, and the intra- and inter-day accuracy was <9.2%. The validated method has been applied to the preclinical pharmacokinetic studies of karanjin following oral administration of 5, 10 and 20 mg/kg karanjin to rats. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Rigor or mortis: best practices for preclinical research in neuroscience.

PubMed

Steward, Oswald; Balice-Gordon, Rita

2014-11-05

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Optimization of high grade glioma cell culture from surgical specimens for use in clinically relevant animal models and 3D immunochemistry.

PubMed

Hasselbach, Laura A; Irtenkauf, Susan M; Lemke, Nancy W; Nelson, Kevin K; Berezovsky, Artem D; Carlton, Enoch T; Transou, Andrea D; Mikkelsen, Tom; deCarvalho, Ana C

2014-01-07

Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor. Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies.

Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in Clinically Relevant Animal Models and 3D Immunochemistry

PubMed Central

Hasselbach, Laura A.; Irtenkauf, Susan M.; Lemke, Nancy W.; Nelson, Kevin K.; Berezovsky, Artem D.; Carlton, Enoch T.; Transou, Andrea D.; Mikkelsen, Tom; deCarvalho, Ana C.

2014-01-01

Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor. Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies. PMID:24429465

Rapid and sensitive ultra-high-pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study.

PubMed

Davanço, Marcelo Gomes; de Campos, Michel Leandro; Peccinini, Rosângela Gonçalves

2015-07-01

Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV-vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C18 protected by an Acquity® UHPLC HSS SB C18 VanGuard guard column and detection at 324 nm. The mobile phase consisted of ultrapure water-acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 μL, and the run time was just 2 min. The samples were kept at 25°C until injection and the column at 45°C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15-20 µg/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies. Copyright © 2014 John Wiley & Sons, Ltd.

An integrated 2-year clinical skills peer tutoring scheme in a UK-based medical school: perceptions of tutees and peer tutors

PubMed Central

2018-01-01

Background Several benefits of peer tutoring in medical school teaching have been described. However, there is a lack of research on the perceptions of peer tutoring, particularly from tutees who partake in a long-term clinical skills scheme integrated into the medical school curriculum. This study evaluates the opinions of preclinical tutees at the end of a 2-year peer-tutored clinical skills program and peer tutors themselves. Methods A cross-sectional study was conducted in a UK-based medical school that primarily utilizes peer tutoring for clinical skills teaching. A questionnaire was designed to assess the views of preclinical tutees and peer tutors. Likert scales were used to grade responses and comment boxes to collect qualitative data. Results Sixty-five questionnaires were collected (52 tutees, 13 peer tutors). Seventy-nine percent of students felt satisfied with their teaching, and 70% felt adequately prepared for clinical placements. Furthermore, 79% believed that peer tutoring is the most effective method for clinical skills teaching. When compared to faculty teaching, tutees preferred being taught by peer tutors (63%), felt more confident (73%), and were more willing to engage (77%). All peer tutors felt that teaching made them more confident in their Objective Structured Clinical Examination performance, and 91% agreed that being a tutor made them consider pursuing teaching in the future. Thematic analysis of qualitative data identified 3 themes regarding peer tutoring: a more comfortable environment (69%), a more personalized teaching approach (34%), and variation in content taught (14%). Conclusion Preclinical tutees prefer being taught clinical skills by peer tutors compared to faculty, with the peer tutors also benefitting. Studies such as this, looking at long-term schemes, further validate peer tutoring and may encourage more medical schools to adopt this method as an effective way of clinical skills teaching. PMID:29922105

Fracture healing: a consensus report from the International Osteoporosis Foundation Fracture Working Group.

PubMed

Silverman, S L; Kupperman, E S; Bukata, S V

2016-07-01

We used the RAND UCLA appropriateness method to decide appropriateness of use of osteoporosis medication after incident fracture and potential for fracture healing and make suggestions for trial design for clinical and preclinical research. To develop appropriateness criteria to assist in the use and study of osteoporosis medications in patients with recent fracture and in the potential use of osteoporosis medications to enhance delayed fracture healing. To promote further research by suggesting preclinical and clinical trial design for studies where fracture healing is the endpoint. RAND/UCLA appropriateness method (RUAM). A panel of experts, both members and non-members of the International Osteoporosis Foundation Fracture Working Group, were identified consisting of geriatricians, rheumatologists, orthopedists, endocrinologists, and internists. This resulted in a round 1 panel of 15 panelists, round 2 panel of 15 members, and a round 3 panel of 14 members. Agreement on statements and scenarios using RUAM. Three rounds of voting by panelists took place. Agreement in a third round was reached for 111 statements and scenarios, measured by median panel ratings and the amount of dispersion of panel ratings, based on the interpercentile range. An expert panel validated a set of statements and scenarios about the use of osteoporosis medications after incident fracture and use of these medications to enhance delayed fracture healing and made recommendations for study designs to investigate the effect of osteoporosis medications on fracture healing. The result of this exercise is intended to assist in improving patient care by identifying the appropriateness of use of osteoporosis medications after fracture and in fracture healing and to make suggestions for further preclinical and clinical research.

Medical students as teachers at CoSMO, Columbia University's student-run clinic: a pilot study and literature review.

PubMed

Hamso, Magni; Ramsdell, Amanda; Balmer, Dorene; Boquin, Cyrus

2012-01-01

Although medical students are expected to teach as soon as they begin residency, medical schools have just recently begun adding teacher training to their curricula. Student-run clinics (SRCs) may provide opportunities in clinical teaching before residency. The aim of this pilot study was to examine students' experiences in clinical teaching at Columbia Student Medical Outreach (CoSMO), Columbia University's SRC, during the 2009-2010 school year. A mixed-methods approach was used. Data included closed and open-ended surveys (n = 34), combined interviews with preclinical and clinical student pairs (n = 5), individual interviews (n = 10), and focus groups (n = 3). The transcripts were analyzed using the principles of grounded theory. Many students had their first clinical teaching experience while volunteering at CoSMO. Clinical students' ability to teach affected the quality of the learning experience for their preclinical peers. Preclinical students who asked questions and engaged in patient care challenged their clinical peers to balance teaching with patient care. Clinical students began to see themselves as teachers while volunteering at CoSMO. The practical experiences in clinical teaching that students have at SRCs can supplement classroom-based trainings. Medical schools might revisit their SRCs as places for exposure to clinical teaching.

[Staged oncological screening with TG test].

PubMed

Bakhlaev, I E; Ageenko, A I; Rolik, I S

2006-01-01

The authors present their analysis of screening methods used for early diagnostics of cancer of various localization and for detection of high-risk individuals. They offer a program of step-by-step screening that makes it possible to cover more population with prophylactic examination and to reduce the need for special examination methods. TG-test is a universal and the most informative blastomatous process indicator at any stage, including the preclinical one. The practical screening results double the revealing rate of oncopathology and allow for three-fold reduction in the diagnostic costs compared with standard methods of cancer diagnostics. The medical efficiency of the oncological screening is high; in one third of the examined patients a tumor is diagnosed at the preclinical stage.

Advances in Progenitor Cell Therapy Using Scaffolding Constructs for Central Nervous System Injury

PubMed Central

Walker, Peter A.; Aroom, Kevin R.; Jimenez, Fernando; Shah, Shinil K.; Harting, Matthew T.; Gill, Brijesh S.

2010-01-01

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Current clinical therapy is focused on optimization of the acute/subacute intracerebral milieu, minimizing continued cell death, and subsequent intense rehabilitation to ameliorate the prolonged physical, cognitive, and psychosocial deficits that result from TBI. Adult progenitor (stem) cell therapies have shown promise in pre-clinical studies and remain a focus of intense scientific investigation. One of the fundamental challenges to successful translation of the large body of pre-clinical work is the delivery of progenitor cells to the target location/organ. Classically used vehicles such as intravenous and intra arterial infusion have shown low engraftment rates and risk of distal emboli. Novel delivery methods such as nanofiber scaffold implantation could provide the structural and nutritive support required for progenitor cell proliferation, engraftment, and differentiation. The focus of this review is to explore the current state of the art as it relates to current and novel progenitor cell delivery methods. PMID:19644777

A Naturalistic Study of Driving Behavior in Older Adults and Preclinical Alzheimer Disease.

PubMed

Babulal, Ganesh M; Stout, Sarah H; Benzinger, Tammie L S; Ott, Brian R; Carr, David B; Webb, Mollie; Traub, Cindy M; Addison, Aaron; Morris, John C; Warren, David K; Roe, Catherine M

2017-01-01

A clinical consequence of symptomatic Alzheimer's disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with ( n = 10) and without ( n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

Examination performances of German and international medical students in the preclinical studying-term – A descriptive study

PubMed Central

Huhn, D.; Resch, F.; Duelli, R.; Möltner, A.; Huber, J.; Karimian Jazi, K.; Amr, A.; Eckart, W.; Herzog, W.; Nikendei, C.

2014-01-01

Introduction: Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. Method: A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). Results: German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all p<.05). The performance of students with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (p<.05). Furthermore, German students completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (<.01). Discussion: Due to its poorer performance in written and oral examinations and its simultaneously longer duration of study, the group of non-German medical students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations. PMID:25228931

Obesity and stroke: Can we translate from rodents to patients?

PubMed Central

Haley, Michael J

2016-01-01

Obesity is a risk factor for stroke and is consequently one of the most common co-morbidities found in patients. There is therefore an identified need to model co-morbidities preclinically to allow better translation from bench to bedside. In preclinical studies, both diet-induced and genetically obese rodents have worse stroke outcome, characterised by increased ischaemic damage and an altered inflammatory response. However, clinical studies have reported an ‘obesity paradox’ in stroke, characterised by reduced mortality and morbidity in obese patients. We discuss the potential reasons why the preclinical and clinical studies may not agree, and review the mechanisms identified in preclinical studies through which obesity may affects stroke outcome. We suggest inflammation plays a central role in this relationship, as obesity features increases in inflammatory mediators such as C-reactive protein and interleukin-6, and chronic inflammation has been linked to worse stroke risk and outcome. PMID:27655337

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

PubMed Central

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

2015-01-01

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

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

PubMed Central

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Ushering in the study and treatment of preclinical Alzheimer disease.

PubMed

Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

2013-07-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

PubMed

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

2015-10-01

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

Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

PubMed Central

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

2015-01-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

A Canine Arthroscopic Anterior Cruciate Ligament Reconstruction Model for Study of Synthetic Augmentation of Tendon Allografts.

PubMed

Cook, James L; Smith, Pat; Stannard, James P; Pfeiffer, Ferris; Kuroki, Keiichi; Bozynski, Chantelle C; Cook, Cristi

2017-09-01

Novel graft types, fixation methods, and means for augmenting anterior cruciate ligament (ACL) reconstructions require preclinical validation prior to safe and effective clinical application. The objective of this study was to describe and validate a translational canine model for all-inside arthroscopic complete ACL reconstruction using a quadriceps tendon allograft with internal brace (QTIB). With institutional approval, adult research hounds underwent complete transection of the native ACL followed by all-inside ACL reconstruction using the novel QTIB construct with suspensory fixation ( n  = 10). Contralateral knees were used as nonoperated controls ( n  = 10). Dogs were assessed over a 6-month period using functional, diagnostic imaging, gross, biomechanical, and histologic outcome measures required for preclinical animal models. Study results suggest that the novel QTIB construct used for complete ACL reconstruction can provide sustained knee stability and function without the development of premature osteoarthritis in a rigorous and valid preclinical model. The unique configuration of the QTIB construct-the combination of a tendon allograft with a synthetic suture tape internal brace-allowed for an effective biologic-synthetic load-sharing ACL construct. It prevented early failure, allowed for direct, four-zone graft-to-bone healing, and functional graft remodeling while avoiding problems noted with use of all-synthetic grafts. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pre-clinical MR elastography: Principles, techniques, and applications

NASA Astrophysics Data System (ADS)

Bayly, P. V.; Garbow, J. R.

2018-06-01

Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

A Randomized, Double-Blind, Crossover Comparison of MK-0929 and Placebo in the Treatment of Adults with ADHD

ERIC Educational Resources Information Center

Rivkin, Anna; Alexander, Robert C.; Knighton, Jennifer; Hutson, Pete H.; Wang, Xiaojing J.; Snavely, Duane B.; Rosah, Thomas; Watt, Alan P.; Reimherr, Fred W.; Adler, Lenard A.

2012-01-01

Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD. Method: A randomized, double-blind, placebo-controlled, crossover study was conducted…

Institute for Molecular Medicine Research Program

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

Phelps, Michael E

2012-12-14

The objectives of the project are the development of new Positron Emission Tomography (PET) imaging instrumentation, chemistry technology platforms and new molecular imaging probes to examine the transformations from normal cellular and biological processes to those of disease in pre-clinical animal models. These technology platforms and imaging probes provide the means to: 1. Study the biology of disease using pre-clinical mouse models and cells. 2. Develop molecular imaging probes for imaging assays of proteins in pre-clinical models. 3. Develop imaging assays in pre-clinical models to provide to other scientists the means to guide and improve the processes for discovering newmore » drugs. 4. Develop imaging assays in pre-clinical models for others to use in judging the impact of drugs on the biology of disease.« less

Imaging technologies for preclinical models of bone and joint disorders

PubMed Central

2011-01-01

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

Update on Standard Operating Procedures in Preclinical Research for DMD and SMA Report of TREAT-NMD Alliance Workshop, Schiphol Airport, 26 April 2015, The Netherlands.

PubMed

van Putten, Maaike; Aartsma-Rus, Annemieke; Grounds, Miranda D; Kornegay, Joe N; Mayhew, Anna; Gillingwater, Thomas H; Takeda, Shin'ichi; Rüegg, Markus A; De Luca, Annamaria; Nagaraju, Kanneboyina; Willmann, Raffaella

A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies.

The basics of preclinical drug development for neurodegenerative disease indications.

PubMed

Steinmetz, Karen L; Spack, Edward G

2009-06-12

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

The basics of preclinical drug development for neurodegenerative disease indications

PubMed Central

Steinmetz, Karen L; Spack, Edward G

2009-01-01

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

A Method of Developing and Introducing Case-Based Learning to a Preclinical Veterinary Curriculum

ERIC Educational Resources Information Center

Crowther, Emma; Baillie, Sarah

2016-01-01

Case-based learning (CBL) has been introduced as part of a major review of the veterinary curriculum at the University of Bristol. The initial aim was to improve integration between all first year subjects, i.e., basic science disciplines (anatomy, physiology, and biochemistry), animal management, and professional studies, while highlighting the…

Preclinical, Clinical, and Over-the-Counter Postmarketing Experience with a New Vaginal Cup: Menstrual Collection

PubMed Central

North, Barbara B.

2011-01-01

Abstract Background Menstrual cups have been available for decades, but their use is limited by bulky design and the need for multiple sizes. The Softcup® (Instead, Inc., San Diego, CA) is a simple single-size disposable over-the-counter (OTC) menstrual cup that compresses to tampon shape to facilitate insertion and can be worn during coitus. This report describes preclinical evaluation, clinical testing, and postmarketing monitoring of the Softcup. Methods Preclinical testing complied with U.S. Food and Drug Administration (FDA) guidelines and used standard United States Pharmacopoeia methodologies for assessment of potential toxicity. Clinical testing enrolled 406 women in seven U.S. centers. A detailed written questionnaire assessed safety, acceptability, and effectiveness for menstrual collection. Study safety parameters included pelvic examinations, Pap smears, colposcopy, urinalysis, vaginal pH, wet mounts, gram stain, and vaginal microflora cultures. Postmarketing surveillance of over 100 million Softcups has been conducted by the manufacturer and by the FDA Medwatch system. Results No toxicity or mutagenicity was observed in preclinical evaluations. In clinical testing, after three cycles of cup use, 37% of subjects rated the cup as better than, 29% as worse than, and 34% as equal to pads or tampons. The cup was preferred for comfort, dryness, and less odor. Cups received lower ratings for disposal and convenience. Eighty-one percent of enrolled women were able to insert and remove their first cup using only written instructions. Use difficulties resulting in study discontinuations included cramping (1%), leakage (1%), and improper fit (3%). No safety parameters were adversely affected. No significant health risks were reported during postmarketing surveillance. Conclusions These results demonstrate that a single-size vaginal device has no significant health risks and is acceptable to many women without the need for fitting or other medical services. PMID:21194348

Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis

PubMed Central

Engel, S S; Williams-Herman, D E; Golm, G T; Clay, R J; Machotka, S V; Kaufman, K D; Goldstein, B J

2010-01-01

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin-based therapies have triggered interest regarding the possibility of a mechanism-based association between pancreatitis and glucagon-like peptide-1 mimetics or dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP-4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient-level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment-related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient-years vs. 0.10 events per 100 patient-years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin. PMID:20412332

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

PubMed Central

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

2015-01-01

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

Determination of a deuterohemin-peptide conjugate in rat plasma by liquid chromatography-tandem mass spectrometry and application to a preclinical pharmacokinetic study.

PubMed

Wang, Hao; Sun, Yantong; Guo, Wei; Fang, Chunxue; Fawcett, J Paul; Li, Wei; Gao, Yin; Yang, Yan; Gu, Jingkai

2014-09-01

The deuterohemin-peptide conjugate (DhHP-6) is a microperoxidase mimetic, which has demonstrated substantial benefits in vivo as a scavenger of reactive oxygen species. This paper reports the development of a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of DhHP-6 in rat plasma using triptorelin as an internal standard (IS). 50μL plasma was used in sample preparation, and a simple protein precipitation procedure with acetonitrile was involved. Satisfactory peak shapes of analyte and IS were obtained on an Agilent HC-C18 column by using a gradient elution with 10mM ammonium acetate-0.5% formic acid (v:v) and acetonitrile, there was no significant interference impacting the determination. A calibration curve obtained from this method was linear within the concentration range 10-3000ng/mL with intra- and inter-day precisions of 4.2-6.8% and 3.2-8.9%, respectively and accuracy of -1.3% to 2.1%. The recovery was above 80% with low matrix effects. The method was successfully applied to support a preclinical pharmacokinetic study in rat. Copyright © 2014 Elsevier B.V. All rights reserved.

Using cost-analyses to inform health professions education - The economic cost of pre-clinical failure.

PubMed

Foo, Jonathan; Ilic, Dragan; Rivers, George; Evans, Darrell J R; Walsh, Kieran; Haines, Terry P; Paynter, Sophie; Morgan, Prue; Maloney, Stephen

2017-12-07

Student failure creates additional economic costs. Knowing the cost of failure helps to frame its economic burden relative to other educational issues, providing an evidence-base to guide priority setting and allocation of resources. The Ingredients Method is a cost-analysis approach which has been previously applied to health professions education research. In this study, the Ingredients Method is introduced, and applied to a case study, investigating the cost of pre-clinical student failure. The four step Ingredients Method was introduced and applied: (1) identify and specify resource items, (2) measure volume of resources in natural units, (3) assign monetary prices to resource items, and (4) analyze and report costs. Calculations were based on a physiotherapy program at an Australian university. The cost of failure was £5991 per failing student, distributed across students (70%), the government (21%), and the university (8%). If the cost of failure and attrition is distributed among the remaining continuing cohort, the cost per continuing student educated increases from £9923 to £11,391 per semester. The economics of health professions education is complex. Researchers should consider both accuracy and feasibility in their costing approach, toward the goal of better informing cost-conscious decision-making.

Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology

PubMed Central

Niendorf, Thoralf; Pohlmann, Andreas; Reimann, Henning M.; Waiczies, Helmar; Peper, Eva; Huelnhagen, Till; Seeliger, Erdmann; Schreiber, Adrian; Kettritz, Ralph; Strobel, Klaus; Ku, Min-Chi; Waiczies, Sonia

2015-01-01

Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed. PMID:26617515

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

Emerging treatments for traumatic brain injury

PubMed Central

Xiong, Ye; Mahmood, Asim; Chopp, Michael

2009-01-01

Background This review summarizes promising approaches for the treatment of traumatic brain injury (TBI), which are either in preclinical or clinical trials. Objective The pathophysiology underlying neurological deficits after TBI is described. An overview of select therapies for TBI with neuroprotective and neurorestorative effects is presented. Methods A literature review of pre-clinical TBI studies and clinical TBI trials related to neuroprotective and neurorestorative therapeutic approaches is provided. Results/conclusion Nearly all phase II/III clinical trials in neuroprotection have failed to show any consistent improvement in outcome for TBI patients. The next decade will witness an increasing number of clinical trials which seek to translate preclinical research discoveries to the clinic. Promising drug- or cell-based therapeutic approaches include erythropoietin and its carbamylated form, statins, bone marrow stromal cells, stem cells singularly or in combination or with biomaterials to reduce brain injury via neuroprotection and promote brain remodeling via angiogenesis, neurogenesis, and synaptogenesis with a final goal to improve functional outcome of TBI patients. In addition, enriched environment and voluntary physical exercise show promise in promoting functional outcome after TBI, and should be evaluated alone or in combination with other treatments as therapeutic approaches for TBI. PMID:19249984

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process

PubMed Central

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-01-01

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery. PMID:27122192

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process.

PubMed

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-04-28

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Clinical Research with Transcranial Direct Current Stimulation (tDCS): Challenges and Future Directions

PubMed Central

Brunoni, Andre Russowsky; Nitsche, Michael A.; Bolognini, Nadia; Bikson, Marom; Wagner, Tim; Merabet, Lotfi; Edwards, Dylan J.; Valero-Cabre, Antoni; Rotenberg, Alexander; Pascual-Leone, Alvaro; Ferrucci, Roberta; Priori, Alberto; Boggio, Paulo; Fregni, Felipe

2011-01-01

Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS. PMID:22037126

Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis.

PubMed

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

2018-04-28

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

Comparison of computer-assisted instruction (CAI) versus traditional textbook methods for training in abdominal examination (Japanese experience).

PubMed

Qayumi, A K; Kurihara, Y; Imai, M; Pachev, G; Seo, H; Hoshino, Y; Cheifetz, R; Matsuura, K; Momoi, M; Saleem, M; Lara-Guerra, H; Miki, Y; Kariya, Y

2004-10-01

This study aimed to compare the effects of computer-assisted, text-based and computer-and-text learning conditions on the performances of 3 groups of medical students in the pre-clinical years of their programme, taking into account their academic achievement to date. A fourth group of students served as a control (no-study) group. Participants were recruited from the pre-clinical years of the training programmes in 2 medical schools in Japan, Jichi Medical School near Tokyo and Kochi Medical School near Osaka. Participants were randomly assigned to 4 learning conditions and tested before and after the study on their knowledge of and skill in performing an abdominal examination, in a multiple-choice test and an objective structured clinical examination (OSCE), respectively. Information about performance in the programme was collected from school records and students were classified as average, good or excellent. Student and faculty evaluations of their experience in the study were explored by means of a short evaluation survey. Compared to the control group, all 3 study groups exhibited significant gains in performance on knowledge and performance measures. For the knowledge measure, the gains of the computer-assisted and computer-assisted plus text-based learning groups were significantly greater than the gains of the text-based learning group. The performances of the 3 groups did not differ on the OSCE measure. Analyses of gains by performance level revealed that high achieving students' learning was independent of study method. Lower achieving students performed better after using computer-based learning methods. The results suggest that computer-assisted learning methods will be of greater help to students who do not find the traditional methods effective. Explorations of the factors behind this are a matter for future research.

Anatomy meets dentistry! Linking anatomy and clinical practice in the preclinical dental curriculum.

PubMed

Rafai, Nicole; Lemos, Martin; Kennes, Lieven Nils; Hawari, Ayichah; Gerhardt-Szép, Susanne; Classen-Linke, Irmgard

2016-11-25

Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes. For the curricular development of the expanded course module, Kern's 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes. The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study. The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.

Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies.

PubMed

Lesueur, Paul; Chevalier, François; Austry, Jean-Baptiste; Waissi, Waisse; Burckel, Hélène; Noël, Georges; Habrand, Jean-Louis; Saintigny, Yannick; Joly, Florence

2017-09-15

Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect. Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported. Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data. PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.

Preclinical Whole-body Fluorescence Imaging: Review of Instruments, Methods and Applications

PubMed Central

Leblond, Frederic; Davis, Scott C.; Valdés, Pablo A.; Pogue, Brain W.

2013-01-01

Fluorescence sampling of cellular function is widely used in all aspects of biology, allowing the visualization of cellular and sub-cellular biological processes with spatial resolutions in the range from nanometers up to centimeters. Imaging of fluorescence in vivo has become the most commonly used radiological tool in all pre-clinical work. In the last decade, full-body pre-clinical imaging systems have emerged with a wide range of utilities and niche application areas. The range of fluorescent probes that can be excited in the visible to near-infrared part of the electromagnetic spectrum continues to expand, with the most value for in vivo use being beyond the 630 nm wavelength, because the absorption of light sharply decreases. Whole-body in vivo fluorescence imaging has not yet reached a state of maturity that allows its routine use in the scope of large-scale pre-clinical studies. This is in part due to an incomplete understanding of what the actual fundamental capabilities and limitations of this imaging modality are. However, progress is continuously being made in research laboratories pushing the limits of the approach to consistently improve its performance in terms of spatial resolution, sensitivity and quantification. This paper reviews this imaging technology with a particular emphasis on its potential uses and limitations, the required instrumentation, and the possible imaging geometries and applications. A detailed account of the main commercially available systems is provided as well as some perspective relating to the future of the technology development. Although the vast majority of applications of in vivo small animal imaging are based on epi-illumination planar imaging, the future success of the method relies heavily on the design of novel imaging systems based on state-of-the-art optical technology used in conjunction with high spatial resolution structural modalities such as MRI, CT or ultra-sound. PMID:20031443

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

PubMed Central

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

2015-01-01

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

The use of audio-visual methods in radiology and physics courses

NASA Astrophysics Data System (ADS)

Holmberg, Peter

1987-03-01

Today's medicine utilizes sophisticated equipment for radiological, biochemical and microbiological investigation procedures and analyses. Hence it is necessary that physicians have adequate scientific and technical knowledge of the apparatus they are using so that the equipment can be used in the most effective way. Partly this knowledge is obtained from science-orientated courses in the preclinical stage of the study program for medical students. To increase the motivation to study science-courses (medical physics) audio-visual methods are used to describe diagnostic and therapeutic procedures in the clinical routines.

[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

PubMed

Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

1998-01-01

The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome.

PubMed

Bagley, Mark C; Davis, Terence; Dix, Matthew C; Fusillo, Vincenzo; Pigeaux, Morgane; Rokicki, Michal J; Kipling, David

2010-09-01

The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use. Microwave irradiation using a stop-flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C-S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield. This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome.

[The role of biotechnology in pharmaceutical drug design].

PubMed

Gaisser, Sibylle; Nusser, Michael

2010-01-01

Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

Prediction of practical performance in preclinical laboratory courses - the return of wire bending for admission of dental students in Hamburg.

PubMed

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen's first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students' performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.

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

PubMed

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

2018-01-01

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

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

PubMed Central

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

2018-01-01

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

Formulation, stability study, and pre-clinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis.

PubMed

de Souza Fernandes, Lígia; Amorim, Yuri Martins; Silva, Elton Libério da; Silva, Samuel Calixto; Santos, Alécia Junia Aparecida; Peixoto, Franciele Natália; Pires, Luara Moniele Neves; Sakamoto, Raquel Yumi; Pinto, Flávia do Carmo Horta; Scarpa, Maria Virgínia Costa; Gonzaga de Freitas Araújo, Marcelo

2018-03-08

Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis METHODS: Curcumin was incorporated in a vaginal cream in three concentrations (0.01, 0.1 and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC RESULTS: The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After six days of pre-clinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction of the inflammatory infiltrate was observed in the group treated with 1.0% cream CONCLUSION: Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Methods for Tumor Targeting with Salmonella typhimurium A1-R.

PubMed

Hoffman, Robert M; Zhao, Ming

2016-01-01

Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies.

Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa

PubMed Central

Oluoch, George O.; Ainsworth, Stuart; Alsolaiss, Jaffer; Bolton, Fiona; Arias, Ana-Silvia; Gutiérrez, José-María; Rowley, Paul; Kalya, Stephen; Ozwara, Hastings; Casewell, Nicholas R.

2017-01-01

Background Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. Methods We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a ‘gold standard’ comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom. Findings None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro assays of the abilities of ‘test’ antivenom IgGs to bind venom proteins were not substantially different from that of the ‘gold standard’ antivenoms. The least effective antivenoms had the lowest IgG content/vial. Conclusions Manufacture-stated preclinical efficacy statements guide decision making by physicians and antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of antivenoms available in Kenya identifies important limitations for two of the most commonly-used antivenoms, and that no antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on antivenom efficacy and the medical and societal value of establishing independent preclinical antivenom-efficacy testing facilities throughout the continent. PMID:29045429

Low-dose 4D cardiac imaging in small animals using dual source micro-CT

NASA Astrophysics Data System (ADS)

Holbrook, M.; Clark, D. P.; Badea, C. T.

2018-01-01

Micro-CT is widely used in preclinical studies, generating substantial interest in extending its capabilities in functional imaging applications such as blood perfusion and cardiac function. However, imaging cardiac structure and function in mice is challenging due to their small size and rapid heart rate. To overcome these challenges, we propose and compare improvements on two strategies for cardiac gating in dual-source, preclinical micro-CT: fast prospective gating (PG) and uncorrelated retrospective gating (RG). These sampling strategies combined with a sophisticated iterative image reconstruction algorithm provide faster acquisitions and high image quality in low-dose 4D (i.e. 3D  +  Time) cardiac micro-CT. Fast PG is performed under continuous subject rotation which results in interleaved projection angles between cardiac phases. Thus, fast PG provides a well-sampled temporal average image for use as a prior in iterative reconstruction. Uncorrelated RG incorporates random delays during sampling to prevent correlations between heart rate and sampling rate. We have performed both simulations and animal studies to validate these new sampling protocols. Sampling times for 1000 projections using fast PG and RG were 2 and 3 min, respectively, and the total dose was 170 mGy each. Reconstructions were performed using a 4D iterative reconstruction technique based on the split Bregman method. To examine undersampling robustness, subsets of 500 and 250 projections were also used for reconstruction. Both sampling strategies in conjunction with our iterative reconstruction method are capable of resolving cardiac phases and provide high image quality. In general, for equal numbers of projections, fast PG shows fewer errors than RG and is more robust to undersampling. Our results indicate that only 1000-projection based reconstruction with fast PG satisfies a 5% error criterion in left ventricular volume estimation. These methods promise low-dose imaging with a wide range of preclinical applications in cardiac imaging.

Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

PubMed Central

Johnstone, Daniel; Milward, Elizabeth A.; Berretta, Regina; Moscato, Pablo

2012-01-01

Background Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages. PMID:22485168

Adjuvant bisphosphonate treatment for breast cancer: Where are we heading and can the pre-clinical literature help us get there?

