RESUMEN
The limitations of using small-brained rodents to model diseases that affect large-brain humans are becoming increasingly obvious as novel therapies emerge. Huntington's disease (HD) is one such disease. In recent years, the desirability of a large-brained, long-lived animal model of HD for preclinical testing has changed into a necessity. Treatment involving gene therapy in particular presents delivery challenges that are currently unsolved. Models using long-lived, large-brained animals would be useful, not only for refining methods of delivery (particularly for gene and other therapies that do not involve small molecules) but also for measuring long-term "off-target" effects, and assessing the efficacy of therapies. With their large brains and convoluted cortices, sheep are emerging as feasible experimental subjects that can be used to bridge the gap between rodents and humans in preclinical drug development. Sheep are readily available, economical to use, and easy to care for in naturalistic settings. With brains of a similar size to a large rhesus macaque, they have much to offer. The only thing that was missing until recently was the means of testing their neurological function and behavior using approaches and methods that are relevant to HD. In this chapter, I will outline the present and future possibilities of using sheep and testing as large animal models of HD.
Asunto(s)
Técnicas de Observación Conductual/métodos , Conducta Animal , Modelos Animales de Enfermedad , Enfermedad de Huntington/fisiopatología , Ovinos , Animales , Animales Modificados Genéticamente , Técnicas de Observación Conductual/economía , Técnicas de Observación Conductual/instrumentación , Encéfalo/patología , Encéfalo/fisiopatología , Terapia Genética/efectos adversos , Terapia Genética/métodos , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Enfermedad de Huntington/terapia , Mutación , Tamaño de los Órganos , Resultado del TratamientoRESUMEN
Large animal models offer novel opportunities in exploring safety, biology, and efficacy of novel therapeutic approaches for Huntington's disease (HD). Challenges in the development of, for example, gene therapy, such as delivery, distribution, and persistence of virus vectors or oligo sense nucleotides, can be explored in large brains and organisms approaching human size. We here introduce the transgenic Libechov minipig as a large animal model of HD. Methods developed to assess motor, cognitive, and behavioral features expected to manifest in an HD model are described. We also outline established protocols for magnetic resonance imaging (MRI) including magnetic resonance spectroscopy (MRS) for minipigs. The successful conduct of long-term follow-up studies over several years with repeated behavioral testing and imaging is reported. We discuss the advantages and limitations of using this model with regard to translational reliability, homology to humans and with respect to feasibility, breeding, housing, handling, and finally ethical considerations. It is concluded that minipigs can fulfill an important role in preclinical development to bridge the gap between rodents and nonhuman primate research in the translation to humans.
Asunto(s)
Técnicas de Observación Conductual/métodos , Modelos Animales de Enfermedad , Enfermedad de Huntington/diagnóstico , Neuroimagen/métodos , Porcinos Enanos , Animales , Animales Modificados Genéticamente , Técnicas de Observación Conductual/economía , Técnicas de Observación Conductual/instrumentación , Conducta Animal , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Terapia Genética/efectos adversos , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/efectos adversos , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Enfermedad de Huntington/terapia , Mutación , Neuroimagen/instrumentación , Tamaño de los Órganos , Porcinos , Resultado del TratamientoRESUMEN
Huntington's disease (HD) is a monogenic, autosomal dominant inherited fatal disease that affects 1 in 10,000 people worldwide. Given its unique genetic characteristics, HD would appear as one of the most straightforward neurodegenerative diseases to replicate in animal models. Indeed, mutations in the HTT gene have been used to generate a variety of animal models that display differential pathologies and have significantly increased our understanding of the pathological mechanisms of HD. However, decades of efforts have also shown the complexity of recapitulating the human condition in other species. Here we describe the three different types of models that have been generated in nonhuman primate species, stating their advantages and limitations and attempt to give a critical perspective of their translational value to test the efficacy of novel therapeutic strategies. Obtaining construct, phenotypic, and predictive validity has proven to be challenging in most animal models of human diseases. In HD in particular, it is hard to assess the predictive validity of a new therapeutic strategy when no effective "benchmark" treatment is available in the clinic. In this light, only phenotypic/face validity and construct validity are discussed.
