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Many highly effective vaccines have been developed to protect dogs against disease caused by canine parvovirus, but despite this vaccine interference by maternally derived antibodies continues to cause immunisation failure. To help overcome this limitation we have developed a novel, recombinant canine parvovirus type 2c vaccine strain, based on the structural and non-structural elements of an established type 2 vaccine. This novel CPV-2c vaccine strain has unique efficacy in the field, it is able to induce sterilising immunity in naïve animals 3 days after vaccination and is able to overcome very high levels of maternally derived antibodies from 4 weeks of age-thus closing the immunity gap to canine parvovirus infection in young puppies. The vaccine strain, named 630a, has been combined with an established canine distemper virus Onderstepoort vaccine strain to produce a new bivalent vaccine (Nobivac DP PLUS), intended to immunise very young puppies in the face of high levels of maternally derived antibody. Here, we describe the onset of immunity and maternal antibody interference studies that support the unique efficacy of the strain, and present overdose studies in both dogs and cats that demonstrate the vaccine to be safe.
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Our study aims are: (1) to evaluate phenotypically normal canine conjunctival and orbital tissue and tissue from canine lobular orbital adenomas (CLOAs) for the presence of viral genomic material and (2) phylogenetically classify detected DNA viruses to determine if a DNA virus is associated with CLOAs. A total of 31 formalin fixed paraffin embedded CLOA tissue samples, 4 papillomas or sarcoid, and 10 fresh clinically normal conjunctival tissues were included in this study. Genomic DNA was isolated from all samples and sequencing libraries were prepared. The libraries were molecularly indexed and pooled and viral DNA was enriched via targeted sequence capture utilizing ViroCap. The libraries were sequenced on the Illumina HiSeq platform and compared to known viral DNA reference genomes to identify viral DNA. Carnivore parvovirus was identified in 6.4% and 20% of CLOA tissue and normal conjunctival samples, respectively. This study showed that conjunctival tissue from healthy dogs and CLOAs uncommonly harbor DNA viruses, and no DNA virus was associated with these tumors. Further studies are needed to evaluate the etiologic cause of CLOAs.
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CLN2 neuronal ceroid lipofuscinosis is a hereditary neurodegenerative disorder characterized by progressive vision loss, neurological decline, and seizures. CLN2 disease results from mutations in TPP1 that encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Children with CLN2 neuronal ceroid lipofuscinosis experience ocular disease, characterized by progressive retinal degeneration associated with impaired retinal function and gradual vision loss culminating in total blindness. A similar progressive loss of retinal function is also observed in a dog CLN2 model with a TPP1 null mutation. A study was conducted to evaluate the efficacy of periodic intravitreal injections of recombinant human (rh) TPP1 in inhibiting retinal degeneration and preserving retinal function in the canine model. TPP1 null dogs received periodic intravitreal injections of rhTPP1 in one eye and vehicle in the other eye beginning at approximately 12 weeks of age. Ophthalmic exams, in vivo ocular imaging, and electroretinography (ERG) were repeated regularly to monitor retinal structure and function. Retinal histology was evaluated in eyes collected from these dogs when they were euthanized at end-stage neurological disease (43-46 weeks of age). Intravitreal rhTPP1 dosing prevented disease-related declines in ERG amplitudes in the TPP1-treated eyes. At end-stage neurologic disease, TPP1-treated eyes retained normal morphology while the contralateral vehicle-treated eyes exhibited loss of inner retinal neurons and photoreceptor disorganization typical of CLN2 disease. The treatment also prevented the development of disease-related focal retinal detachments observed in the control eyes. Uveitis occurred secondary to the administration of the rhTPP1 but did not hinder the therapeutic benefits. These findings demonstrate that periodic intravitreal injection of rhTPP1 preserves retinal structure and function in canine CLN2 disease.