PubMed

Russell, Kent; Clemons, Mark; Costa, Luis; Addison, Christina L

2012-06-01

Bisphosphonates have demonstrated anti-tumour activity in preclinical studies of bone metastatic disease, thus it was natural to transition these agents into the adjuvant cancer therapy setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest to no benefit or even harm. We sought to explore whether the preclinical results supporting bisphosphonate use provided clues to help explain the current clinical data. Interestingly, the majority of preclinical data suggested that bisphosphonate treatment was more efficacious when administered after the establishment of osseous metastases. This is similar to the findings of one clinical study whereby patients with biopsy evidence of osseous micrometastases derive greater survival benefit from bisphosphonate treatment. Another clinical study found bisphosphonates were associated with increased incidence of visceral metastases, similar to what has been previously published in preclinical models using "preventative" dosing strategies. While the current clinical data suggest bisphosphonates may be more efficacious in post-menopausal or oestrogen depleted patients, or those with hormone receptor positive tumours, to date no appropriately designed preclinical studies have evaluated these effects. Furthermore, putative mechanisms that regulate response to bisphosphonates in other tumour types remain to be evaluated in breast cancer. Despite the initial optimism regarding adjuvant bisphosphonate therapy, the conflicting clinical results from large trials suggest that we should return to the bench to further investigate factors that may influence response to bisphosphonate treatment or identify appropriate characteristics that would indicate the sub-groups of patients most likely to benefit from bisphosphonate treatment.

X-ray energy optimization in minibeam radiation therapy.

PubMed

Prezado, Y; Thengumpallil, S; Renier, M; Bravin, A

2009-11-01

The purpose of this work is to assess which energy in minibeam radiation therapy provides the best compromise between the deposited dose in the tumor and the sparing of the healthy tissues. Monte Carlo simulations (PENELOPE 2006) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) in the healthy tissues and in the tumor for different beam energies. The maximization of the ratio of PVDR in the healthy tissues and in the tumor has been used as a criterion. The main result of this work is that, for the parameters being used in preclinical trials (minibeam sizes of 600 microm and 1200 microm center-to-center separation), the optimum beam energy is 375 keV. The conclusion is that this is the energy of minibeams that should be used in the preclinical studies.

System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test

PubMed Central

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing. PMID:25010690

The Effect of Sequence of Instruction on Students' Cognitive Preferences and Recall in the Context of a Problem-Oriented Method of Teaching.

ERIC Educational Resources Information Center

Boreham, N. C.; And Others

1985-01-01

This study investigated the effects of two sequences of instruction--theory-to-application and application-to-theory--on medical students' cognitive preferences in preclinical science teaching. Results indicate that presenting an example of the clinical application of biochemical theory before presenting the theory itself increased students'…

Micro-Dose Calibrator for Pre-clinical Radiotracer Assays | NCI Technology Transfer Center | TTC

Cancer.gov

Pre-clinical radiotracer biomedical research involves the use of compounds labeled with radioisotopes, including cell binding studies, immune cell labeling techniques, and radio-ligand bio-distribution studies. Before this Micro-Dose Calibrator, measurement of pre-clinical level dosage for small animal studies was inaccurate and unreliable. This dose calibrator is a prototype ready for manufacturing. It is designed to accurately measure radioactive doses in the range of 50 nCi (1.8 kBq) to 100 µCi (3.7 MBq) with 1% precision. The NCI seeks co-development or licensing to commercialize it. Alternative uses will be considered.

Detecting cell death with optical coherence tomography and envelope statistics

NASA Astrophysics Data System (ADS)

Farhat, Golnaz; Yang, Victor X. D.; Czarnota, Gregory J.; Kolios, Michael C.

2011-02-01

Currently no standard clinical or preclinical noninvasive method exists to monitor cell death based on morphological changes at the cellular level. In our past work we have demonstrated that quantitative high frequency ultrasound imaging can detect cell death in vitro and in vivo. In this study we apply quantitative methods previously used with high frequency ultrasound to optical coherence tomography (OCT) to detect cell death. The ultimate goal of this work is to use these methods for optically-based clinical and preclinical cancer treatment monitoring. Optical coherence tomography data were acquired from acute myeloid leukemia cells undergoing three modes of cell death. Significant increases in integrated backscatter were observed for cells undergoing apoptosis and mitotic arrest, while necrotic cells induced a decrease. These changes appear to be linked to structural changes observed in histology obtained from the cell samples. Signal envelope statistics were analyzed from fittings of the generalized gamma distribution to histograms of envelope intensities. The parameters from this distribution demonstrated sensitivities to morphological changes in the cell samples. These results indicate that OCT integrated backscatter and first order envelope statistics can be used to detect and potentially differentiate between modes of cell death in vitro.

Quantification Assays for Total and Polyglutamine-Expanded Huntingtin Proteins

PubMed Central

Boogaard, Ivette; Smith, Melanie; Pulli, Kristiina; Szynol, Agnieszka; Albertus, Faywell; Lamers, Marieke B. A. C.; Dijkstra, Sipke; Kordt, Daniel; Reindl, Wolfgang; Herrmann, Frank; McAllister, George; Fischer, David F.; Munoz-Sanjuan, Ignacio

2014-01-01

The expansion of a CAG trinucleotide repeat in the huntingtin gene, which produces huntingtin protein with an expanded polyglutamine tract, is the cause of Huntington's disease (HD). Recent studies have reported that RNAi suppression of polyglutamine-expanded huntingtin (mutant HTT) in HD animal models can ameliorate disease phenotypes. A key requirement for such preclinical studies, as well as eventual clinical trials, aimed to reduce mutant HTT exposure is a robust method to measure HTT protein levels in select tissues. We have developed several sensitive and selective assays that measure either total human HTT or polyglutamine-expanded human HTT proteins on the electrochemiluminescence Meso Scale Discovery detection platform with an increased dynamic range over other methods. In addition, we have developed an assay to detect endogenous mouse and rat HTT proteins in pre-clinical models of HD to monitor effects on the wild type protein of both allele selective and non-selective interventions. We demonstrate the application of these assays to measure HTT protein in several HD in vitro cellular and in vivo animal model systems as well as in HD patient biosamples. Furthermore, we used purified recombinant HTT proteins as standards to quantitate the absolute amount of HTT protein in such biosamples. PMID:24816435

Effectiveness of early cardiology undergraduate learning using simulation on retention, application of learning and level of confidence during clinical clerkships

PubMed Central

Lin, Weiqin; Lee, Glenn K; Loh, Joshua P; Tay, Edgar L; Sia, Winnie; Lau, Tang-Ching; Hooi, Shing-Chuan; Poh, Kian-Keong

2015-01-01

INTRODUCTION This study aimed to assess the effectiveness of the use of a cardiopulmonary patient simulator in the teaching of second-year medical students. Effectiveness was measured in terms of the extent of knowledge retention and students’ ability to apply the skills learned in subsequent real-life patient contact. METHODS In this study, ten third-year medical students who had previously undergone simulator training as part of their second-year curriculum underwent an objective structured clinical examination (OSCE) and a multiple-choice question (MCQ) test to assess their ability to apply the knowledge gained during the simulator training when dealing with real patients. The performance of this group of students was compared with that of a group of ten fourth-year medical students who did not undergo simulation training. RESULTS Although the third-year medical students performed well in the OSCE, they were outperformed by the group of fourth-year medical students, who had an extra year of clinical exposure. The MCQ scores of the two groups of students were similar. Post-simulation training survey revealed that students were generally in favour of incorporating cardiopulmonary simulator training in the preclinical curriculum. CONCLUSION Cardiopulmonary simulator training is a useful tool for the education of preclinical medical students. It aids the translation of preclinical knowledge into real-life clinical skills. PMID:25715855

Mesenchymal stem cells for acute lung injury: Preclinical evidence

PubMed Central

Matthay, Michael A.; Goolaerts, Arnaud; Howard, James P.; Lee, Jae Woo

2013-01-01

Several experimental studies have suggested that mesenchymal stem cells may have value for the treatment of clinical disorders, including myocardial infarction, diabetes, acute renal failure, sepsis, and acute lung injury. In preclinical studies, mesenchymal stem cells have been effective in reducing lung injury from endotoxin, live bacteria, bleomycin, and hyperoxia. In some studies, the cultured medium from mesenchymal stem cells has been as effective as the mesenchymal stem cells themselves. Several paracrine mediators that can mediate the effect of mesenchymal stem cells have been identified, including interleukin-10, interleukin-1ra, keratinocyte growth factor, and prostaglandin E2. Further preclinical studies are needed, as is planning for clinical trials for acute lung injury. PMID:21164399

A Comprehensive Review of mTOR-Inhibiting Pharmacotherapy for the Treatment of Non-Infectious Uveitis.

PubMed

Blair, Joshua; Barry, Robert; Moore, David J; Denniston, Alastair K

2017-01-01

Non-infectious uveitis is a sight-threatening inflammatory disease that often necessitates prolonged use of high-dose corticosteroids, resulting in significant systemic side effects. There is a need for efficacious steroid-sparing immunomodulatory therapy for these patients, and the mTOR inhibitors (sirolimus and everolimus) may be contenders for this role. A comprehensive review of preclinical and clinical research on mTOR inhibitors for non-infectious uveitis was performed. Articles were identified by a search of MEDLINE (PubMed/OVID) and EMBASE (OVID) the terms (uveitis OR non-infectious uveitis) AND (mTOR inhibitor OR sirolimus OR everolimus). Assessment of study aims, methods, efficacy outcomes and adverse events was performed. Seven pre-clinical and nine clinical studies were identified. One study in each group was on everolimus, the rest sirolimus. Preclinical studies have been performed in rabbit, rat, mouse and in-vitro models. Clinical studies range from comparative open-label trials to case reports, with reported clinical efficacy ranging from 40% to 100% depending on endpoint assessed. The overall rate of drug-related adverse events (such as ocular irritation, visual floaters, nausea and vomiting) was 0.640 events per patient-year with sirolimus, and 0.111 events per patient-year with everolimus. Published evidence suggests that sirolimus and everolimus may be useful in the management of noninfectious uveitis. Both appear to be well tolerated, especially when locally administered. Further high-quality RCTs adopting standardised end-points are required to definitively determine the efficacy of each agent. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

PubMed Central

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

2010-01-01

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

Fast magnetic resonance fingerprinting for dynamic contrast-enhanced studies in mice.

PubMed

Gu, Yuning; Wang, Charlie Y; Anderson, Christian E; Liu, Yuchi; Hu, He; Johansen, Mette L; Ma, Dan; Jiang, Yun; Ramos-Estebanez, Ciro; Brady-Kalnay, Susann; Griswold, Mark A; Flask, Chris A; Yu, Xin

2018-05-09

The goal of this study was to develop a fast MR fingerprinting (MRF) method for simultaneous T 1 and T 2 mapping in DCE-MRI studies in mice. The MRF sequences based on balanced SSFP and fast imaging with steady-state precession were implemented and evaluated on a 7T preclinical scanner. The readout used a zeroth-moment-compensated variable-density spiral trajectory that fully sampled the entire k-space and the inner 10 × 10 k-space with 48 and 4 interleaves, respectively. In vitro and in vivo studies of mouse brain were performed to evaluate the accuracy of MRF measurements with both fully sampled and undersampled data. The application of MRF to dynamic T 1 and T 2 mapping in DCE-MRI studies were demonstrated in a mouse model of heterotopic glioblastoma using gadolinium-based and dysprosium-based contrast agents. The T 1 and T 2 measurements in phantom showed strong agreement between the MRF and the conventional methods. The MRF with spiral encoding allowed up to 8-fold undersampling without loss of measurement accuracy. This enabled simultaneous T 1 and T 2 mapping with 2-minute temporal resolution in DCE-MRI studies. Magnetic resonance fingerprinting provides the opportunity for dynamic quantification of contrast agent distribution in preclinical tumor models on high-field MRI scanners. © 2018 International Society for Magnetic Resonance in Medicine.

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.

PubMed

Goldberg, Andy; Mitchell, Katrina; Soans, Julian; Kim, Louise; Zaidi, Razi

2017-03-09

The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place.

Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings.

PubMed

Arentz, Susan; Abbott, Jason Anthony; Smith, Caroline Anne; Bensoussan, Alan

2014-12-18

Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions. We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism. A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism. Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre-clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre-clinical data.

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

Cancer.gov

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

Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

PubMed

Arias, Jalayne J; Cummings, Jeffrey; Grant, Alexander Rae; Ford, Paul J

2015-01-01

Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit

PubMed Central

Molinuevo, José L.; Cami, Jordi; Carné, Xavier; Carrillo, Maria C.; Georges, Jean; Isaac, Maria B.; Khachaturian, Zaven; Kim, Scott Y. H.; Morris, John C.; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

2016-01-01

Alzheimer’s disease (AD) is among the most significant healthcare burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals’ biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants and disclose or not biomarker status with attention to study type (observational studies versus clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools. PMID:24872857

Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease.

PubMed

Müller, Stephan; Preische, Oliver; Sohrabi, Hamid R; Gräber, Susanne; Jucker, Mathias; Dietzsch, Janko; Ringman, John M; Martins, Ralph N; McDade, Eric; Schofield, Peter R; Ghetti, Bernardino; Rossor, Martin; Graff-Radford, Neill R; Levin, Johannes; Galasko, Douglas; Quaid, Kimberly A; Salloway, Stephen; Xiong, Chengjie; Benzinger, Tammie; Buckles, Virginia; Masters, Colin L; Sperling, Reisa; Bateman, Randall J; Morris, John C; Laske, Christoph

2017-04-27

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

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

PubMed

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

2018-05-14

Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to develop any specialist surgical tooling required. The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator. © 2018 IOP Publishing Ltd.

A checklist is associated with increased quality of reporting preclinical biomedical research: A systematic review

PubMed Central

Olonisakin, Tolani F.; Pribis, John P.; Zupetic, Jill; Yoon, Joo Heung; Holleran, Kyle M.; Jeong, Kwonho; Shaikh, Nader; Rubio, Doris M.; Lee, Janet S.

2017-01-01

Irreproducibility of preclinical biomedical research has gained recent attention. It is suggested that requiring authors to complete a checklist at the time of manuscript submission would improve the quality and transparency of scientific reporting, and ultimately enhance reproducibility. Whether a checklist enhances quality and transparency in reporting preclinical animal studies, however, has not been empirically studied. Here we searched two highly cited life science journals, one that requires a checklist at submission (Nature) and one that does not (Cell), to identify in vivo animal studies. After screening 943 articles, a total of 80 articles were identified in 2013 (pre-checklist) and 2015 (post-checklist), and included for the detailed evaluation of reporting methodological and analytical information. We compared the quality of reporting preclinical animal studies between the two journals, accounting for differences between journals and changes over time in reporting. We find that reporting of randomization, blinding, and sample-size estimation significantly improved when comparing Nature to Cell from 2013 to 2015, likely due to implementation of a checklist. Specifically, improvement in reporting of the three methodological information was at least three times greater when a mandatory checklist was implemented than when it was not. Reporting the sex of animals and the number of independent experiments performed also improved from 2013 to 2015, likely from factors not related to a checklist. Our study demonstrates that completing a checklist at manuscript submission is associated with improved reporting of key methodological information in preclinical animal studies. PMID:28902887

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

PubMed

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

2015-07-01

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

Quantifying lead-time bias in risk factor studies of cancer through simulation.

PubMed

Jansen, Rick J; Alexander, Bruce H; Anderson, Kristin E; Church, Timothy R

2013-11-01

Lead-time is inherent in early detection and creates bias in observational studies of screening efficacy, but its potential to bias effect estimates in risk factor studies is not always recognized. We describe a form of this bias that conventional analyses cannot address and develop a model to quantify it. Surveillance Epidemiology and End Results (SEER) data form the basis for estimates of age-specific preclinical incidence, and log-normal distributions describe the preclinical duration distribution. Simulations assume a joint null hypothesis of no effect of either the risk factor or screening on the preclinical incidence of cancer, and then quantify the bias as the risk-factor odds ratio (OR) from this null study. This bias can be used as a factor to adjust observed OR in the actual study. For this particular study design, as average preclinical duration increased, the bias in the total-physical activity OR monotonically increased from 1% to 22% above the null, but the smoking OR monotonically decreased from 1% above the null to 5% below the null. The finding of nontrivial bias in fixed risk-factor effect estimates demonstrates the importance of quantitatively evaluating it in susceptible studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Assessment of preclinical students’ academic motivation before and after a three-day academic affair program

PubMed Central

Aung, Myo Nyein; Somboonwong, Juraiporn; Jaroonvanichkul, Vorapol; Wannakrairot, Pongsak

2015-01-01

Background Medical students’ motivation is an important driving factor for academic performance, and therefore medical teachers and educators are often highly interested in this topic. This study evaluated the impact of an academic affair program upon preclinical year medical students’ motivation to study. Design and methods An intervention study was conducted using a pretest-posttest study design. A total of 296 preclinical year medical students who had just passed their first year and were about to attend their second year at the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, participated in the study. The intervention comprised of dialogues for personality development, pictorial expression in groups, as well as small group lectures delivered by senior students giving information on how to prepare for the forthcoming classes. Students’ academic motivation was measured before and after the intervention program, applying the transculturally translated Academic Motivation Scale (AMS). Cronbach’s alpha of Thai version AMS was 0.8992. The average scores in seven scales of AMS were compared between the pre- and posttest results, using the Wilcoxon signed-rank test. The differences were confirmed by using the multivariate analysis of variance. Results Students’ academic motivation increased after participation in the three-day academic program. There was also a significant increase in introjected extrinsic motivation, which can enhance the students’ self-esteem and feeling of self-worth (P<0.001). Moreover, intrinsic motivation toward accomplishment increased significantly (P<0.001). This is related to the enjoyment of passing academic milestones, and a step ahead of autonomous motivation. Amotivation level declined significantly (P<0.001). The change of academic motivational constructs before and after the intervention was altogether significant (P=0.036, multivariate analysis of variance). Conclusion After experiencing a three-day intervention, the new students’ motivation advanced along the continuum of self-determination toward autonomous motivation. Therefore, it is considered to be worthwhile conducting an academic intervention to catalyze the evolution of preclinical year medical students’ academic motivation. Moreover, educators and faculties should evaluate the impact of interventions in evidence-based approaches to secure both controlled and autonomous types of motivation. PMID:26719719

The state of radiologic teaching practice in preclinical medical education: survey of American medical, osteopathic, and podiatric schools.

PubMed

Rubin, Zachary; Blackham, Kristine

2015-04-01

This study describes the state of preclinical radiology curricula in North American allopathic, osteopathic, and podiatric medical schools. An online survey of teaching methods, radiology topics, and future plans was developed. The Associations of American Medical Colleges, Colleges of Osteopathic Medicine, and Colleges of Podiatric Medicine listing for all US, Canadian, and Puerto Rican schools was used for contact information for directors of anatomy and/or radiology courses. Letters were sent via e-mail to 198 schools, with a link to the anonymous survey. Of 198 schools, 98 completed the survey (48%). Radiology curricula were integrated with other topics (91%), and taught by anatomists (42%) and radiologists (43%). The majority of time was spent on the topic of anatomy correlation (35%). Time spent teaching general radiology topics in the curriculum, such as physics (3%), modality differences (6%), radiation safety (2%), and contrast use (2%) was limited. Most schools had plans to implement an innovative teaching method in the near future (62%). The major challenges included limits on: time in the curriculum (73%); resources (32%); and radiology faculty participation (30%). A total of 82% reported that their curriculum did not model the suggestions made by the Alliance of Medical Student Educators in Radiology. This survey describes the current state of preclinical radiology teaching: curricula were nonstandard, integrated into other courses, and predominantly used for anatomy correlation. Other important contextual principles of the practice of radiology were seldom taught. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

PubMed

Sarker, Marjana Rahman; Franks, Susan F

2018-04-21

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

Preclinical diagnosis of Alzheimer’s disease: Prevention or prediction?

PubMed Central

Nitrini, Ricardo

2010-01-01

The diagnosis of Alzheimer’s disease (AD) for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer’s Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD’s dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD. PMID:29213696

Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students

ERIC Educational Resources Information Center

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut

2014-01-01

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

The Impact of Interactive, Computerized Educational Modules on Preclinical Medical Education

ERIC Educational Resources Information Center

Bryner, Benjamin S.; Saddawi-Konefka, Daniel; Gest, Thomas R.

2008-01-01

Interactive computerized modules have been linked to improved retention of material in clinical medicine. This study examined the effects of a new series of interactive learning modules for preclinical medical education, specifically in the areas of quiz performance, perceived difficulty of concepts, study time, and perceived stress level. We…

Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs

PubMed Central

Kusner, Linda L.; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

2015-01-01

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID:25743217

A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation.

PubMed

Kleikers, Pamela W M; Hooijmans, Carlijn; Göb, Eva; Langhauser, Friederike; Rewell, Sarah S J; Radermacher, Kim; Ritskes-Hoitinga, Merel; Howells, David W; Kleinschnitz, Christoph; Schmidt, Harald H H W

2015-08-27

Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.

Coping With Preclinical Disability: Older Women’s Experiences of Everyday Activities

PubMed Central

Lorenz, Rebecca Ann

2010-01-01

Purpose The purpose of this paper is to describe coping practices used by older women during preclinical disability. Design This paper was derived from qualitative data gathered during a larger multimethod longitudinal study. Twelve women (60 to 80 years of age) participated in baseline functional performance measures and then repeated in-depth interviews and participant observations over 18 months. Methods A hermeneutic approach was used to interpret the in-depth interviews, participant observations, and field notes using three interrelated processes of thematic, exemplar, and identification of paradigm cases to identify coping practices. Findings Women coped with functional decline, such as difficulty getting up from the floor, in many different ways. Coping practices were grouped into five themes: resist, adapt, substitute, endure, and eliminate. Clinical Relevance These findings suggest that nurses need to realize outward appearances may mask the level of effort required for older women to complete daily activities. PMID:21091627

Implementation of compressive sensing for preclinical cine-MRI

NASA Astrophysics Data System (ADS)

Tan, Elliot; Yang, Ming; Ma, Lixin; Zheng, Yahong Rosa

2014-03-01

This paper presents a practical implementation of Compressive Sensing (CS) for a preclinical MRI machine to acquire randomly undersampled k-space data in cardiac function imaging applications. First, random undersampling masks were generated based on Gaussian, Cauchy, wrapped Cauchy and von Mises probability distribution functions by the inverse transform method. The best masks for undersampling ratios of 0.3, 0.4 and 0.5 were chosen for animal experimentation, and were programmed into a Bruker Avance III BioSpec 7.0T MRI system through method programming in ParaVision. Three undersampled mouse heart datasets were obtained using a fast low angle shot (FLASH) sequence, along with a control undersampled phantom dataset. ECG and respiratory gating was used to obtain high quality images. After CS reconstructions were applied to all acquired data, resulting images were quantitatively analyzed using the performance metrics of reconstruction error and Structural Similarity Index (SSIM). The comparative analysis indicated that CS reconstructed images from MRI machine undersampled data were indeed comparable to CS reconstructed images from retrospective undersampled data, and that CS techniques are practical in a preclinical setting. The implementation achieved 2 to 4 times acceleration for image acquisition and satisfactory quality of image reconstruction.

Cardiovascular photodynamic therapy: state of the art

NASA Astrophysics Data System (ADS)

Woodburn, Kathryn W.; Rockson, Stanley G.

2000-05-01

Photodynamic therapy (PDT) has been used traditionally for oncologic and ophthalmic indications. In addition, the enormous potential for the use of PDT agents in cardiovascular diseases is currently being translated into reality. Preclinical studies with various photosensitizers have demonstrated reduction in atheromatous plaque and prevention of intimal hyperplasia. With recent advances in light-based vascular devices and laser diode technology, the clinical use of cardiovascular photodynamic therapy is even more likely. Two photosensitizers, 5-aminolevulinic acid (ALA) and AntrinR (motexafin lutetium) Injection, are under clinical evaluation with many other agents in preclinical testing. Here, preclinical studies are reviewed and the clinical viability of cardiovascular photodynamic therapy is discussed.

Voluntary undergraduate technical skills training course to prepare students for clerkship assignment: tutees’ and tutors’ perspectives

PubMed Central

2014-01-01

Background Skills lab training has become a widespread tool in medical education, and nowadays, skills labs are ubiquitous among medical faculties across the world. An increasingly prevalent didactic approach in skills lab teaching is peer-assisted learning (PAL), which has been shown to be not only effective, but can be considered to be on a par with faculty staff-led training. The aim of the study is to determine whether voluntary preclinical skills teaching by peer tutors is a feasible method for preparing medical students for effective workplace learning in clerkships and to investigate both tutees’ and tutors’ attitudes towards such an intervention. Methods A voluntary clerkship preparation skills course was designed and delivered. N = 135 pre-clinical medical students visited the training sessions. N = 10 tutors were trained as skills-lab peer tutors. Voluntary clerkship preparation skills courses as well as tutor training were evaluated by acceptance ratings and pre-post self-assessment ratings. Furthermore, qualitative analyses of skills lab tutors’ attitudes towards the course were conducted following principles of grounded theory. Results Results show that a voluntary clerkship preparation skills course is in high demand, is highly accepted and leads to significant changes in self-assessment ratings. Regarding qualitative analysis of tutor statements, clerkship preparation skills courses were considered to be a helpful and necessary asset to preclinical medical education, which benefits from the tutors’ own clerkship experiences and a high standardization of training. Tutor training is also highly accepted and regarded as an indispensable tool for peer tutors. Conclusions Our study shows that the demand for voluntary competence-oriented clerkship preparation is high, and a peer tutor-led skills course as well as tutor training is well accepted. The focused didactic approach for tutor training is perceived to be effective in preparing tutors for their teaching activity in this context. A prospective study design would be needed to substantiate the results objectively and confirm the effectiveness. PMID:24708782

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.

PubMed

Andrews, Nick A; Latrémolière, Alban; Basbaum, Allan I; Mogil, Jeffrey S; Porreca, Frank; Rice, Andrew S C; Woolf, Clifford J; Currie, Gillian L; Dworkin, Robert H; Eisenach, James C; Evans, Scott; Gewandter, Jennifer S; Gover, Tony D; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P; Kennedy, Jeffrey D; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P; McMahon, Stephen B; Price, Theodore J; Ross, Sarah E; Scherrer, Grégory; Seal, Rebecca P; Sena, Emily S; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I; Turk, Dennis C; Whiteside, Garth

2016-04-01

There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues.

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

PubMed

Nielsen, Suzanne; Sabioni, Pamela; Trigo, Jose M; Ware, Mark A; Betz-Stablein, Brigid D; Murnion, Bridin; Lintzeris, Nicholas; Khor, Kok Eng; Farrell, Michael; Smith, Andrew; Le Foll, Bernard

2017-08-01

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Free and Cued Memory in relation to Biomarker-Defined Abnormalities in Clinically Normal Older Adults and Those at Risk for Alzheimer’s Disease

PubMed Central

Papp, Kathryn V.; Amariglio, Rebecca E.; Mormino, Elizabeth; Hedden, Trey; Dekhytar, Maria; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.

2015-01-01

Objectives Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer’s disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. Methods A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ−/ND−), Stage 1 (Aβ+/ND−), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer’s associated pathology (SNAP; Aβ−/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). Results Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. Conclusions Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design. PMID:26002757

The Australian Medical Schools Assessment Collaboration: benchmarking the preclinical performance of medical students.

PubMed

O'Mara, Deborah A; Canny, Ben J; Rothnie, Imogene P; Wilson, Ian G; Barnard, John; Davies, Llewelyn

2015-02-02

To report the level of participation of medical schools in the Australian Medical Schools Assessment Collaboration (AMSAC); and to measure differences in student performance related to medical school characteristics and implementation methods. Retrospective analysis of data using the Rasch statistical model to correct for missing data and variability in item difficulty. Linear model analysis of variance was used to assess differences in student performance. 6401 preclinical students from 13 medical schools that participated in AMSAC from 2011 to 2013. Rasch estimates of preclinical basic and clinical science knowledge. Representation of Australian medical schools and students in AMSAC more than doubled between 2009 and 2013. In 2013 it included 12 of 19 medical schools and 68% of medical students. Graduate-entry students scored higher than students entering straight from school. Students at large schools scored higher than students at small schools. Although the significance level was high (P < 0.001), the main effect sizes were small (4.5% and 2.3%, respectively). The time allowed per multiple choice question was not significantly associated with student performance. The effect on performance of multiple assessments compared with the test items as part of a single end-of-year examination was negligible. The variables investigated explain only 12% of the total variation in student performance. An increasing number of medical schools are participating in AMSAC to monitor student performance in preclinical sciences against an external benchmark. Medical school characteristics account for only a small part of overall variation in student performance. Student performance was not affected by the different methods of administering test items.

Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

PubMed

Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J; Williams, Kayode; Guan, Yun

2018-01-01

Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology. © 2017 International Neuromodulation Society.

Tissue engineering of the bladder--reality or myth? A systematic review.

PubMed

Sloff, Marije; Simaioforidis, Vasileios; de Vries, Rob; Oosterwijk, Egbert; Feitz, Wout

2014-10-01

We systematically reviewed preclinical studies in the literature to evaluate the potential of tissue engineering of the bladder. Study outcomes were compared to the available clinical evidence to assess the feasibility of tissue engineering for future clinical use. Preclinical studies of tissue engineering for bladder augmentation were identified through a systematic search of PubMed and Embase™ from January 1, 1980 to January 1, 2014. Primary studies in English were included if bladder reconstruction after partial cystectomy was performed using a tissue engineered biomaterial in any animal species, with cystometric bladder capacity as an outcome measure. Outcomes were compared to clinical studies available at http://www.clinicaltrials.gov and published clinical studies. A total of 28 preclinical studies are included, demonstrating remarkable heterogeneity in study characteristics and design. Studies in which preoperative bladder volumes were compared to postoperative volumes were considered the most clinically relevant (18 studies). Bladder augmentation through tissue engineering resulted in a normal bladder volume in healthy animals, with the influence of a cellular component being negligible. Furthermore, experiments in large animal models (pigs and dogs) approximated the desired bladder volume more accurately than in smaller species. The initial clinical experience was based on seemingly predictive healthy animal models with a promising outcome. Unfortunately these results were not substantiated in all clinical trials, revealing dissimilar outcomes in different clinical/disease backgrounds. Thus, the translational predictability of a model using healthy animals might be questioned. Through this systematic approach we present an unbiased overview of all published preclinical studies investigating the effect of bladder tissue engineering on cystometric bladder capacity. Preclinical research in healthy animals appears to show the feasibility of bladder augmentation by tissue engineering. However, in view of the disappointing clinical results based on healthy animal models new approaches should also be evaluated in preclinical models using dysfunctional/diseased bladders. This endeavor may aid in the development of clinically applicable tissue engineered bladder augmentation with satisfactory long-term outcome. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

18F-Labeling of Sensitive Biomolecules for Positron Emission Tomography

PubMed Central

Krishnan, Hema S.; Ma, Longle; Vasdev, Neil; Liang, Steven H.

2017-01-01

Positron emission tomography (PET) imaging study of fluorine-18 labeled biomolecules is an emerging and rapidly growing area for preclinical and clinical research. The present review focuses on recent advances in radiochemical methods for incorporating fluorine-18 into biomolecules via ‘direct’ or ‘indirect’ bioconjugation. Recently developed prosthetic groups and pre-targeting strategies, as well as representative examples in 18F-labeling of biomolecules in PET imaging research studies are highlighted. PMID:28704575

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

PubMed

Vos, Stephanie J B; Visser, Pieter Jelle

2018-05-23

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

Adaptive marker-free registration using a multiple point strategy for real-time and robust endoscope electromagnetic navigation.

