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Novel therapies, including molecular targeted therapies, are being developed for the treatment of human gliomas. To use such therapies for canine gliomas, more complete characterization of molecular targets is required. Epidermal growth factor receptor (EGFR) is one such therapeutic target used in human glioma trials, and the Ki-67 labeling index (LI) is a marker of proliferation and a prognostic indicator. The objectives of this cross-sectional study were to evaluate the expression of EGFR and Ki-67 in canine gliomas and to determine if immunopositivity is associated with tumor type and histologic grade. Thirty-one formalin-fixed, paraffin-embedded canine gliomas were evaluated for EGFR and Ki-67 expression by immunohistochemistry. EGFR immunopositivity was evaluated using a semi-quantitative score and the Ki-67 LI calculated based on the percentage of positive cells. EGFR and Ki-67 expression were identified in 16 of 31 (52%) and 28 of 31 (90%) tumors, respectively. EGFR expression was significantly greater in high-grade tumors compared with low-grade tumors ( P = .04) and was significantly greater in gliomatosis cerebri compared with oligodendroglioma ( P = .002), astrocytoma ( P = .01), and oligoastrocytoma ( P = .04). The Ki-67 LI was significantly greater in high-grade tumors compared with low grade tumors ( P = .02); the median Ki-67 LI was 2.3% (range, 0%–17.6%) for low-grade tumors and 9.3% (range, 1.7%–41.0%) for high-grade tumors. A significant moderate correlation was identified between EGFR immunopositivity and Ki-67 LI ( r = 0.47, P = .007). Overall, EGFR may be a suitable therapeutic target for some canine gliomas, particularly gliomatosis cerebri.

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disorder prevalent in the canine population. It may represent a unique, naturally occurring disease model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs and association with superoxide dismutase 1 gene (SOD1) mutations. Misfolded SOD1 aggregates and endoplasmic reticulum (ER) stress are major pathophysiological features associated with ALS. Interestingly, an ER foldase, protein disulphide isomerase (PDI) is upregulated during ALS and it co-localizes with SOD1 inclusions in ALS patient tissues. Furthermore, mutations in the gene encoding PDI were recently associated with ALS. Given the genetic similarity between DM and ALS, we investigated whether ER stress and PDI were associated with DM. Protein extracts from spinal cord tissue of DM-affected dogs bearing a SOD1 mutation were examined for ER stress by western blotting. Immunohistochemical staining was also carried out to examine co-localization between endogenous PDI and SOD1 inclusions in spinal cord tissues of dogs affected with DM. PDI and CHOP, the proapoptotic protein induced during ER stress, were significantly upregulated in DM-affected dogs compared with controls. Furthermore, PDI co-localized with intracellular SOD1 aggregates in DM-affected dogs in all motor neurons examined, indicating that PDI may be a cellular defence mechanism against SOD1 misfolding in DM. Our results imply that ER stress is induced in DM-affected dogs; hence, it is a common pathological mechanism associated with both ALS and DM. The possibility that PDI may be a therapeutic target to inhibit SOD1 aggregation in DM dogs is also raised by this study.

Summary Mutation of the isocitrate dehydrogenase 1 (IDH1) gene at codon 132 has been identified in approximately 70% of low-grade (II and III) human gliomas and secondary glioblastomas, with the IDH1 R132H point mutation representing 92.7% of these mutations. In people, the presence of an IDH1 gene mutation is associated with a better prognosis (both progression-free survival time and overall survival time) and a better response to therapy, including chemotherapy and radiation therapy. Furthermore, IDH1 mutations are included in diagnostic panels to improve diagnosis and molecular classification. Canine gliomas resemble their human counterpart both morphologically and immunohistochemically, therefore they are likely to share similar genetic abnormalities. The IDH1 gene is also comparable between man and dogs. If the IDH1 R132H point mutation is demonstrated in canine gliomas, the prognostic significance of this mutation in people may be transferable to the dog. The objective of this study was to investigate canine gliomas for the IDH1 R132H point mutation using immunohistochemistry. Thirty-one formalin-fixed and paraffin wax-embedded canine gliomas were examined for both IDH1 R132H expression and pan-IDH1 (IDH1 wild-type and point mutated IDH1). Glial tumour specimens were recorded to be either positive or negative for expression. Pan-IDH1 expression was identified in all 31 tumours (100%), while the IDH1 R132H point mutation was identified in none of the tumours (0%). Therefore, the IDH1 R132H point mutation was not identified in this population of canine gliomas and may not be a suitable biomarker or treatment target in canine gliomas. Further investigation is required to determine if other point mutations occur in the IDH1 gene of canine gliomas.