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Aminopeptidasas/administración & dosificación , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/administración & dosificación , Terapia de Reemplazo Enzimático/métodos , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Retina/efectos de los fármacos , Serina Proteasas/administración & dosificación , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Electrorretinografía , Inyecciones Intravítreas , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Reflejo Pupilar/fisiología , Retina/patología , Resultado del Tratamiento , Tripeptidil Peptidasa 1RESUMEN
BACKGROUND: Canine lobular orbital adenomas are benign tumors that arise from orbital glandular tissue and extend into the orbit, conjunctiva, and third eyelid. Surgical excision is challenging and recurrence rates are high following excision alone. Enucleation and exenteration reduces the likelihood of recurrence, but is a radical therapeutic option for an otherwise visual and comfortable eye. Human papillomavirus causes 4.5% of worldwide cancers in people and has been identified in up to 23% of benign salivary gland tumors. To date, the etiology of canine lobular orbital adenomas has not been established and it is reasonable to consider canine papillomaviruses as an associative agent with benign glandular tumors in dogs. Identification of the underlying etiology of these tumors may help establish treatment or preventative measures. The purpose of this study was to evaluate conjunctival and orbital tissue of phenotypically normal dogs and tissue from canine lobular orbital adenomas for the presence of papillomavirus DNA. RESULTS: Thirty seven canine lobular orbital adenoma samples (36 formalin fixed paraffin embedded (FFPE) tissue samples from 33 dogs and one freshly collected sample) were evaluated via polymerase chain reaction for the presence of papillomavirus DNA. Conjunctival tissue samples, from 10 dogs with normal ocular examinations, excised immediately following euthanasia, were used as phenotypically normal controls. Three FFPE and one freshly collected tissue samples previously confirmed to be positive for papillomavirus DNA were used as positive controls. PCR products verified positive controls. Papillomavirus DNA was not detected in fresh conjunctival tissue of the phenotypically normal control dogs or in samples of fresh or FFPE canine lobular orbital adenoma tissue. CONCLUSIONS: An association between papillomavirus and the development of canine lobular orbital adenomas is unlikely. Further research is needed to evaluate if other viruses play a role in the pathogenesis of canine lobular orbital adenomas.
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Adenoma/veterinaria , Enfermedades de los Perros/virología , Neoplasias Orbitales/veterinaria , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/veterinaria , Adenoma/patología , Adenoma/virología , Animales , Conjuntiva/virología , ADN Viral/análisis , Enfermedades de los Perros/patología , Perros , Femenino , Masculino , Neoplasias Orbitales/patología , Neoplasias Orbitales/virología , Papillomaviridae/genética , Infecciones por Papillomavirus/patologíaRESUMEN
This corrects the article DOI: 10.1038/srep43918.
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A 11-year-old neutered male Labrador retriever-cross dog was presented to the University of Missouri-Columbia Veterinary Ophthalmology Service for subtle visual deficits. Indirect ophthalmoscopy revealed a smooth, bullous elevation in the superior-temporal retina OU. Optical coherence tomography (OCT) performed OU showed inner retinal separation consistent with retinoschisis. Electroretinography (ERG) revealed markedly reduced b-wave amplitudes in the more severely affected eye (OD) compared with the less severely affected eye (OS). The most notable reductions were in the rod response and 30-Hz flicker b-waves OD which were approximately 50% of the corresponding amplitudes OS. Implicit times, particularly the a-wave implicit times, were noticeably longer OD compared with OS. Lesions remained unchanged over 4 months at which time the dog was humanely euthanized for reasons unrelated to the ocular disease. Significant light microscopic ocular findings were bilateral superior temporal peripheral retinoschisis. The separation of the retinal tissue was similar between eyes and effectively divided the outer plexiform layer. In addition, thinning of the surrounding retinal layers was present. To the authors' knowledge, this is the first case of canine retinoschisis diagnosed with OCT, evaluated with electroretinography, and confirmed with light microscopic examination. History, clinical, and diagnostic findings, with the absence of disease progression over time, are analogous with cases of acquired senile retinoschisis in humans.
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Enfermedades de los Perros/diagnóstico por imagen , Retinosquisis/veterinaria , Animales , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/patología , Perros , Electrorretinografía/veterinaria , Fondo de Ojo , Masculino , Retina/patología , Retinosquisis/diagnóstico , Retinosquisis/diagnóstico por imagen , Retinosquisis/patología , Tomografía de Coherencia Óptica/veterinariaRESUMEN
The aim of this study was to establish normal ophthalmic parameters for select diagnostic tests in American white pelicans (Pelecanuserythrorhynchos). Twenty-one zoo-housed American white pelicans were manually restrained for noninvasive ocular diagnostic testing and complete ophthalmic examination. Tear production quantification using the phenol red thread test (PRTT), fluorescein staining, and intraocular pressure (IOP) evaluation were performed. In addition, conjunctival aerobic bacterial culture and culture-independent 16S rRNA amplicon sequencing were performed on select eyes. Normal variations and ocular abnormalities detected during complete ophthalmic examination were documented and photographed. Direct pupillary light reflex, menace response, and palpebral reflex were present in all birds. The value (mean ± SD) for PRRT and IOP was 14.9 ± 7.84 mm/15 sec and 9.0 ± 1.41 mm Hg oculus uterque, respectively. Conjunctival culture in nine birds revealed no growth for six birds and Staphylococcus aureus growth in three birds. A high relative abundance of Mycoplasma sp. was detected in all samples based on 16S rRNA sequencing. The normal pelican eye was found to have relative conjunctival hyperemia, absent filoplumes, iris color ranging from light blue to brown, and a subcircular vertically elongated pupil. Ophthalmic abnormalities were noted in 10 of 21 birds. Common findings included corneal fibrosis, cataracts, and asteroid hyalosis. The most common ophthalmic abnormality in this species was cataracts.
