RESUMEN
BACKGROUND: Despite aggressive multimodal treatment, survival for patients with glioblastoma remains dismal. One obstacle to improving patient outcomes is the difficulty in delivering adequate therapeutic to the central nervous system due to the presence of the blood-brain barrier. Although direct drug infusion by convection-enhanced delivery (CED) can bypass the blood-brain barrier and facilitate delivery to intracranial tumors, determining the distribution of delivered therapeutic remains problematic. Image guidance is a strategy that can optimize the accuracy of therapeutic delivery. METHODS: Here we performed an open-label clinical trial in 10 pet dogs with spontaneous intracranial tumors to examine the target coverage accuracy of delivering polymeric magnetite nanoparticles (PMNPs) encapsulating temozolomide (TMZ). A modified small animal frame was applied to the head of each subject, and PMNPs were delivered stereotactically to the center of the tumor. Magnetic resonance imaging (MRI) was performed immediately postoperatively to examine PMNP distribution, and the animals were followed until death. RESULTS: Nine of the 10 dogs underwent PMNP infusion without complications. No infusate backflow was observed during any procedure. In 70% of the cases, the infusion accurately targeted the tumor mass, as determined by the presence of PMNP signal in the tumor on immediate postoperative MRI. CONCLUSIONS: These data suggest that CED of PMNPs carrying TMZ is safe in dogs with intracranial tumors and can lead to nanoparticle distribution in the region of the target. Image guidance is an important adjunct to CED, because distribution is unpredictable, with the potential for missed target delivery.
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Antineoplásicos/administración & dosificación , Dacarbazina/análogos & derivados , Enfermedades de los Perros/tratamiento farmacológico , Glioma/veterinaria , Nanopartículas de Magnetita , Neoplasias Supratentoriales/veterinaria , Animales , Encéfalo/diagnóstico por imagen , Convección , Dacarbazina/administración & dosificación , Enfermedades de los Perros/diagnóstico por imagen , Perros , Sistemas de Liberación de Medicamentos , Femenino , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Imagen por Resonancia Magnética , Masculino , Nanopartículas , Proyectos Piloto , Polímeros , Neoplasias Supratentoriales/diagnóstico por imagen , Neoplasias Supratentoriales/tratamiento farmacológico , Temozolomida , Resultado del Tratamiento , Carga TumoralRESUMEN
PURPOSE: Glioblastoma is a deadly brain cancer with a median survival time of â¼15 months. Ionizing radiation plus the DNA alkylator temozolomide (TMZ) is the current standard therapy. PAC-1, a procaspase-3 activating small molecule, is blood-brain barrier penetrant and has previously demonstrated ability to synergize with diverse pro-apoptotic chemotherapeutics. We studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas. EXPERIMENTAL DESIGN: Using cell lines and online gene expression data, we identified procaspase-3 as a potential molecular target for most glioblastomas. We investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma. Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1. RESULTS: Procaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis. PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models. PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models. Addition of PAC-1 to TMZ and radiation was well-tolerated in 3 out of 3 pet dogs with spontaneous glioma, and partial to complete tumor reductions were observed. CONCLUSIONS: Procaspase-3 is a clinically relevant target for treatment of glioblastoma. Synergistic activity of PAC-1/TMZ in rodent models and the demonstration of feasibility of the combined regime in canine patients suggest potential for PAC-1 in the treatment of glioblastoma.
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Traditionally, histological investigations of the epileptic brain are required to identify epileptogenic brain lesions, to evaluate the impact of seizure activity, to search for mechanisms of drug-resistance and to look for comorbidities. For many instances, however, neuropathological studies fail to add substantial data on patients with complete clinical work-up. This may be due to sparse training in epilepsy pathology and or due to lack of neuropathological guidelines for companion animals.The protocols introduced herein shall facilitate systematic sampling and processing of epileptic brains and therefore increase the efficacy, reliability and reproducibility of morphological studies in animals suffering from seizures.Brain dissection protocols of two neuropathological centres with research focus in epilepsy have been optimised with regards to their diagnostic yield and accuracy, their practicability and their feasibility concerning clinical research requirements.The recommended guidelines allow for easy, standardised and ubiquitous collection of brain regions, relevant for seizure generation. Tissues harvested the prescribed way will increase the diagnostic efficacy and provide reliable material for scientific investigations.
