Distributed brain co-processor for tracking spikes, seizures and behaviour during electrical brain stimulation.

Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioural inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behaviour and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a handheld device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from nine humans and eight canines with epilepsy, and then implemented prospectively in out-of-sample testing in two pet canines and four humans with drug-resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain-stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures and correlation with patient behavioural reports. In the future, correlation of spikes and seizures with behaviour will allow more detailed investigation of the clinical impact of spikes and seizures on patients.

Thalamic deep brain stimulation modulates cycles of seizure risk in epilepsy.

Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and multiday cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and multiday IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and multiday (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.

Ethylene vinyl alcohol copolymer to treat an intracranial arteriovenous malformation in a dog.

A 6-year-old neutered male German shepherd dog was evaluated for obtundation, blindness, and bilateral exophthalmos. A magnetic resonance imaging scan of the brain was performed and identified an arteriovenous malformation (AVM) with several feeding arterial branches, and venous drainage through the cavernous sinus. Venous vessels rostral to the AVM were severely distended and extended into the retrobulbar spaces. Liquid embolization by injection of ethylene vinyl alcohol copolymer was performed from access points in the maxillary arteries and internal carotid arteries. No intraprocedural complications were encountered, and the dog was discharged the next day. Bilateral enucleation eventually was performed because of exposure keratopathy. At 31 months post-embolization, owners reported that the dog was doing very well clinically with high activity level and normal appetite, and the dog also appeared to be pain free. Although intracranial AVMs are very rare in companion animals, successful treatment using liquid embolization is possible and should be considered.

Semi-supervised Training Data Selection Improves Seizure Forecasting in Canines with Epilepsy.

OBJECTIVE: Conventional selection of pre-ictal EEG epochs for seizure prediction algorithm training data typically assumes a continuous pre-ictal brain state preceding a seizure. This is carried out by defining a fixed duration, pre-ictal time period before seizures from which pre-ictal training data epochs are uniformly sampled. However, stochastic physiological and pathological fluctuations in EEG data characteristics and underlying brain states suggest that pre-ictal state dynamics may be more complex, and selection of pre-ictal training data segments to reflect this could improve algorithm performance. METHODS: We propose a semi-supervised technique to select pre-ictal training data most distinguishable from interictal EEG according to pre-specified data characteristics. The proposed method uses hierarchical clustering to identify optimal pre-ictal data epochs. RESULTS: In this paper we compare the performance of a seizure forecasting algorithm with and without hierarchical clustering of pre-ictal periods in chronic iEEG recordings from six canines with naturally occurring epilepsy. Hierarchical clustering of training data improved results for Time In Warning (TIW) (0.18 vs. 0.23) and False Positive Rate (FPR) (0.5 vs. 0.59) when evaluated across all subjects (p<0.001, n=6). Results were mixed when evaluating TIW, FPR, and Sensitivity for individual dogs. CONCLUSION: Hierarchical clustering is a helpful method for training data selection overall, but should be evaluated on a subject-wise basis. SIGNIFICANCE: The clustering method can be used to optimize results of forecasting towards sensitivity or TIW or FPR, and therefore can be useful for epilepsy management.

Diagnosis and clinical outcome following surgical resection of an intracranial grade III anaplastic gemistocytic astrocytoma in a cat.

CASE SUMMARY: A 10-year-old Maine Coon cat was presented for acute onset seizures and cerebrothalamic signs. An intracranial mass, suspected to be a meningioma, was diagnosed on MRI and surgically excised. Histopathology appeared consistent with an atypical meningioma. However, following rapid regrowth of the neoplasm, the patient was humanely euthanized 3 months later. On post-mortem histopathology, the neoplasm was diagnosed as a grade III anaplastic gemistocytic astrocytoma. RELEVANCE AND NOVEL INFORMATION: Gemistocytic astrocytomas are rare brain tumors in the feline patient. This case represents the first report of a feline grade III anaplastic gemistocytic astrocytoma in the cerebrum of a cat with surgical excision and recurrence. The challenging nature of ante-mortem diagnosis and the guarded prognosis, despite surgical intervention, are presented in this report.

Circadian and multiday seizure periodicities, and seizure clusters in canine epilepsy.

Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.

Clinicopathological characteristics of histiocytic sarcoma affecting the central nervous system in dogs.

BACKGROUND: Histiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic. OBJECTIVE: To characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS. ANIMALS: One hundred two dogs with HS, 62 dogs with meningioma. METHODS: Retrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data. RESULTS: Predisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P <.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P < .001), but overall prognosis was poor. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

Nanomedicine for Spontaneous Brain Tumors: A Companion Clinical Trial.

Nanoparticles' enhanced permeation and retention (EPR) variations due to tumor heterogeneity in naturally occurring brain tumors are commonly neglected in preclinical nanomedicine studies. Recent pathological studies have shown striking similarities between brain tumors in humans and dogs, indicating that canine brain tumors may be a valuable model to evaluate nanoparticles' EPR in this context. We recruited canine clinical cases with spontaneous brain tumors to investigate nanoparticles' EPR in different brain tumor pathologies using surface-enhanced Raman spectroscopy (SERS). We used gold nanoparticles due to their surface plasmon effect that enables their sensitive and microscopic resolution detection using the SERS technique. Raman microscopy of the resected tumors showed heterogeneous EPR of nanoparticles into oligodendrogliomas and meningiomas of different grades, without any detectable traces in necrotic parts of the tumors or normal brain. Raman observations were confirmed by scanning electron microscopy (SEM) and X-ray elemental analyses, which enabled localization of individual nanoparticles embedded in tumor tissues. Our results demonstrate nanoparticles' EPR and its variations in clinically relevant, spontaneous brain tumors. Such heterogeneities should be considered alongside routine preoperative imaging and histopathological analyses in order to accelerate clinical management of brain tumors using nanomedicine approaches.

Intracranial pressure monitoring in normal dogs using subdural and intraparenchymal miniature strain-gauge transducers.

BACKGROUND: Monitoring of intracranial pressure (ICP) is a critical component in the management of intracranial hypertension. Safety, efficacy, and optimal location of microsensor devices have not been defined in dogs. HYPOTHESIS/OBJECTIVE: Assessment of ICP using a microsensor transducer is feasible in anesthetized and conscious animals and is independent of transducer location. Intraparenchymal transducer placement is associated with more adverse effects. ANIMALS: Seven adult, bred-for-research dogs. METHODS: In a prospective investigational study, microsensor ICP transducers were inserted into subdural and intraparenchymal locations at defined rostral or caudal locations within the rostrotentorial compartment under general anesthesia. Mean arterial pressure and ICP were measured continuously during physiological maneuvers, and for 20 hours after anesthesia. RESULTS: Baseline mean ± SD values for ICP and cerebral perfusion pressure were 7.2 ± 2.3 and 78.9 ± 7.6 mm Hg, respectively. Catheter position did not have a significant effect on ICP measurements. There was significant variation from baseline ICP accompanying physiological maneuvers (P < .001) and with normal activities, especially with changes in head position (P < .001). Pathological sequelae were more evident after intraparenchymal versus subdural placement. CONCLUSIONS AND CLINICAL IMPORTANCE: Use of a microsensor ICP transducer was technically straightforward and provided ICP measurements within previously reported reference ranges. Results support the use of an accessible dorsal location and subdural positioning. Transient fluctuations in ICP are normal events in conscious dogs and large variations associated with head position should be accounted for when evaluating animals with intracranial hypertension.

Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds.

Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.

Integrating Brain Implants With Local and Distributed Computing Devices: A Next Generation Epilepsy Management System.