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Enfermedades de las Aves/diagnóstico , Aves/fisiología , Anomalías del Ojo/veterinaria , Presión Intraocular/fisiología , Tonometría Ocular/veterinaria , Animales , Animales de Zoológico , Conjuntiva/microbiología , Anomalías del Ojo/diagnóstico , Femenino , MasculinoRESUMEN
African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.
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Atrofia/veterinaria , Proteínas de Unión a Calmodulina/genética , Enfermedades de los Gatos/genética , Enfermedades de la Retina/veterinaria , Animales , Atrofia/genética , Atrofia/patología , Enfermedades de los Gatos/patología , Gatos , Homocigoto , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Secuenciación Completa del GenomaRESUMEN
The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.
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Aminopeptidasas/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Terapia de Reemplazo Enzimático/métodos , Terapia Genética/métodos , Lipofuscinosis Ceroideas Neuronales/complicaciones , Degeneración Retiniana/prevención & control , Serina Proteasas/metabolismo , Trasplante de Células Madre/métodos , Células Madre/citología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Electrorretinografía , Inyecciones Intravítreas , Lipofuscinosis Ceroideas Neuronales/terapia , Degeneración Retiniana/etiología , Células Madre/enzimología , Tripeptidil Peptidasa 1RESUMEN
CLN2 disease is one of a group of lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs). The disease results from mutations in the TPP1 gene that cause an insufficiency or complete lack of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). TPP1 is involved in lysosomal protein degradation, and lack of this enzyme results in the accumulation of protein-rich autofluorescent lysosomal storage bodies in numerous cell types including neurons throughout the central nervous system and the retina. CLN2 disease is characterized primarily by progressive loss of neurological functions and vision as well as generalized neurodegeneration and retinal degeneration. In children the progressive loss of neurological functions typically results in death by the early teenage years. A Dachshund model of CLN2 disease with a null mutation in TPP1 closely recapitulates the human disorder with a progression from disease onset at approximately 4 months of age to end-stage at 10-11 months. Delivery of functional TPP1 to the cerebrospinal fluid (CSF), either by periodic infusion of the recombinant protein or by a single administration of a TPP1 gene therapy vector to the CSF, significantly delays the onset and progression of neurological signs and prolongs life span but does not prevent the loss of vision or modest retinal degeneration that occurs by 11 months of age. In this study we found that in dogs that received the CSF gene therapy treatment, the degeneration of the retina and loss of retinal function continued to progress during the prolonged life spans of the treated dogs. Eventually the normal cell layers of the retina almost completely disappeared. An exception was the ganglion cell layer. In affected dogs that received TPP1 gene therapy to the CSF and survived an average of 80 weeks, ganglion cell axons were present in numbers comparable to those of normal Dachshunds of similar age. The selective preservation of the retinal ganglion cells suggests that while TPP1 protein delivered via the CSF may protect these cells, preservation of the remainder of the retina will require delivery of normal TPP1 more directly to the retina, probably via the vitreous body.