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Encéfalo/patología , Enfermedades de los Gatos/patología , Enfermedades de los Perros/patología , Epilepsia/veterinaria , Manejo de Especímenes/veterinaria , Animales , Gatos , Perros , Epilepsia/patologíaRESUMEN
Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, "a common language", for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.
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Enfermedades de los Perros/diagnóstico , Epilepsia/veterinaria , Terminología como Asunto , Medicina Veterinaria/organización & administración , Animales , Enfermedades de los Perros/clasificación , Perros , Epilepsia/clasificación , Epilepsia/diagnóstico , Internacionalidad , MascotasRESUMEN
This article outlines the consensus proposal on diagnosis of epilepsy in dogs by the International Veterinary Epilepsy Task Force. The aim of this consensus proposal is to improve consistency in the diagnosis of epilepsy in the clinical and research settings. The diagnostic approach to the patient presenting with a history of suspected epileptic seizures incorporates two fundamental steps: to establish if the events the animal is demonstrating truly represent epileptic seizures and if so, to identify their underlying cause. Differentiation of epileptic seizures from other non-epileptic episodic paroxysmal events can be challenging. Criteria that can be used to make this differentiation are presented in detail and discussed. Criteria for the diagnosis of idiopathic epilepsy (IE) are described in a three-tier system. Tier I confidence level for the diagnosis of IE is based on a history of two or more unprovoked epileptic seizures occurring at least 24 h apart, age at epileptic seizure onset of between six months and six years, unremarkable inter-ictal physical and neurological examination, and no significant abnormalities on minimum data base blood tests and urinalysis. Tier II confidence level for the diagnosis of IE is based on the factors listed in tier I and unremarkable fasting and post-prandial bile acids, magnetic resonance imaging (MRI) of the brain (based on an epilepsy-specific brain MRI protocol) and cerebrospinal fluid (CSF) analysis. Tier III confidence level for the diagnosis of IE is based on the factors listed in tier I and II and identification of electroencephalographic abnormalities characteristic for seizure disorders. The authors recommend performing MRI of the brain and routine CSF analysis, after exclusion of reactive seizures, in dogs with age at epileptic seizure onset <6 months or >6 years, inter-ictal neurological abnormalities consistent with intracranial neurolocalisation, status epilepticus or cluster seizure at epileptic seizure onset, or a previous presumptive diagnosis of IE and drug-resistance with a single antiepileptic drug titrated to the highest tolerable dose.This consensus article represents the basis for a more standardised diagnostic approach to the seizure patient. These recommendations will evolve over time with advances in neuroimaging, electroencephalography, and molecular genetics of canine epilepsy.
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Enfermedades de los Perros/diagnóstico , Epilepsia/veterinaria , Internacionalidad , Medicina Veterinaria/organización & administración , Animales , Perros , Epilepsia/diagnóstico , Predisposición Genética a la Enfermedad , Guías de Práctica Clínica como AsuntoRESUMEN
In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors' experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.
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Anticonvulsivantes/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Epilepsia/veterinaria , Internacionalidad , Medicina Veterinaria/organización & administración , Animales , Anticonvulsivantes/efectos adversos , Enfermedades de los Perros/epidemiología , Perros , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Europa (Continente)/epidemiología , Guías de Práctica Clínica como Asunto , Medicina Veterinaria/normasRESUMEN
Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature.There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6-7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed.