PubMed

Luo, Xiongbiao; Wan, Ying; He, Xiangjian; Mori, Kensaku

2015-02-01

Registration of pre-clinical images to physical space is indispensable for computer-assisted endoscopic interventions in operating rooms. Electromagnetically navigated endoscopic interventions are increasingly performed at current diagnoses and treatments. Such interventions use an electromagnetic tracker with a miniature sensor that is usually attached at an endoscope distal tip to real time track endoscope movements in a pre-clinical image space. Spatial alignment between the electromagnetic tracker (or sensor) and pre-clinical images must be performed to navigate the endoscope to target regions. This paper proposes an adaptive marker-free registration method that uses a multiple point selection strategy. This method seeks to address an assumption that the endoscope is operated along the centerline of an intraluminal organ which is easily violated during interventions. We introduce an adaptive strategy that generates multiple points in terms of sensor measurements and endoscope tip center calibration. From these generated points, we adaptively choose the optimal point, which is the closest to its assigned the centerline of the hollow organ, to perform registration. The experimental results demonstrate that our proposed adaptive strategy significantly reduced the target registration error from 5.32 to 2.59 mm in static phantoms validation, as well as from at least 7.58 mm to 4.71 mm in dynamic phantom validation compared to current available methods. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Medical Students' Use of Different Coping Strategies and Relationship With Academic Performance in Preclinical and Clinical Years.

PubMed

Schiller, Jocelyn H; Stansfield, R Brent; Belmonte, David C; Purkiss, Joel A; Reddy, Rishindra M; House, Joseph B; Santen, Sally A

2018-01-01

Phenomenon: Medical students' coping abilities are important for academic success and emotional health. The authors explored differences in students' use of active, problem-solving strategies and emotional, inwardly directed approaches; the change in coping strategies used during medical school; and coping strategy impact on performance. One hundred eighty-three students completed the Ways of Coping Scale at matriculation and end of the 2nd and 3rd years. Frequency of each of 8 ways of coping, changes in coping strategy use over time, and relationship of coping method with preclinical and clinical scores were calculated. Students varied widely in use of coping mechanisms. Over time, students shifted to using emotional strategies more frequently while decreasing their use of active strategies. Coping strategies were unrelated to preclinical academic performance (R 2 = .09, adjusted R 2 = .04, ns) but were related to clinical performance (R 2 = .23, adjusted R 2 = .18, p < .0001), with active coping associated with higher performance and emotional methods associated with lower performance. Insights: Students decreased use of active coping strategies and increased use of emotional coping strategies over time, but emotional strategies were associated with poorer clinical academic performance. These shifts in coping methods may be detrimental to student performance and learning. Improving students' ability to cope should be an educational priority.

Chinese medicine for treatment of chronic hepatitis B.

PubMed

Wang, Guqi; Zhang, Lingyi; Bonkovsky, Herbert L

2012-04-01

Contemporary Western medicines approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis B (CHB), although available in China, have high costs, or major side effects and limited effectiveness. Research efforts have focused on looking for natural products as alternative medicines with low cost and good safety for CHB treatment. Chinese medicine (CM) has ancient, time-honored theories about methods of diagnosis and treatment for liver diseases. In recent decades, a large number of clinical trials and pre-clinical studies, which were performed in China and other countries, indicated that CM has potential benefit in several aspects of the treatment of CHB, e.g., anti-inflammatory, anticancer, antioxidant, immunomodulating, antifibrosis, and antiviral. However, there are many concerns regarding the study design and the quality of clinical trials. Further larger, stringently designed, double-blind, placebo control, randomized clinical trials and long-term follow-up are needed to provide conclusive evidence of their efficacy and safety. Components of CM deserve further study in pre-clinical models of HBV infection and in clinical trials world-wide.

Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease.

PubMed

Goldstein, David S; Holmes, Courtney; Lopez, Grisel J; Wu, Tianxia; Sharabi, Yehonatan

2018-05-01

Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). In people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase. Published by Elsevier Ltd.

Impact of ionic current variability on human ventricular cellular electrophysiology.

PubMed

Romero, Lucía; Pueyo, Esther; Fink, Martin; Rodríguez, Blanca

2009-10-01

Abnormalities in repolarization and its rate dependence are known to be related to increased proarrhythmic risk. A number of repolarization-related electrophysiological properties are commonly used as preclinical biomarkers of arrhythmic risk. However, the variability and complexity of repolarization mechanisms make the use of cellular biomarkers to predict arrhythmic risk preclinically challenging. Our goal is to investigate the role of ionic current properties and their variability in modulating cellular biomarkers of arrhythmic risk to improve risk stratification and identification in humans. A systematic investigation into the sensitivity of the main preclinical biomarkers of arrhythmic risk to changes in ionic current conductances and kinetics was performed using computer simulations. Four stimulation protocols were applied to the ten Tusscher and Panfilov human ventricular model to quantify the impact of +/-15 and +/-30% variations in key model parameters on action potential (AP) properties, Ca(2+) and Na(+) dynamics, and their rate dependence. Simulations show that, in humans, AP duration is moderately sensitive to changes in all repolarization current conductances and in L-type Ca(2+) current (I(CaL)) and slow component of the delayed rectifier current (I(Ks)) inactivation kinetics. AP triangulation, however, is strongly dependent only on inward rectifier K(+) current (I(K1)) and delayed rectifier current (I(Kr)) conductances. Furthermore, AP rate dependence (i.e., AP duration rate adaptation and restitution properties) and intracellular Ca(2+) and Na(+) levels are highly sensitive to both I(CaL) and Na(+)/K(+) pump current (I(NaK)) properties. This study provides quantitative insights into the sensitivity of preclinical biomarkers of arrhythmic risk to variations in ionic current properties in humans. The results show the importance of sensitivity analysis as a powerful method for the in-depth validation of mathematical models in cardiac electrophysiology.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

PubMed Central

Sprouse, Alyssa A.

2016-01-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

PubMed

Sprouse, Alyssa A; van Breemen, Richard B

2016-02-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Improving the quality of preclinical research echocardiography: Observations, training and guidelines for measurement.

PubMed

Donner, Daniel G; Kiriazis, Helen; Du, Xiao-Jun; Marwick, Thomas H; McMullen, Julie R

2018-04-20

Informal training in preclinical research may be a contributor to the poor reproducibility of preclinical cardiology research and low rates of translation into clinical research and practice. Mouse echocardiography is a widely used technique to assess cardiac structure and function in drug intervention studies using disease models. The inter-observer variability (IOV) of clinical echocardiographic measurements has been shown to improve with formalized training, but preclinical echocardiography lacks similarly critical standardization of training. The aims of this investigation were to assess the IOV of echocardiographic measurements from studies in mice, and address any technical impediments to reproducibility by implementing standardized guidelines through formalized training. In this prospective, single-site, observational cohort study, 13 scientists performing preclinical echocardiographic image analysis were assessed for measurement of short-axis M-mode-derived dimensions and calculated left ventricular mass (LVMass). Ten M-mode images of mouse hearts acquired and analyzed by an expert researcher with a spectrum of LVMass were selected for assessment, and validated by autopsy weight. Following the initial observation, a structured formal training program was introduced, and accuracy and reproducibility were re-evaluated. Mean absolute percentage error (MAPE) for Expert-calculated LVMass was 6{plus minus}4% compared to autopsy LVMass, and 25{plus minus}21% for participants before training. Standardized formal training improved participant MAPE by approximately 30% relative to expert-calculated LVMass (p<0.001). Participants initially categorized with high-range error (25-45%) improved to low-moderate error ranges (<15-25%). This report reveals an example of technical skill training insufficiency likely endemic to preclinical research and provides validated guidelines for echocardiographic measurement for adaptation to formalized in-training programs.

Insights from Preclinical Choice Models on Treating Drug Addiction

PubMed Central

Banks, Matthew L.; Negus, S. Stevens

2016-01-01

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

Characterization of novel preclinical dose distributions for micro irradiator

NASA Astrophysics Data System (ADS)

Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

2017-05-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

Stem Cells in Spinal Fusion

PubMed Central

Haudenschild, Dominik R.; Wegner, Adam M.; Klineberg, Eric O.

2017-01-01

Study Design: Review of literature. Objectives: This review of literature investigates the application of mesenchymal stem cells (MSCs) in spinal fusion, highlights potential uses in the development of bone grafts, and discusses limitations based on both preclinical and clinical models. Methods: A review of literature was conducted looking at current studies using stem cells for augmentation of spinal fusion in both animal and human models. Results: Eleven preclinical studies were found that used various animal models. Average fusion rates across studies were 59.8% for autograft and 73.7% for stem cell–based grafts. Outcomes included manual palpation and stressing of the fusion, radiography, micro–computed tomography (μCT), and histological analysis. Fifteen clinical studies, 7 prospective and 8 retrospective, were found. Fusion rates ranged from 60% to 100%, averaging 87.1% in experimental groups and 87.2% in autograft control groups. Conclusions: It appears that there is minimal clinical difference between commercially available stem cells and bone marrow aspirates indicating that MSCs may be a good choice in a patient with poor marrow quality. Overcoming morbidity and limitations of autograft for spinal fusion, remains a significant problem for spinal surgeons and further studies are needed to determine the efficacy of stem cells in augmenting spinal fusion. PMID:29238646

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging

PubMed Central

Ikeno, Yuji; Niedernhofer, Laura; McIndoe, Richard A.; Ciol, Marcia A.; Ritchey, Jerry; Liggitt, Denny

2016-01-01

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations. PMID:26243216

Preclinical Alzheimer disease and risk of falls

PubMed Central

Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.

2013-01-01

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

Modeling the Western Diet for Preclinical Investigations.

PubMed

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

2018-05-01

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

Sentinel lymph nodes detection with an imaging system using Patent Blue V dye as fluorescent tracer

NASA Astrophysics Data System (ADS)

Tellier, F.; Steibel, J.; Chabrier, R.; Rodier, J. F.; Pourroy, G.; Poulet, P.

2013-03-01

Sentinel lymph node biopsy is the gold standard to detect metastatic invasion from primary breast cancer. This method can help patients avoid full axillary chain dissection, thereby decreasing the risk of morbidity. We propose an alternative to the traditional isotopic method, to detect and map the sentinel lymph nodes. Indeed, Patent Blue V is the most widely used dye in clinical routine for the visual detection of sentinel lymph nodes. A Recent study has shown the possibility of increasing the fluorescence quantum yield of Patent Blue V, when it is bound to human serum albumin. In this study we present a preclinical fluorescence imaging system to detect sentinel lymph nodes labeled with this fluorescent tracer. The setup is composed of a black and white CCD camera and two laser sources. One excitation source with a laser emitting at 635 nm and a second laser at 785 nm to illuminate the region of interest. The prototype is operated via a laptop. Preliminary experiments permitted to determine the device sensitivity in the μmol.L-1 range as regards the detection of PBV fluorescence signals. We also present a preclinical evaluation performed on Lewis rats, during which the fluorescence imaging setup detected the accumulation and fixation of the fluorescent dye on different nodes through the skin.

A reproducible method for the isolation and expansion of ovine mesenchymal stromal cells from bone marrow for use in regenerative medicine preclinical studies.

PubMed

Caminal, Marta; Vélez, Roberto; Rabanal, Rosa Maria; Vivas, Daniel; Batlle-Morera, Laura; Aguirre, Màrius; Barquinero, Jordi; García, Joan; Vives, Joaquim

2017-12-01

The use of multipotent mesenchymal stromal cells (MSCs) as candidate medicines for treating a variety of pathologies is based on their qualities as either progenitors for the regeneration of damaged tissue or producers of a number of molecules with pharmacological properties. Preclinical product development programmes include the use of well characterized cell populations for proof of efficacy and safety studies before testing in humans. In the field of orthopaedics, an increasing number of translational studies use sheep as an in vivo test system because of the similarities with humans in size and musculoskeletal architecture. However, robust and reproducible methods for the isolation, expansion, manipulation and characterization of ovine MSCs have not yet been standardised. The present study describes a method for isolation and expansion of fibroblastic-like, adherent ovine MSCs that express CD44, CD90, CD140a, CD105 and CD166, and display trilineage differentiation potential. The 3-week bioprocess proposed here typically yielded cell densities of 1.4 × 10 4 MSCs/cm 2 at passage 2, with an expansion factor of 37.8 and approximately eight cumulative population doublings. The osteogenic potential of MSCs derived following this methodology was further evaluated in vivo in a translational model of osteonecrosis of the femoral head, in which the persistence of grafted cells in the host tissue and their lineage commitment into osteoblasts and osteocytes was demonstrated by tracking enhanced green fluorescent protein-labelled cells. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA.

PubMed

Canetta, Sarah E; Brown, Alan S

2012-12-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

Zebrafish for the Study of the Biological Effects of Nicotine

PubMed Central

Klee, Eric W.; Schneider, Henning; Hurt, Richard D.; Ekker, Stephen C.

2011-01-01

Introduction: Zebrafish are emerging as a powerful animal model for studying the molecular and physiological effects of nicotine exposure. The zebrafish have many advantageous physical characteristics, including small size, high fecundity rates, and externally developing transparent embryos. When combined with a battery of molecular–genetic tools and behavioral assays, these attributes enable studies to be conducted that are not practical using traditional animal models. Methods: We reviewed the literature on the application of the zebrafish model as a preclinical model to study the biological effects of nicotine exposure. Results: The identified studies used zebrafish to examine the effects of nicotine exposure on early development, addiction, anxiety, and learning. The methods used included green fluorescent protein–labeled proteins to track in vivo nicotine-altered neuron development, nicotine-conditioned place preference, and locomotive sensitization linked with high-throughput molecular and genetic screens and behavioral models of learning and stress response to nicotine. Data are presented on the complete homology of all known human neural nicotinic acetylcholine receptors in zebrafish and on the biological similarity of human and zebrafish dopaminergic signaling. Conclusions: Tobacco dependence remains a major health problem worldwide. Further understanding of the molecular effects of nicotine exposure and genetic contributions to dependence may lead to improvement in patient treatment strategies. While there are limitations to the use of zebrafish as a preclinical model, it should provide a valuable tool to complement existing model systems. The reviewed studies demonstrate the enormous opportunity zebrafish have to advance the science of nicotine and tobacco research. PMID:21385906

Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

NASA Astrophysics Data System (ADS)

Bass, Christopher Paul

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

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

PubMed

Banks, Matthew L

2017-04-01

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

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

PubMed Central

Banks, Matthew L.

2016-01-01

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

A comparative analysis of acute-phase proteins as inflammatory biomarkers in preclinical toxicology studies: implications for preclinical to clinical translation.

PubMed

Watterson, Claire; Lanevschi, Anne; Horner, Judith; Louden, Calvert

2009-01-01

Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.

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

PubMed Central

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

2016-01-01

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

Preclinical and clinical properties of trimegestone: a potent and selective progestin.

PubMed

Sitruk-Ware, Regine; Bossemeyer, Ronald; Bouchard, Phillipe

2007-06-01

Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.

Preclinical safety testing for cell-based products using animals.

PubMed

McBlane, James W

2015-09-01

The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation. Copyright © 2015.

Reform in Teaching Preclinical Pathophysiology

ERIC Educational Resources Information Center

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

2015-01-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

18 F-Labeling of Sensitive Biomolecules for Positron Emission Tomography.

PubMed

Krishnan, Hema S; Ma, Longle; Vasdev, Neil; Liang, Steven H

2017-11-07

Positron emission tomography (PET) imaging study of fluorine-18 labeled biomolecules is an emerging and rapidly growing area for preclinical and clinical research. The present review focuses on recent advances in radiochemical methods for incorporating fluorine-18 into biomolecules via "direct" or "indirect" bioconjugation. Recently developed prosthetic groups and pre-targeting strategies, as well as representative examples in 18 F-labeling of biomolecules in PET imaging research studies are highlighted. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Videotaped Feedback Method to Enhance Learning in Preclinical Operative Dentistry: An Experimental Study.

PubMed

Shah, Dipali Yogesh; Dadpe, Ashwini Manish; Kalra, Dheeraj Deepak; Garcha, Vikram P

2015-12-01

The aim of this study was to investigate if a videotaped feedback method enhanced teaching and learning outcomes in a preclinical operative laboratory setting for novice learners. In 2013, 60 dental students at a dental school in India were randomly assigned to two groups: control (n=30) and experimental (n=30). The control group prepared a Class II tooth preparation for amalgam after receiving a video demonstration of the exercise. The experimental group received the same video demonstration as the control group, but they also participated in a discussion and analysis of the control groups' videotaped performance and then performed the same exercise. The self-evaluation scores (SS) and examiner evaluation scores (ES) of the two groups were compared using the unpaired t-test. The experimental group also used a five-point Likert scale to rate each item on the feedback form. The means of SS (13.65±2.43) and ES (14.75±1.97) of the experimental group were statistically higher than the means of SS (11.55±2.09) and ES (11.60±1.82) of the control group. Most students in the experimental group perceived that this technique enhanced their learning experience. Within the limits of this study, the videotaped feedback using both ideal and non-ideal examples enhanced the students' performance.

Novel technology to prepare oral formulations for preclinical safety studies.

PubMed

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies.

PubMed

Dos Santos, Rafael G; Hallak, Jaime E C

2017-01-01

Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.

Is immunotherapy an opportunity for effective treatment of drug addiction?

PubMed

Zalewska-Kaszubska, Jadwiga

2015-11-27

Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations

PubMed Central

Andrews, Nick A.; Latrémolière, Alban; Basbaum, Allan I.; Mogil, Jeffrey S.; Porreca, Frank; Rice, Andrew S.C.; Woolf, Clifford J.; Currie, Gillian L.; Dworkin, Robert H.; Eisenach, James C.; Evans, Scott; Gewandter, Jennifer S.; Gover, Tony D.; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P.; Kennedy, Jeffrey D.; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P.; McMahon, Stephen B.; Price, Theodore J.; Ross, Sarah E.; Scherrer, Grégory; Seal, Rebecca P.; Sena, Emily S.; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I.; Turk, Dennis C.; Whiteside, Garth

2015-01-01

Abstract There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues. PMID:26683237

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

PubMed Central

Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

2013-01-01

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review.

PubMed

Roffi, Alice; Di Matteo, Berardo; Krishnakumar, Gopal Shankar; Kon, Elizaveta; Filardo, Giuseppe

2017-02-01

The treatment of large bone defects represents a significant challenge for orthopaedic surgeons. In recent years, biologic agents have also been used to further improve bone healing. Among these, platelet-rich plasma (PRP) is the most exploited strategy. The aim of the present study was to systematically review the available literature to identify: 1) preclinical in-vivo results supporting the rational of PRP use for bone healing; 2) evidence from the clinical practice on the actual clinical benefit of PRP for the treatment of fractures and complications such as delayed unions and non-unions. A systematic review of the literature was performed on the application of PRP in bone healing, using the following inclusion criteria: pre-clinical and clinical reports of any level of evidence, written in English language, published in the last 20 years (1996-2016), on the use of PRP to stimulate long-bone defect treatment, with focus on fracture and delayed/non-unions healing. The search in the Pubmed database identified 64 articles eligible for inclusion: 45 were preclinical in-vivo studies and 19 were clinical studies. Despite the fact that the overall pre-clinical results seem to support the benefit of PRP in 91.1 % of the studies, a more in depth analysis underlined a lower success rate, with a positive outcome of 84.4 % in terms of histological analysis, and even lower values considering radiological and biomechanical results (75.0 % and 72.7 % positive outcome respectively). This was also mirrored in the clinical literature, where the real benefit of PRP use to treat fractures and non-unions is still under debate. Overall, the available literature presents major limitations in terms of low quality and extreme heterogeneity, which hamper the possibility to optimize PRP treatment and translate it into a real clinical benefit despite positive preclinical findings on its biological potential to favour bone healing.

Insights from Preclinical Choice Models on Treating Drug Addiction.

PubMed

Banks, Matthew L; Negus, S Stevens

2017-02-01

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

Automated location detection of injection site for preclinical stereotactic neurosurgery procedure

NASA Astrophysics Data System (ADS)

Abbaszadeh, Shiva; Wu, Hemmings C. H.

2017-03-01

Currently, during stereotactic neurosurgery procedures, the manual task of locating the proper area for needle insertion or implantation of electrode/cannula/optic fiber can be time consuming. The requirement of the task is to quickly and accurately find the location for insertion. In this study we investigate an automated method to locate the entry point of region of interest. This method leverages a digital image capture system, pattern recognition, and motorized stages. Template matching of known anatomical identifiable regions is used to find regions of interest (e.g. Bregma) in rodents. For our initial study, we tackle the problem of automatically detecting the entry point.

Comparative preclinical pharmacokinetics study of 3,3′-diindolylmethane formulations: is personalized treatment and targeted chemoprevention in the horizon?

PubMed Central

2013-01-01

Background 3,3′-Diindolylmethane (DIM) is known as an agent of natural origin that provides protection against different cancers due to the broad spectrum of its biological activities in vivo. However, this substance has a very poor biodistribution and absorption in animal tissues. This preclinical trial was conducted to evaluate the pharmacokinetics and bioavailability of various DIM formulations in animal model. Materials and methods The pharmacokinetic parameters of one crystalline DIM formulation and one liquid DIM formulation (oil solution) compared to non-formulated crystalline DIM (control) were tested in 200 rats. The formulations were orally administered to animals by gavage at doses of 200 mg/kg per DIM (crystalline DIM formulation and non-formulated crystalline DIM) and 0.1 mg/kg per DIM (DIM in oil solution). DIM plasma elimination was measured using HPLC method; after that, the area under the curve (AUC), relative bioavailability, and absolute bioavailability were estimated for two formulations in relation to non-formulated crystalline DIM. Results and conclusion The highest bioavailability was achieved by administering liquid DIM (oil solution), containing cod liver oil and polysorbate. The level of DIM in rat blood plasma was about fivefold higher, though the 2,000-fold lower dose was administered compared to crystalline DIM forms. The novel pharmacological DIM substance with high bioavailability may be considered as a promising targeted antitumor chemopreventive agent. It could be used to prevent breast and ovarian cancer development in patients with heterozygous inherited and sporadic BRCA1 gene mutations. Further preclinical and clinical trials are needed to prove this concept. PMID:24325835

Machine learning plus optical flow: a simple and sensitive method to detect cardioactive drugs

NASA Astrophysics Data System (ADS)

Lee, Eugene K.; Kurokawa, Yosuke K.; Tu, Robin; George, Steven C.; Khine, Michelle

2015-07-01

Current preclinical screening methods do not adequately detect cardiotoxicity. Using human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs), more physiologically relevant preclinical or patient-specific screening to detect potential cardiotoxic effects of drug candidates may be possible. However, one of the persistent challenges for developing a high-throughput drug screening platform using iPS-CMs is the need to develop a simple and reliable method to measure key electrophysiological and contractile parameters. To address this need, we have developed a platform that combines machine learning paired with brightfield optical flow as a simple and robust tool that can automate the detection of cardiomyocyte drug effects. Using three cardioactive drugs of different mechanisms, including those with primarily electrophysiological effects, we demonstrate the general applicability of this screening method to detect subtle changes in cardiomyocyte contraction. Requiring only brightfield images of cardiomyocyte contractions, we detect changes in cardiomyocyte contraction comparable to - and even superior to - fluorescence readouts. This automated method serves as a widely applicable screening tool to characterize the effects of drugs on cardiomyocyte function.

Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

PubMed

Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

2015-04-06

In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key ethical and resource matter.

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

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

Grant, Claire, E-mail: claire.grant@astrazeneca.com; Ewart, Lorna; Muthas, Daniel

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility ofmore » integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used to confirm and quantify the risk.« less

A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

PubMed Central

Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

2011-01-01

Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals.

PubMed

Palma, Eduardo Celia; Laureano, João Victor; de Araújo, Bibiana Verlindo; Meinhardt, Nelson Guardiola; Stein, Airton Tetelbom; Dalla Costa, Teresa

2018-04-14

Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C 18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 μg/mL in human plasma, 2 μg/mL in rat plasma, and 0.5 and 0.025 μg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations. Copyright © 2018 John Wiley & Sons, Ltd.

Management of Respiratory Motion in Extracorporeal High-Intensity Focused Ultrasound Treatment in Upper Abdominal Organs: Current Status and Perspectives

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

Muller, A., E-mail: arnaud.muller@chu-lyon.fr; Petrusca, L.; Auboiroux, V.

2013-12-15

Extracorporeal high-intensity focused ultrasound (HIFU) is a minimally invasive therapy considered with increased interest for the ablation of small tumors in deeply located organs while sparing surrounding critical tissues. A multitude of preclinical and clinical studies have showed the feasibility of the method; however, concurrently they showed several obstacles, among which the management of respiratory motion of abdominal organs is at the forefront. The aim of this review is to describe the different methods that have been proposed for managing respiratory motion and to identify their advantages and weaknesses. First, we specify the characteristics of respiratory motion for the liver,more » kidneys, and pancreas and the problems it causes during HIFU planning, treatment, and monitoring. Second, we make an inventory of the preclinical and clinical approaches used to overcome the problem of organ motion. Third, we analyze their respective benefits and drawbacks to identify the remaining physical, technological, and clinical challenges. We thereby consider the outlook of motion compensation techniques and those that would be the most suitable for clinical use, particularly under magnetic resonance thermometry monitoring.« less

Innovations in the Teaching of Behavioral Sciences in the Preclinical Curriculum

ERIC Educational Resources Information Center

Mack, Kevin

2005-01-01

Objective: In problem-based learning curricula, cases are usually clustered into identified themes or organ systems. While this method of aggregating cases presents clear advantages in terms of resource alignment and student focus, an alternative "hidden cluster" approach provides rich opportunities for content integration. Method: The author…

Early bedside care during preclinical medical education: can technology-enhanced patient simulation advance the Flexnerian ideal?

PubMed

Gordon, James A; Hayden, Emily M; Ahmed, Rami A; Pawlowski, John B; Khoury, Kimberly N; Oriol, Nancy E

2010-02-01

Flexner wanted medical students to study at the patient bedside-a remarkable innovation in his time-so that they could apply science to clinical care under the watchful eye of senior physicians. Ever since his report, medical schools have reserved the latter years of their curricula for such an "advanced" apprenticeship, providing clinical clerkship experiences only after an initial period of instruction in basic medical sciences. Although Flexner codified the segregation of preclinical and clinical instruction, he was committed to ensuring that both domains were integrated into a modern medical education. The aspiration to fully integrate preclinical and clinical instruction continues to drive medical education reform even to this day. In this article, the authors revisit the original justification for sequential preclinical-clinical instruction and argue that modern, technology-enhanced patient simulation platforms are uniquely powerful for fostering simultaneous integration of preclinical-clinical content in a way that Flexner would have applauded. To date, medical educators tend to focus on using technology-enhanced medical simulation in clinical and postgraduate medical education; few have devoted significant attention to using immersive clinical simulation among preclinical students. The authors present an argument for the use of dynamic robot-mannequins in teaching basic medical science, and describe their experience with simulator-based preclinical instruction at Harvard Medical School. They discuss common misconceptions and barriers to the approach, describe their curricular responses to the technique, and articulate a unifying theory of cognitive and emotional learning that broadens the view of what is possible, feasible, and desirable with simulator-based medical education.

Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research.

PubMed

Sandberg, Kathryn; Umans, Jason G

2015-05-01

The U.S. National Institutes of Health (NIH) announced last May that steps will be taken to address the over-reliance on male cells and animals in preclinical research. To further address this announcement, in September 2014, scientists with varying perspectives came together at Georgetown University to discuss the following questions. (1) What metrics should the NIH use to assess tangible progress on policy changes designed to address the over-reliance on male cells and animals in preclinical research? (2) How effective can education be in reducing the over-reliance on male cells and animals in preclinical research and what educational initiatives sponsored by the NIH would most likely effect change? (3) What criteria should the NIH use to determine rigorously defined exceptions to the future proposal requirement of a balance of male and female cells and animals in preclinical studies? (4) What additional strategies in addition to proposal requirements should NIH use to reduce the overreliance of male cells and animals in preclinical research? The resulting consensus presented herein includes input from researchers not only from diverse disciplines of basic and translational science including biology, cell and molecular biology, biochemistry, physiology, pharmacology, neuroscience, cardiology, endocrinology, nephrology, psychiatry, and obstetrics and gynecology, but also from recognized experts in publishing, industry, advocacy, science policy, clinical medicine, and population health. We offer our recommendations to aid the NIH as it selects, implements, monitors, and optimizes strategies to correct the over-reliance on male cells and animals in preclinical research. © FASEB.

Improved decision making for prioritizing tumor targeting antibodies in human xenografts: Utility of fluorescence imaging to verify tumor target expression, antibody binding and optimization of dosage and application schedule.

PubMed

Dobosz, Michael; Haupt, Ute; Scheuer, Werner

2017-01-01

Preclinical efficacy studies of antibodies targeting a tumor-associated antigen are only justified when the expression of the relevant antigen has been demonstrated. Conventionally, antigen expression level is examined by immunohistochemistry of formalin-fixed paraffin-embedded tumor tissue section. This method represents the diagnostic "gold standard" for tumor target evaluation, but is affected by a number of factors, such as epitope masking and insufficient antigen retrieval. As a consequence, variances and discrepancies in histological staining results can occur, which may influence decision-making and therapeutic outcome. To overcome these problems, we have used different fluorescence-labeled therapeutic antibodies targeting human epidermal growth factor receptor (HER) family members and insulin-like growth factor-1 receptor (IGF1R) in combination with fluorescence imaging modalities to determine tumor antigen expression, drug-target interaction, and biodistribution and tumor saturation kinetics in non-small cell lung cancer xenografts. For this, whole-body fluorescence intensities of labeled antibodies, applied as a single compound or antibody mixture, were measured in Calu-1 and Calu-3 tumor-bearing mice, then ex vivo multispectral tumor tissue analysis at microscopic resolution was performed. With the aid of this simple and fast imaging method, we were able to analyze the tumor cell receptor status of HER1-3 and IGF1R, monitor the antibody-target interaction and evaluate the receptor binding sites of anti-HER2-targeting antibodies. Based on this, the most suitable tumor model, best therapeutic antibody, and optimal treatment dosage and application schedule was selected. Predictions drawn from obtained imaging data were in excellent concordance with outcome of conducted preclinical efficacy studies. Our results clearly demonstrate the great potential of combined in vivo and ex vivo fluorescence imaging for the preclinical development and characterization of monoclonal antibodies.

Development of transplantable human chordoma xenograft for preclinical assessment of novel therapeutic strategies

PubMed Central

Bozzi, Fabio; Manenti, Giacomo; Conca, Elena; Stacchiotti, Silvia; Messina, Antonella; Dagrada, GianPaolo; Gronchi, Alessandro; Panizza, Pietro; Pierotti, Marco A.; Tamborini, Elena; Pilotti, Silvana

2014-01-01

Background Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies. Methods In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor. Results All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and posttreatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors. Conclusions Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies. PMID:24366975

Using Bayesian analysis in repeated preclinical in vivo studies for a more effective use of animals.