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Aminopeptidasas/uso terapéutico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/uso terapéutico , Terapia Genética/métodos , Lipofuscinosis Ceroideas Neuronales/terapia , Degeneración Retiniana/terapia , Células Ganglionares de la Retina/patología , Serina Proteasas/uso terapéutico , Aminopeptidasas/administración & dosificación , Aminopeptidasas/genética , Análisis de Varianza , Animales , Axones/patología , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/administración & dosificación , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Electrorretinografía , Vectores Genéticos/líquido cefalorraquídeo , Infusiones Intraventriculares , Nervio Óptico/citología , Reflejo Pupilar/fisiología , Degeneración Retiniana/etiología , Degeneración Retiniana/fisiopatología , Serina Proteasas/administración & dosificación , Serina Proteasas/genética , Tripeptidil Peptidasa 1RESUMEN
The CLN2 form of neuronal ceroid lipofuscinosis is an autosomal recessively inherited lysosomal storage disease that is characterized by progressive vision loss culminating in blindness, cognitive and motor decline, neurodegeneration, and premature death. CLN2 disease results from mutations in the gene that encodes the soluble lysosomal enzyme tripeptidyl peptidase-1. A null mutation in the TPP1 gene encoding this enzyme causes a CLN2-like disease in Dachshunds. Dachshunds that are homozygous for this mutation serve as a model for human CLN2 disease, exhibiting clinical signs and neuropathology similar to those of children with this disorder. Affected dogs reach end-stage terminal disease status at 10-11 months of age. In addition to retinal changes typical of CLN2 disease, a retinopathy consisting of multifocal, bullous retinal detachment lesions was identified in 65% of (TPP1-/-) dogs in an established research colony. These lesions did not occur in littermates that were heterozygous or homozygous for the normal TPP1 allele. Retinal changes and the functional effects of this multifocal retinopathy were examined objectively over time using ophthalmic examinations, fundus photography, electroretinography (ERG), quantitative pupillary light response (PLR) recording, fluorescein angiography, optical coherence tomography (OCT) and histopathology. The retinopathy consisted of progressive multifocal serous retinal detachments. The severity of the disease-related retinal thinning was no more serious in most detached areas than in adjacent areas of the retina that remained in close apposition to the retinal pigment epithelium. The retinopathy observed in these dogs was somewhat similar to canine multifocal retinopathy (CMR), a disease caused by a mutation of the bestrophin gene BEST1. ERG a-wave amplitudes were relatively preserved in the Dachshunds with CLN2 disease, whether or not they developed the multifocal retinopathy. The retinopathy also had minimal effects on the PLR. Histological evaluation indicated that the CLN2 disease-related retinal degeneration was not exacerbated in areas where the retina was detached except where the detached areas were very large. DNA sequence analysis ruled out a mutation in the BEST1 exons or splice junctions as a cause for the retinopathy. Perfect concordance between the TPP1 mutation and the retinopathy in the large number of dogs examined indicates that the retinopathy most likely occurs as a direct result of the TPP1 mutation. Therefore, inhibition of the development and progression of these lesions can be used as an indicator of the efficacy of therapeutic interventions currently under investigation for the treatment of CLN2 disease in the Dachshund model. In addition, these findings suggest that TPP1 mutations may underlie multifocal retinopathies of unknown cause in animals and humans.
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Aminopeptidasas/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Retina/patología , Desprendimiento de Retina/genética , Serina Proteasas/genética , Aminopeptidasas/uso terapéutico , Animales , Canales de Cloruro/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/uso terapéutico , Modelos Animales de Enfermedad , Perros , Electrorretinografía , Terapia de Reemplazo Enzimático , Femenino , Angiografía con Fluoresceína , Técnicas de Inactivación de Genes , Masculino , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Reflejo Pupilar/fisiología , Desprendimiento de Retina/tratamiento farmacológico , Desprendimiento de Retina/fisiopatología , Serina Proteasas/uso terapéutico , Tomografía de Coherencia Óptica , Tripeptidil Peptidasa 1RESUMEN
A 10-mo-old female red kangaroo (Macropus rufus) presented with a unilateral congenital corneal opacity OD. Complete ophthalmic examination revealed a shallow anterior chamber and a focal area of corneal edema with multiple persistent pupillary membranes extending from the iris colarette to the corneal endothelium adjacent to the edematous area of cornea. High-resolution B-scan ultrasound of the anterior segment showed an area consistent with thinning of Descemet's membrane in the area of corneal edema. Ophthalmic examination and ultrasound findings are consistent with a diagnosis of Peters anomaly, a form of anterior segment dysgenesis. An electroretinogram performed on the affected animal did not reveal any specific abnormalities. Karyotype analyses revealed a normal diploid number (2n = 20, -XX), with an abnormal pericentric inversion in the second largest chromosomal pair. The kangaroo exhibits mild compensated vision deficits in the affected eye. The maternal and paternal adult pairing has been discontinued in an effort to prevent future offspring anomalies.