Early postoperative neuroimaging has been performed in people for over 20 years to detect residual brain tumor tissue and surgical complications. The purpose of this retrospective study was to describe characteristics observed using early postoperative magnetic resonance imaging in a group of dogs undergoing craniotomy for brain tumor removal. Two independent observers came to a consensus opinion for presence/absence of the following MRI characteristics: residual tumor tissue; hemorrhage and ischemic lesions; abnormal enhancement (including the margins of the resection cavity, choroid plexus, meninges) and signal intensity changes on diffusion-weighted imaging. Five dogs were included in the study, having had preoperative and early postoperative MRI acquired within four days after surgery. The most commonly observed characteristics were abnormal meningeal enhancement, linear enhancement at margins of the resection cavity, hemorrhage, and a thin rim of hyperintensity surrounding the resection cavity on diffusion-weighted imaging. Residual tumor tissue was detected in one case of an enhancing tumor and in one case of a tumor containing areas of hemorrhage preoperatively. Residual tumor tissue was suspected but could not be confirmed when tumors were nonenhancing. Findings supported the use of early postoperative MRI as a method for detecting residual brain tumor tissue in dogs.

BACKGROUND: Acute polyradiculoneuritis (APN) is an immune-mediated peripheral nerve disorder in dogs that shares many similarities with Guillain-Barre syndrome (GBS) in humans, in which the bacterial pathogen Campylobacter spp. now is considered to be a major triggering agent. Little information is available concerning the relationship between APN and Campylobacter spp. in dogs. HYPOTHESIS/OBJECTIVES: To estimate the association between Campylobacter spp. infection and APN. Associations with additional potential risk factors also were investigated, particularly consumption of raw chicken. ANIMALS: Twenty-seven client-owned dogs suffering from suspected APN and 47 healthy dogs, client-owned or owned by staff members. METHODS: Case-control study with incidence density-based sampling. Fecal samples were collected from each enrolled animal to perform direct culture, DNA extraction, and polymerase chain reaction (PCR) for detection of Campylobacter spp. In some cases, species identification was performed by sequence analysis of the amplicon. Data were obtained from the medical records and owner questionnaires in both groups. RESULTS: In cases in which the fecal sample was collected within 7 days from onset of clinical signs, APN cases were 9.4 times more likely to be positive for Campylobacter spp compared to control dogs (P < 0.001). In addition, a significant association was detected between dogs affected by APN and the consumption of raw chicken (96% of APN cases; 26% of control dogs). The most common Campylobacter spp. identified was Campylobacter upsaliensis. CONCLUSIONS AND CLINICAL IMPORTANCE: Raw chicken consumption is a risk factor in dogs for the development of APN, which potentially is mediated by infection with Campylobacter spp.

Background Deep brain stimulation (DBS) together with concurrent EEG recording has shown promise in the treatment of epilepsy. A novel device is capable of combining these 2 functions and may prove valuable in the treatment of epilepsy in dogs. However, stereotactic implantation of electrodes in dogs has not yet been evaluated. Objective To evaluate the feasibility and safety of implanting stimulating and recording electrodes in the brain of normal dogs using the Brainsight system and to evaluate the function of a novel DBS and recording device. Animals Four male intact Greyhounds, confirmed to be normal by clinical and neurologic examinations and hematology and biochemistry testing. Methods MRI imaging of the brain was performed after attachment of fiducial markers. MRI scans were used to calculate trajectories for electrode placement in the thalamus and hippocampus, which was performed via burr hole craniotomy. Postoperative CT scanning was performed to evaluate electrode location and accuracy of placement was calculated. Serial neurologic examinations were performed to evaluate neurologic deficits and EEG recordings obtained to evaluate the effects of stimulation. Results Electrodes were successfully placed in 3 of 4 dogs with a mean accuracy of 4.6 ± 1.5 mm. EEG recordings showed evoked potentials in response to stimulation with a circadian variation in time-to-maximal amplitude. No neurologic deficits were seen in any dog. Conclusions and Clinical Importance Stereotactic placement of electrodes is safe and feasible in the dog. The development of a novel device capable of providing simultaneous neurostimulation and EEG recording potentially represents a major advance in the treatment of epilepsy.