Asunto(s)
Técnicas de Observación Conductual/métodos , Modelos Animales de Enfermedad , Enfermedad de Huntington/patología , Primates , Investigación Biomédica Traslacional/métodos , Animales , Animales Modificados Genéticamente , Atrofia/inducido químicamente , Técnicas de Observación Conductual/economía , Técnicas de Observación Conductual/instrumentación , Conducta Animal , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Terapia Genética/efectos adversos , Terapia Genética/métodos , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/etiología , Enfermedad de Huntington/fisiopatología , Enfermedad de Huntington/terapia , Mutación , Neurotoxinas/administración & dosificación , Neurotoxinas/toxicidad , Técnicas Estereotáxicas/instrumentación , Investigación Biomédica Traslacional/instrumentación , Resultado del TratamientoRESUMEN
In hospitals, use of constant observation (CO) causes significant economic burden without demonstrated reduction in adverse events. A novel quality improvement (QI) project was developed to reduce use of CO by integrating proactive behavioral health management of all patients requiring CO in a general hospital. Specific nonpharmacologic and pharmacologic interventions used in this project, which included 491 patients, are discussed. Data collected were compared with data from a baseline period before project implementation. The average monthly cost of observers was reduced by 33%, and length of stay was reduced 15% without increased complications. Using QI to develop proactive and consistent involvement of a designated behavioral health team and potentially reproducible care protocols for patients requiring CO resulted in improvement in quality, reduction in cost, and enhanced behavioral health integration in the general hospital.
Asunto(s)
Técnicas de Observación Conductual , Hospitales Generales , Tiempo de Internación , Servicios de Salud Mental , Grupo de Atención al Paciente , Mejoramiento de la Calidad , Técnicas de Observación Conductual/economía , Técnicas de Observación Conductual/organización & administración , Técnicas de Observación Conductual/normas , Hospitales Generales/economía , Hospitales Generales/organización & administración , Hospitales Generales/normas , Humanos , Tiempo de Internación/economía , Servicios de Salud Mental/economía , Servicios de Salud Mental/organización & administración , Servicios de Salud Mental/normas , Modelos Organizacionales , Grupo de Atención al Paciente/economía , Grupo de Atención al Paciente/organización & administración , Grupo de Atención al Paciente/normas , Mejoramiento de la Calidad/economía , Mejoramiento de la Calidad/organización & administración , Mejoramiento de la Calidad/normasRESUMEN
Simple and low-cost observational-tools to detect symptoms of Autism Spectrum Disorder (ASD) are still necessary. The OERA is a new assessment tool to screen children eliciting observable behaviors with no substantial knowledge on ASD required. The sample was 99 children aged 3-10: 76 with ASD and 23 without ASD (11/23 had intellectual disability). The 13 remained items exhibited high interrater agreement and high reliability loaded onto a single latent trait. Such model showed excellent fit indices evaluated via confirmatory factor analysis and no item showed differential function in terms of age/sex/IQ. A cutoff of five points or higher resulted in the highest sensitivity (92.75) and specificity (90.91) percentages. OERA is a brief, stable, low-cost standardized observational-screening to identify ASD children.
Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/economía , Técnicas de Observación Conductual/economía , Técnicas de Observación Conductual/normas , Tamizaje Masivo/economía , Tamizaje Masivo/normas , Trastorno del Espectro Autista/psicología , Niño , Preescolar , Análisis Costo-Beneficio , Análisis Factorial , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/economía , Discapacidad Intelectual/psicología , Masculino , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: 1:1 care is applied for patients requiring close psychiatric monitoring and care like patients with acute suicidality. The article describes the frequency of 1:1 care across different diagnoses and age groups in German psychiatric hospitals. METHODS: The analysis was based on the VIPP Project from the years 2011 and 2012. A total of 47 hospitals with more than 120,000 cases were included. Object of the analysis was the OPS code 9-640.0 1:1 care. The evaluation was performed on case level. RESULTS: Data of 47 hospitals were included. Of the 121,454 cases evaluated in 2011 3.8â% documented a 1:1 care within the meaning of OPS 9-640.0 additional code. Of the 66â245 male cases a 1:1 care was documented in 3.5â% and the 55â207 female cases was 4.1â%. Compared to 2011, the proportion of 1:1 care in 2012 rose to 4.8â%. CONCLUSION: The results show that 1:1 care is frequently applied in German psychiatric hospitals. The Data of the VIPP project have proven to be a useful tool to gain information on the frequency of cost-intensive interventions in German psychiatric hospitals. Further analyses should create the possibility of evaluation at the level of the individual codes.