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Segmento Anterior del Ojo/anomalías , Opacidad de la Córnea/veterinaria , Anomalías del Ojo/veterinaria , Macropodidae , Animales , Segmento Anterior del Ojo/patología , Opacidad de la Córnea/diagnóstico , Opacidad de la Córnea/patología , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/patología , Femenino , CariotipoRESUMEN
Five related Boer goat kids (≤4 months of age) were presented to the University of Missouri, Veterinary Teaching Hospital (MU-VMTH) with epiphora and blepharospasm of several weeks duration and commencing prior to 1 month of age in all animals. Clinical examination confirmed euryblepharon and entropion bilaterally in two females and one male and unilaterally in two female kids. Deep stromal corneal ulceration was present in two eyes, and corneal granulation tissue and fibrosis were present in half (5/10) the affected eyes. A combination Hotz-Celsus and lateral eyelid wedge resection procedure was performed on all affected eyelids. Recheck examinations and long-term follow-up confirmed resolution of the entropion, preservation of normal eyelid conformation, and restoration of ocular comfort. Pedigree analysis ruled out sex-linked and autosomal dominant inheritance patterns; a specific mode of inheritance could not be determined. The Boer goat breed may be at increased risk for the development of entropion. This cases series represents the first report of entropion in the caprine species.
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Entropión/veterinaria , Enfermedades de las Cabras/congénito , Procedimientos Quirúrgicos Oftalmológicos/veterinaria , Animales , Entropión/congénito , Entropión/cirugía , Femenino , Predisposición Genética a la Enfermedad , Enfermedades de las Cabras/genética , Enfermedades de las Cabras/cirugía , Cabras , Masculino , Procedimientos Quirúrgicos Oftalmológicos/métodos , LinajeRESUMEN
OBJECTIVE: (i) To report the successful treatment of 10 cases of equine periocular squamous cell carcinoma (PSCC) with surgical excision and photodynamic therapy (PDT) using verteporfin. (ii) To evaluate time to first tumor recurrence between PDT-treated horses and horses treated with surgical excision and cryotherapy. METHODS: A total of 24 equine PSCC cases were included: group 1 (n = 14) had excision and cryotherapy (19932003), group 2 (n = 10), excision and local PDT (20062010). Evaluated data: signalment, treatment method, tumor location, size, and time to first recurrence. Groups were compared via chi-square test for categorical variables and Wilcoxon rank-sum test for numeric variables. Time to tumor recurrence was examined using KaplanMeier product-limit survival analysis. RESULTS: Of 24 cases, nine breeds were affected. Mean age at treatment in years: 14 (range 524) in group 1; 11 (range 818) in group 2. Median tumor size: 163 mm2 (range 20625 mm2) in group 1; 195 mm2 (range 45775 mm2) in group 2. Signalment, tumor laterality, and size were not significantly different between groups. Time to recurrence was significantly different between groups (Logrank test, P = 0.0006). In group 1, 11/14 horses had tumor regrowth with median time to recurrence in months: 10 (range 144). In group 2 (minimum follow-up of 25 months; range 2550), no horse demonstrated tumor recurrence after one treatment with excision and PDT. CONCLUSIONS: This represents the first report of local PDT using verteporfin for treatment of equine PSCC. Following surgery, the likelihood of tumor recurrence was significantly reduced with local PDT compared with cryotherapy.
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Carcinoma de Células Escamosas/veterinaria , Criocirugía/veterinaria , Neoplasias del Ojo/veterinaria , Enfermedades de los Caballos/terapia , Fotoquimioterapia/veterinaria , Animales , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/cirugía , Criocirugía/métodos , Neoplasias del Ojo/tratamiento farmacológico , Neoplasias del Ojo/cirugía , Femenino , Caballos , Estimación de Kaplan-Meier , Masculino , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/veterinaria , Fotoquimioterapia/métodos , Porfirinas/uso terapéutico , VerteporfinaRESUMEN
Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TPP1-/- Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG.