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Enfermedades de los Perros/diagnóstico , Epilepsia/veterinaria , Imagen por Resonancia Magnética/veterinaria , Medicina Veterinaria/organización & administración , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades de los Perros/patología , Perros , Epilepsia/diagnóstico , Epilepsia/patología , Internacionalidad , Imagen por Resonancia Magnética/métodos , RadiografíaRESUMEN
Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered.
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Anticonvulsivantes/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Internacionalidad , Medicina Veterinaria/organización & administración , Animales , Gatos , Perros , Resultado del TratamientoRESUMEN
OBJECTIVES: There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people. METHODS: A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured. RESULTS: Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 µg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064). SIGNIFICANCE: This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds.
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Anticonvulsivantes/uso terapéutico , Fenitoína/análogos & derivados , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/veterinaria , Animales , Benzodiazepinas/administración & dosificación , Perros , Método Doble Ciego , Femenino , Infusiones Intravenosas , Masculino , Fenitoína/sangre , Fenitoína/uso terapéutico , Estudios Prospectivos , Estado Epiléptico/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
Over the past 2 decades, the number of antiepileptic drugs (AEDs) available to veterinarians has grown exponentially. Coupled with this increase is the ability to rapidly and accurately diagnose underlying brain disease with readily accessible magnetic resonance imaging. As a result, the veterinary community is attuned to the need for early treatment intervention. As more treatment choices become available, the unrelenting questions still arise are when should treatment begin, which initial drug therapy is best for our patients, when should treatment changes be considered, and finally, what are the advantages that newer drugs provide for our patients. The purpose of this chapter is to review decision-making strategies for AED therapy, provide an overview of the applicability of current AED available, and present information on the therapeutic advances in epilepsy.
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Anticonvulsivantes/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico , Epilepsia/veterinaria , Animales , Anticonvulsivantes/efectos adversos , Gatos , Perros , Monitoreo de Drogas/veterinaria , Epilepsia/tratamiento farmacológicoRESUMEN
Lion lentivirus (LLV; also known as feline immunodeficiency virus of lion, Panthera leo [FIVPle]) is present in free-ranging and captive lion populations at a seroprevalence of up to 100%; however, clinical signs are rarely reported. LLV displays up to 25% interclade sequence diversity, suggesting that it has been in the lion population for some time and may be significantly host adapted. Three captive lions diagnosed with LLV infection displayed lymphocyte subset alterations and progressive behavioral, locomotor, and neuroanatomic abnormalities. No evidence of infection with other potential neuropathogens was found. Antemortem electrodiagnostics and radiologic imaging indicated a diagnosis consistent with lentiviral neuropathy. PCR was used to determine a partial lentiviral genomic sequence and to quantify the proviral burden in eight postmortem tissue specimens. Phylogenetic analysis demonstrated that the virus was consistent with the LLV detected in other captive and free-ranging lions. Despite progressive neurologic signs, the proviral load in tissues, including several regions of the brain, was low; furthermore, gross and histopathologic changes in the brain were minimal. These findings suggest that the symptoms in these animals resulted from nonspecific encephalopathy, similar to human immunodeficiency virus, FIV, and simian immunodeficiency virus (SIV) neuropathies, rather than a direct effect of active viral replication. The association of neuropathy and lymphocyte subset alterations with chronic LLV infection suggests that long-term LLV infection can have detrimental effects for the host, including death. This is similar to reports of aged sootey mangabeys dying from diseases typically associated with end-stage SIV infection and indicates areas for further research of lentiviral infections of seemingly adapted natural hosts, including mechanisms of host control and viral adaptation.