OBJECTIVE To develop representative MRI atlases of the canine brain and to evaluate 3 methods of atlas-based segmentation (ABS). ANIMALS 62 dogs without clinical signs of epilepsy and without MRI evidence of structural brain disease. PROCEDURES The MRI scans from 44 dogs were used to develop 4 templates on the basis of brain shape (brachycephalic, mesaticephalic, dolichocephalic, and combined mesaticephalic and dolichocephalic). Atlas labels were generated by segmenting the brain, ventricular system, hippocampal formation, and caudate nuclei. The MRI scans from the remaining 18 dogs were used to evaluate 3 methods of ABS (manual brain extraction and application of a brain shape–specific template [A], automatic brain extraction and application of a brain shape–specific template [B], and manual brain extraction and application of a combined template [C]). The performance of each ABS method was compared by calculation of the Dice and Jaccard coefficients, with manual segmentation used as the gold standard. RESULTS Method A had the highest mean Jaccard coefficient and was the most accurate ABS method assessed. Measures of overlap for ABS methods that used manual brain extraction (A and C) ranged from 0.75 to 0.95 and compared favorably with repeated measures of overlap for manual extraction, which ranged from 0.88 to 0.97. CONCLUSIONS AND CLINICAL RELEVANCE Atlas-based segmentation was an accurate and repeatable method for segmentation of canine brain structures. It could be performed more rapidly than manual segmentation, which should allow the application of computer-assisted volumetry to large data sets and clinical cases and facilitate neuroimaging research and disease diagnosis.

Nonalcoholic steatohepatitis (NASH) is caused by an elevation in oxidative stress, which might further lead to hepatic fibrogenesis. Importantly, both peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) play roles in modulating oxidative stress-mediated hepatic dysfunction. The objective of this study was to investigate the mechanisms of the multifunctional effects of cyanidin on regulating antioxidant enzymes and oxidative stress-induced hepatotoxicity. The data indicated that cyanidin-mediated antioxidant enzyme expression involved the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways and Nrf2 activation. Furthermore, the synergistic effect of cyanidin and the PPAR agonist, troglitazone, on Nrf2-PPAR activation, was also observed. Besides, treatment of cyanidin and troglitazone abolished H₂O₂-induced downregulation of genes involved in lipid metabolism. In addition, H₂O₂-mediated cytotoxicity, which was caused by inducing ROS formation and apoptotic cell death, was also ameliorated upon cyanidin and troglitazone stimulation. In conclusion, mitogen-activated protein kinases (MAPKs) and the transcription factor Nrf2 played regulatory roles in cyanidin-mediated antioxidant enzyme activation. Furthermore, the combination of cyanidin and troglitazone activated PPARγ-Nrf2 and improved H₂O₂-mediated perturbation of genes involved in lipid metabolism. These data suggested that cyanidin and PPAR agonists might have synergistic benefits against metabolic dysfunction-related oxidative damage.

Recent attention has been given to the influence of dietary factors on health and mental well-being. Oxidative stress is associated with many diseases including neurodegenerative disorders. Dietary flavonoids exert cardioprotective, chemopreventive, and neuroprotective effects. The biological activities of flavonoids have been attributed to their antioxidant, anti-inflammatory, and signaling properties. A clear understanding of the mechanisms of action, as either antioxidants or signaling molecules, is crucial for the application of flavonoids as interventions in neurodegeneration and as brain foods. Citrus flavonoids exert little adverse effect and have low or no cytotoxicity to healthy, normal cells. The main citrus flavonoids can also traverse the blood-brain barrier; hence, they are promising candidates for intervention in neurodegeneration and as constituents in brain foods. In this review, we discuss the bioactivity, multiple neuroprotection mechanisms, and antioxidant and signaling properties of citrus flavonoids. Receptor-mediated neuroprotective actions and parallel signaling pathways are also explored. Finally, the induction of cellular defense proteins against oxidative stress and neurotoxicity by hesperetin, a main and widespread citrus flavonoid, are also discussed. It is suggested that citrus fruits, which are rich in abundant sources of hesperetin and other flavonoids, are promising for the development of general food-based neuroprotection and brain foods.