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Aminopeptidasas/uso terapéutico , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/uso terapéutico , Terapia de Reemplazo Enzimático , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Reflejo Pupilar/efectos de los fármacos , Serina Proteasas/uso terapéutico , Aminopeptidasas/deficiencia , Análisis de Varianza , Animales , Axones , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/deficiencia , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Electrorretinografía/efectos de los fármacos , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Nervio Óptico/citología , Proteínas Recombinantes/uso terapéutico , Serina Proteasas/deficiencia , Tripeptidil Peptidasa 1RESUMEN
OBJECTIVE: To investigate long-term outcomes and owner-perceived quality of life associated with sudden acquired retinal degeneration syndrome (SARDS) in dogs. DESIGN: Survey study. ANIMALS: 100 dogs with SARDS examined at 5 academic veterinary institutions from 2005 to 2010. PROCEDURES: The diagnosis was based on documented acute vision loss, normal results of ophthalmic examinations, and evaluation of extinguished bright-flash electroretinograms. Primary owners of affected dogs completed a questionnaire addressing outcome measures including vision, systemic signs, and perceived quality of life for their dogs. RESULTS: Age at diagnosis was significantly correlated with positive outcome measures; dogs in which SARDS was diagnosed at a younger age were more likely to have alleged partial vision and higher owner-perceived quality of life. Polyphagia was the only associated systemic sign found to increase in severity over time. Medical treatment was attempted in 22% of dogs; visual improvement was not detected in any. Thirty-seven percent of respondents reported an improved relationship with their dog after diagnosis, and 95% indicated they would discourage euthanasia of dogs with SARDS. CONCLUSIONS AND CLINICAL RELEVANCE: Blindness and concurrent systemic signs associated with SARDS appeared to persist indefinitely, but only polyphagia increased in severity over time. Most owners believed their pets had good quality of life and would discourage euthanasia of dogs with SARDS.
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Ceguera/veterinaria , Enfermedades de los Perros/patología , Degeneración Retiniana/veterinaria , Enfermedad Aguda , Animales , Recolección de Datos , Perros , Femenino , Masculino , Oportunidad Relativa , Calidad de Vida , Degeneración Retiniana/patología , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Late-infantile neuronal ceroid lipofuscinosis (CLN2) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. The progressive loss of neurological functions eventually leads to death, usually by the early teenage years. Utilizing a canine model of CLN2, therapeutic studies to inhibit the brain and retinal degenerations are currently under way. Using this dog model, studies were undertaken to compare quantitative assessments of the pupillary light reflex (PLR) and electroretinography (ERG) as tools for evaluating the effects of the disease on retinal function. The PLR and ERG were recorded in normal and CLN2-affected Dachshunds at 2 month intervals between the ages of 4 and 10 months. Using custom instrumentation for quantitative PLR assessments, a series of white light stimuli of varying intensity was used to elicit pupil constriction, and pupil images were recorded using continuous infrared illumination and an infrared-sensitive camera. Electroretinography was used to evaluate retinal function in the same dogs. As the disease progressed, affected dogs exhibited progressive and profound declines in ERG amplitudes under both scotopic and photopic conditions. With low intensity light stimuli, CLN2 was also accompanied by progressive deficits in the PLR. Changes in the PLR to dim light stimuli included significant deficits in latency, constriction velocity, constriction amplitude, and redilation velocity. However, despite the almost complete loss of detectable ERG responses by disease end stage, the PLR to bright stimuli was well preserved throughout the disease progression. These findings demonstrate that the PLR is much more sensitive than the ERG in detecting residual retinal function in animal models of retinal degenerative disease. The preservation of the PLR in dogs with profoundly depressed ERGs correlates with a preservation of visually-mediated behavior even late in the disease progression. Quantitative analysis of the PLR has potential as a biomarker in animal models of retinal degenerative diseases and in evaluating the efficacy of therapeutic interventions in preserving retinal function.
Asunto(s)
Electrorretinografía , Luz , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Reflejo Pupilar/efectos de la radiación , Retina/fisiopatología , Animales , Modelos Animales de Enfermedad , Perros , Estimulación Luminosa/métodosRESUMEN
A litter of recently-vaccinated puppies in Sweden experienced signs of severe haemorrhagic gastroenteritis. Canine parvovirus (CPV) was suspected as the cause of this outbreak on the basis of the clinical signs and the presence of parvoviral antigen in the faeces from one of the affected pups - confirmed using a commercial in-clinic faecal antigen ELISA test kit. A concern was raised about whether the vaccine (which contained a live, attenuated strain of CPV) could have caused the disease and so further faecal samples from the affected pups were submitted for laboratory virus isolation and identification.On cell culture, two out of four faecal samples were found to be virus-positive. This was confirmed as being canine parvovirus by immuno-staining with CPV specific monoclonal antibody. The virus was then tested using a series of PCR probes designed to confirm the identity of CPV and to distinguish the unique vaccine strain from field virus. This confirmed that the virus was indeed CPV but that it was not vaccine strain. The virus was then typed by sequencing the 426 amino acid region of the capsid gene which revealed this to be a type 2c virus.Since its emergence in the late 1970s, canine parvovirus 2 (CPV2) has spread worldwide and is recognised as an important canine pathogen in all countries. The original CPV2 rapidly evolved into two antigenic variants, CPV2a and CPV2b, which progressively replaced the original CPV2. More recently a new antigenic variant, CPV2c, has appeared. To date this variant has been identified in many countries worldwide but there have been no reports yet of its presence in any Scandinavian countries. This case report therefore represents the first published evidence of the involvement of CPV2c in a severe outbreak of typical haemorrhagic gastroenteritis in a susceptible litter of pups in Scandinavia.