PubMed

Walley, Rosalind; Sherington, John; Rastrick, Joe; Detrait, Eric; Hanon, Etienne; Watt, Gillian

2016-05-01

Whilst innovative Bayesian approaches are increasingly used in clinical studies, in the preclinical area Bayesian methods appear to be rarely used in the reporting of pharmacology data. This is particularly surprising in the context of regularly repeated in vivo studies where there is a considerable amount of data from historical control groups, which has potential value. This paper describes our experience with introducing Bayesian analysis for such studies using a Bayesian meta-analytic predictive approach. This leads naturally either to an informative prior for a control group as part of a full Bayesian analysis of the next study or using a predictive distribution to replace a control group entirely. We use quality control charts to illustrate study-to-study variation to the scientists and describe informative priors in terms of their approximate effective numbers of animals. We describe two case studies of animal models: the lipopolysaccharide-induced cytokine release model used in inflammation and the novel object recognition model used to screen cognitive enhancers, both of which show the advantage of a Bayesian approach over the standard frequentist analysis. We conclude that using Bayesian methods in stable repeated in vivo studies can result in a more effective use of animals, either by reducing the total number of animals used or by increasing the precision of key treatment differences. This will lead to clearer results and supports the "3Rs initiative" to Refine, Reduce and Replace animals in research. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs.

PubMed

Köster, Ursula; Nolte, Ingo; Michel, Martin C

2016-02-01

Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

Computerized Virtual Reality Simulation in Preclinical Dentistry: Can a Computerized Simulator Replace the Conventional Phantom Heads and Human Instruction?

PubMed

Plessas, Anastasios

2017-10-01

In preclinical dental education, the acquisition of clinical, technical skills, and the transfer of these skills to the clinic are paramount. Phantom heads provide an efficient way to teach preclinical students dental procedures safely while increasing their dexterity skills considerably. Modern computerized phantom head training units incorporate features of virtual reality technology and the ability to offer concurrent augmented feedback. The aims of this review were to examine and evaluate the dental literature for evidence supporting their use and to discuss the role of augmented feedback versus the facilitator's instruction. Adjunctive training in these units seems to enhance student's learning and skill acquisition and reduce the required faculty supervision time. However, the virtual augmented feedback cannot be used as the sole method of feedback, and the facilitator's input is still critical. Well-powered longitudinal randomized trials exploring the impact of these units on student's clinical performance and issues of cost-effectiveness are warranted.

The nature of outsourced preclinical research--the example of chemical synthesis.

PubMed

Festel, Gunter W

2013-09-01

The possibility to buy standardized external services or even new and innovative methods within drug discovery has increased dramatically during the last decades. Service providers are able to provide timely and efficient solutions to any given problem within preclinical research. The outsourcing behavior depends on the specific company type. Generally, the outsourcing level of emerging pharmaceutical and biotechnology companies is much higher than established companies due to low or missing internal resources. Whereas the "make-or-buy" decisions of large and fully integrated pharmaceutical companies are mainly competency driven, those of mid-size and small pharmaceutical, as well as biotech companies show a specific combination of cost/capacity and competency. The three different cooperation models "price competition", "project selection," and "strategic partnership" were identified. For all types of companies, the cooperation model of "strategic partnership" offers access to high-level expertise while reducing fixed costs and complexity. This was shown using chemical synthesis as an example but is also true for other areas of preclinical research.

(125)I-Tetrazines and Inverse-Electron-Demand Diels-Alder Chemistry: A Convenient Radioiodination Strategy for Biomolecule Labeling, Screening, and Biodistribution Studies.

PubMed

Albu, Silvia A; Al-Karmi, Salma A; Vito, Alyssa; Dzandzi, James P K; Zlitni, Aimen; Beckford-Vera, Denis; Blacker, Megan; Janzen, Nancy; Patel, Ramesh M; Capretta, Alfredo; Valliant, John F

2016-01-20

A convenient method to prepare radioiodinated tetrazines was developed, such that a bioorthogonal inverse electron demand Diels-Alder reaction can be used to label biomolecules with iodine-125 for in vitro screening and in vivo biodistribution studies. The tetrazine was prepared by employing a high-yielding oxidative halo destannylation reaction that concomitantly oxidized the dihydrotetrazine precursor. The product reacts quickly and efficiently with trans-cyclooctene derivatives. Utility was demonstrated through antibody and hormone labeling experiments and by evaluating products using standard analytical methods, in vitro assays, and quantitative biodistribution studies where the latter was performed in direct comparison to Bolton-Hunter and direct iodination methods. The approach described provides a convenient and advantageous alternative to conventional protein iodination methods that can expedite preclinical development and evaluation of biotherapeutics.

Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

PubMed

Martin, Frederic D C; Benjamin, Amanda; MacLean, Ruth; Hollinshead, David M; Landqvist, Claire

2017-12-01

In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. Copyright © 2017 Elsevier Ltd. All rights reserved.

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA

PubMed Central

Canetta, Sarah E.; Brown, Alan S.

2013-01-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed. PMID:23956839

Development and validation of a UPLC-MS method for the determination of galantamine in guinea pig plasma and its application to a pre-clinical bioavailability study of novel galantamine formulations.

PubMed

Wang, Jiang; Pavurala, Naresh; Xu, Xiaoming; Krishnaiah, Yellela S R; Faustino, Patrick J

2018-05-04

To evaluate the bioavailability and pharmacokinetic profiles of two novel galantamine formulations as medical countermeasure products, an ultra-performance liquid chromatography-single quadrupole mass spectrometry (UPLC-MS) method was developed and validated for quantifying galantamine in guinea pig plasma using solid-phase extraction with a mixed mode strong cation exchange reversed-phase cartridge. Chromatographic separation was achieved on a Waters Acquity UPLC BEH C 18 column maintained at 40°C. The mobile phases were solution A, acetonitrile-water, 5:95 (v/v) and solution B, acetonitrile-water 90:10 (v/v), both containing 2 mM ammonium formate and 0.2% formic acid. The mobile phase was delivered utilizing a 3 min gradient program start with 95%A-5%B at a flow rate of 0.6 mL/min. The analyte and internal standard, galantamine-d3, were detected by selected ion monitoring mode on a Waters 3100 single quadrupole mass spectrometer with positive electrospray ionization. The method was validated according to the US Food and Drug Administration bioanalytical guidance. The method was selective and was linear over the analytical range of 2-2000 ng/mL. Accuracy and precision were acceptable with intra- and inter-day accuracies between 96.8 and 101% and precisions (RSD) <4.88%. The method was successfully implemented to measure galantamine plasma levels in a series of pre-clinical bioavailability studies for the evaluation of novel galantamine formulations. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Simultaneous Quantification of Apolipoprotein A-I and Apolipoprotein B by Liquid-Chromatography–Multiple-Reaction–Monitoring Mass Spectrometry

PubMed Central

Agger, Sean A.; Marney, Luke C.; Hoofnagle, Andrew N.

2011-01-01

BACKGROUND If liquid-chromatography–multiple-reaction–monitoring mass spectrometry (LC-MRM/MS) could be used in the large-scale preclinical verification of putative biomarkers, it would obviate the need for the development of expensive immunoassays. In addition, the translation of novel biomarkers to clinical use would be accelerated if the assays used in preclinical studies were the same as those used in the clinical laboratory. To validate this approach, we developed a multiplexed assay for the quantification of 2 clinically well-known biomarkers in human plasma, apolipoprotein A-I and apolipoprotein B (apoA-I and apoB). METHODS We used PeptideAtlas to identify candidate peptides. Human samples were denatured with urea or trifluoroethanol, reduced and alkylated, and digested with trypsin. We compared reversed-phase chromatographic separation of peptides with normal flow and microflow, and we normalized endogenous peptide peak areas to internal standard peptides. We evaluated different methods of calibration and compared the final method with a nephelometric immunoassay. RESULTS We developed a final method using trifluoroethanol denaturation, 21-h digestion, normal flow chromatography-electrospray ionization, and calibration with a single normal human plasma sample. For samples injected in duplicate, the method had intraassay CVs <6% and interassay CVs <12% for both proteins, and compared well with immunoassay (n = 47; Deming regression, LC-MRM/MS = 1.17 × immunoassay – 36.6; Sx|y = 10.3 for apoA-I and LC-MRM/MS = 1.21 × immunoassay + 7.0; Sx|y = 7.9 for apoB). CONCLUSIONS Multiplexed quantification of proteins in human plasma/serum by LC-MRM/MS is possible and compares well with clinically useful immunoassays. The potential application of single-point calibration to large clinical studies could simplify efforts to reduce day-to-day digestion variability. PMID:20923952

Acceptability of instructional videos.

PubMed

Rayyan, Mohammad; Elagra, Marwa; Alfataftah, Nida; Alammar, Amirah

2017-08-01

Over the past few decades, instructional videos have been incorporated as important tools in the dental classroom setting. This study aimed to investigate the acceptability of video demonstrations in comparison with live broadcasting and with the traditional face-to-face demonstrations in preclinical fixed prosthodontic classes. A group of dental students who have been exposed to three different methods of delivering practical demonstrations - face-to-face demonstrations, live broadcasting and recorded instructional videos - were included in the study. Preferences regarding these three methods were investigated using a questionnaire comprising a number of closed- and open-ended questions. Descriptive statistics were used to analyse the survey data using spss software. Survey comments were summarised and coded into categories. A total of 163 questionnaires were distributed, and 145 responses were returned (a response rate of 89%). Ninety-two students (63%) considered the recorded video demonstrations to be the most convenient. Moreover, ninety-seven students (67%) found live demonstrations to be the least convenient. The majority of students either agreed (67 students) or strongly agreed (60 students) that watching the video before the session made it easier for them to perform the procedure in the lab. Recorded instructional videos were the preferred method of delivering practical demonstrations for students in the preclinical courses of fixed prosthodontics. Instructors must focus on using the technological aids to increase their positive interaction with students. Instructional videos have been incorporated as important tools in the dental classroom setting. © 2016 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

PubMed

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

2016-01-01

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

Simulation study of the second-generation MR-compatible SPECT system based on the inverted compound-eye gamma camera design

NASA Astrophysics Data System (ADS)

Lai, Xiaochun; Meng, Ling-Jian

2018-02-01

In this paper, we present simulation studies for the second-generation MRI compatible SPECT system, MRC-SPECT-II, based on an inverted compound eye (ICE) gamma camera concept. The MRC-SPECT-II system consists of a total of 1536 independent micro-pinhole-camera-elements (MCEs) distributed in a ring with an inner diameter of 6 cm. This system provides a FOV of 1 cm diameter and a peak geometrical efficiency of approximately 1.3% (the typical levels of 0.1%-0.01% found in modern pre-clinical SPECT instrumentations), while maintaining a sub-500 μm spatial resolution. Compared to the first-generation MRC-SPECT system (MRC-SPECT-I) (Cai 2014 Nucl. Instrum. Methods Phys. Res. A 734 147-51) developed in our lab, the MRC-SPECT-II system offers a similar resolution with dramatically improved sensitivity and greatly reduced physical dimension. The latter should allow the system to be placed inside most clinical and pre-clinical MRI scanners for high-performance simultaneous MRI and SPECT imaging.

Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo.

PubMed

Proulx, Steven T; Luciani, Paola; Alitalo, Annamari; Mumprecht, Viviane; Christiansen, Ailsa J; Huggenberger, Reto; Leroux, Jean-Christophe; Detmar, Michael

2013-07-01

Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease models.

Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo

PubMed Central

Proulx, Steven T.; Luciani, Paola; Alitalo, Annamari; Mumprecht, Viviane; Christiansen, Ailsa J.; Huggenberger, Reto

2013-01-01

Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease models. PMID:23325334

Understanding disease processes in multiple sclerosis through magnetic resonance imaging studies in animal models

PubMed Central

Nathoo, Nabeela; Yong, V. Wee; Dunn, Jeff F.

2014-01-01

There are exciting new advances in multiple sclerosis (MS) resulting in a growing understanding of both the complexity of the disorder and the relative involvement of grey matter, white matter and inflammation. Increasing need for preclinical imaging is anticipated, as animal models provide insights into the pathophysiology of the disease. Magnetic resonance (MR) is the key imaging tool used to diagnose and to monitor disease progression in MS, and thus will be a cornerstone for future research. Although gadolinium-enhancing and T2 lesions on MRI have been useful for detecting MS pathology, they are not correlative of disability. Therefore, new MRI methods are needed. Such methods require validation in animal models. The increasing necessity for MRI of animal models makes it critical and timely to understand what research has been conducted in this area and what potential there is for use of MRI in preclinical models of MS. Here, we provide a review of MRI and magnetic resonance spectroscopy (MRS) studies that have been carried out in animal models of MS that focus on pathology. We compare the MRI phenotypes of animals and patients and provide advice on how best to use animal MR studies to increase our understanding of the linkages between MR and pathology in patients. This review describes how MRI studies of animal models have been, and will continue to be, used in the ongoing effort to understand MS. PMID:24936425

WE-EF-BRA-07: High Performance Preclinical Irradiation Through Optimized Dual Focal Spot Dose Painting and Online Virtual Isocenter Radiation Field Targeting

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

Stewart, J; Princess Margaret Cancer Centre, University Health Network, Toronto, CA; Lindsay, P

Purpose: Advances in radiotherapy practice facilitated by collimation systems to shape radiation fields and image guidance to target these conformal beams have motivated proposals for more complex dose patterns to improve the therapeutic ratio. Recent progress in small animal radiotherapy platforms has provided the foundation to validate the efficacy of such interventions, but robustly delivering heterogeneous dose distributions at the scale and accuracy demanded by preclinical studies remains challenging. This work proposes a dual focal spot optimization method to paint spatially heterogeneous dose regions and an online virtual isocenter targeting method to accurately target the dose distributions. Methods: Two-dimensional dosemore » kernels were empirically measured for the 1 mm diameter circular collimator with radiochromic film in a solid water phantom for the small and large x-ray focal spots on the X-RAD 225Cx microirradiator. These kernels were used in an optimization framework which determined a set of animal stage positions, beam-on times, and focal spot settings to optimally deliver a given desired dose distribution. An online method was developed which defined a virtual treatment isocenter based on a single image projection of the collimated radiation field. The method was demonstrated by optimization of a 6 mm circular 2 Gy target adjoining a 4 mm semicircular avoidance region. Results: The dual focal spot technique improved the optimized dose distribution with the proportion of avoidance region receiving more than 0.5 Gy reduced by 40% compared to the large focal spot technique. Targeting tests performed by irradiating ball bearing targets on radiochromic film pieced revealed the online targeting method improved the three-dimensional accuracy from 0.48 mm to 0.15 mm. Conclusion: The dual focal spot optimization and online virtual isocenter targeting framework is a robust option for delivering dose at the preclinical level and provides a new experimental option for unique radiobiological investigations This work is supported, in part, by the Natural Sciences and Engineering Research Council of Canada and a Mitacs-Accelerate fellowship. P.E. Lindsay, and D.A. Jaffray are listed as inventors of the system described herein. This system has been licensed to Precision X-Ray Inc. for commercial development.« less

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

PubMed Central

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

2008-01-01

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

Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity.

PubMed

Sanders, R D; Ma, D; Brooks, P; Maze, M

2008-11-01

Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.

Common data elements for preclinical epilepsy research: Standards for data collection and reporting. A TASK3 report of the AES/ILAE Translational Task Force of the ILAE.

PubMed

Harte-Hargrove, Lauren C; French, Jacqueline A; Pitkänen, Asla; Galanopoulou, Aristea S; Whittemore, Vicky; Scharfman, Helen E

2017-11-01

The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

PubMed

Baylis, Francoise; McLeod, Marcus

2017-01-01

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

PubMed Central

Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

2015-01-01

Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases. PMID:25767435

Trends in Handheld Computing Among Medical Students

PubMed Central

Grasso, Michael A.; Yen, M. Jim; Mintz, Matthew L.

2005-01-01

The purpose of this study was to identify trends in the utilization and acceptance of handheld computers (personal digital assistants) among medical students during preclinical and clinical training. These results can be used to identify differences between preclinical and clinical users, differences between current use and idealized use, and perceived limitations of these devices. PMID:16779255

SU-E-CAMPUS-I-05: Internal Dosimetric Calculations for Several Imaging Radiopharmaceuticals in Preclinical Studies and Quantitative Assessment of the Mouse Size Impact On Them. Realistic Monte Carlo Simulations Based On the 4D-MOBY Model

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

Kostou, T; Papadimitroulas, P; Kagadis, GC

2014-06-15

Purpose: Commonly used radiopharmaceuticals were tested to define the most important dosimetric factors in preclinical studies. Dosimetric calculations were applied in two different whole-body mouse models, with varying organ size, so as to determine their impact on absorbed doses and S-values. Organ mass influence was evaluated with computational models and Monte Carlo(MC) simulations. Methods: MC simulations were executed on GATE to determine dose distribution in the 4D digital MOBY mouse phantom. Two mouse models, 28 and 34 g respectively, were constructed based on realistic preclinical exams to calculate the absorbed doses and S-values of five commonly used radionuclides in SPECT/PETmore » studies (18F, 68Ga, 177Lu, 111In and 99mTc).Radionuclide biodistributions were obtained from literature. Realistic statistics (uncertainty lower than 4.5%) were acquired using the standard physical model in Geant4. Comparisons of the dosimetric calculations on the two different phantoms for each radiopharmaceutical are presented. Results: Dose per organ in mGy was calculated for all radiopharmaceuticals. The two models introduced a difference of 0.69% in their brain masses, while the largest differences were observed in the marrow 18.98% and in the thyroid 18.65% masses.Furthermore, S-values of the most important target-organs were calculated for each isotope. Source-organ was selected to be the whole mouse body.Differences on the S-factors were observed in the 6.0–30.0% range. Tables with all the calculations as reference dosimetric data were developed. Conclusion: Accurate dose per organ and the most appropriate S-values are derived for specific preclinical studies. The impact of the mouse model size is rather high (up to 30% for a 17.65% difference in the total mass), and thus accurate definition of the organ mass is a crucial parameter for self-absorbed S values calculation.Our goal is to extent the study for accurate estimations in small animal imaging, whereas it is known that there is a large variety in the anatomy of the organs.« less

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

PubMed Central

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

2013-01-01

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

New Kids on the Block: RNA-Based Influenza Virus Vaccines.

PubMed

Scorza, Francesco Berlanda; Pardi, Norbert

2018-04-01

RNA-based immunization strategies have emerged as promising alternatives to conventional vaccine approaches. A substantial body of published work demonstrates that RNA vaccines can elicit potent, protective immune responses against various pathogens. Consonant with its huge impact on public health, influenza virus is one of the best studied targets of RNA vaccine research. Currently licensed influenza vaccines show variable levels of protection against seasonal influenza virus strains but are inadequate against drifted and pandemic viruses. In recent years, several types of RNA vaccines demonstrated efficacy against influenza virus infections in preclinical models. Additionally, comparative studies demonstrated the superiority of some RNA vaccines over the currently used inactivated influenza virus vaccines in animal models. Based on these promising preclinical results, clinical trials have been initiated and should provide valuable information about the translatability of the impressive preclinical data to humans. This review briefly describes RNA-based vaccination strategies, summarizes published preclinical and clinical data, highlights the roadblocks that need to be overcome for clinical applications, discusses the landscape of industrial development, and shares the authors' personal perspectives about the future of RNA-based influenza virus vaccines.

Osteogenic Potential of Dental Mesenchymal Stem Cells in Preclinical Studies: A Systematic Review Using Modified ARRIVE and CONSORT Guidelines

PubMed Central

Ramamoorthi, Murali; Bakkar, Mohammed; Jordan, Jack; Tran, Simon D.

2015-01-01

Background and Objective. Dental stem cell-based tissue engineered constructs are emerging as a promising alternative to autologous bone transfer for treating bone defects. The purpose of this review is to systematically assess the preclinical in vivo and in vitro studies which have evaluated the efficacy of dental stem cells on bone regeneration. Methods. A literature search was conducted in Ovid Medline, Embase, PubMed, and Web of Science up to October 2014. Implantation of dental stem cells in animal models for evaluating bone regeneration and/or in vitro studies demonstrating osteogenic potential of dental stem cells were included. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to ensure the quality of the search. Modified ARRIVE (Animal research: reporting in invivo experiments) and CONSORT (Consolidated reporting of trials) were used to critically analyze the selected studies. Results. From 1914 citations, 207 full-text articles were screened and 137 studies were included in this review. Because of the heterogeneity observed in the studies selected, meta-analysis was not possible. Conclusion. Both in vivo and in vitro studies indicate the potential use of dental stem cells in bone regeneration. However well-designed randomized animal trials are needed before moving into clinical trials. PMID:26106427

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

PubMed

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Microstructural white matter alterations in preclinical Alzheimer’s disease detected using free water elimination diffusion tensor imaging

PubMed Central

Ly, Martina; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Zetterberg, Henrik; Blennow, Kaj; Sager, Mark A.; Asthana, Sanjay; Johnson, Sterling C.; Alexander, Andrew L.; Bendlin, Barbara B.

2017-01-01

Brain changes associated with Alzheimer’s disease (AD) begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47–76 years) from the Wisconsin Registry for Alzheimer’s Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI. PMID:28291839

Benefits of Case-Based versus Traditional Lecture-Based Instruction in a Preclinical Removable Prosthodontics Course.

PubMed

Samuelson, David B; Divaris, Kimon; De Kok, Ingeborg J

2017-04-01

This study compared the acceptability and relative effectiveness of case-based learning (CBL) versus traditional lecture-based (LB) instruction in a preclinical removable prosthodontics course in the University of North Carolina at Chapel Hill School of Dentistry DDS curriculum. The entire second-year class (N=82) comprised this crossover study's sample. Assessments of baseline comprehension and confidence in removable partial denture (RPD) treatment planning were conducted at the beginning of the course. Near the end of the course, half of the class received CBL and LB instruction in an RPD module in alternating sequence, with students serving as their own control group. Assessments of perceived RPD treatment planning efficacy, comprehension, and instruction method preference were administered directly after students completed the RPD module and six months later. Analyses of variance accounting for period, carryover, and sequence effects were used to determine the relative effects of each approach using a p<0.05 statistical significance threshold. The results showed that the students preferred CBL (81%) over LB instruction (9%), a pattern that remained unchanged after a six-month period. Despite notable period and carryover effects, CBL was also associated with higher gains in RPD treatment planning comprehension (p=0.04) and perceived efficacy (p=0.01) compared to LB instruction. These gains diminished six months after the course-a finding based on a 49% follow-up response rate. Overall, the students overwhelmingly preferred CBL to LB instruction, and the findings suggest small albeit measurable educational benefits associated with CBL. This study's findings support the introduction and further testing of CBL in the preclinical dental curriculum, in anticipation of possible future benefits evident during clinical training.

Antibody-linked drug shrinks various types of tumors in preclinical study | Center for Cancer Research

Cancer.gov

A preclinical study by Center for Cancer Research investigators and colleagues shows that a drug guided by an attached target-seeking antibody can recognize cells infiltrating tumors, the tumor stroma, and cause various types of tumors to shrink, and in many cases, disappear. Their findings suggest that when stromal cells take up the ADC, they cleave the drug from the antibody

Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents

PubMed Central

German-Ponciano, León Jesús; Rosas-Sánchez, Gilberto Uriel; Rivadeneyra-Domínguez, Eduardo

2018-01-01

Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, and γ-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans. PMID:29623232

Electromagnetic navigated positioning of the maxilla after Le Fort I osteotomy in preclinical orthognathic surgery cases.

PubMed

Berger, Moritz; Nova, Igor; Kallus, Sebastian; Ristow, Oliver; Eisenmann, Urs; Freudlsperger, Christian; Seeberger, Robin; Hoffmann, Jürgen; Dickhaus, Hartmut

2017-03-01

Inaccuracies in orthognathic surgery can be caused during face-bow registration, model surgery on plaster models, and intermaxillary splint manufacturing. Electromagnetic (EM) navigation is a promising method for splintless digitized maxillary positioning. After performing Le Fort I osteotomy on 10 plastic skulls, the target position of the maxilla was guided by an EM navigation system. Specially implemented software illustrated the target position by real-time multistage colored three-dimensional imaging. Accuracy was determined by using pre- and postoperative cone beam computed tomography. The high accuracy of the EM system was underlined by the fact that it had a navigated maxilla position discrepancy of only 0.4 mm, which was verified by postoperative cone beam computed tomography. This preclinical study demonstrates a precise digitized approach for splintless maxillary repositioning after Le Fort I osteotomy. The accuracy and intuitive illustration of the introduced EM navigation system is promising for potential daily use in orthognathic surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Considerations of sex and gender differences in preclinical and clinical trials.

PubMed

Raz, Limor; Miller, Virginia M

2012-01-01

Women continue to be underrepresented in clinical trials, particularly in Phases I and II of experimental drug studies in spite of legislative guidelines in the USA, Canada, the European Union, Australia, and Japan requiring the inclusion of women in clinical trials. As such, women remain a vulnerable population subject to the adverse effects of pharmacological therapies. Thus, women experience higher rates of adverse drug reactions than do men and for women of reproductive age or who may be pregnant, therapeutic options may be limited. This chapter provides a brief history of inclusion of sex and gender as variables in clinical trials, summarizes governmental legislation for consideration of sex and gender in clinical trials and provides specific examples of drugs which have been withdrawn from the market because of side effects in women. Additional information related to sex and gender in preclinical testing, trial design, challenges to recruitment of women for clinical trials and statistical methods for analysis of data also is considered.

Smoking and increased Alzheimer’s disease risk: A review of potential mechanisms

PubMed Central

Durazzo, Timothy C.; Mattsson, Niklas; Weiner, Michael W.

2014-01-01

Background Cigarette smoking has been linked with both increased and decreased risk for Alzheimer’s disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. Methods Systematic review of published studies on the association between smoking and increased risk for AD, and preclinical and human literature on the relationships between smoking, nicotine exposure and AD-related neuropathology. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. Results Overall, the literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathophysiology and increased risk for AD. Conclusions A reduction in the incidence of smoking will likely reduce the future prevalence of AD. PMID:24924665

[Microalgae as the source of natural products].

PubMed

Vasas, Gábor

2018-05-01

More than 90% of herbal products and herbal medicines have been derived from higher plants recently, but due to independent circumstances, several photosynthetic microalgal species are in focus in this point of view. In the last 50 years, many carbohydrate-, peptide-, terpenoid-, alkaloid- and phenol-type components were described from algae because of the developing structural determination and analytical methods, algae mass production and also artificial algae technologies. At the same time, based partly on traditional causes and partly on the clinical and preclinical data of today, some dried products of algae are directly used as food supplements. Hereinafter, the historical background, economic significance and metabolic background of the mostly used microalgal species will be reviewed. The diverse metabolite production of these organisms will be demonstrated by some molecules with special bioactivity. Several preclinical and clinical studies will be described relating to the microalgal species Spirulina sp., Chlorella sp., Haematococcus sp. and Dunaliella sp. Orv Hetil. 2018; 159(18): 703-708.

Assessment of variability in cerebral vasculature for neuro-anatomical surgery planning in rodent brain

NASA Astrophysics Data System (ADS)

Rangarajan, J. R.; Van Kuyck, K.; Himmelreich, U.; Nuttin, B.; Maes, F.; Suetens, P.

2011-03-01

Clinical and pre-clinical studies show that deep brain stimulation (DBS) of targeted brain regions by neurosurgical techniques ameliorate psychiatric disorder such as anorexia nervosa. Neurosurgical interventions in preclinical rodent brain are mostly accomplished manually with a 2D atlas. Considering both the large number of animals subjected to stereotactic surgical experiments and the associated imaging cost, feasibility of sophisticated pre-operative imaging based surgical path planning and/or robotic guidance is limited. Here, we spatially normalize vasculature information and assess the intra-strain variability in cerebral vasculature for a neurosurgery planning. By co-registering and subsequently building a probabilistic vasculature template in a standard space, we evaluate the risk of a user defined electrode trajectory damaging a blood vessel on its path. The use of such a method may not only be confined to DBS therapy in small animals, but also could be readily applicable to a wide range of stereotactic small animal surgeries like targeted injection of contrast agents and cell labeling applications.

Guidelines for pre-clinical assessment of the acetylcholine receptor--specific passive transfer myasthenia gravis model-Recommendations for methods and experimental designs.

PubMed

Kusner, Linda L; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

2015-08-01

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2014-01-01

Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

Transition from Longitudinal to Block Structure of Preclinical Courses: Outcomes and Experiences

PubMed Central

Marinović, Darko; Hren, Darko; Sambunjak, Dario; Rašić, Ivan; Škegro, Ivan; Marušić, Ana; Marušić, Matko

2009-01-01

Aim To evaluate the transition from a longitudinal to block/modular structure of preclinical courses in a medical school adapting to the process of higher education harmonization in Europe. Methods Average grades and the exam pass rates were compared for 11 preclinical courses before and after the transition from the longitudinal (academic years 1999/2000 to 2001/2002) to block/modular curriculum (academic years 2002/2003 to 2004/2005) at Zagreb University School of Medicine, Croatia. Attitudes of teachers toward the 2 curriculum structures were assessed by a semantic differential scale, and the experiences during the transition were explored in focus groups of students and teachers. Results With the introduction of the block/modular curriculum, average grades mostly increased, except in 3 major courses: Anatomy, Physiology, and Pathology. The proportion of students who passed the exams at first attempt decreased in most courses, but the proportion of students who successfully passed the exam by the end of the summer exam period increased. Teachers generally had more positive attitudes toward the longitudinal (median [C]±intequartile range [Q], 24 ± 16) than block/modular curriculum (C±Q, 38 ± 26) (P = 0.001, Wilcoxon signed rank test). The qualitative inquiry indicated that the dissatisfaction of students and teachers with the block/modular preclinical curriculum was caused by perceived hasty introduction of the reform under pressure and without much adaptation of the teaching program and materials, which reflected negatively on the learning processes and outcomes. Conclusion Any significant alteration in the temporal structure of preclinical courses should be paralleled by a change in the content and teaching methodology, and carefully planned and executed in order to achieve better academic outcomes. PMID:19839073

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

PubMed

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

PubMed Central

Wingstrand, Vibe Lindeblad; Jensen, David H.; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

2016-01-01

Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. PMID:27631373

Reprogramming T-cells for adoptive immunotherapy of ovarian cancer.

PubMed

Genta, Sofia; Ghisoni, Eleonora; Giannone, Gaia; Mittica, Gloria; Valabrega, Giorgio

2018-04-01

Epithelial ovarian cancer (EOC) is the most common cause of death among gynecological malignancies. Despite surgical and pharmacological efforts to improve patients' outcome, persistent and recurrent EOC remains an un-eradicable disease. Chimeric associated antigens (CAR) T cells are T lymphocytes expressing an engineered T cell receptor that activate the immune response after an MHC unrestricted recognition of specific antigens, including tumor associated antigens (TAAs). CART cells have been shown to be effective in the treatment of hematologic tumors even if frequently associated with potentially severe toxicity and high production costs. Areas covered: In this review, we will focus on preclinical and clinical studies evaluating CART activity in EOC in order to identify possible difficulties and advantages of their use in this particular setting. Expert Opinion: The pattern of diffusion within the peritoneal cavity, the tumor microenvironment and the high rate of TAAs make EOC a particularly interesting model for CART cells use. Data from preclinical studies indicate a potential activity of CARTs in EOC, but robust clinical data are still awaited. Further studies are needed to determine the best methods of administration and the most effective CAR type to treat EOC patients.

Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies

PubMed Central

Cai, Shuang; Bagby, Taryn R; Forrest, M Laird

2011-01-01

Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development. PMID:22229080

[Impact of microdose clinical trials in the preclinical stage].

PubMed

Kim, Soonih

2014-01-01

A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

PubMed Central

Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

2016-01-01

Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes. PMID:27445678

Preclinical Evaluation of Novel Dendritic Cell-Based Prostate Cancer Vaccines

DTIC Science & Technology

2008-01-01

relative to other activation modalities(1). Hence the chimeric CD40 was named inducible CD40 (iCD40). The high utility of iCD40-activated DCs (iCD40...recent published (1) studies have suggested a new method to promote DC function in vivo, manipulation of a chimeric inducible CD40. While we have...number of HLA alleles using peptide candidate approach. This precluded the development of immunoassays for direct measurements of PSMA-specific Th

Pancreatic islet isolation variables in non-human primates (rhesus macaques).

PubMed

Andrades, P; Asiedu, C K; Gansuvd, B; Inusah, S; Goodwin, K J; Deckard, L A; Jargal, U; Thomas, J M

2008-07-01

Non-human primates (NHPs) are important preclinical models for pancreatic islet transplantation (PIT) because of their close phylogenetic and immunological relationship with humans. However, low availability of NHP tissue, long learning curves and prohibitive expenses constrain the consistency of isolated NHP islets for PIT studies. To advance preclinical studies, we attempted to identify key variables that consistently influence the quantity and quality of NHP islets. Seventy-two consecutive pancreatic islet isolations from rhesus macaques were reviewed retrospectively. A scaled down, semi-automated islet isolation method was used, and monkeys with streptozotocin-induced diabetes, weighing 3-7 kg, served as recipients for allotransplantation. We analysed the effects of 22 independent variables grouped as donor factors, surgical factors and isolation technique factors. Islet yields, success of isolation and transplantation results were used as quantitative and qualitative outcomes. In the multivariate analysis, variables that significantly affected islet yield were the type of monkey, pancreas preservation, enzyme lot and volume of enzyme delivered. The variables associated with successful isolation were the enzyme lot and volume delivered. The transplant result was correlated with pancreas preservation, enzyme lot, endotoxin levels and COBE collection method. Islet quantity and quality are highly variable between isolations. The data reviewed suggest that future NHP isolations should use bilayer preservation, infuse more than 80 ml of Liberase into the pancreas, collect non-fractioned tissue from the COBE, and strictly monitor for infection.

VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

ERIC Educational Resources Information Center

Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

2016-01-01

Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

Comparative Analysis of Nursing Students' Perspectives toward Avatar Learning Modality: Gain Pre-Clinical Experience via Self-Paced Cognitive Tool

ERIC Educational Resources Information Center

Commendador, Kathleen; Chi, Robert

2013-01-01

This study was undertaken to better understand the nature of nursing students' perspectives toward simulative learning modality for gaining pre-clinical experience via self-paced cognitive tool--Avatar. Findings indicates that participants engaged in synchronous Avatar learning environment had higher levels of appreciation toward Avatar learning…

Methods for Dissecting Motivation and Related Psychological Processes in Rodents.

PubMed

Ward, Ryan D

2016-01-01

Motivational impairments are increasingly recognized as being critical to functional deficits and decreased quality of life in patients diagnosed with psychiatric disease. Accordingly, much preclinical research has focused on identifying psychological and neurobiological processes which underlie motivation . Inferring motivation from changes in overt behavioural responding in animal models, however, is complicated, and care must be taken to ensure that the observed change is accurately characterized as a change in motivation , and not due to some other, task-related process. This chapter discusses current methods for assessing motivation and related psychological processes in rodents. Using an example from work characterizing the motivational impairments in an animal model of the negative symptoms of schizophrenia, we highlight the importance of careful and rigorous experimental dissection of motivation and the related psychological processes when characterizing motivational deficits in rodent models . We suggest that such work is critical to the successful translation of preclinical findings to therapeutic benefits for patients.

Cardiac tissue engineering: state of the art.

PubMed

Hirt, Marc N; Hansen, Arne; Eschenhagen, Thomas

2014-01-17

The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade. Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing.

SU-F-T-682: In-Vivo Simulation of the Relative Biological Effectiveness in Proton Therapy Using a Monte Carlo Method

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

Oesten, H; Massachusetts General Hospital, Boston, MA; Loeck, S

2016-06-15

Purpose: In proton therapy, the relative biological effectiveness (RBE) – compared with conventional photon therapy – is routinely set to 1.1. However, experimental in vitro studies indicate evidence for the variability of the RBE. To clarify the impact on patient treatment, investigation of the RBE in a preclinical case study should be performed. Methods: The Monte Carlo software TOPAS was used to simulate the radiation field of an irradiation setup at the experimental beamline of the proton therapy facility (OncoRay) in Dresden, Germany. Simulations were performed on cone beam CT-data (CBCT) of a xenogeneous mouse with an orthotopic lung carcinomamore » obtained by an in-house developed small animal image-guided radiotherapy device. A homogeneous physical fraction dose of 1.8Gy was prescribed for the contoured tumor volume. Simulated dose and linear energy transfer distributions were used to estimate RBE values in the mouse based on an RBE model by Wedenberg et al. To characterize radiation sensitivity of normal and tumor tissue, α/β-ratios were taken from the literature for NB1RGB (10.1Gy) and human squamous lung cancer (6.2Gy) cell lines, respectively. Results: Good dose coverage of the target volume was achieved with a spread-out Bragg peak (SOBP). The contra-lateral lung was completely spared from receiving radiation. An increase in RBE towards the distal end of the SOBP from 1.07 to 1.35 and from 1.05 to 1.3 was observed when considering normal tissue and tumor, respectively, with the highest RBE values located distal to the target volume. Conclusion: Modeled RBE values simulated on CBCT for experimental preclinical proton therapy varied with tissue type and depth in a mouse and differed therefore from a constant value of 1.1. Further translational work will include, first, conducting preclinical experiments and, second, analogous RBE studies in patients using experimentally verified simulation settings for our clinically used patient-specific beam conforming technique.« less

Spectral Clustering Predicts Tumor Tissue Heterogeneity Using Dynamic 18F-FDG PET: A Complement to the Standard Compartmental Modeling Approach.

PubMed

Katiyar, Prateek; Divine, Mathew R; Kohlhofer, Ursula; Quintanilla-Martinez, Leticia; Schölkopf, Bernhard; Pichler, Bernd J; Disselhorst, Jonathan A

2017-04-01

In this study, we described and validated an unsupervised segmentation algorithm for the assessment of tumor heterogeneity using dynamic 18 F-FDG PET. The aim of our study was to objectively evaluate the proposed method and make comparisons with compartmental modeling parametric maps and SUV segmentations using simulations of clinically relevant tumor tissue types. Methods: An irreversible 2-tissue-compartmental model was implemented to simulate clinical and preclinical 18 F-FDG PET time-activity curves using population-based arterial input functions (80 clinical and 12 preclinical) and the kinetic parameter values of 3 tumor tissue types. The simulated time-activity curves were corrupted with different levels of noise and used to calculate the tissue-type misclassification errors of spectral clustering (SC), parametric maps, and SUV segmentation. The utility of the inverse noise variance- and Laplacian score-derived frame weighting schemes before SC was also investigated. Finally, the SC scheme with the best results was tested on a dynamic 18 F-FDG measurement of a mouse bearing subcutaneous colon cancer and validated using histology. Results: In the preclinical setup, the inverse noise variance-weighted SC exhibited the lowest misclassification errors (8.09%-28.53%) at all noise levels in contrast to the Laplacian score-weighted SC (16.12%-31.23%), unweighted SC (25.73%-40.03%), parametric maps (28.02%-61.45%), and SUV (45.49%-45.63%) segmentation. The classification efficacy of both weighted SC schemes in the clinical case was comparable to the unweighted SC. When applied to the dynamic 18 F-FDG measurement of colon cancer, the proposed algorithm accurately identified densely vascularized regions from the rest of the tumor. In addition, the segmented regions and clusterwise average time-activity curves showed excellent correlation with the tumor histology. Conclusion: The promising results of SC mark its position as a robust tool for quantification of tumor heterogeneity using dynamic PET studies. Because SC tumor segmentation is based on the intrinsic structure of the underlying data, it can be easily applied to other cancer types as well. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Learning style preferences: A study of pre-clinical medical students in Barbados

PubMed Central

OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

2017-01-01

Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching strategies to cater to the students’ needs as well as help the students in becoming aware of their learning style preferences to enhance learning. PMID:28979913

Sex Differences in Stroke Therapies

PubMed Central

Sohrabji, Farida; Park, Min Jung; Mahnke, Amanda H

2016-01-01

Stroke is the 5th leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these were found to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few therapeutics, both preclinically and clinically, take into account possible sex differences in treatment. Reanalysis of data from the only currently FDA-approved stroke therapy, tPA, has shown to not only improve stroke outcomes for both sexes, but to also show sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (IGF-1), and inhibitors of cell death pathways (pharmacological inhibition of PARP-1, NO production, and caspase activation), as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analyses in clinical trials, as well as in preclinical studies, must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systemized/structured way to translate promising therapies to both sexes and increase stroke recovery. PMID:27870437

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

PubMed

Opal, Steven M; Dellinger, R Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C

2014-07-01

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

Dietary and Lifestyle Factors Associated with Dyspepsia among Pre-clinical Medical Students in Ajman, United Arab Emirates

PubMed Central

Jaber, Noorallah; Oudah, Marwa; Kowatli, Amer; Jibril, Jabir; Baig, Inbisat; Mathew, Elsheba; Gopakumar, Aji; Muttappallymyalil, Jayakumary

2016-01-01

Introduction: Dyspepsia is a common gastrointestinal diseases worldwide with a prevalence ranging from 7 to 40%. Dyspepsia, more commonly known as heartburn or indigestion, is defined as one or more of the following symptoms: postprandial fullness, early satiation (the inability to finish a normal size meal), or epigastric pain or burning for at least 3 months in the past year. Dyspepsia has been studied extensively, but little is known of factors associated with dyspepsia among medical students. Objectives: The purpose of this study was to analyze the prevalence of dyspepsia and to evaluate the association between lifestyle and dietary factors associated with dyspepsia among pre-clinical medical students in Ajman, United Arab Emirates. Methods: A cross-sectional survey study was conducted among pre-clinical medical students at Gulf Medical University, Ajman and collected basic demographic data, dyspepsia prevalence, dietary factors, and lifestyle factors. Data was analyzed using Microsoft Excel and SPSS software. Descriptive statistics were used to summarize the participant characteristics. Chi-square tests were used to test the association between dietary and lifestyle factors and dyspepsia. Logistic regression was used to measure the association of predictors (dietary and lifestyle factors) on the odds of having dyspepsia, independently. Multinomial logistic regression was used to examine the full association of predictors on the odds of having dyspepsia. Results: The resulting sample was 176 pre-clinical medical students, with a mean age of 20.67 ± 2.57 years. A total of 77 (43.8%) respondents reported having dyspepsia while 99 (56.2%) did not. There was a significant association between smoking and dyspepsia (p<0.05), as well as a marginally significant association between inadequate sleep and dyspepsia (p<0.10). There was no significant association with alcohol or analgesic use on dyspesia. Dietary habits showed no association with dyspepsia. Conclusion: Dyspepsia was reported by 43.8% of the repondents. These findings emphasize the importance of improving lifestyle and dietary factors associated with dyspepsia and raising awareness of reducing risk factors associated with dyspepsia. Further studies are needed on dyspepsia in a larger cohort of students in order to fully understand the complexity of this problem and be able to generalize the findings to other cohorts. PMID:29138728

Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review

PubMed Central

Deane, Kevin D.

2014-01-01

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

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

PubMed Central

Walther, Sebastian; Halpern, Michael

2010-01-01

The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. PMID:27713372

Preclinical Testing of a Translocator Protein Ligand for the Treatment of Amyotrophic Lateral Sclerosis

DTIC Science & Technology

2017-03-01

Accessed October 26, 2015]. Barneoud, P. et al., 1997. Quantitative motor assessment in FALS mice: a longitudinal study . Neuroreport, 8, pp.2861–2865...cell study , we found that PK acts directly on motor neurons to prevent their death, not via the astrocytes. Then, we evidenced that PK protects not...in TSPO content may protect motor neurons against ALS. Second, in our preclinical study in ALS mice, we have determined that the best route to

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

PubMed

Xie, Tianwu; Zaidi, Habib

2016-01-01

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

Reversible Nerve Conduction Block Using Kilohertz Frequency Alternating Current

PubMed Central

Kilgore, Kevin L.; Bhadra, Niloy

2013-01-01

Objectives The features and clinical applications of balanced-charge kilohertz frequency alternating currents (KHFAC) are reviewed. Preclinical studies of KHFAC block have demonstrated that it can produce an extremely rapid and reversible block of nerve conduction. Recent systematic analysis and experimentation utilizing KHFAC block has resulted in a significant increase in interest in KHFAC block, both scientifically and clinically. Materials and Methods We review the history and characteristics of KHFAC block, the methods used to investigate this type of block, the experimental evaluation of block, and the electrical parameters and electrode designs needed to achieve successful block. We then analyze the existing clinical applications of high frequency currents, comparing the early results with the known features of KHFAC block. Results Although many features of KHFAC block have been characterized, there is still much that is unknown regarding the response of neural structures to rapidly fluctuating electrical fields. The clinical reports to date do not provide sufficient information to properly evaluate the mechanisms that result in successful or unsuccessful treatment. Conclusions KHFAC nerve block has significant potential as a means of controlling nerve activity for the purpose of treating disease. However, early clinical studies in the use of high frequency currents for the treatment of pain have not been designed to elucidate mechanisms or allow direct comparisons to preclinical data. We strongly encourage the careful reporting of the parameters utilized in these clinical studies, as well as the development of outcome measures that could illuminate the mechanisms of this modality. PMID:23924075

Is adiponectin a marker of preclinical atherosclerosis in kidney transplantation?

PubMed

Cañas, Laura; Bayés, Beatriz; Granada, Maria L; Ibernon, Meritxell; Porrini, Esteban; Benítez, Rosa; Díaz, Juan M; Lauzurica, Ricardo; Moreso, Francesc; Torres, Armando; Lampreabe, Ildefonso; Serra, Assumpta; Romero, Ramon

2012-01-01

The aim of this study was to analyze the relationship between pre-transplant adiponectin (pre-ADP), abnormalities in glucose homeostasis (AGH) at three months post-transplantation, and preclinical atherosclerosis in non-diabetic patients prior to kidney transplantation (KT). We carried out a multicenter study in 157 non-diabetic KT patients (66.5% men; age: 50±13 yr). Pre-ADP levels were analyzed using radioimmunoassay. Carotid ultrasound was performed to determine carotid intima-media thickness (c-IMT). Oral glucose tolerance test was carried out to classify patients according ADA criteria. Of the patients, 52.8% had AGH. Median pre-ADP was 19.5 (14-27) μg/mL. An inverse correlation was found between ADP and HOMA index (r=-0.432; p<0.001). Median c-IMT was 0.6 (0.48-0.71) mm. Significant inverse correlation existed between ADP and c-IMT on both sides (p<0.05). Patients with c-IMT >0.6 mm had more AGH (p=0.012) and lower ADP levels (p=0.02). We performed a logistic regression analysis using preclinical atherosclerosis (c-IMT ≥0.6 mm) as dependent variable and sex, age, BMI, ADP, AGH, and HOMA index as independent variables of altered c-IMT. Age, pre-ADP, and AGH were independent risk factors for elevated c-IMT. Patients with AGH have a greater presence of preclinical atherosclerosis. ADP has an inverse relationship with AGH and is an independent marker of preclinical atherosclerosis. © 2011 John Wiley & Sons A/S.

Preconditioning methods influence tumor property in an orthotopic bladder urothelial carcinoma rat model

PubMed Central

MIYAZAKI, KOZO; MORIMOTO, YUJI; NISHIYAMA, NOBUHIRO; SATOH, HIROYUKI; TANAKA, MASAMITSU; SHINOMIYA, NARIYOSHI; ITO, KEIICHI

2014-01-01

Urothelial carcinoma (UC) is an extremely common type of cancer that occurs in the bladder. It has a particularly high rate of recurrence. Therefore, preclinical studies using animal models are essential to determine effective forms of treatment. In the present study, in order to establish an orthotopic bladder UC animal model with clinical relevance, the effects of preconditioning methods on properties of the developed tumor were evaluated. The bladder cavity was pretreated with phosphate-buffered saline (PBS), acid-base, trypsin (TRY) or poly (L-lysine) (PLL) and then rat UC cells (AY-27) (4×106 cells) were inoculated. The results demonstrated that, two weeks later, the tumorigenic rate (88%) and tumor count (2.3 per rat) were not significantly different among the preconditioning methods, whereas tumor volume and invasion depth into bladder tissue were significantly different. Average tumor volumes were >50 mm3 in the PBS and acid-base-treated groups and <10 mm3 in the TRY- and PLL-treated groups. The percentage of invasive tumors (T2 or more advanced stage) was ∼75% of total tumors in the PBS- and acid-base-treated groups, whereas the percentages were reduced in the TRY- and PLL-treated groups (58 and 32%, respectively). Non-invasive tumors (Ta or T1) accounted for 54% of tumors in the PLL-treated group, which was 2-5-fold higher than the percentages in the remaining groups. Properties of the developed tumor in the rat orthotopic UC model were different depending on preconditioning methods. Therefore, different animal models suitable for a discrete preclinical examination may be established by using the appropriate preconditioning condition. PMID:24649309

Quantitative imaging biomarkers: the application of advanced image processing and analysis to clinical and preclinical decision making.

PubMed

Prescott, Jeffrey William

2013-02-01

The importance of medical imaging for clinical decision making has been steadily increasing over the last four decades. Recently, there has also been an emphasis on medical imaging for preclinical decision making, i.e., for use in pharamaceutical and medical device development. There is also a drive towards quantification of imaging findings by using quantitative imaging biomarkers, which can improve sensitivity, specificity, accuracy and reproducibility of imaged characteristics used for diagnostic and therapeutic decisions. An important component of the discovery, characterization, validation and application of quantitative imaging biomarkers is the extraction of information and meaning from images through image processing and subsequent analysis. However, many advanced image processing and analysis methods are not applied directly to questions of clinical interest, i.e., for diagnostic and therapeutic decision making, which is a consideration that should be closely linked to the development of such algorithms. This article is meant to address these concerns. First, quantitative imaging biomarkers are introduced by providing definitions and concepts. Then, potential applications of advanced image processing and analysis to areas of quantitative imaging biomarker research are described; specifically, research into osteoarthritis (OA), Alzheimer's disease (AD) and cancer is presented. Then, challenges in quantitative imaging biomarker research are discussed. Finally, a conceptual framework for integrating clinical and preclinical considerations into the development of quantitative imaging biomarkers and their computer-assisted methods of extraction is presented.

An automatic rat brain extraction method based on a deformable surface model.

PubMed

Li, Jiehua; Liu, Xiaofeng; Zhuo, Jiachen; Gullapalli, Rao P; Zara, Jason M

2013-08-15

The extraction of the brain from the skull in medical images is a necessary first step before image registration or segmentation. While pre-clinical MR imaging studies on small animals, such as rats, are increasing, fully automatic imaging processing techniques specific to small animal studies remain lacking. In this paper, we present an automatic rat brain extraction method, the Rat Brain Deformable model method (RBD), which adapts the popular human brain extraction tool (BET) through the incorporation of information on the brain geometry and MR image characteristics of the rat brain. The robustness of the method was demonstrated on T2-weighted MR images of 64 rats and compared with other brain extraction methods (BET, PCNN, PCNN-3D). The results demonstrate that RBD reliably extracts the rat brain with high accuracy (>92% volume overlap) and is robust against signal inhomogeneity in the images. Copyright © 2013 Elsevier B.V. All rights reserved.

Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

PubMed

Polyzois, Ioannis; Claffey, Noel; McDonald, Albhe; Hussey, David; Quinn, Frank

2011-05-01

The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson's linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level. © 2011 John Wiley & Sons A/S.

Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status.

PubMed

Haedersdal, Merete; Erlendsson, Andrés M; Paasch, Uwe; Anderson, R Rox

2016-05-01

Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice. We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy. We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence. All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long-lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas. Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The failure to detect drug-induced sensory loss in standard preclinical studies.

PubMed

Gauvin, David V; Abernathy, Matthew M; Tapp, Rachel L; Yoder, Joshua D; Dalton, Jill A; Baird, Theodore J

2015-01-01

Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols. Copyright © 2015 Elsevier Inc. All rights reserved.

Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.

PubMed

Hovens, Iris B; Schoemaker, Regien G; van der Zee, Eddy A; Heineman, Erik; Izaks, Gerbrand J; van Leeuwen, Barbara L

2012-10-01

Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. Copyright © 2012 Elsevier Inc. All rights reserved.

A quantitative analysis of statistical power identifies obesity endpoints for improved in vivo preclinical study design

PubMed Central

Selimkhanov, Jangir; Thompson, W. Clayton; Guo, Juen; Hall, Kevin D.; Musante, Cynthia J.

2017-01-01

The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design. PMID:28392555

Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds.

PubMed

Ma, Shuguang; Li, Zhiling; Lee, Keun-Joong; Chowdhury, Swapan K

2010-12-20

A simple, reliable, and accurate method was developed for quantitative assessment of metabolite coverage in preclinical safety species by mixing equal volumes of human plasma with blank plasma of animal species and vice versa followed by an analysis using high-resolution full-scan accurate mass spectrometry. This approach provided comparable results (within (±15%) to those obtained from regulated bioanalysis and did not require synthetic standards or radiolabeled compounds. In addition, both qualitative and quantitative data were obtained from a single LC-MS analysis on all metabolites and, therefore, the coverage of any metabolite of interest can be obtained.

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

PubMed

Carnicella, Sebastien; Ron, Dorit; Barak, Segev

2014-05-01

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

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

PubMed Central

Carnicella, Sebastien; Ron, Dorit; Barak, Segev

2014-01-01

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

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

PubMed

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

2015-04-01

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

Biological augmentation and tissue engineering approaches in meniscus surgery.

PubMed

Moran, Cathal J; Busilacchi, Alberto; Lee, Cassandra A; Athanasiou, Kyriacos A; Verdonk, Peter C

2015-05-01

The purpose of this review was to evaluate the role of biological augmentation and tissue engineering strategies in meniscus surgery. Although clinical (human), preclinical (animal), and in vitro tissue engineering studies are included here, we have placed additional focus on addressing preclinical and clinical studies reported during the 5-year period used in this review in a systematic fashion while also providing a summary review of some important in vitro tissue engineering findings in the field over the past decade. A search was performed on PubMed for original works published from 2009 to March 31, 2014 using the term "meniscus" with all the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were the following: English-language articles and original clinical, preclinical (in vivo), and in vitro studies of tissue engineering and regenerative medicine application in knee meniscus lesions published from 2009 to March 31, 2014. Three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. These reports show the increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types to be of promise for meniscus replacement. Limitations include a relatively low number of clinical or preclinical in vivo studies, in addition to the fact there is as yet no report in the literature of a tissue-engineered meniscus construct used clinically. Neither does the literature provide clarity on the optimal meniscus scaffold type or biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process, however, and it is hoped that this may lead to improvements in this strategy. There appears to be significant potential for biological augmentation and tissue engineering strategies in meniscus surgery to enhance options for repair and replacement. However, there are still relatively few clinical studies being reported in this regard. There is a strong need for improved translational activities and infrastructure to link the large amounts of in vitro and preclinical biological and tissue engineering data to clinical application. Level IV, systematic review of Level I-IV studies. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

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

PubMed

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

2013-09-01

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

Drugs for solid cancer: the productivity crisis prompts a rethink

PubMed Central

Rösel, Daniel; Brábek, Jan; Veselý, Pavel; Fernandes, Michael

2013-01-01

Despite remarkable progress in cancer-drug discovery, the delivery of novel, safe, and sustainably effective products to the clinic has stalled. Using Src as a model, we examine key steps in drug development. The preclinical evidence on the relationship between Src and solid cancer is in sharp contrast with the modest anticancer effect noted in conventional clinical trials. Here, we consider Src inhibitors as an example of a promising drug class directed to invasion and metastasis and identify roadblocks in translation. We question the assumption that a drug-induced tumor shrinkage in preclinical and clinical studies predicts a successful outcome. Our analysis indicates that the key areas requiring attention are related, and include preclinical models (in vitro and mouse models), meaningful clinical trial end points, and an appreciation of the role of metastasis in morbidity and mortality. Current regulations do not reflect the natural history of the disease, and may be unrelated to the key complications: local invasion, metastasis, and the development of resistance. Alignment of preclinical and clinical studies and regulations based on mechanistic trial end points and platforms may help in overcoming these roadblocks. Viewed kaleidoscopically, most elements necessary and sufficient for a novel translational paradigm are in place. PMID:23836990

[Application of role-play simulation in pre-clinical practice of the fourth grade students in department of endodontics].

PubMed

Zhu, Lin-lin; Qiu, Li-hong; Qu, Liu; Xue, Ming; Yan, Lu

2014-10-01

To apply role- play simulation in pre-clinical practice of the fourth grade students in department of endodontics. Thirty-two students were randomly divided into 2 groups, there were 16 students in each group. Students in one group were taught with role-play simulation while the other group with lecture-based learning method. The teaching effect was measured with examination and questionnaire survey. The data was analyzed by using SPSS 17.0 software package. There were no significant differences in basic knowledge, case analysis and oral examination between 2 groups (P>0.05), but there was significant difference in history taking and medical records writing, practical examination and total scores between 2 groups (P<0.05). The role-play simulation was generally approved by both teachers and students in experimental group. The abilities of the fourth grade students can be developed by role-play simulation in different aspects. Role-play simulation can be applied in pre-clinical practice of the fourth grade students in department of endodontics.

Combining 3D human in vitro methods for a 3Rs evaluation of novel titanium surfaces in orthopaedic applications.

PubMed

Stevenson, G; Rehman, S; Draper, E; Hernández-Nava, E; Hunt, J; Haycock, J W

2016-07-01

In this study, we report on a group of complementary human osteoblast in vitro test methods for the preclinical evaluation of 3D porous titanium surfaces. The surfaces were prepared by additive manufacturing (electron beam melting [EBM]) and plasma spraying, allowing the creation of complex lattice surface geometries. Physical properties of the surfaces were characterized by SEM and profilometry and 3D in vitro cell culture using human osteoblasts. Primary human osteoblast cells were found to elicit greater differences between titanium sample surfaces than an MG63 osteoblast-like cell line, particularly in terms of cell survival. Surface morphology was associated with higher osteoblast metabolic activity and mineralization on rougher titanium plasma spray coated surfaces than smoother surfaces. Differences in osteoblast survival and metabolic activity on titanium lattice structures were also found, despite analogous surface morphology at the cellular level. 3D confocal microscopy identified osteoblast organization within complex titanium surface geometries, adhesion, spreading, and alignment to the biomaterial strut geometries. Mineralized nodule formation throughout the lattice structures was also observed, and indicative of early markers of bone in-growth on such materials. Testing methods such as those presented are not traditionally considered by medical device manufacturers, but we suggest have value as an increasingly vital tool in efficiently translating pre-clinical studies, especially in balance with current regulatory practice, commercial demands, the 3Rs, and the relative merits of in vitro and in vivo studies. Biotechnol. Bioeng. 2016;113: 1586-1599. © 2015 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. © 2015 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

Preclinical experimental stress studies: protocols, assessment and comparison.

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2015-01-05

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

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

PubMed Central

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

2012-01-01

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

Sex differences in stroke therapies.

PubMed

Sohrabji, Farida; Park, Min Jung; Mahnke, Amanda H

2017-01-02

Stroke is the fifth leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these have been shown to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few preclinical or clinical therapeutics take into account possible sex differences in treatment. Reanalysis of data from studies of tissue plasminogen activator (tPA), the only currently FDA-approved stroke therapy, has shown that tPA improves stroke outcomes for both sexes and also shows sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (insulin-like growth factor-1), and inhibitors of cell death pathways (pharmacological inhibition of poly[ADP-ribose] polymerase-1, nitric oxide production, and caspase activation) as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analysis in clinical trials as well as in preclinical studies must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systematic/structured ways to allow promising therapies for both sexes and increase stroke recovery. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.

PubMed

Serabian, M A; Pilaro, A M

1999-01-01

Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unnecessary use of animals.

The Effects of Cannabinoids on Executive Functions: Evidence from Cannabis and Synthetic Cannabinoids-A Systematic Review.

PubMed

Cohen, Koby; Weinstein, Aviv

2018-02-27

Background-Cannabis is the most popular illicit drug in the Western world. Repeated cannabis use has been associated with short and long-term range of adverse effects. Recently, new types of designer-drugs containing synthetic cannabinoids have been widespread. These synthetic cannabinoid drugs are associated with undesired adverse effects similar to those seen with cannabis use, yet, in more severe and long-lasting forms. Method-A literature search was conducted using electronic bibliographic databases up to 31 December 2017. Specific search strategies were employed using multiple keywords (e.g., "synthetic cannabinoids AND cognition," "cannabis AND cognition" and "cannabinoids AND cognition"). Results-The search has yielded 160 eligible studies including 37 preclinical studies (5 attention, 25 short-term memory, 7 cognitive flexibility) and 44 human studies (16 attention, 15 working memory, 13 cognitive flexibility). Both pre-clinical and clinical studies demonstrated an association between synthetic cannabinoids and executive-function impairment either after acute or repeated consumptions. These deficits differ in severity depending on several factors including the type of drug, dose of use, quantity, age of onset and duration of use. Conclusions-Understanding the nature of the impaired executive function following consumption of synthetic cannabinoids is crucial in view of the increasing use of these drugs.

A LabVIEW Platform for Preclinical Imaging Using Digital Subtraction Angiography and Micro-CT.

PubMed

Badea, Cristian T; Hedlund, Laurence W; Johnson, G Allan

2013-01-01

CT and digital subtraction angiography (DSA) are ubiquitous in the clinic. Their preclinical equivalents are valuable imaging methods for studying disease models and treatment. We have developed a dual source/detector X-ray imaging system that we have used for both micro-CT and DSA studies in rodents. The control of such a complex imaging system requires substantial software development for which we use the graphical language LabVIEW (National Instruments, Austin, TX, USA). This paper focuses on a LabVIEW platform that we have developed to enable anatomical and functional imaging with micro-CT and DSA. Our LabVIEW applications integrate and control all the elements of our system including a dual source/detector X-ray system, a mechanical ventilator, a physiological monitor, and a power microinjector for the vascular delivery of X-ray contrast agents. Various applications allow cardiac- and respiratory-gated acquisitions for both DSA and micro-CT studies. Our results illustrate the application of DSA for cardiopulmonary studies and vascular imaging of the liver and coronary arteries. We also show how DSA can be used for functional imaging of the kidney. Finally, the power of 4D micro-CT imaging using both prospective and retrospective gating is shown for cardiac imaging.