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Enfermedades Virales del Sistema Nervioso Central/veterinaria , Virus de la Inmunodeficiencia Felina/aislamiento & purificación , Infecciones por Lentivirus/veterinaria , Leones , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/virología , Enfermedades Virales del Sistema Nervioso Central/patología , Enfermedades Virales del Sistema Nervioso Central/fisiopatología , Enfermedades Virales del Sistema Nervioso Central/virología , ADN Viral/análisis , ADN Viral/genética , Electroencefalografía , Potenciales Evocados Auditivos , Genes pol , Genoma Viral , Histocitoquímica , Virus de la Inmunodeficiencia Felina/clasificación , Virus de la Inmunodeficiencia Felina/genética , Virus de la Inmunodeficiencia Felina/fisiología , Infecciones por Lentivirus/patología , Infecciones por Lentivirus/fisiopatología , Infecciones por Lentivirus/virología , Subgrupos Linfocitarios/inmunología , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la Polimerasa , Provirus/genética , Radiografía , Análisis de Secuencia de ADN , Carga ViralAsunto(s)
Enfermedades de los Gatos/diagnóstico , Enfermedades de los Gatos/terapia , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/terapia , Fasciculación/veterinaria , Trastornos del Movimiento/veterinaria , Temblor/veterinaria , Animales , Gatos , Árboles de Decisión , Perros , Fasciculación/diagnóstico , Fasciculación/terapia , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/terapia , Temblor/diagnóstico , Temblor/terapiaRESUMEN
We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinson's disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.
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Ácido Aspártico/análogos & derivados , Cuerpo Estriado/metabolismo , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Ácido Aspártico/genética , Ácido Aspártico/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Gatos , Colina/análisis , Colina/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Creatina/análisis , Creatina/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inositol/análisis , Inositol/metabolismo , Examen Neurológico , Pargilina/farmacología , Trastornos Parkinsonianos/inducido químicamente , Valor Predictivo de las Pruebas , Protones , Tirosina 3-Monooxigenasa/biosíntesisRESUMEN
A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.
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Enfermedad de Charcot-Marie-Tooth/veterinaria , Enfermedades de los Perros/genética , Enfermedades de los Perros/fisiopatología , Nervios Periféricos/fisiopatología , Potenciales de Acción/genética , Animales , Modelos Animales de Enfermedad , Enfermedades de los Perros/patología , Perros , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/veterinaria , Cojera Animal/genética , Cojera Animal/patología , Cojera Animal/fisiopatología , Masculino , Microscopía Electrónica , Neuronas Motoras/patología , Neuronas Motoras/ultraestructura , Contracción Muscular/genética , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Mielínicas/ultraestructura , Linaje , Nervios Periféricos/patologíaRESUMEN
5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.
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Atrofia Muscular Espinal/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Transgenes , Animales , Axones/metabolismo , Southern Blotting , Western Blotting , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Electromiografía , Electrofisiología , Genotipo , Glutatión Transferasa/metabolismo , Homocigoto , Inmunohistoquímica , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Biológicos , Modelos Genéticos , Neuronas Motoras/patología , Músculos/citología , Músculos/metabolismo , Músculos/patología , Mutación , Fenotipo , Unión Proteica , Proteínas de Unión al ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas del Complejo SMN , Proteína 1 para la Supervivencia de la Neurona Motora , Proteína 2 para la Supervivencia de la Neurona Motora , Factores de Tiempo , Distribución TisularRESUMEN
We assessed the feasibility, accuracy, and safety of securing site-selective brain biopsy specimens by using a real-time CT-guided stereotactic navigation system through a mini-burr hole in the skulls of two dogs. Two beagle dogs each underwent two biopsy procedures. Our results indicated that the navigation system was accurate, safe, fast, and reliable for performing real-time brain biopsy in dogs and eliminated the need or risk of a standard-flap craniotomy.