Brain stimulation has emerged as an effective treatment for a wide range of neurological and psychiatric diseases. Parkinson's disease, epilepsy, and essential tremor have FDA indications for electrical brain stimulation using intracranially implanted electrodes. Interfacing implantable brain devices with local and cloud computing resources have the potential to improve electrical stimulation efficacy, disease tracking, and management. Epilepsy, in particular, is a neurological disease that might benefit from the integration of brain implants with off-the-body computing for tracking disease and therapy. Recent clinical trials have demonstrated seizure forecasting, seizure detection, and therapeutic electrical stimulation in patients with drug-resistant focal epilepsy. In this paper, we describe a next-generation epilepsy management system that integrates local handheld and cloud-computing resources wirelessly coupled to an implanted device with embedded payloads (sensors, intracranial EEG telemetry, electrical stimulation, classifiers, and control policy implementation). The handheld device and cloud computing resources can provide a seamless interface between patients and physicians, and realtime intracranial EEG can be used to classify brain state (wake/sleep, preseizure, and seizure), implement control policies for electrical stimulation, and track patient health. This system creates a flexible platform in which low demand analytics requiring fast response times are embedded in the implanted device and more complex algorithms are implemented in offthebody local and distributed cloud computing environments. The system enables tracking and management of epileptic neural networks operating over time scales ranging from milliseconds to months.

FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs.

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. Independent genome-wide association analyses for skeletal dysplasia (short limbs) within a single breed (PBonferroni = 0.01) and intervertebral disc disease (IVDD) across breeds (PBonferroni = 4.0 × 10-10) both identified a significant association to the same region on CFA12. Whole genome sequencing identified a highly expressed FGF4 retrogene within this shared region. The FGF4 retrogene segregated with limb length and had an odds ratio of 51.23 (95% CI = 46.69, 56.20) for IVDD. Long bone length in dogs is a unique example of multiple disease-causing retrocopies of the same parental gene in a mammalian species. FGF signaling abnormalities have been associated with skeletal dysplasia in humans, and our findings present opportunities for both selective elimination of a medically and financially devastating disease in dogs and further understanding of the ever-growing complexity of retrogene biology.

Biomechanical Comparison of Locking Compression Plate versus Positive Profile Pins and Polymethylmethacrylate for Stabilization of the Canine Lumbar Vertebrae.

OBJECTIVE: To compare the stiffness, angular deformation, and mode of failure of lumbar vertebral column constructs stabilized with bilateral pins and polymethylmethacrylate (Pin-PMMA) or with a unilateral (left) locking compression plate (LCP) with monocortical screws. STUDY DESIGN: Ex vivo biomechanical, non-randomized. SAMPLES: Cadaveric canine thoracolumbar specimens (n=16). METHODS: Thoracolumbar (T13-L3) vertebral specimens had the L1-L2 vertebral motion unit stabilized with either Pin-PMMA or LCP. Stiffness in flexion, extension, and right and left lateral bending after nondestructive testing were compared between intact (pretreated) specimens and Pin-PMMA, and LCP constructs. The Pin-PMMA and LCP constructs were then tested to failure in flexion and left lateral bending. RESULTS: Both the Pin-PMMA and LCP constructs had reduced range of motion at the stabilized L1-L2 vertebral motion unit compared to intact specimens. The Pin-PMMA constructs had less range of motion for the flexion elastic zone than LCP constructs. The Pin-PMMA constructs were stiffer than intact specimens in flexion, extension, and lateral bending, and stiffer than LCP constructs in flexion and left lateral bending. The Pin-PMMA constructs had less angular deformation at construct yield and lower residual deformation at L1-L2 than LCP constructs after destructive testing to failure in flexion. The Pin-PMMA constructs were stiffer, stronger, and had less deformation at yield than LCP constructs after destructive testing to failure in lateral bending. Most constructs failed distant to the implant and fixation site. CONCLUSIONS: Pin-PMMA constructs had greater lumbar vertebral stiffness and reduced ROM than LCP constructs; however, both Pin-PMMA and LCP constructs were stronger than intact specimens.

Kinetic and kinematic gait analysis in the pelvic limbs of normal and post-hemilaminectomy Dachshunds.