A LabVIEW Platform for Preclinical Imaging Using Digital Subtraction Angiography and Micro-CT

PubMed Central

Badea, Cristian T.; Hedlund, Laurence W.; Johnson, G. Allan

2013-01-01

CT and digital subtraction angiography (DSA) are ubiquitous in the clinic. Their preclinical equivalents are valuable imaging methods for studying disease models and treatment. We have developed a dual source/detector X-ray imaging system that we have used for both micro-CT and DSA studies in rodents. The control of such a complex imaging system requires substantial software development for which we use the graphical language LabVIEW (National Instruments, Austin, TX, USA). This paper focuses on a LabVIEW platform that we have developed to enable anatomical and functional imaging with micro-CT and DSA. Our LabVIEW applications integrate and control all the elements of our system including a dual source/detector X-ray system, a mechanical ventilator, a physiological monitor, and a power microinjector for the vascular delivery of X-ray contrast agents. Various applications allow cardiac- and respiratory-gated acquisitions for both DSA and micro-CT studies. Our results illustrate the application of DSA for cardiopulmonary studies and vascular imaging of the liver and coronary arteries. We also show how DSA can be used for functional imaging of the kidney. Finally, the power of 4D micro-CT imaging using both prospective and retrospective gating is shown for cardiac imaging. PMID:27006920

Nanoparticles in targeted cancer therapy: mesoporous silica nanoparticles entering preclinical development stage.

PubMed

Rosenholm, Jessica M; Mamaeva, Veronika; Sahlgren, Cecilia; Lindén, Mika

2012-01-01

Nanotechnology may help overcome persisting limitations of current cancer treatment and thus contribute to the creation of more effective, safer and more affordable therapies. While some nanotechnology-based drug delivery systems are already being marketed and others are in clinical trial, most still remain in the preclinical development stage. Mesoporous silica nanoparticles have been highlighted as an interesting drug delivery platform, due to their flexibility and high drug load potential. Although numerous reports demonstrate sophisticated drug delivery mechanisms in vitro, the therapeutic benefit of these systems for in vivo applications have been under continuous debate. This has been due to nontranslatable conditions used in the in vitro studies, as well as contradictory conclusions drawn from preclinical (in vivo) studies. However, recent studies have indicated that the encouraging cellular studies could in fact be repeated also in vivo. Here, we report on these recent advances regarding therapeutic efficacy, targeting and safety issues related to the application of mesoporous silica nanoparticles in cancer therapy.

Peer-assisted learning: filling the gaps in basic science education for preclinical medical students.

PubMed

Sammaraiee, Yezen; Mistry, Ravi D; Lim, Julian; Wittner, Liora; Deepak, Shantal; Lim, Gareth

2016-09-01

In contrast to peer-assisted learning (PAL) in clinical training, there is scant literature on the efficacy of PAL during basic medical sciences teaching for preclinical students. A group of senior medical students aimed to design and deliver clinically oriented small-group tutorials after every module in the preclinical curriculum at a United Kingdom medical school. Twenty tutorials were delivered by senior students throughout the year to first- and second-year students. A baseline questionnaire was delivered to inform the development of the program followed by an end-point questionnaire the next year (n = 122). Quizzes were administered before and after five separate tutorials to assess changes in mean student scores. Additionally, each tutorial was evaluated via a questionnaire for participants (n = 949). All five posttutorial quizzes showed a significant improvement in mean student score (P < 0.05). Questionnaires showed students found the program to be relevant and useful for revision purposes and appreciated how tutorials contextualized basic science to clinical medicine. Students appreciated the interactive nature of the sessions and found receiving personalized feedback about their learning and consolidating information with someone familiar with the material to be useful. With the inclusion of the program, students felt there were now an adequate number of tutorials during the year. In conclusion, this study shows that senior medical students can design and deliver a program that adds value to the mostly lecture-based formal preclinical curriculum. We hope that our study can prompt further work to explore the effect of PAL on the teaching of basic sciences during preclinical studies. Copyright © 2016 The American Physiological Society.

Microbial exposure in infancy and subsequent appearance of type 1 diabetes mellitus-associated autoantibodies: a cohort study.

PubMed

Virtanen, Suvi M; Takkinen, Hanna-Mari; Nwaru, Bright I; Kaila, Minna; Ahonen, Suvi; Nevalainen, Jaakko; Niinistö, Sari; Siljander, Heli; Simell, Olli; Ilonen, Jorma; Hyöty, Heikki; Veijola, Riitta; Knip, Mikael

2014-08-01

The role of microbial exposure during early life in the development of type 1 diabetes mellitus is unclear. To investigate whether animal contact and other microbial exposures during infancy are associated with the development of preclinical and clinical type 1 diabetes. A birth cohort of children with HLA antigen-DQB1-conferred susceptibility to type 1 diabetes was examined. Participants included 3143 consecutively born children at 2 hospitals in Finland between 1996 and 2004. The following exposures during the first year of life were assessed: indoor and outdoor dogs and cats, farm animals, farming, visit to a stable, day care, and exposure to antibiotics during the first week of life. Clinical and preclinical type 1 diabetes were used as outcomes. The latter was defined as repeated positivity for islet-cell antibodies plus for at least 1 of 3 other diabetes-associated autoantibodies analyzed and/or clinical type 1 diabetes. The autoantibodies were analyzed at 3- to 12-month intervals since the birth of the child. Children exposed to an indoor dog, compared with otherwise similar children without an indoor dog exposure, had a reduced odds of developing preclinical type 1 diabetes (adjusted odds ratio [OR], 0.47; 95% CI, 0.28-0.80; P = .005) and clinical type 1 diabetes (adjusted OR, 0.40; 95% CI, 0.14-1.14; P = .08). All of the other microbial exposures studied were not associated with preclinical or clinical diabetes: the odds ratios ranged from 0.74 to 1.58. Among the 9 early microbial exposures studied, only the indoor dog exposure during the first year of life was inversely associated with the development of preclinical type 1 diabetes. This finding needs to be confirmed in other populations.

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

PubMed

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

2015-06-01

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

The interplay between academic performance and quality of life among preclinical students.

PubMed

Shareef, Mohammad Abrar; AlAmodi, Abdulhadi A; Al-Khateeb, Abdulrahman A; Abudan, Zainab; Alkhani, Mohammed A; Zebian, Sanderlla I; Qannita, Ahmed S; Tabrizi, Mariam J

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p < 0.001), psychological health (r = 0.29, p < 0.001), social relations (r = 0.11, p = 0.03) and environment (r = 0.23, p < 0.001). Male student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

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

PubMed Central

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

2015-01-01

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

Mitigating risk in academic preclinical drug discovery.

PubMed

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

2015-04-01

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

Acquisition of dental skills in preclinical technique courses: influence of spatial and manual abilities.

PubMed

Schwibbe, Anja; Kothe, Christian; Hampe, Wolfgang; Konradt, Udo

2016-10-01

Sixty years of research have not added up to a concordant evaluation of the influence of spatial and manual abilities on dental skill acquisition. We used Ackerman's theory of ability determinants of skill acquisition to explain the influence of spatial visualization and manual dexterity on the task performance of dental students in two consecutive preclinical technique courses. We measured spatial and manual abilities of applicants to Hamburg Dental School by means of a multiple choice test on Technical Aptitude and a wire-bending test, respectively. Preclinical dental technique tasks were categorized as consistent-simple and inconsistent-complex based on their contents. For analysis, we used robust regression to circumvent typical limitations in dental studies like small sample size and non-normal residual distributions. We found that manual, but not spatial ability exhibited a moderate influence on the performance in consistent-simple tasks during dental skill acquisition in preclinical dentistry. Both abilities revealed a moderate relation with the performance in inconsistent-complex tasks. These findings support the hypotheses which we had postulated on the basis of Ackerman's work. Therefore, spatial as well as manual ability are required for the acquisition of dental skills in preclinical technique courses. These results support the view that both abilities should be addressed in dental admission procedures in addition to cognitive measures.

Pharmacologic therapy for acute pancreatitis

PubMed Central

Kambhampati, Swetha; Park, Walter; Habtezion, Aida

2014-01-01

While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

Pediatric cardiovascular safety: challenges in drug and device development and clinical application.

PubMed

Bates, Katherine E; Vetter, Victoria L; Li, Jennifer S; Cummins, Susan; Aguel, Fernando; Almond, Christopher; Dubin, Anne M; Elia, Josephine; Finkle, John; Hausner, Elizabeth A; Joseph, Francesca; Karkowsky, Abraham M; Killeen, Matthew; Lemacks, Jodi; Mathis, Lisa; McMahon, Ann W; Pinnow, Ellen; Rodriguez, Ignacio; Stockbridge, Norman L; Stockwell, Margaret; Tassinari, Melissa; Krucoff, Mitchell W

2012-10-01

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic. Copyright © 2012 Mosby, Inc. All rights reserved.

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

PubMed

Marshall, John C

2005-12-01

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

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

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

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

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

Dental Students' Perceptions of Digital Assessment Software for Preclinical Tooth Preparation Exercises.

PubMed

Park, Carly F; Sheinbaum, Justin M; Tamada, Yasushi; Chandiramani, Raina; Lian, Lisa; Lee, Cliff; Da Silva, John; Ishikawa-Nagai, Shigemi

2017-05-01

Objective self-assessment is essential to learning and continued competence in dentistry. A computer-assisted design/computer-assisted manufacturing (CAD/CAM) learning software (prepCheck, Sirona) allows students to objectively assess their performance in preclinical prosthodontics. The aim of this study was to evaluate students' perceptions of CAD/CAM learning software for preclinical prosthodontics exercises. In 2014, all third-year dental students at Harvard School of Dental Medicine (n=36) were individually instructed by a trained faculty member in using prepCheck. Each student completed a preclinical formative exercise (#18) and summative examination (#30) for ceramometal crown preparation and evaluated the preparation using five assessment tools (reduction, margin width, surface finish, taper, and undercut) in prepCheck. The students then rated each of the five tools for usefulness, user-friendliness, and frequency of use on a scale from 1=lowest to 5=highest. Faculty members graded the tooth preparations as pass (P), marginal-pass (MP), or fail (F). The survey response rate was 100%. The tools for undercut and taper had the highest scores for usefulness, user-friendliness, and frequency of use. The reduction tool score was significantly lower in all categories (p<0.01). There were significant differences in usefulness (p<0.05) and user-friendliness (p<0.05) scores among the P, MP, and F groups. These results suggest that the prepCheck taper and undercut tools were useful for the students' learning process in a preclinical exercise. The students' perceptions of prepCheck and their preclinical performance were related, and those students who performed poorest rated the software as significantly more useful.

Medical students' exposure to pharmaceutical industry marketing: a survey at one U.S. medical school.

PubMed

Bellin, Melena; McCarthy, Susan; Drevlow, Laurel; Pierach, Claus

2004-11-01

While much is known about the interactions between the pharmaceutical industry and physicians, very little is known about pharmaceutical marketing directed toward medical students. This study sought to characterize the extent and forms of medical students' exposure to pharmaceutical industry marketing. In 2001-02, an anonymous, 17-item questionnaire was distributed to 165 preclinical and 116 clinical students at the University of Minnesota Medical School-Twin Cities. The main outcome measures were the number and forms of exposures to pharmaceutical industry marketing reported by medical students and whether students had discussed these exposures with teachers or advisors. Preclinical and clinical students were compared using chi(2) analysis (p < .05). One hundred fourteen (69.1%) preclinical students and 107 (92.2%) clinical students responded. Nearly all students reported at least one exposure to pharmaceutical industry marketing. Seventy-six (71.7%) clinical students compared to 38 (33.3%) preclinical students recalled over 20 exposures (p < .005). Clinical students were more likely to have received a free meal (p < .01), textbook (p < .005), pocket text (p < .005), or trinket (p < .005) than were their preclinical colleagues. Most students (68.2%) had not discussed pharmaceutical marketing with an instructor or advisor; 59 (55.7%) clinical students as compared to 87 (80.6%) preclinical students recalled no such discussion (p < .005). Medical students have extensive exposure to pharmaceutical industry marketing during their early years of training. Given existing evidence that such exposure influences physicians' practice and prescribing patterns, the authors propose that medical school curricula include formal instruction to prepare students to critically assess these contacts.

Reproducibility2020: Progress and priorities

PubMed Central

Freedman, Leonard P.; Venugopalan, Gautham; Wisman, Rosann

2017-01-01

The preclinical research process is a cycle of idea generation, experimentation, and reporting of results. The biomedical research community relies on the reproducibility of published discoveries to create new lines of research and to translate research findings into therapeutic applications. Since 2012, when scientists from Amgen reported that they were able to reproduce only 6 of 53 “landmark” preclinical studies, the biomedical research community began discussing the scale of the reproducibility problem and developing initiatives to address critical challenges. Global Biological Standards Institute (GBSI) released the “Case for Standards” in 2013, one of the first comprehensive reports to address the rising concern of irreproducible biomedical research. Further attention was drawn to issues that limit scientific self-correction, including reporting and publication bias, underpowered studies, lack of open access to methods and data, and lack of clearly defined standards and guidelines in areas such as reagent validation. To evaluate the progress made towards reproducibility since 2013, GBSI identified and examined initiatives designed to advance quality and reproducibility. Through this process, we identified key roles for funders, journals, researchers and other stakeholders and recommended actions for future progress. This paper describes our findings and conclusions. PMID:28620458

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

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

Shang, M; Sands, M; Bolch, W

2015-06-15

Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adultmore » beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.« less

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

PubMed Central

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

2017-01-01

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

Mortality Patterns in Patients with Multiple Trauma: A Systematic Review of Autopsy Studies

PubMed Central

Pfeifer, Roman; Teuben, Michel; Andruszkow, Hagen; Barkatali, Bilal M.; Pape, Hans-Christoph

2016-01-01

Purpose A high percentage (50%-60%) of trauma patients die due to their injuries prior to arrival at the hospital. Studies on preclinical mortality including post-mortem examinations are rare. In this review, we summarized the literature focusing on clinical and preclinical mortality and studies included post-mortem examinations. Methods A literature search was conducted using PubMed/Medline database for relevant medical literature in English or German language published within the last four decades (1980–2015). The following MeSH search terms were used in different combinations: “multiple trauma”, “epidemiology”, “mortality “, “cause of death”, and “autopsy”. References from available studies were searched as well. Results Marked differences in demographic parameters and injury severity between studies were identified. Moreover, the incidence of penetrating injuries has shown a wide range (between 4% and 38%). Both unimodal and bimodal concepts of trauma mortality have been favored. Studies have shown a wide variation in time intervals used to analyze the distribution of death. Thus, it is difficult to say which distribution is correct. Conclusions We have identified variable results indicating bimodal or unimodal death distribution. Further more stundardized studies in this field are needed. We would like to encourage investigators to choose the inclusion criteria more critically and to consider factors affecting the pattern of mortality. PMID:26871937

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

PubMed

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

2015-03-01

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

Renal Perfusion and Function during Pneumoperitoneum: A Systematic Review and Meta-Analysis of Animal Studies

PubMed Central

Warlé, Michiel C.; Hooijmans, Carlijn R.

2016-01-01

Both preclinical and clinical studies indicate that raised intra-abdominal pressure (IAP) associated with pneumoperitoneum during laparoscopic surgical procedures can cause renal damage, the severity of which may be influenced by variables such as pressure level and duration. Several of these variables have been investigated in animal studies, but synthesis of all preclinical data has not been performed. This systematic review summarizes all available pre-clinical evidence on this topic, including an assessment of its quality and risk of bias. We performed meta-analysis to assess which aspects of the pneumoperitoneum determine the severity of its adverse effects. A systematic search in two databases identified 55 studies on the effect of pneumoperitoneum on renal function which met our inclusion criteria. There was high heterogeneity between the studies regarding study design, species, sex, pressure and duration of pneumoperitoneum, and type of gas used. Measures to reduce bias were poorly reported, leading to an unclear risk of bias in the majority of studies. Details on randomisation, blinding and a sample size calculation were not reported in ≥80% of the studies. Meta-analysis showed an overall increase in serum creatinine during pneumoperitoneum, and a decrease in urine output and renal blood flow. Subgroup analysis indicated that for serum creatinine, this effect differed between species. Subgroup analysis of pressure level indicated that urine output decreased as IAP level increased. No differences between types of gas were observed. Data were insufficient to reliably assess whether sex or IAP duration modulate the effect of pneumoperitoneum. Four studies assessing long-term effects indicated that serum creatinine normalized ≥24 hours after desufflation of pneumoperitoneum at 15mmHg. We conclude that harmful effects on renal function and perfusion during pneumoperitoneum appear to be robust, but evidence on long-term effects is very limited. The reliability and clinical relevance of these findings for healthy patients and patients at high risk of renal impairment remain uncertain. We emphasize the need for rigorous reporting of preclinical research methodology, which is of vital importance for clinical translation of preclinical data. PMID:27657740

Induction of cellular and molecular immunomodulatory pathways by vitamin A and Flavonoids

PubMed Central

Patel, Sapna; Vajdy, Michael

2016-01-01

Introduction A detailed study of reports on the immunomodulatory properties of vitamin A and select flavonoids may pave the way for using these natural compounds or compounds with similar structures in novel drug and vaccine designs against infectious and autoimmune diseases and cancers. Areas Covered Intracellular transduction pathways, cellular differentiation and functional immunomodulatory responses have been reviewed. The reported studies encompass in vitro, in vivo preclinical and clinical studies that address the role of Vitamin A and select flavonoids in induction of innate and adaptive B and T cell responses, including TH1, TH2 and Treg. Expert Opinion While the immunomodulatory role of vitamin A, and related compounds, is well-established in many preclinical studies, its role in humans has begun to gain wider acceptance. In contrast, the role of flavonoids is mostly controversial in clinical trials, due to the diversity of the various classes of these compounds, and possibly due to the purity and the selected doses of the compounds. However, current preclinical and clinical studies warrant further detailed studies of these promising immuno-modulatory compounds. PMID:26185959

A[Beta] Deposits in Older Non-Demented Individuals with Cognitive Decline Are Indicative of Preclinical Alzheimer's Disease

ERIC Educational Resources Information Center

Villemagne, V. L.; Pike, K. E.; Darby, D.; Maruff, P.; Savage, G.; Ng, S.; Ackermann, U.; Cowie, T. F.; Currie, J.; Chan, S. G.; Jones, G.; Tochon-Danguy, H.; O'Keefe, G.; Masters, C. L.; Rowe, C. C.

2008-01-01

Approximately 30% of healthy persons aged over 75 years show A[beta] deposition at autopsy. It is postulated that this represents preclinical Alzheimer's disease (AD). We evaluated the relationship between A[beta] burden as assessed by PiB PET and cognitive decline in a well-characterized, non-demented, elderly cohort. PiB PET studies and…

A new method for teaching physical examination to junior medical students

PubMed Central

Sayma, Meelad; Williams, Hywel Rhys

2016-01-01

Introduction Teaching effective physical examination is a key component in the education of medical students. Preclinical medical students often have insufficient clinical knowledge to apply to physical examination recall, which may hinder their learning when taught through certain understanding-based models. This pilot project aimed to develop a method to teach physical examination to preclinical medical students using “core clinical cases”, overcoming the need for “rote” learning. Methods This project was developed utilizing three cycles of planning, action, and reflection. Thematic analysis of feedback was used to improve this model, and ensure it met student expectations. Results and discussion A model core clinical case developed in this project is described, with gout as the basis for a “foot and ankle” examination. Key limitations and difficulties encountered on implementation of this pilot are discussed for future users, including the difficulty encountered in “content overload”. Conclusion This approach aims to teach junior medical students physical examination through understanding, using a simulated patient environment. Robust research is now required to demonstrate efficacy and repeatability in the physical examination of other systems. PMID:26937208

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

PubMed

Smith, Tracy T; Rupprecht, Laura E; Denlinger-Apte, Rachel L; Weeks, Jillian J; Panas, Rachel S; Donny, Eric C; Sved, Alan F

2017-09-01

A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy. Convergence between clinical and preclinical research is important, given the ease with which clinical trial participants can access nonstudy tobacco products in the current marketplace. Herein, we review contributions of preclinical animal research, with a focus on rodent self-administration, to the science of nicotine reduction. Throughout this review, we highlight areas where clinical and preclinical research converge and areas where the two differ. Preclinical research has provided data on many important topics such as the threshold for nicotine reinforcement, the likelihood of compensation, moderators of the impact of nicotine reduction, the impact of environmental stimuli on nicotine reduction, the impact of nonnicotine cigarette smoke constituents on nicotine reduction, and the impact of nicotine reduction on vulnerable populations. Special attention is paid to current research gaps including the dramatic rise in alternative tobacco products, including electronic nicotine delivery systems (ie, e-cigarettes). The evidence reviewed here will be critical for policy makers as well as clinical researchers interested in nicotine reduction. This review will provide policy makers and clinical researchers interested in nicotine reduction with an overview of the preclinical animal research conducted on nicotine reduction and the regulatory implications of that research. The review also highlights the utility of preclinical research for research questions related to nicotine reduction. © The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Preclinical restorative training.

PubMed

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

2002-10-01

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

Vasopressin, cortisol, and catecholamine concentrations in dogs with dilated cardiomyopathy.

PubMed

Tidholm, Anna; Häggström, Jens; Hansson, Kerstin

2005-10-01

To evaluate plasma concentrations and urinary excretion of vasopressin and cortisol and urinary excretion of catecholamines in dogs with dilated cardiomyopathy (DCM). 15 dogs with clinical signs of DCM, 15 dogs with preclinical DCM, and 15 control dogs. Physical examinations, thoracic radiography, ECG, and echocardiography were performed on all dogs. Blood and urine samples were collected. Plasma concentration of vasopressin and the urine cortisol-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM and dogs with preclinical DCM, compared with control dogs. Plasma vasopressin concentration was significantly higher in dogs with clinical signs of DCM, compared with dogs with preclinical DCM. Urine vasopressin-to-urine creatinine ratio was significantly increased in dogs with clinical signs of DCM, compared with dogs with preclinical DCM and control dogs. Urine epinephrine-to-urine creatinine ratio and urine norepinephrine-to-urine creatinine ratio were significantly increased in dogs with clinical signs of DCM, compared with control dogs. Plasma concentration of cortisol and urine dopamine-to-urine creatinine ratio did not differ significantly among groups. According to this study, the neuroendocrine pattern is changed in dogs with preclinical DCM. These changes are even more pronounced in dogs with clinical signs of DCM. Analysis of concentrations of vasopressin, cortisol, and catecholamines may aid in identification of the clinical stages of DCM. These findings may also provide a basis for additional studies of the possible beneficial effects of vasopressin antagonists and beta-adrenergic receptor antagonists in the treatment of dogs with congestive heart failure and DCM.

Animal Models in Genomic Research: Techniques, Applications, and Roles for Nurses

PubMed Central

Osier, Nicole D.; Pham, Lan; Savarese, Amanda; Sayles, Kendra

2016-01-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID:27969037

Animal models in genomic research: Techniques, applications, and roles for nurses.

PubMed

Osier, Nicole D; Pham, Lan; Savarese, Amanda; Sayles, Kendra; Alexander, Sheila A

2016-11-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

Mitigating risk in academic preclinical drug discovery

PubMed Central

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

2018-01-01

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

Stem Cell Therapies for Knee Cartilage Repair: The Current Status of Preclinical and Clinical Studies

PubMed Central

Anderson, John A.; Little, Dianne; Toth, Alison P.; Moorman, Claude T.; Tucker, Bradford S.; Ciccotti, Michael G.; Guilak, Farshid

2014-01-01

Background Articular cartilage damage of the knee is common, causing significant morbidity worldwide. Many adult tissues contain cells that are able to differentiate into multiple cell types, including chondrocytes. These stem cells have gained significant attention over the past decade and may become frontline management for cartilage defects in the very near future. Purpose The role of stem cells in the treatment of knee osteochondral defects was reviewed. Recent animal and clinical studies were reviewed to determine the benefits and potential outcomes of using stem cells for cartilage defects. Study Design Literature review. Methods A PubMed search was undertaken. The key phrase “stem cells and knee” was used. The search included reviews and original articles over an unlimited time period. From this search, articles outlining animal and clinical trials were selected. A search of current clinical trials in progress was performed on the clinicaltrials.gov website, and “stem cells and knee” was used as the search phrase. Results Stem cells have been used in many recent in vitro and animal studies. A number of cell-based approaches for cartilage repair have progressed from preclinical animal studies into clinical trials. Conclusion The use of stem cells for the treatment of cartilage defects is increasing in animal and clinical studies. Methods of delivery of stem cells to the knee’s cartilage vary from direct injection to implantation with scaffolds. While these approaches are highly promising, there is currently limited evidence of a direct clinical benefit, and further research is required to assess the overall outcome of stem cell therapies for knee cartilage repair. PMID:24220016

Adoptive immunotherapy against ovarian cancer.

PubMed

Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

2016-05-17

The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting.

Intraoperative intravital microscopy permits the study of human tumour vessels

PubMed Central

Fisher, Daniel T.; Muhitch, Jason B.; Kim, Minhyung; Doyen, Kurt C.; Bogner, Paul N.; Evans, Sharon S.; Skitzki, Joseph J.

2016-01-01

Tumour vessels have been studied extensively as they are critical sites for drug delivery, anti-angiogenic therapies and immunotherapy. As a preclinical tool, intravital microscopy (IVM) allows for in vivo real-time direct observation of vessels at the cellular level. However, to date there are no reports of intravital high-resolution imaging of human tumours in the clinical setting. Here we report the feasibility of IVM examinations of human malignant disease with an emphasis on tumour vasculature as the major site of tumour-host interactions. Consistent with preclinical observations, we show that patient tumour vessels are disorganized, tortuous and ∼50% do not support blood flow. Human tumour vessel diameters are larger than predicted from immunohistochemistry or preclinical IVM, and thereby have lower wall shear stress, which influences delivery of drugs and cellular immunotherapies. Thus, real-time clinical imaging of living human tumours is feasible and allows for detection of characteristics within the tumour microenvironment. PMID:26883450

A practical blueprint to systematically study life-long health consequences of novel medically assisted reproductive treatments

PubMed Central

Mulder, Callista L; Serrano, Joana B; Catsburg, Lisa A E; Roseboom, Tessa J; Repping, Sjoerd; van Pelt, Ans M M

2018-01-01

Abstract In medicine, safety and efficacy are the two pillars on which the implementation of novel treatments rest. To protect the patient from unnecessary or unsafe treatments, usually, a stringent path of (pre) clinical testing is followed before a treatment is introduced into routine patient care. However, in reproductive medicine several techniques have been clinically introduced without elaborate preclinical studies. Moreover, novel reproductive techniques may harbor safety risks not only for the patients undergoing treatment, but also for the offspring conceived through these techniques. If preclinical (animal) studies were performed, efficacy and functionality the upper hand. When a new medically assisted reproduction (MAR) treatment was proven effective (i.e. if it resulted in live birth) the treatment was often rapidly implemented in the clinic. For IVF, the first study on the long-term health of IVF children was published a decade after its clinical implementation. In more recent years, prospective follow-up studies have been conducted that provided the opportunity to study the health of large groups of children derived from different reproductive techniques. Although such studies have indicated differences between children conceived through MAR and children conceived naturally, results are often difficult to interpret due to the observational nature of these studies (and the associated risk of confounding factors, e.g. subfertility of the parents), differences in definitions of clinical outcome measures, lack of uniformity in assessment protocols and heterogeneity of the underlying reasons for fertility treatment. With more novel MARs waiting at the horizon, there is a need for a framework on how to assess safety of novel reproductive techniques in a preclinical (animal) setting before they are clinically implemented. In this article, we provide a blueprint for preclinical testing of safety and health of offspring generated by novel MARs using a mouse model involving an array of tests that comprise the entire lifespan. We urge scientists to perform the proposed extensive preclinical tests for novel reproductive techniques with the goal to acquire knowledge on efficacy and the possible health effects of to-be implemented reproductive techniques to safeguard quality of novel MARs. PMID:29635479

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging.

PubMed

Ladiges, Warren; Ikeno, Yuji; Niedernhofer, Laura; McIndoe, Richard A; Ciol, Marcia A; Ritchey, Jerry; Liggitt, Denny

2016-04-01

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Performance Simulation: The Method.

ERIC Educational Resources Information Center

Rucker, Lance M.

A logical, performer-based approach to teaching psychomotor skills is described. Four phases of surgical psychomotor skills training are identified, using an example from a dental preclinical training curriculum: (1) dental students are acquainted with the postural and positional parameters of balanced psychomotor performances; (2) students learn…

Measurement of the levels anxiety, self-perception of preparation and expectations for success using an objective structured clinical examination, a written examination, and a preclinical preparation test in Kerman dental students.

PubMed

Kalantari, Mahsa; Zadeh, Nazila Lashkari; Agahi, Raha Habib; Navabi, Nader; Hashemipour, Maryam Alsadat; Nassab, Amir Hossein Gandjalikhan

2017-01-01

Examinations have an important role in evaluating students' learning outcomes and their mastery of a subject. Passing or failing an examination can have far-reaching consequences for the students. Therefore, it is not surprising that international studies consistently show that dental students report examinations and grades among the highest ranking stressors in dental schools. The aim of this research was to measure the levels of anxiety, self-perception of preparation and expectations for success using an objective structured clinical examination (OSCE), a written examination and a preclinical preparation test, and to examine the effects of the three predictive variables on the outcomes of assessments. The present research is a cross-sectional study. The population under consideration was students of Kerman Dental School in 2013. Examination anxiety was measured with Spielberger's state anxiety inventory. Preparation for the assessment (I am fully prepared = 4, I am prepared = 3, I'm not prepared = 2, I'm not fully prepared = 1) and expectation to succeed (I am quite successful = 4, I am successful = 3, I'm not successful = 2, I'm not quite successful = 1) were quantified with Likert scale. The questionnaire was completed during an OSCE, a written examination, a preclinical crown and bridge preparation test and a nonexamination situation. The study population consisted of 138 4 th , 5 th , and 6 th year Kerman dental students (65 males and 73 females). The results showed that all the assessment methods induced a significant increase in state anxiety compared to baseline levels with the highest anxiety levels reported during an OSCE (62.4 ± 8.1, P = 0.04) and a written examination (48.8 ± 9.2, P = 0.04). The preparation levels in females were significantly higher than those in males in OSCE ( P = 0.03) and written ( P = 0.04). State anxiety was high in all the three assessment methods. OSCE induced more anxiety than other assessment formats. However, anxiety was not predictive of performance outcomes in contrast to preparation and expectation to succeed, which were good predictors of the outcome scores. Also, this study showed that despite a better answer to the assessment of (I prepared myself well for the test), the students showed high levels of state anxiety.

Nonwoven-Based Gelatin/Polycaprolactone Membrane Proves Suitability in a Preclinical Assessment for Treatment of Soft Tissue Defects

PubMed Central

Schulz, Simon; Angarano, Marco; Fabritius, Martin; Mülhaupt, Rolf; Dard, Michel; Obrecht, Marcel; Tomakidi, Pascal

2014-01-01

Standard preclinical assessments in vitro often have limitations regarding their transferability to human beings, mainly evoked by their nonhuman and tissue-different/nontissue-specific source. Here, we aimed at employing tissue-authentic simple and complex interactive fibroblast-epithelial cell systems and their in vivo-relevant biomarkers for preclinical in vitro assessment of nonwoven-based gelatin/polycaprolactone membranes (NBMs) for treatment of soft tissue defects. NBMs were composed of electrospun gelatin and polycaprolactone nanofiber nonwovens. Scanning electron microscopy in conjunction with actin/focal contact integrin fluorescence revealed successful adhesion and proper morphogenesis of keratinocytes and fibroblasts, along with cells' derived extracellular matrix deposits. The “feel-good factor” of cells under study on the NBM was substantiated by forming a confluent connective tissue entity, which was concomitant with a stratified epithelial equivalent. Immunohistochemistry proved tissue authenticity over time by abundance of the biomarker vimentin in the connective tissue entity, and chronological increase of keratins KRT1/10 and involucrin expression in epithelial equivalents. Suitability of the novel NBM as wound dressing was evidenced by an almost completion of epithelial wound closure in a pilot mini-pig study, after a surgical intervention-caused gingival dehiscence. In summary, preclinical assessment by tissue-authentic cell systems and the animal pilot study revealed the NBM as an encouraging therapeutic medical device for prospective clinical applications. PMID:24494668

Is medical students' moral orientation changeable after preclinical medical education?