Asunto(s)
Brotes de Enfermedades/veterinaria , Gastroenteritis/veterinaria , Infecciones por Parvoviridae/veterinaria , Parvovirus Canino/clasificación , Animales , Perros , Gastroenteritis/epidemiología , Gastroenteritis/virología , Infecciones por Parvoviridae/epidemiología , Infecciones por Parvoviridae/virología , Parvovirus Canino/aislamiento & purificación , Suecia/epidemiologíaRESUMEN
PURPOSE: To develop instrumentation and methods for thorough quantitative assessment of the pupillary light reflex (PLR) in dogs under varying stimulus conditions. METHODS: The PLR was recorded in normal Dachshunds using a custom system allowing full user control over stimulus intensity, color, and duration. Chemical restraint protocols were compared to determine which protocol provided for optimal baseline stability of pupil size and appropriate eye positioning. A series of white light stimuli of increasing intensity was used to elicit pupil constriction. Pupil images were concurrently recorded using continuous infrared illumination and an infrared-sensitive camera. The PLR was also recorded in response to blue and red stimuli. RESULTS: With injectable chemical restraint alone, spontaneous fluctuations in pupil size occurred independent of light stimulation, and spontaneous eye movements made it difficult to fully visualize the pupil. Combined injectable chemical and inhalation restraint provided a steady baseline pupil size throughout PLR assessment and allowed for stable positioning of the eye using a conjunctival stay suture. Robust PLRs were elicited with all light colors. PLR constriction amplitude increased with increasing flash intensity and ranged from 5% to 70%. CONCLUSIONS: A recording system and protocol have been developed to reliably quantify the canine PLR. The techniques and instrumentation will be useful for objective quantitative assessment of the PLR in dogs and other species in research applications and may be useful in clinical veterinary ophthalmology and neurology if PLR abnormalities detected with these procedures can be associated with specific diseases.
Asunto(s)
Pupila/fisiología , Reflejo Pupilar/fisiología , Animales , Perros , Electrorretinografía , Movimientos Oculares/fisiología , Estimulación Luminosa , Opsinas de Bastones/metabolismoRESUMEN
A 27 kg, 6-year-old, male castrated German shorthaired pointer presented to the University of Missouri, Veterinary Teaching Hospital with the complaint of progressive exophthalmia of 2 years duration optical density (OD). Lack of retropulsion OD was noted on physical examination. Anterior segment examination OU and fundic examination OS did not reveal any abnormalities. Examination of the fundus OD revealed focal scleral indentation of the inferior nasal globe. The indentation changed location with globe movement OD. MRI and CT scan revealed a well-circumscribed, approximately 2 cm in diameter mass located caudal and ventral to the affected globe that appeared to communicate with the nictitating membrane with absence of any bony involvement. A modified lateral orbitotomy was recommended and performed to remove the orbital mass and nictitating membrane en-bloc. Histopathology and immunohistochemistry of the mass confirmed a diagnosis of nodular granulomatous episcleritis (NGE). Postoperatively, the dog developed absolute keratoconjunctivitis sicca (KCS). Examples of primary episcleral inflammation in the dog include diffuse episcleritis, NGE, nodular fasciitis, fibrous histiocytoma, proliferative conjunctivitis/keratoconjunctivitis, pseudotumor, and Collie granuloma. The etiology of these episcleral inflammations is presumed to be immune mediated. To our knowledge, this is the first report of NGE affecting the orbital region of a dog. Development of absolute KCS resulting from excision of the nictitating membrane is also supported by this case.