OBJECTIVE: To compare pelvic limb kinetic and kinematic gait parameters between Dachshunds six months following hemilaminectomy for treatment of thoracolumbar disc extrusion (post-hemilaminectomy; PHL) and Dachshunds without history and clinical evidence of spinal cord disease (control; CON). METHODS: The CON (n = 8) and PHL (n = 6) Dachshunds were recruited for objective gait evaluation. Kinetic data collected included peak vertical force (PVF), stance phase duration and swing phase duration. Kinematic data collected included tarsal, stifle and hip range of motion (ROM) during stance and swing phases of the trot, tail ROM, and horizontal and vertical components of pelvis ROM. RESULTS: No significant differences were identified between tarsal, stifle, hip, and tail ROM between CON and PHL Dachshunds. Although PVF was not significantly different between CON and PHL Dachshunds, PVF varied on average by 14% between the pelvic limbs in PHL Dachshunds (p <0.01). Horizontal and vertical components of pelvic ROM were on average 51% and 36% greater in PHL Dachshunds compared to CON Dachshunds (p = 0.04 and p = 0.02 respectively). CLINICAL SIGNIFICANCE: Six months after decompressive hemilaminectomy, Dachshunds have abnormal pelvic motion and asymmetric pelvic limb weight bearing. Pelvic sway (ROM) may be a more sensitive indicator of myelopathy than pelvic limb joint ROM and may serve as a useful objective tool to characterize response to treatment in patients with spinal cord disease.

COLQ variant associated with Devon Rex and Sphynx feline hereditary myopathy.

Some Devon Rex and Sphynx cats have a variably progressive myopathy characterized by appendicular and axial muscle weakness, megaesophagus, pharyngeal weakness and fatigability with exercise. Muscle biopsies from affected cats demonstrated variable pathological changes ranging from dystrophic features to minimal abnormalities. Affected cats have exacerbation of weakness following anticholinesterase dosing, a clue that there is an underlying congenital myasthenic syndrome (CMS). A genome-wide association study and whole-genome sequencing suggested a causal variant for this entity was a c.1190G>A variant causing a cysteine to tyrosine substitution (p.Cys397Tyr) within the C-terminal domain of collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). Alpha-dystroglycan expression, which is associated with COLQ anchorage at the motor end-plate, has been shown to be deficient in affected cats. Eighteen affected cats were identified by genotyping, including cats from the original clinical descriptions in 1993 and subsequent publications. Eight Devon Rex and one Sphynx not associated with the study were identified as carriers, suggesting an allele frequency of ~2.0% in Devon Rex. Over 350 tested cats from other breeds did not have the variant. Characteristic clinical features and variant presence in all affected cats suggest a model for COLQ CMS. The association between the COLQ variant and this CMS affords clinicians the opportunity to confirm diagnosis via genetic testing and permits owners and breeders to identify carriers in the population. Moreover, accurate diagnosis increases available therapeutic options for affected cats based on an understanding of the pathophysiology and experience from human CMS associated with COLQ variants.

Feasibility Study of Canine Epidermal Neural Crest Stem Cell Transplantation in the Spinal Cords of Dogs.

UNLABELLED: This pilot feasibility study aimed to determine the outcome of canine epidermal neural crest stem cell (cEPI-NCSC) grafts in the normal spinal cords of healthy bred-for-research dogs. This included developing novel protocols for (a) the ex vivo expansion of cEPI-NCSCs, (b) the delivery of cEPI-NCSCs into the spinal cord, and (c) the labeling of the cells and subsequent tracing of the graft in the live animal by magnetic resonance imaging. A total of four million cEPI-NCSCs were injected into the spinal cord divided in two locations. Differences in locomotion at baseline and post-treatment were evaluated by gait analysis and compared with neurological outcome and behavioral exams. Histopathological analyses of the spinal cords and cEPI-NCSC grafts were performed at 3 weeks post-transplantation. Neurological and gait parameters were minimally affected by the stem cell injection. cEPI-NCSCs survived in the canine spinal cord for the entire period of investigation and did not migrate or proliferate. Subsets of cEPI-NCSCs expressed the neural crest stem cell marker Sox10. There was no detectable expression of markers for glial cells or neurons. The tissue reaction to the cell graft was predominantly vascular in addition to a degree of reactive astrogliosis and microglial activation. In the present study, we demonstrated that cEPI-NCSC grafts survive in the spinal cords of healthy dogs without major adverse effects. They persist locally in the normal spinal cord, may promote angiogenesis and tissue remodeling, and elicit a tissue response that may be beneficial in patients with spinal cord injury. SIGNIFICANCE: It has been established that mouse and human epidermal neural crest stem cells are somatic multipotent stem cells with proved innovative potential in a mouse model of spinal cord injury (SCI) offering promise of a valid treatment for SCI. Traumatic SCI is a common neurological problem in dogs with marked similarities, clinically and pathologically, to the syndrome in people. For this reason, dogs provide a readily accessible, clinically realistic, spontaneous model for evaluation of epidermal neural crest stem cells therapeutic intervention. The results of this study are expected to give the baseline data for a future clinical trial in dogs with traumatic SCI.