PubMed

Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

2012-03-01

Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

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

NASA Astrophysics Data System (ADS)

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

2016-03-01

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

Preclinical Magnetic Resonance Imaging and Systems Biology in Cancer Research

PubMed Central

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

2014-01-01

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

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

PubMed

Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

2017-10-03

To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

PubMed

Koontz, Bridget F; Verhaegen, Frank; De Ruysscher, Dirk

2017-01-01

Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation.

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

PubMed Central

Verhaegen, Frank; De Ruysscher, Dirk

2017-01-01

Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation. PMID:27612010

Quantifying the vascular response to ischemia with speckle variance optical coherence tomography

PubMed Central

Poole, Kristin M.; McCormack, Devin R.; Patil, Chetan A.; Duvall, Craig L.; Skala, Melissa C.

2014-01-01

Longitudinal monitoring techniques for preclinical models of vascular remodeling are critical to the development of new therapies for pathological conditions such as ischemia and cancer. In models of skeletal muscle ischemia in particular, there is a lack of quantitative, non-invasive and long term assessment of vessel morphology. Here, we have applied speckle variance optical coherence tomography (OCT) methods to quantitatively assess vascular remodeling and growth in a mouse model of peripheral arterial disease. This approach was validated on two different mouse strains known to have disparate rates and abilities of recovering following induction of hind limb ischemia. These results establish the potential for speckle variance OCT as a tool for quantitative, preclinical screening of pro- and anti-angiogenic therapies. PMID:25574425

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study

PubMed Central

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Background: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Methods: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. Results: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Conclusion: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research. PMID:27536242

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.

PubMed

Carman, A J; Dacks, P A; Lane, R F; Shineman, D W; Fillit, H M

2014-04-01

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

3D printing of preclinical X-ray computed tomographic data sets.

PubMed

Doney, Evan; Krumdick, Lauren A; Diener, Justin M; Wathen, Connor A; Chapman, Sarah E; Stamile, Brian; Scott, Jeremiah E; Ravosa, Matthew J; Van Avermaete, Tony; Leevy, W Matthew

2013-03-22

Three-dimensional printing allows for the production of highly detailed objects through a process known as additive manufacturing. Traditional, mold-injection methods to create models or parts have several limitations, the most important of which is a difficulty in making highly complex products in a timely, cost-effective manner.(1) However, gradual improvements in three-dimensional printing technology have resulted in both high-end and economy instruments that are now available for the facile production of customized models.(2) These printers have the ability to extrude high-resolution objects with enough detail to accurately represent in vivo images generated from a preclinical X-ray CT scanner. With proper data collection, surface rendering, and stereolithographic editing, it is now possible and inexpensive to rapidly produce detailed skeletal and soft tissue structures from X-ray CT data. Even in the early stages of development, the anatomical models produced by three-dimensional printing appeal to both educators and researchers who can utilize the technology to improve visualization proficiency. (3, 4) The real benefits of this method result from the tangible experience a researcher can have with data that cannot be adequately conveyed through a computer screen. The translation of pre-clinical 3D data to a physical object that is an exact copy of the test subject is a powerful tool for visualization and communication, especially for relating imaging research to students, or those in other fields. Here, we provide a detailed method for printing plastic models of bone and organ structures derived from X-ray CT scans utilizing an Albira X-ray CT system in conjunction with PMOD, ImageJ, Meshlab, Netfabb, and ReplicatorG software packages.

Preclinical manufacture of anti-HER2 liposome-inserting, scFv-PEG-lipid conjugate. 2. Conjugate micelle identity, purity, stability, and potency analysis.

PubMed

Nellis, David F; Giardina, Steven L; Janini, George M; Shenoy, Shilpa R; Marks, James D; Tsai, Richard; Drummond, Daryl C; Hong, Keelung; Park, John W; Ouellette, Thomas F; Perkins, Shelley C; Kirpotin, Dmitri B

2005-01-01

Analytical methods optimized for micellar F5cys-MP-PEG(2000)-DPSE protein-lipopolymer conjugate are presented. The apparent micelle molecular weight, determined by size exclusion chromatography, ranged from 330 to 960 kDa. The F5cys antibody and conjugate melting points, determined by differential scanning calorimetry, were near 82 degrees C. Traditional methods for characterizing monodisperse protein species were inapplicable to conjugate analysis. The isoelectric point of F5cys (9.2) and the conjugate (8.9) were determined by capillary isoelectric focusing (cIEF) after addition of the zwitterionic detergent CHAPS to the buffer. Conjugate incubation with phospholipase B selectively removed DSPE lipid groups and dispersed the conjugate prior to separation by chromatographic methods. Alternatively, adding 2-propanol (29.4 vol %) and n-butanol (4.5 vol %) to buffers for salt-gradient cation exchange chromatography provided gentler, nonenzymatic dispersion, resulting in well-resolved peaks. This method was used to assess stability, identify contaminants, establish lot-to-lot comparability, and determine the average chromatographic purity (93%) for conjugate lots, described previously. The F5cys amino acid content was confirmed after conjugation. The expected conjugate avidity for immobilized HER-2/neu was measured by bimolecular interaction analysis (BIAcore). Mock therapeutic assemblies were made by conjugate insertion into preformed doxorubicin-encapsulating liposomes for antibody-directed uptake of doxorubicin by HER2-overexpressing cancer cells in vitro. Together these developed assays established that the manufacturing method as described in the first part of this study consistently produced F5cys-MP-PEG(2000)-DSPE having sufficient purity, stability, and functionality for use in preclinical toxicology investigations.

MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

PubMed

Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James; Jiang, Steve B; Mason, Ralph P; Stojadinovic, Strahinja

2018-01-01

Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol is wide-ranging and not limited to the orthotopic prostate tumor study presented in the study.

Tracking stem cell migration and survival in brain injury: current approaches and future prospects.

PubMed

Darkazalli, Ali; Levenson, Cathy W

2012-10-01

In recent years, stem cell-mediated therapies have gained considerable ground as potential treatments for a wide variety of brain pathologies including traumatic brain injury, stroke and neurodegenerative diseases. Despite extensive preclinical studies, many of these therapies have not been fully translated into viable clinical approaches. This is partly due to our inability to reliably track and monitor transplanted stem cells longitudinally over long periods of time in vivo. In this review, we discuss the predominant histological cell tracing methodologies, such as immunohistochemistry, and fluorescent cellular dyes and proteins, and compare them to emerging cellular imaging technologies. We show that advances in magnetic resonance imaging (MRI) have resulted in opportunities to use this technology to further our understanding of stem cell characteristics and behaviors in vivo. While MRI may not completely replace conventional cell tracking methods in pre-clinical, mechanistic work, it is clear that it has the potential to function as a powerful diagnostic tool for tracking stem cell migration and survival as well as for evaluating the efficacy of stem cell-mediated therapies.

Review of SPECT collimator selection, optimization, and fabrication for clinical and preclinical imaging

PubMed Central

Van Audenhaege, Karen; Van Holen, Roel; Vandenberghe, Stefaan; Vanhove, Christian; Metzler, Scott D.; Moore, Stephen C.

2015-01-01

In single photon emission computed tomography, the choice of the collimator has a major impact on the sensitivity and resolution of the system. Traditional parallel-hole and fan-beam collimators used in clinical practice, for example, have a relatively poor sensitivity and subcentimeter spatial resolution, while in small-animal imaging, pinhole collimators are used to obtain submillimeter resolution and multiple pinholes are often combined to increase sensitivity. This paper reviews methods for production, sensitivity maximization, and task-based optimization of collimation for both clinical and preclinical imaging applications. New opportunities for improved collimation are now arising primarily because of (i) new collimator-production techniques and (ii) detectors with improved intrinsic spatial resolution that have recently become available. These new technologies are expected to impact the design of collimators in the future. The authors also discuss concepts like septal penetration, high-resolution applications, multiplexing, sampling completeness, and adaptive systems, and the authors conclude with an example of an optimization study for a parallel-hole, fan-beam, cone-beam, and multiple-pinhole collimator for different applications. PMID:26233207

Development and Assessment of Transgenic Rodent Parasites for the Preclinical Evaluation of Malaria Vaccines.

PubMed

Espinosa, Diego A; Radtke, Andrea J; Zavala, Fidel

2016-01-01

Rodent transgenic parasites are useful tools for the preclinical evaluation of malaria vaccines. Over the last decade, several studies have reported the development of transgenic rodent parasites expressing P. falciparum antigens for the assessment of vaccine-induced immune responses, which traditionally have been limited to in vitro assays. However, the genetic manipulation of rodent Plasmodium species can have detrimental effects on the parasite's infectivity and development. In this chapter, we present a few guidelines for designing transfection plasmids, which should improve transfection efficiency and facilitate the generation of functional transgenic parasite strains. In addition, we provide a transfection protocol for the development of transgenic P. berghei parasites as well as practical methods to assess the viability and infectivity of these newly generated strains throughout different stages of their life cycle. These techniques should allow researchers to develop novel rodent malaria parasites expressing antigens from human malaria species and to determine whether these transgenic strains are fully infectious and thus represent stringent platforms for the in vivo evaluation of malaria vaccine candidates.

PRP Augmentation for ACL Reconstruction

PubMed Central

Di Matteo, Berardo; Kon, Elizaveta; Marcacci, Maurilio

2015-01-01

Current research is investigating new methods to enhance tissue healing to speed up recovery time and decrease the risk of failure in Anterior Cruciate Ligament (ACL) reconstructive surgery. Biological augmentation is one of the most exploited strategies, in particular the application of Platelet Rich Plasma (PRP). Aim of the present paper is to systematically review all the preclinical and clinical papers dealing with the application of PRP as a biological enhancer during ACL reconstructive surgery. Thirty-two studies were included in the present review. The analysis of the preclinical evidence revealed that PRP was able to improve the healing potential of the tendinous graft both in terms of histological and biomechanical performance. Looking at the available clinical evidence, results were not univocal. PRP administration proved to be a safe procedure and there were some evidences that it could favor the donor site healing in case of ACL reconstruction with patellar tendon graft and positively contribute to graft maturation over time, whereas the majority of the papers did not show beneficial effects in terms of bony tunnels/graft area integration. Furthermore, PRP augmentation did not provide superior functional results at short term evaluation. PMID:26064903

A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design.

PubMed

Selimkhanov, J; Thompson, W C; Guo, J; Hall, K D; Musante, C J

2017-08-01

The design of well-powered in vivo preclinical studies is a key element in building the knowledge of disease physiology for the purpose of identifying and effectively testing potential antiobesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic end points such as food intake and body composition. This, combined with limitations inherent in the measurement of certain end points, presents challenges to study design that can have significant consequences for an antiobesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of the key metabolic end points. To demonstrate how conclusions can change as a function of study size, we show that a simulated preclinical study properly powered for one end point may lead to false conclusions based on secondary end points. We then propose the guidelines for end point selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design.

Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material

NASA Technical Reports Server (NTRS)

Janis, Abram D. (Inventor); Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor)

2014-01-01

The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.

Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material

NASA Technical Reports Server (NTRS)

Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor); Janis, Abram D. (Inventor)

2015-01-01

The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.

Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material

NASA Technical Reports Server (NTRS)

Kentner, Kimberly A. (Inventor); Stuart, Katherine A. (Inventor); Janis, Abram D. (Inventor)

2016-01-01

The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.

Methods of Manufacturing Bioactive Gels from Extracellular Matrix Material

NASA Technical Reports Server (NTRS)

Kentner, Kimberly (Inventor); Janis, Abram D. (Inventor); Stuart, Katherine A. (Inventor)

2017-01-01

The present invention is directed to methods of manufacturing bioactive gels from ECM material, i.e., gels which retain bioactivity, and can serve as scaffolds for preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. The manufacturing methods take advantage of a new recognition that bioactive gels from ECM material can be created by digesting particularized ECM material in an alkaline environment and neutralizing to provide bioactive gels.

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

PubMed

Barajaz, Ashley M; Kliethermes, Christopher L

2017-12-01

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

Evaluating the short-term effects of a communication skills program for preclinical medical students.

PubMed

Lee, Young-Mee; Lee, Young Hee

2014-09-01

Regardless of the growing importance of communication skills as a core clinical competence, few studies have determined the effects of communication skills courses in undergraduate medical curricula in Asian medical schools. The purpose of this study was to examine the effectiveness of a communication skills program for preclinical medical students. A communication skills course was provided to 111 second-year medical students in a medical college in Korea. Students' self-assessed competency of communication skills was evaluated by a questionnaire survey. To examine the improvement in observed communication skills, the students' encounters with standardized patients (SPs) were assessed at the first session and at the final course assessment. A structured checklist, consisting of 25 communication skills items, was used for the assessment. Students' self-assessed competency of communication skills increased significantly after completion of the course (p<0.001). The observed communication skills scores also improved significantly at the end of the course; the mean scores of the first SPs encounters was 49.6 (standard deviation [SD], 11.1), and those of cases A and B at the final assessment were 61.5 (SD, 8.4) and 69.6 (SD, 7.8), respectively (F₆₁=269.54, p<0.001). Even a short period of medical communication skills course was beneficial in developing and improving communication skills competency in preclinical medical students. Further studies should be followed to examine whether the acquisition of communication skills during preclinical studies can be sustained into clerkship and actual practice.

Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk.

PubMed

Gintant, Gary A

2008-08-01

The successful development of novel drugs requires the ability to detect (and avoid) compounds that may provoke Torsades-de-Pointes (TdeP) arrhythmia while endorsing those compounds with minimal torsadogenic risk. As TdeP is a rare arrhythmia not readily observed during clinical or post-marketing studies, numerous preclinical models are employed to assess delayed or altered ventricular repolarization (surrogate markers linked to enhanced proarrhythmic risk). This review evaluates the advantages and limitations of selected preclinical models (ranging from the simplest cellular hERG current assay to the more complex in vitro perfused ventricular wedge and Langendorff heart preparations and in vivo chronic atrio-ventricular (AV)-node block model). Specific attention is paid to the utility of concentration-response relationships and "risk signatures" derived from these studies, with the intention of moving beyond predicting clinical QT prolongation and towards prediction of TdeP risk. While the more complex proarrhythmia models may be suited to addressing questionable or conflicting proarrhythmic signals obtained with simpler preclinical assays, further benchmarking of proarrhythmia models is required for their use in the robust evaluation of safety margins. In the future, these models may be able to reduce unwarranted attrition of evolving compounds while becoming pivotal in the balanced integrated risk assessment of advancing compounds.

The 'dark side' and 'bright side' of personality: when too much conscientiousness and too little anxiety are detrimental with respect to the acquisition of medical knowledge and skill.

PubMed

Ferguson, Eamonn; Semper, Heather; Yates, Janet; Fitzgerald, J Edward; Skatova, Anya; James, David

2014-01-01

Theory suggests that personality traits evolved to have costs and benefits, with the effectiveness of a trait dependent on how these costs and benefits relate to the present circumstances. This suggests that traits that are generally viewed as positive can have a 'dark side' and those generally viewed as negative can have a 'bright side' depending on changes in context. We test this in a sample of 220 UK medical students with respect to associations between the Big 5 personality traits and learning outcomes across the 5 years of a medical degree. The medical degree offers a changing learning context from pre-clinical years (where a more methodical approach to learning is needed) to the clinical years (where more flexible learning is needed, in a more stressful context). We argue that while trait conscientiousness should enhance pre-clinical learning, it has a 'dark side' reducing the acquisition of knowledge in the clinical years. We also suggest that anxiety has a 'bright side' enhancing the acquisition of skills in the clinical years. We also explore if intelligence enhances learning across the medical degree. Using confirmatory factor analysis and structural equation modelling we show that medical skills and knowledge assessed in the pre-clinical and clinical years are psychometrically distinguishable, forming a learning 'backbone', whereby subsequent learning outcomes are predicted by previous ones. Consistent with our predictions conscientiousness enhanced preclinical knowledge acquisition but reduced the acquisition of clinical knowledge and anxiety enhanced the acquisition of clinical skills. We also identified a curvilinear U shaped association between Surgency (extraversion) and pre-clinical knowledge acquisition. Intelligence predicted initial clinical knowledge, and had a positive total indirect effect on clinical knowledge and clinical skill acquisition. For medical selection, this suggests that selecting students high on conscientiousness may be problematic, as it may be excluding those with some degree of moderate anxiety.

The ‘Dark Side’ and ‘Bright Side’ of Personality: When Too Much Conscientiousness and Too Little Anxiety Are Detrimental with Respect to the Acquisition of Medical Knowledge and Skill

PubMed Central

Ferguson, Eamonn; Semper, Heather; Yates, Janet; Fitzgerald, J. Edward; Skatova, Anya; James, David

2014-01-01

Theory suggests that personality traits evolved to have costs and benefits, with the effectiveness of a trait dependent on how these costs and benefits relate to the present circumstances. This suggests that traits that are generally viewed as positive can have a ‘dark side’ and those generally viewed as negative can have a ‘bright side’ depending on changes in context. We test this in a sample of 220 UK medical students with respect to associations between the Big 5 personality traits and learning outcomes across the 5 years of a medical degree. The medical degree offers a changing learning context from pre-clinical years (where a more methodical approach to learning is needed) to the clinical years (where more flexible learning is needed, in a more stressful context). We argue that while trait conscientiousness should enhance pre-clinical learning, it has a ‘dark side’ reducing the acquisition of knowledge in the clinical years. We also suggest that anxiety has a ‘bright side’ enhancing the acquisition of skills in the clinical years. We also explore if intelligence enhances learning across the medical degree. Using confirmatory factor analysis and structural equation modelling we show that medical skills and knowledge assessed in the pre-clinical and clinical years are psychometrically distinguishable, forming a learning ‘backbone’, whereby subsequent learning outcomes are predicted by previous ones. Consistent with our predictions conscientiousness enhanced preclinical knowledge acquisition but reduced the acquisition of clinical knowledge and anxiety enhanced the acquisition of clinical skills. We also identified a curvilinear U shaped association between Surgency (extraversion) and pre-clinical knowledge acquisition. Intelligence predicted initial clinical knowledge, and had a positive total indirect effect on clinical knowledge and clinical skill acquisition. For medical selection, this suggests that selecting students high on conscientiousness may be problematic, as it may be excluding those with some degree of moderate anxiety. PMID:24586353

The in vitro and in vivo investigation of a novel small chamber dry powder inhalation delivery system for preclinical dosing to rats.

PubMed

Sellers, Shari; Horodnik, Walter; House, Aileen; Wylie, Jennifer; Mauser, Peter; Donovan, Brent

2015-01-01

This research describes a novel "minitower" dry powder delivery system for nose-only delivery of dry powder aerosols to spontaneously breathing rats. The minitower system forces pressurized air through pre-filled capsules to deliver aerosolized drug to four nose ports; three of which house spontaneously breathing rats, with the fourth used as a control. Within each port are vent filters which capture drug that was not inhaled for further quantitation. These vent filters along with a novel control system referred to as the "artificial rat lung", allow for the theoretical amount of drug delivered and subsequently inhaled by each rat to be calculated. In vitro and in vivo studies have demonstrated this system's ability to deliver aerosolized drug to rats. The in vitro study showed that ∼30% of the starting dose reached the 4 ports and was available for inhalation. During in-vivo studies, rats inhaled ∼34% of the delivered dose. Of the estimated inhaled dose, 12-18% was detectable in the various tissue samples, with over 30% of the recovered dose found in the rat's lungs. Results show that this system is capable of reproducibly delivering drug to the lungs of spontaneously breathing rats. Advantages over current delivery methods include being amenable to the administration of multiple doses and using less (milligram) amount of starting material. In addition, this technique avoids anesthesia which is typically required for instillation or insufflation, and thus has the potential as an efficient and noninvasive aerosol delivery method for preclinical drug development.

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

PubMed

Maze, Mervyn

2016-02-01

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

Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy.

PubMed Central

Mittereder, N; March, K L; Trapnell, B C

1996-01-01

Development of adenovirus vectors as potential therapeutic agents for multiple applications of in vivo human gene therapy has resulted in numerous preclinical and clinical studies. However, lack of standardization of the methods for quantifying the physical concentration and functionally active fraction of virions in these studies has often made comparison between various studies difficult or impossible. This study was therefore carried out to define the variables for quantification of the concentration of adenovirus vectors. The methods for evaluation of total virion concentration included electron microscopy and optical absorbance. The methods for evaluation of the concentration of functional virions included detection of gene transfer (transgene transfer and expression) and the plaque assay on 293 cells. Enumeration of total virion concentration by optical absorbance was found to be a precise procedure, but accuracy was dependent on physical disruption of the virion to eliminate artifacts from light scattering and also on a correct value for the extinction coefficient. Both biological assays for enumerating functional virions were highly dependent on the assay conditions and in particular the time of virion adsorption and adsorption volume. Under optimal conditions, the bioactivity of the vector, defined as the fraction of total virions which leads to detected target cell infection, was determined to be 0.10 in the plaque assay and 0.29 in the gene transfer assay. This difference is most likely due to the fact that detection by gene transfer requires only measurement of levels of transgene expression in the infected cell whereas plaque formation is dependent on a series of biological events of much greater complexity. These results show that the exact conditions for determination of infectious virion concentration and bioactivity of recombinant adenovirus vectors are critical and must be standardized for comparability. These observations may be very useful in comparison of data from different preclinical and clinical studies and may also have important implications for how adenovirus vectors can optimally be used in human gene therapy. PMID:8892868

Implementing the Flipped Classroom in a Veterinary Pre-clinical Science Course: Student Engagement, Performance, and Satisfaction.

PubMed

Dooley, Laura M; Frankland, Sarah; Boller, Elise; Tudor, Elizabeth

2018-01-01

There has been a recent move toward active learning pedagogies in veterinary education, with increasing use of a blended approach that incorporates both online resources and live classroom sessions. In this study, an established veterinary pre-clinical course in introductory animal health was transitioned from a traditional didactic lecture delivery mode to a flipped classroom approach with core content delivered online. This study compared the experiences of two cohorts of students who studied the same course in the different formats in consecutive years. Online learning resources included short video segments and a variety of short problems and activities. Online materials were complemented with weekly small-group case-based learning classes facilitated by academic staff. A mixed methods evaluation strategy was applied using student grades, surveys, and focus groups to compare student academic performance, satisfaction, and engagement between the two cohorts. The flipped classroom cohort achieved significantly higher grades in the written answer section of the final examination. Student satisfaction with learning resources was also higher in this cohort. However, satisfaction with other aspects of the course was largely the same for both cohorts. This study revealed some of the challenges associated with achieving adequate student preparation for class using online resources. The outcomes of this study have implications for veterinary educators considering the design and development of new online learning resources.

Maternal intake of fatty acids and their food sources during lactation and the risk of preclinical and clinical type 1 diabetes in the offspring.

PubMed

Niinistö, S; Takkinen, H-M; Uusitalo, L; Rautanen, J; Vainio, N; Ahonen, S; Nevalainen, J; Kenward, M G; Lumia, M; Simell, O; Veijola, R; Ilonen, J; Knip, M; Virtanen, S M

2015-08-01

We examined maternal dietary intake of fatty acids and foods which are sources of fatty acids during lactation and whether they are associated with the risk of preclinical and clinical type 1 diabetes in the offspring. The subjects comprised a cohort of 2,939 mother-child pairs from the prospective Type 1 Diabetes Prediction and Prevention Study. Composition of maternal diet during the third month of lactation was assessed by a validated food frequency questionnaire. Among the children with HLA-conferred susceptibility to type 1 diabetes, 172 developed preclinical and 81 clinical diabetes. Average follow-up for preclinical type 1 diabetes was 7.5 years (range 0.2-14.0 years) and for clinical type 1 diabetes 7.7 years (0.2-14.0 years). Maternal intake of fatty acids during lactation was not associated with the risk of type 1 diabetes in the offspring. After adjusting for putative confounders, maternal total consumption of red meat and meat products during lactation was associated both with increased risk for preclinical [hazard ratio (HR) 1.19, 95 % CI 1.02-1.40, p = 0.038] and clinical type 1 diabetes (HR 1.27, 95 % CI 1.06-1.52, p = 0.025). In particular, consumption of processed meat products showed an association with increased risk for type 1 diabetes (HR 1.23, 95 % CI 1.02-1.48, p = 0.045). Maternal use of vegetable oils was associated with increased risk for preclinical type 1 diabetes (HR 1.21, 95 % CI 1.03-1.41, p = 0.023). Maternal consumption of red meat, especially processed meat, during lactation may increase the risk of type 1 diabetes.

Medical Ethics Education: Coming of Age.

ERIC Educational Resources Information Center

Miles, Steven H.; And Others

1989-01-01

A discussion of medical ethics in the medical curriculum reviews its recent history, examines areas of consensus, and describes teaching objectives and methods, course content, and program evaluation at preclinical and clinical levels. Prerequisites for successful institutionalization of medical ethics education are defined, and its future is…

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

PubMed

Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L; Albert, Marylin; Weintraub, S; Fortin, Norbert J; Cotman, Carl W

2013-07-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap

PubMed Central

Snigdha, Shikha; Milgram, Norton W.; Willis, Sherry L.; Albert, Marylin; Weintraub, S.; Fortin, Norbert J.; Cotman, Carl W.

2013-01-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer’s disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer’s disease. PMID:23434040

A new method for teaching physical examination to junior medical students.

PubMed

Sayma, Meelad; Williams, Hywel Rhys

2016-01-01

Teaching effective physical examination is a key component in the education of medical students. Preclinical medical students often have insufficient clinical knowledge to apply to physical examination recall, which may hinder their learning when taught through certain understanding-based models. This pilot project aimed to develop a method to teach physical examination to preclinical medical students using "core clinical cases", overcoming the need for "rote" learning. This project was developed utilizing three cycles of planning, action, and reflection. Thematic analysis of feedback was used to improve this model, and ensure it met student expectations. A model core clinical case developed in this project is described, with gout as the basis for a "foot and ankle" examination. Key limitations and difficulties encountered on implementation of this pilot are discussed for future users, including the difficulty encountered in "content overload". This approach aims to teach junior medical students physical examination through understanding, using a simulated patient environment. Robust research is now required to demonstrate efficacy and repeatability in the physical examination of other systems.

Emerging MRI Methods in Translational Cardiovascular Research

PubMed Central

Vandsburger, Moriel H; Epstein, Frederick H

2011-01-01

Cardiac magnetic resonance imaging (CMR) has become a reference standard modality for imaging of left ventricular (LV) structure and function, and, using late gadolinium enhancement, for imaging myocardial infarction. Emerging CMR techniques enable a more comprehensive examination of the heart, making CMR an excellent tool for use in translational cardiovascular research. Specifically, emerging CMR methods have been developed to measure the extent of myocardial edema, changes in ventricular mechanics, changes in tissue composition as a result of fibrosis, and changes in myocardial perfusion as a function of both disease and infarct healing. New CMR techniques also enable the tracking of labeled cells, molecular imaging of biomarkers of disease, and changes in calcium flux in cardiomyocytes. In addition, MRI can quantify blood flow velocity and wall shear stress in large blood vessels. Almost all of these techniques can be applied in both pre-clinical and clinical settings, enabling both the techniques themselves and the knowledge gained using such techniques in pre-clinical research to be translated from the lab bench to the patient bedside. PMID:21452060

Using guinea pigs in studies relevant to asthma and COPD

PubMed Central

Canning, Brendan J.; Chou, Yangling

2010-01-01

The guinea pig has been the most commonly used small animal species in preclinical studies related to asthma and COPD. The primary advantages of the guinea pig are the similar potencies and efficacies of agonists and antagonists in human and guinea pig airways and the many similarities in physiological processes, especially airway autonomic control and the response to allergen. The primary disadvantages to using guinea pigs are the lack of transgenic methods, limited numbers of guinea pig strains for comparative studies and a prominent axon reflex that is unlikely to be present in human airways. These attributes and various models developed in guinea pigs are discussed. PMID:18462968

[Undergraduate psychiatric training in Turkey].

PubMed

Cıngı Başterzi, Ayşe Devrim; Tükel, Raşit; Uluşahin, Aylin; Coşkun, Bülent; Alkın, Tunç; Murat Demet, Mehmet; Konuk, Numan; Taşdelen, Bahar

2010-01-01

The current trend in medical education is to abandon the experience-based traditional model and embrace the competency-based education model (CBE). The basic principle behind CBE is standardization. The first step in standardization is to determine what students must know, what they must accomplish, and what attitude they should display, and the establishment of educational goals. One of the goals of the Psychiatric Association of Turkey, Psychiatric Training Section is to standardize psychiatric training in Turkish medical schools. This study aimed to determine the current state of undergraduate psychiatric training in Turkish medical schools. Questionnaires were sent to the psychiatry department chairs of 41 medical schools. Data were analyzed using descriptive statistical methods. Of the 41 department chairs that were sent the questionnaire, 29 (70%) completed and returned them, of which 16 (66.7%) reported that they had already defined goals and educational objectives for their undergraduate psychiatric training programs. The Core Education Program, prepared by the Turkish Medicine and Health Education Council, was predominately used at 9 (37.5%) medical schools. Pre-clinical and clinical training schedules varied between medical schools. In all, 3 of the medical schools did not offer internships in psychiatry. The majority of chairs emphasized the importance of mood disorders (49.9%) and anxiety disorders (40%), suggesting that these disorders should be treated by general practitioners. Computer technology was commonly used for lecturing; however, utilization of interactive and skill-based teaching methods was limited. The most commonly used evaluation methods were written examination (87.5%) during preclinical training and oral examination (91.6%) during clinical training. The most important finding of this study was the lack of a standardized curriculum for psychiatric training in Turkey. Standardization of psychiatric training in Turkish medical schools must be developed.

Comparison of haematology, coagulation and clinical chemistry parameters in blood samples from the sublingual vein and vena cava in Sprague-Dawley rats.