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Encéfalo/patología , Procedimientos Quirúrgicos Mínimamente Invasivos , Técnicas Estereotáxicas/instrumentación , Tomografía Computarizada por Rayos X/instrumentación , Tomografía Computarizada por Rayos X/métodos , Animales , Biopsia , Perros , Diseño de Equipo , Masculino , Modelos Animales , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
Human immunodeficiency virus (HIV) infection among substance abusers is on the rise worldwide. Psychostimulants, and in particular methamphetamine (METH), have detrimental effects on the immune system as well as causing a progressive neurodegeneration, similar to HIV infection. Many Lentivirinae, including feline immunodeficiency virus (FIV), penetrate into the central nervous system early in the course of infection with astrocytes serving as a reservoir of chronic brain infection. We demonstrate that the FIV-Maryland isolate infects feline primary and cell line (G355-5)-cultured astrocytes only under cell-associated conditions. Infected astrocytes yielded a new astrocytotropic isolate, capable of cell-free infection (termed FIV-MD-A). This isolate contained four amino acid substitutions in the envelope polyprotein resulting in a change in net charge as compared to FIV-MD. Infection for both isolates was dependent upon a functional astrocyte CXCR4 receptor. Methamphetamine increased significantly FIV replication in feline astrocytes for cell-associated infection only, with no effect on peripheral blood mononuclear cells or astrocytes infected with FIV-MD-A. This viral replication was related to proviral copy number, suggesting the effect of METH is at the viral entry or integration into host genome levels, but not at the translational level. Thus, lentiviral infection of the brain in the presence of the psychostimulant METH may result in enhanced astrocyte viral replication, producing a more rapid and increased brain viral load.
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Astrocitos/virología , Síndrome de Inmunodeficiencia Adquirida del Felino/virología , Virus de la Inmunodeficiencia Felina/genética , Metanfetamina/farmacología , Simpatomiméticos/farmacología , Replicación Viral/efectos de los fármacos , Animales , Astrocitos/citología , Gatos , Citometría de Flujo , Dosificación de Gen , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/virología , Mutación , Provirus/genética , Organismos Libres de Patógenos Específicos , Trastornos Relacionados con Sustancias/virologíaRESUMEN
Inflammatory myopathies are the result of infiltration of inflammatory cells into striated muscle, with or without an association with an underlying cause. Two broad classifications are IIMs and secondary inflammatory myopathies associated with other diseases. Standard diagnostic criteria for inflammatory myopathy include the presence of weakness or loss of specific muscle group function, an increase in CK, EMG changes associated with muscle membrane instability, and histologic evidence of inflammation. Not all these criteria, however, must be present. Fresh-frozen biopsy from two proximal muscles is recommended for biopsy confirmation. IIM can either focally affect head or neck muscles or be more diffuse. MMM is an immune-mediated disease characterized by a humoral antibody produced against the unique type IIM and type I variant mvofibers of masticatory muscles of dogs, which causes inflammation and loss of function of the muscles of mastication. Idiopathic polymyositis can affect focal muscle groups (extraocular, laryngeal) or present as multifocal or diffuse involvement of skeletal muscle in the cat and dog. Familial canine DM is an inflammatory disease of the striated muscle, skin, and vasculature in young Collies, Shetland Sheepdogs (Shelties), and, rarely, Collie-crossbred dogs. Immunosuppressive therapy is the key to successful treatment. Protozoal parasitic myopathies are the most common cause of clinically relevant secondary inflammatory myopathies. The degree of systemic involvement is often the limiting factor to successful treatment. Early recognition of the clinical signs for proper diagnostic testing and institution of appropriate therapy can result in a rewarding outcome in treating inflammatory myopathies in the cat and dog.
Asunto(s)
Enfermedades de los Gatos/diagnóstico , Enfermedades de los Perros/diagnóstico , Miositis/veterinaria , Examen Físico/veterinaria , Animales , Gatos , Diagnóstico Diferencial , Perros , Miositis/diagnósticoRESUMEN
Human immunodeficiency virus infection in children and adults results in a progressive neurodegenerative disease consistent with a predominant subcortical mediated dementia. Techniques for developing a feline model of the early stages of lentiviral-associated neurodegeneration are presented. The behavioral, neurophysiologic, immunologic, virologic, and neuropathologic aspects of this model are also described.