Stem cells in canine spinal cord injury--promise for regenerative therapy in a large animal model of human disease.

The use of cell transplantation for spinal cord injury is a rapidly evolving field in regenerative medicine. Numerous animal models are currently being used. However, translation to human patients is still a challenging step. Dogs are of increasing importance as a translational model for human disease since there is a greater awareness of the need to increase the quality of preclinical data. The use of dogs ultimately brings benefit to both human and veterinary medicine. In this review we analyze experimental and clinical studies using cell transplantation for canine spinal cord injury. Overall, in experimental studies, transplantation groups showed improvement over control groups. Improvements were measured at the functional, electrophysiological, histological, RNA and protein levels. Most clinical studies support beneficial effects of cell transplantation despite the fact that methodological limitations preclude definitive conclusions. However, the mechanisms of action and underlying the behavior of transplanted cells in the injured spinal cord remain unclear. Overall, we conclude here that stem cell interventions are a promising avenue for the treatment of spinal cord injury. Canines are a promising model that may help bridge the gap between translational research and human clinical trials.

Canine epidermal neural crest stem cells: characterization and potential as therapy candidate for a large animal model of spinal cord injury.

The discovery of multipotent neural crest-derived stem cells, named epidermal neural crest stem cells (EPI-NCSC), that persist postnatally in an easy-to-access location-the bulge of hair follicles-opens a spectrum of novel opportunities for patient-specific therapies. We present a detailed characterization of canine EPI-NCSC (cEPI-NCSC) from multiple dog breeds and protocols for their isolation and ex vivo expansion. Furthermore, we provide novel tools for research in canines, which currently are still scarce. In analogy to human and mouse EPI-NCSC, the neural crest origin of cEPI-NCSC is shown by their expression of the neural crest stem cell molecular signature and other neural crest-characteristic genes. Similar to human EPI-NCSC, cEPI-NCSC also expressed pluripotency genes. We demonstrated that cEPI-NCSC can generate all major neural crest derivatives. In vitro clonal analyses established multipotency and self-renewal ability of cEPI-NCSC, establishing cEPI-NCSC as multipotent somatic stem cells. A critical analysis of the literature on canine spinal cord injury (SCI) showed the need for novel treatments and suggested that cEPI-NCSC represent viable candidates for cell-based therapies in dog SCI, particularly for chondrodystrophic dogs. This notion is supported by the close ontological relationship between neural crest stem cells and spinal cord stem cells. Thus, cEPI-NCSC promise to offer not only a potential treatment for canines but also an attractive and realistic large animal model for human SCI. Taken together, we provide the groundwork for the development of a novel cell-based therapy for a condition with extremely poor prognosis and no available effective treatment.

Magnetic resonance imaging features of intracranial granular cell tumors in six dogs.

Magnetic resonance (MR) imaging characteristics of intracranial granular cell tumors (GCTs) have been previously reported in three dogs. The goal of this retrospective study was to examine a larger number of dogs and determine whether distinctive MR characteristics of intracranial GCTs could be identified. Six dogs with histologically confirmed intracranial GCTs and MR imaging were included. Tumor location, size, mass effect, T1- and T2-weighted signal intensity, and peritumoral edema MR characteristics were recorded. In all dogs, GCTs appeared as well-defined, extra-axial masses with a plaque-form, sessile distribution involving the meninges. All tumors were located along the convexity of the cerebrum, the falx cerebri, or the ventral floor of the cranial vault. All tumors were mildly hyperintense on T1-weighted images, and iso- to hyperintense on T2-weighted images. A moderate-to-severe degree of peritumoral edema and mass effect were evident in all dogs. Findings indicated that, while several MR imaging characteristics were consistently identified in canine cerebral GCTs, none of these characteristics were unique or distinctive for this tumor type alone.