PubMed

Seibel, J; Bodié, K; Weber, S; Bury, D; Kron, M; Blaich, G

2010-10-01

The investigation of clinical pathology parameters (haematology, clinical chemistry and coagulation) is an important part of the preclinical evaluation of drug safety. However, the blood sampling method employed should avoid or minimize stress and injury in laboratory animals. In the present study, we compared the clinical pathology results from blood samples collected terminally from the vena cava (VC) immediately before necropsy with samples taken from the sublingual vein (VS) also prior to necropsy in order to determine whether the sampling method has an influence on clinical pathology parameters. Forty-six 12-week-old male Sprague-Dawley rats were assigned to two groups (VC or VS; n = 23 each). All rats were anaesthetized with isoflurane prior to sampling. In the VC group, blood was withdrawn from the inferior VC. For VS sampling, the tongue was gently pulled out and the VS was punctured. The haematology, coagulation and clinical chemistry parameters were compared. Equivalence was established for 13 parameters, such as mean corpuscular volume, white blood cells and calcium. No equivalence was found for the remaining 26 parameters, although they were considered to be similar when compared with the historical data and normal ranges. The most conspicuous finding was that activated prothrombin time was 30.3% less in blood taken from the VC (16.6 ± 0.89 s) than that in the VS samples (23.8 ± 1.58 s). Summing up, blood sampling from the inferior VC prior to necropsy appears to be a suitable and reliable method for terminal blood sampling that reduces stress and injury to laboratory rats in preclinical drug safety studies.

Wedding Rigorous Scientific Methodology and Ancient Herbal Wisdom to Benefit Cancer Patients: The Development of PHY906.

PubMed

Chu, Edward

2018-02-15

Our research group has extensively characterized the preclinical and clinical activities of PHY906, a traditional Chinese herbal medicine, as a modulator of irinotecan-based chemotherapy for the treatment of colorectal cancer. This article reviews the critical issues of quality control and standardization of PHY906 and highlights the importance of high-quality material for the conduct of preclinical and clinical studies. Studies to investigate the potential biological mechanisms of action using a systems biology approach play a pivotal role in providing the preclinical rationale to move forward with clinical studies. For early-phase clinical studies, translational biomarkers should be incorporated to characterize the biological effects of the herbal medicine. These biomarkers include tumor mutational load, cytokine/chemokine expression, metabolomic profiling, and the presence of key herbal metabolites. Sophisticated bioinformatic approaches are critical for mining the data and identifying those biomarkers that can define the subset of patients who will benefit from PHY906 or any other herbal medicine, in terms of reduced treatment toxicity, improved quality of life, and/or enhanced clinical activity of treatment.

A pre-clinical safety study of PEGylated recombinant human endostatin (M2ES) in Sprague Dawley rats.

PubMed

Geng, Xingchao; Guo, Lifang; Liu, Li; Wang, Chao; Peng, Qian; Qi, Weihong; Sun, Li; Liu, Xiaomeng; Miao, Yufa; Lin, Zhi; Fu, Yan; Luo, Yongzhang; Li, Bo

2018-06-01

PEGylated recombinant human endostatin (M 2 ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A pre-clinical study was performed to evaluate the safety of M 2 ES in rats. After intravenous (IV) infusions of M 2 ES at a dose level of 3, 15 and 75 mg/kg in Sprague Dawley (SD) rats, M 2 ES was well tolerated in animals, with no observable changes in clinical observation, body weight, food consumption, urine analysis, hematology and serum biochemical analysis. The increase of kidney weights, and slight to severe vacuolation and necrosis of proximal tubule epithelial cells in kidney were observed in 15 and 75 mg/kg M 2 ES groups, but this adverse-effect was reversible. In summary, the major toxicity target organ of M 2 ES might be kidney, and the no observed adverse effect level (NOAEL) of M 2 ES in rats was 3 mg/kg in this study. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. Copyright © 2018. Published by Elsevier Inc.

Assessment of tobacco heating product THP1.0. Part 9: The placement of a range of next-generation products on an emissions continuum relative to cigarettes via pre-clinical assessment studies.

PubMed

Murphy, James; Liu, Chuan; McAdam, Kevin; Gaҫa, Marianna; Prasad, Krishna; Camacho, Oscar; McAughey, John; Proctor, Christopher

2018-03-01

This series of nine papers described the operation and pre-clinical assessment of a tobacco heating product THP1.0. This last paper contextualises the pre-clinical assessment data on THP1.0 with data from other next generation products relative to cigarette smoke. The tobacco and nicotine risk continuum is a concept that ranks products according to their potential harm, with cigarettes at the highest risk extreme and Nicotine Replacement Therapy at the least risky extreme. Data generated in pre-clinical studies on THP1.0 and a range of Next Generation Products (NGPs) may provide some initial indication of potential ranking of these products, although importantly, data from such studies are limited and cannot take into consideration several important aspects for risk such as long term product use patterns. In each of the studies, the responses to the emissions from THP1.0 were substantially reduced relative to cigarette smoke. Additionally, responses from THP1.0 were very similar to those from the other NGP emissions. A comparison of the results clearly showed the emissions from all the NGPs were considerably lower than those from cigarettes and all in around the same emissions level. These results show that THP1.0 could have the potential to be a reduced risk product compared to cigarettes, though further studies assessing the exposure, individual and population risk reduction profile would be required to substantiate this potential. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Affective Biases in Humans and Animals.

PubMed

Robinson, E S J; Roiser, J P

Depression is one of the most common but poorly understood psychiatric conditions. Although drug treatments and psychological therapies are effective in some patients, many do not achieve full remission and some patients receive no apparent benefit. Developing new improved treatments requires a better understanding of the aetiology of symptoms and evaluation of novel therapeutic targets in pre-clinical studies. Recent developments in our understanding of the basic cognitive processes that may contribute to the development of depression and its treatment offer new opportunities for both clinical and pre-clinical research. This chapter discusses the clinical evidence supporting a cognitive neuropsychological model of depression and antidepressant efficacy, and how this information may be usefully translated to pre-clinical investigation. Studies using neuropsychological tests in depressed patients and at risk populations have revealed basic negative emotional biases and disrupted reward and punishment processing, which may also impact on non-affective cognition. These affective biases are sensitive to antidepressant treatments with early onset effects observed, suggesting an important role in recovery. This clinical work into affective biases has also facilitated back-translation to animals and the development of assays to study affective biases in rodents. These animal studies suggest that, similar to humans, rodents in putative negative affective states exhibit negative affective biases on decision-making and memory tasks. Antidepressant treatments also induce positive biases in these rodent tasks, supporting the translational validity of this approach. Although still in the early stages of development and validation, affective biases in depression have the potential to offer new insights into the clinical condition, as well as facilitating the development of more translational approaches for pre-clinical studies.

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

PubMed Central

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

2018-01-01

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

Transcleral delivery of triamcinolone acetonide and ranibizumab to retinal tissues using macroesis.

PubMed

Singh, Rishi P; Mathews, Michael Ellen; Kaufman, Michael; Riga, Alan

2010-02-01

To determine the feasibility of macroesis for the delivery of ranibizumab and triamcinolone acetonide via a transcleral route. Macroesis is a non-invasive method of drug delivery that uses alternating current (AC) to deliver drugs to target tissues. Two preclinical models of drug delivery were used for feasibility studies of delivering ranibizumab and triamcinolone acetonide to ocular tissues. In the first model, full-thickness sections of rabbit ocular tissue (conjunctiva to retina) were placed on an interdigitated electrode platform, and the drug was placed on the surface of the tissue. A non-uniform electrical field was applied to the ocular tissue, and electrical conductivity, a measurement of drug delivery, was monitored during the course of the experiment. In a second model, termed a 'simulated vitreous model,' the same full-thickness sections of rabbit ocular tissue were mounted below the electrode device, and the test compounds were placed on the electrodes. The fluid below the tissue, which simulated the vitreous cavity, was analysed using UV spectroscopy at the end of the study for the presence of drug. In the electrical conductivity studies, the electric characteristics of the tissue-drug system clearly showed movement of the drug through the tissue to the dielectric sensor based on changes in the electrical conductivity of the tissue sample with triamcinolone. No change in tissue conductivity was observed when no drug was placed. No heat generation occurred during the course of the study; nor was any gross tissue destruction noted. In the simulated vitreous model, studies using triamcinolone yielded concentrations ranging from 0.280 to 0.970 mg/ml, depending on the voltage, frequency and time applied. In as little as 6.7 min, clinically efficacious doses could be obtained in the preclinical system. Studies using ranibizumab yielded concentrations of 0.070-0.171 mg/ml, depending on the voltage, frequency, and time applied. In as little at 6.7 min, 92.8% throughput could be achieved. Successful delivery of ranibizumab and triamcinolone acetonide can be achieved with macroesis in preclinical studies.

"Anatomy and imaging": 10 years of experience with an interdisciplinary teaching project in preclinical medical education - from an elective to a curricular course.

PubMed

Schober, A; Pieper, C C; Schmidt, R; Wittkowski, W

2014-05-01

Presentation of an interdisciplinary, interactive, tutor-based preclinical teaching project called "Anatomy and Imaging". Experience report, analysis of evaluation results and selective literature review. From 2001 to 2012, 618 students took the basic course (4 periods per week throughout the semester) and 316 took the advanced course (2 periods per week). We reviewed 557 (return rate 90.1 %) and 292 (92.4 %) completed evaluation forms of the basic and the advanced course. Results showed overall high satisfaction with the courses (1.33 and 1.56, respectively, on a 5-point Likert scale). The recognizability of the relevance of the course content for medical training, the promotion of the interest in medicine and the quality of the student tutors were evaluated especially positively. The "Anatomy and Imaging" teaching project is a successful concept for integrating medical imaging into the preclinical stage of medical education. The course was offered as part of the curriculum in 2013 for the first time. "Anatomia in mortuis" and "Anatomia in vivo" are not regarded as rivaling entities in the delivery of knowledge, but as complementary methods. © Georg Thieme Verlag KG Stuttgart · New York.

Aging, practice effects, and genetic risk in the Wisconsin Registry for Alzheimer’s Prevention

PubMed Central

Jonaitis, Erin M.; Koscik, Rebecca L.; La Rue, Asenath; Johnson, Sterling C.; Hermann, Bruce; Sager, Mark A.

2015-01-01

BACKGROUND In the last five years, a consensus has developed that Alzheimer’s disease (AD) may begin years before overt cognitive impairment (Sperling et al., 2011). Accordingly, the focus has shifted to identifying preclinical disease in order to match treatments to those most likely to benefit. Subtle cognitive changes, including reduced benefit from practice, may be one such preclinical sign. In this paper, we explore cognitive aging trajectories within a large cohort of clinically intact late-middle-aged adults. METHOD Longitudinal cognitive data were analyzed from 594 participants in the Wisconsin Registry for Alzheimer’s Prevention. Mixed models were used to examine trajectories, adjusting for prior exposure, and the moderation thereof by markers of dementia risk, APOE-ε4 status, and family history of AD. RESULTS Practice effects were observed for Verbal Learning & Memory, Working Memory, Speed & Flexibility, and Visual Learning. However, for Working Memory and Speed & Flexibility, these effects were attenuated for FH+ subjects. CONCLUSION Reduced practice effects have previously been observed in clinical groups (Cooper et al., 2001; Machulda et al., 2013). These results in middle-aged adults suggest that they may also indicate preclinical changes on the path to AD. PMID:26012360

Learning style preferences: A study of pre-clinical medical students in Barbados.

PubMed

Ojeh, Nkemcho; Sobers-Grannum, Natasha; Gaur, Uma; Udupa, Alaya; Majumder, Md Anwarul Azim

2017-10-01

Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students' learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching strategies to cater to the students' needs as well as help the students in becoming aware of their learning style preferences to enhance learning.

Voluntary undergraduate technical skills training course to prepare students for clerkship assignment: tutees' and tutors' perspectives.

PubMed

Blohm, Mats; Krautter, Markus; Lauter, Jan; Huber, Julia; Weyrich, Peter; Herzog, Wolfgang; Jünger, Jana; Nikendei, Christoph

2014-04-04

Skills lab training has become a widespread tool in medical education, and nowadays, skills labs are ubiquitous among medical faculties across the world. An increasingly prevalent didactic approach in skills lab teaching is peer-assisted learning (PAL), which has been shown to be not only effective, but can be considered to be on a par with faculty staff-led training. The aim of the study is to determine whether voluntary preclinical skills teaching by peer tutors is a feasible method for preparing medical students for effective workplace learning in clerkships and to investigate both tutees' and tutors' attitudes towards such an intervention. A voluntary clerkship preparation skills course was designed and delivered. N = 135 pre-clinical medical students visited the training sessions. N = 10 tutors were trained as skills-lab peer tutors. Voluntary clerkship preparation skills courses as well as tutor training were evaluated by acceptance ratings and pre-post self-assessment ratings. Furthermore, qualitative analyses of skills lab tutors' attitudes towards the course were conducted following principles of grounded theory. Results show that a voluntary clerkship preparation skills course is in high demand, is highly accepted and leads to significant changes in self-assessment ratings. Regarding qualitative analysis of tutor statements, clerkship preparation skills courses were considered to be a helpful and necessary asset to preclinical medical education, which benefits from the tutors' own clerkship experiences and a high standardization of training. Tutor training is also highly accepted and regarded as an indispensable tool for peer tutors. Our study shows that the demand for voluntary competence-oriented clerkship preparation is high, and a peer tutor-led skills course as well as tutor training is well accepted. The focused didactic approach for tutor training is perceived to be effective in preparing tutors for their teaching activity in this context. A prospective study design would be needed to substantiate the results objectively and confirm the effectiveness.

Assessing HIV/AIDS Knowledge and Stigmatizing Attitudes among Medical Students in Universiti Putra Malaysia.

PubMed

Chew, B H; Cheong, A T

2013-01-01

Medical students are future doctors who are trained to treat all kind of diseases including people living with HIV/AIDS (PLWHA) without prejudice. This study was to determine the factors associated with knowledge on HIV/AIDS and stigma towards PLWHA among medical students. This was a cross sectional study with stratified random sampling conducted in a public university, Malaysia. The participants were preclinical-year (year 1 and year 2) and clinical-year (year 3 and year 4) medical students. Simple randomisation was carried out after stratification of medical students into preclinical and clinical-year. The selfadministered questionnaires were consisted of sociodemographic data, items assessing HIV/AIDS knowledge and items assessing stigmatisation attitudes towards PLWHA. We had 100% response rate of 340 participants. Pre-clinical and clinical year medical students each contributed 170 (50%). Majority was female (64.1%). About two-thirds (60.6%) was Malay, followed by Chinese (31.2%) and Indian (7.1%). Pre-clinical students were significantly more stigmatizing in subscale of "attitudes towards imposed measures" (t=3.917, p<0.001), even with adjustment for previous encounter and ethnicity (B= 1.2, 95% CI 0.48 to 1.83, p=0.001). On the other hand, clinical students were found to be significantly less comfortable in handling HIV/AIDS cases (t=0.039, p=0.039), even after controlled for previous encounter and ethnicity (B=0.6, 95% CI 0.29 to 0.98, p< 0.001). Clinical encounter with PLWHA was associated with higher knowledge in HIV/AIDS. Medical students in preclinical years were having stigmatizing attitude towards imposed measures compared to the clinical years who had more stigmatizing attitude in being less comfortable with PLWHA.

Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

PubMed Central

Xiong, Jianghui; Liu, Juan; Rayner, Simon; Tian, Ze; Li, Yinghui; Chen, Shanguang

2010-01-01

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies. PMID:21085674

Optical diagnostics of vascular reactions triggered by weak allergens using laser speckle-contrast imaging technique

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

Kuznetsov, Yu L; Kalchenko, V V; Astaf'eva, N G

2014-08-31

The capability of using the laser speckle contrast imaging technique with a long exposure time for visualisation of primary acute skin vascular reactions caused by a topical application of a weak contact allergen is considered. The method is shown to provide efficient and accurate detection of irritant-induced primary acute vascular reactions of skin. The presented technique possesses a high potential in everyday diagnostic practice, preclinical studies, as well as in the prognosis of skin reactions to the interaction with potentially allergenic materials. (laser biophotonics)

Target Identification of Grape Seed Extract in Colorectal Cancer using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

PubMed Central

Derry, Molly M.; Somasagara, Ranganatha; Raina, Komal; Kumar, Sushil; Gomez, Joe; Patel, Manisha; Agarwal, Rajesh; Agarwal, Chapla

2014-01-01

Various natural agents, including grape seed extract (GSE), have shown considerable chemopreventive and anti-cancer efficacy against different cancers in pre-clinical studies; however, their specific protein targets are largely unknown and thus, their clinical usefulness is marred by limited scientific evidences about their direct cellular targets. Accordingly, herein, employing, for the first time, the recently developed drug affinity responsive target stability (DARTS) technique, we aimed to profile the potential protein targets of GSE in human colorectal cancer (CRC) cells. Unlike other methods, which can cause chemical alteration of the drug components to allow for detection, this approach relies on the fact that a drug bound protein may become less susceptible to proteolysis and hence the enriched proteins can be detected by Mass Spectroscopy methods. Our results, utilizing the DARTS technique followed by examination of the spectral output by LC/MS and the MASCOT data, revealed that GSE targets endoplasmic reticulum (ER) stress response proteins resulting in overall down regulation of proteins involved in translation and that GSE also causes oxidative protein modifications, specifically on methionine amino acids residues on its protein targets. Corroborating these findings, mechanistic studies revealed that GSE indeed caused ER stress and strongly inhibited PI3k-Akt–mTOR pathway for its biological effects in CRC cells. Furthermore, bioenergetics studies indicated that GSE also interferes with glycolysis and mitochondrial metabolism in CRC cells. Together, the present study identifying GSE molecular targets in CRC cells, combined with its efficacy in vast pre-clinical CRC models, further supports its usefulness for CRC prevention and treatment. PMID:24724981

Influence of Teaching Strategies and its Order of Exposure on Pre-Clinical Teeth Arrangement – A Pilot Study

PubMed Central

Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar

2016-01-01

Introduction Teeth arrangement is a vital skill for the undergraduate dental student. The attainment of skills depends largely on the methodology of teaching. In a dental curriculum, the students are exposed to a wide variety of inputs and teaching methodologies from different sources. The educational unit in dental school must identify the sequence of teaching methods that enhance the learning and practising ability of students. Aim The aim of this study was to evaluate the effectiveness of three different teaching methodologies for teeth arrangement and compare the differences between the orders of exposure to each teaching methodology on the development of teeth arrangement skills. Materials and Methods The first year B.D.S students were study participants and were divided into three groups A, B, C. They were exposed to three teaching patterns namely live demonstration with video assisted teaching, group discussion with hand-outs and lectures with power point presentation. After each teaching methodology, their skill was assessed. The groups were exposed to three methodologies in different order for three arrangements. The scores obtained were analysed using Kruskal Wallis rank sum test and Dunn test for statistical significance. Results Significantly higher scores in the teeth arrangement procedure were obtained by the Group A students who were exposed initially to live demonstration with video-assisted teaching. Difference in the scores was noted among and within the groups. The difference between Group A and Group C was statistically significant after both first and third teeth arrangement (p=0.0031, p=0.0057). Conclusion The study suggests each pre-clinical practice should begin with a live demonstration to enhance immediate learning absorption followed by lectures with power point presentation and group discussion for retention of knowledge and memory retrieval. PMID:27891468

Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

PubMed Central

Hartung, Thomas

2013-01-01

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

Use of multimodality imaging and artificial intelligence for diagnosis and prognosis of early stages of Alzheimer's disease.

PubMed

Liu, Xiaonan; Chen, Kewei; Wu, Teresa; Weidman, David; Lure, Fleming; Li, Jing

2018-04-01

Alzheimer's disease (AD) is a major neurodegenerative disease and the most common cause of dementia. Currently, no treatment exists to slow down or stop the progression of AD. There is converging belief that disease-modifying treatments should focus on early stages of the disease, that is, the mild cognitive impairment (MCI) and preclinical stages. Making a diagnosis of AD and offering a prognosis (likelihood of converting to AD) at these early stages are challenging tasks but possible with the help of multimodality imaging, such as magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG)-positron emission topography (PET), amyloid-PET, and recently introduced tau-PET, which provides different but complementary information. This article is a focused review of existing research in the recent decade that used statistical machine learning and artificial intelligence methods to perform quantitative analysis of multimodality image data for diagnosis and prognosis of AD at the MCI or preclinical stages. We review the existing work in 3 subareas: diagnosis, prognosis, and methods for handling modality-wise missing data-a commonly encountered problem when using multimodality imaging for prediction or classification. Factors contributing to missing data include lack of imaging equipment, cost, difficulty of obtaining patient consent, and patient drop-off (in longitudinal studies). Finally, we summarize our major findings and provide some recommendations for potential future research directions. Copyright © 2018 Elsevier Inc. All rights reserved.

Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection

PubMed Central

Guedes-da-Silva, F. H.; Batista, D. G. J.; da Silva, C. F.; Meuser, M. B.; Simões-Silva, M. R.; de Araújo, J. S.; Ferreira, C. G.; Moreira, O. C.; Britto, C.; Lepesheva, G. I.

2015-01-01

The lack of translation between preclinical assays and clinical trials for novel therapies for Chagas disease (CD) indicates a need for more feasible and standardized protocols and experimental models. Here, we investigated the effects of treatment with benznidazole (Bz) and with the potent experimental T. cruzi CYP51 inhibitor VNI in mouse models of Chagas disease by using different animal genders and parasite strains and employing distinct types of therapeutic schemes. Our findings confirm that female mice are less vulnerable to the infection than males, show that male models are less susceptible to treatment with both Bz and VNI, and thus suggest that male models are much more suitable for selection of the most promising antichagasic agents. Additionally, we have found that preventive protocols (compound given at 1 dpi) result in higher treatment success rates, which also should be avoided during advanced steps of in vivo trials of novel anti-T. cruzi drug candidates. Another consideration is the relevance of immunosuppression methods in order to verify the therapeutic profile of novel compounds, besides the usefulness of molecular diagnostic tools (quantitative PCR) to ascertain compound efficacy in experimental animals. Our study aims to contribute to the development of more reliable methods and decision gates for in vivo assays of novel antiparasitic compounds in order to move them from preclinical to clinical trials for CD. PMID:26416857

Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study

PubMed Central

Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea D.; Etienne, Wiguins; Ashcraft, Kathleen A.; McNerny, Katie L.; Mashal, Alireza; Nouls, John; Maccarini, Paolo F.; Beyer, Wayne F.; Inman, Brant; Dewhirst, Mark W.

2014-01-01

Purpose This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with Magnetic Fluid Hyperthermia (MFH), performed by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Materials and Methods The bladders of twenty-five female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42°C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fiberoptic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterization method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. Results Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1°C/min to a steady-state of 42°C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. Conclusion These data demonstrate that our MFH system with magnetite-based nanoparticles provide well-localized heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues. PMID:24050253

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

Cancer.gov

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

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

PubMed

Sewing, A Charlotte P; Lagerweij, Tonny; van Vuurden, Dannis G; Meel, Michaël H; Veringa, Susanna J E; Carcaboso, Angel M; Gaillard, Pieter J; Peter Vandertop, W; Wesseling, Pieter; Noske, David; Kaspers, Gertjan J L; Hulleman, Esther

2017-05-01

OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

Preclinical magnetic resonance imaging and systems biology in cancer research: current applications and challenges.

PubMed

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

2013-02-01

Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The neurologic control of arousal and orgasm with specific attention to spinal cord lesions: Integrating preclinical and clinical sciences.

PubMed

Alexander, Marcalee Sipski; Marson, Lesley

2018-01-01

Preclinical research in animal models is important for understanding the neural pathways and pathophysiology underlying changes in sexual function after SCI. In vivo animal models, primarily rodents, have provided valuable information on the central pathways regulating sexual arousal and orgasm; however, further research is required in females and preclinical modeling of SCI that can be better translated to men and women. Translation of the autonomic and somatic regulation of sexual responses from preclinical models through clinical research correlates well with respect to the peripheral-spinal systems involved. However, due to the nature of sexual responses, parallel studies are necessary in animals and humans. Human studies of individuals with SCIs have provided information about the neurologic control of arousal and orgasm. Psychogenic arousal is related to the preservation of sensation at T11-L2 whereas orgasm requires the presence of an intact sacral reflex arc. Studies point to evidence of a spinal pattern generator at L3-5. Because of the exact nature of SCIs, further research using neuroimaging will be beneficial, not only to elucidate the neurological control of sexual responses after SCI, but also in able-bodied individuals. Understanding and ameliorating the effects of SCI on sexual function is important to the well-being and quality of life of individuals with SCIs and their partners, thus future research should focus more on this important topic. Published by Elsevier B.V.

Connecting drug delivery reality to smart materials design.

PubMed

Grainger, David W

2013-09-15

Inflated claims to both design and mechanistic novelty in drug delivery and imaging systems, including most nanotechnologies, are not supported by the generally poor translation of these systems to clinical efficacy. The "form begets function" design paradigm is seductive but perhaps over-simplistic in translation to pharmaceutical efficacy. Most innovations show few clinically important distinctions in their therapeutic benefits in relevant preclinical disease and delivery models, despite frequent claims to the contrary. Long-standing challenges in drug delivery issues must enlist more realistic, back-to-basics approaches to address fundamental materials properties in complex biological systems, preclinical test beds, and analytical methods to more reliably determine fundamental pharmaceutical figures of merit, including drug carrier purity and batch-batch variability, agent biodistribution, therapeutic index (safety), and efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

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

NASA Astrophysics Data System (ADS)

Gendron, Denis J.; Ménage, Alexander R.

2017-02-01

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

Amyloid-β, anxiety, and cognitive decline in preclinical Alzheimer disease: a multicenter, prospective cohort study.

PubMed

Pietrzak, Robert H; Lim, Yen Ying; Neumeister, Alexander; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Restrepo, Carolina; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

2015-03-01

Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-β (Aβ) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of Aβ-related cognitive decline, such as anxiety and depressive symptoms. To evaluate the association between Aβ status and cognitive changes, and the role of anxiety and depressive symptoms in moderating Aβ-related cognitive changes in the preclinical phase of AD. In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of Aβ, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. A positive Aβ (Aβ+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the Aβ+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the Aβ+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms; furthermore, depressive symptoms and subjective memory complaints did not moderate the association between Aβ and cognitive decline. These results provide additional support for the deleterious effect of elevated Aβ levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of Aβ on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.

[DIFFERENCE IN THE PREVALENCE OF BURNOUT SYNDROME IN PRECLINICAL AND CLINICAL TEACHING DOCTORS OF MOSTAR SCHOOL OF MEDICINE].

PubMed

Vukojevič, Mladenka; Antunovič, Andelka; Petrov, Božo

2015-01-01

The aim of this study was to determine the difference in the prevalence of burnout syndrome in preclinical and clinical teaching doctors of Mostar School of Medicine in the academic year 2011/2012. Special attention was also focused on finding out the possible difference between the syndrome incidence that was correlated to gender and years of service. The main hypothesis was that the probability of burnout syndrome incidence was higher in the group of female clinical teaching doctors having more years of service. The study involved 62 people with high academic education employed at Mostar School of Medicine who were surveyed during a randomly selected consecutive 3-month period (February to May) of the academic year 2011/2012. The data were prospectively collected through a standardized questionnaire survey. The studied parameters were gender, years of work experience and the engagement in preclinical or clinical departments of the Medical School. The survey showed that 43 out of 62 (69.4%) respondents did not suffer the burnout syndrome, while moderate syndrome was recodred in 19 (30.6%) of them. No person had serious symptoms of the syndrome. The difference between the respondents who suffered the syndrome and those who did not was not statistically significant (P=0.002). Considering the gender of respondents, statistically significant differences were not confirmed (P=0.444). Considering the years of service, the highest incidence of the syndrome was found in people with more work experience (in the group of 21-25 years), but the difference between the groups was not statistically significant (P=0.271). Observing the work in preclinical and clinical departments, because of the limited number of patients we could not confirm the hypothesis. The syndrome had affected 13 (21%) clinical teaching doctors and 6 (9,7%) preclinical doctors, while the differenece between them was not statistically significant (P=0.054). Considering the results of this research, it has not been proven that the burnout syndrome occurred more frequently in doctors who were involved in clinical teaching than in doctors who tought in preclinical departments. Also, there was no difference in the appearance of the syndrome that was related to gender and years of service.

Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

PubMed

Dolman, M Emmy M; Poon, Evon; Ebus, Marli E; den Hartog, Ilona J M; van Noesel, Carel J M; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P; Petrie, Kevin; Sparidans, Rolf W; Kok, Robbert J; Versteeg, Rogier; Caron, Huib N; Chesler, Louis; Molenaar, Jan J

2015-11-15

MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. ©2015 American Association for Cancer Research.

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

PubMed

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

2007-09-01

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

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

PubMed

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

2014-05-01

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

Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer’s disease clinical trials

PubMed Central

Grill, Joshua; Zhou, Yan; Elashoff, David; Karlawish, Jason

2016-01-01

Preclinical Alzheimer’s disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria to enroll. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with one of two hypothetical informed consent forms (ICF) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography (PET) scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials. PMID:26923411

A review of vagus nerve stimulation as a therapeutic intervention

PubMed Central

Johnson, Rhaya L; Wilson, Christopher G

2018-01-01

In this review, we provide an overview of the US Food and Drug Administration (FDA)-approved clinical uses of vagus nerve stimulation (VNS) as well as information about the ongoing studies and preclinical research to expand the use of VNS to additional applications. VNS is currently FDA approved for therapeutic use in patients aged >12 years with drug-resistant epilepsy and depression. Recent studies of VNS in in vivo systems have shown that it has anti-inflammatory properties which has led to more preclinical research aimed at expanding VNS treatment across a wider range of inflammatory disorders. Although the signaling pathway and mechanism by which VNS affects inflammation remain unknown, VNS has shown promising results in treating chronic inflammatory disorders such as sepsis, lung injury, rheumatoid arthritis (RA), and diabetes. It is also being used to control pain in fibromyalgia and migraines. This new preclinical research shows that VNS bears the promise of being applied to a wider range of therapeutic applications. PMID:29844694

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

PubMed

Prinzing, Brooke L; Gottschalk, Stephen M; Krenciute, Giedre

2018-05-01

The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.

Observations on Patient and Family Coping with Huntington's Disease.

ERIC Educational Resources Information Center

Falek, Arthur

1979-01-01

Huntington's disease is an autosomal dominantly inherited disorder. No definitive method for the preclinical detection of carriers is known. The consequences of this diagnosis are discussed. The significance of genetic counseling and a description of the phases in psychological coping is presented to enable informed decision making by family…

Outpatient Treatment of Dyslexia through Stimulation of the Cerebral Hemispheres.

ERIC Educational Resources Information Center

Kappers, E. Jan

1997-01-01

Integrated treatment methods of neuropsychological and cognitive origin were evaluated with 80 Dutch children (ages 6-15) with severe dyslexia. Treatment with flash cards, which exercised automatic letter-sound conversions, had a robust and slight effect in preclinical and clinical phases respectively, whereas hemisphere stimulation produced…

Optically Based Rapid Screening Method for Proven Optimal Treatment Strategies Before Treatment Begins

DTIC Science & Technology

to rapidly test /screen breast cancer therapeutics as a strategy to streamline drug development and provide individualized treatment. The results...system can therefore be used to streamline pre-clinical drug development, by reducing the number of animals , cost, and time required to screen new drugs

Designing, Implementing and Evaluating Preclinical Simulation Lab for Maternity Nursing Course

ERIC Educational Resources Information Center

ALFozan, Haya; El Sayed, Yousria; Habib, Farida

2015-01-01

Background: The opportunity for students to deliver care safely in today's, complex health care environment is limited. Simulation allows students to practice skills in a safe environment. Purpose: to assess the students' perception, satisfaction, and learning outcomes after a simulation based maternity course. Method: a quasi experimental design…