Hypoxic ischemic encephalopathy (HIE) is a condition that occurs in both human newborns and foals. The condition is the subject of extensive current research in human infants, but there have been no direct studies of HIE in foals, and hence, knowledge of the condition has been extrapolated from studies in humans and other animal models. The purpose of this review article is to highlight the most up-to-date and relevant research in the human field, and discuss how this potentially might have an impact in the management of foals with HIE.

Hesperetin is known to activate estrogen receptors (ERs). Estrogen-mediated neuroprotection could be via both ER and tyrosine kinase receptor (Trk) signaling. This study tested whether hesperetin protected PC12 cells from hydrogen peroxide induced oxidative damage via ER- and/or TrkA-mediated actions. Hesperetin (0.1, 1, and 50 μM) inhibited cell viability decreases and reactive oxygen species, intracellular calcium level, and caspase-3 activity increases in H(2)O(2)-induced PC12 cells. Such actions were significantly (p0.05) suppressed by ICI 182,780 (an ER antagonist) or K252a (a TrkA antagonist) at low concentrations (0.1 or 1 μM) only. Hesperetin also stimulated the activation of Akt, ERK, and CREB as well as induced brain-derived neurotrophic factor, PPARγ coactivator 1α (PGC-1α), and seladin-1 (selective Alzheimer's disease indicator-1) via both ER and TrkA in the cells. This study demonstrates that the neuroprotective effects of hesperetin, at low concentrations, are attributed to its stimulation on receptor signaling. Moreover, ER and TrkA are known to be expressed in most Alzheimer's disease (AD) vulnerable brain regions. This study thus suggests that hesperetin might have potential for intervention in neurodegenerative disorders, particularly for AD.

A case of granulomatous amoebic meningoencephalitis in a previously healthy, mature, apparently immunocompetent dog, with a history of exposure to stagnant water, is reported. The case presented with ataxia and a tendency to fall to the left side. A computed tomography (CT) showed a ring-enhancing lesion within the cerebellum; an examination of cerebrospinal fluid (CSF) revealed nonspecific mixed-cell pleocytosis. Despite antibiotic and anti-inflammatory therapy, clinical signs progressed rapidly to decerebellate rigidity over 4 days, and the dog was euthanased. Significant post-mortem findings were restricted to the brain, with a localised lytic lesion in the deep cerebellar white matter. Histopathological examination of the brain showed focally extensive cavitation of the white matter and communication of the lesion with the fourth ventricle. The affected area contained structures consistent with amoebae and was infiltrated by neutrophils mixed with lower numbers of macrophages, plasma cells and lymphocytes. The amoebae were identified as Balamuthia mandrillaris, based on specific immunofluorescence detection. Amoebic meningeoencephalitis should be considered in dogs with evidence of focal cavitary lesions in the brain, particularly in cases with a history of swimming in stagnant water.

Objective: To report surgical planning, technique, and outcome of stabilization surgery in an adult dog with occipitoatlantoaxial malformation (OAAM). Study Design: Clinical report. Animal: A 19-month-old, 25.5 kg, male castrated, Shiba Inu. Methods: Radiographic and magnetic resonance imaging were used to identify and characterize OAAM. Using a ventral approach to the cranial cervical region 2 cortical bone screws were inserted from the axis into the malformed atlas and occiput. Results: Ambulation was conserved postoperatively. Within 4 weeks, neurologic examination was mostly normal except for decreased proprioception in the right pelvic limb. At 9 months, the dog retained an extended neck posture, but had no neurologic abnormalities. Conclusion: OAAM should be considered as a differential diagnosis in an adult dog with cervical myelopathy. Surgical fixation with cortical bone screws using a ventral approach can be successful.

Objective—To determine incidence of and risk factors for postoperative pneumonia in dogs anesthetized for diagnosis or treatment of intervertebral disk disease (IVDD). Design—Retrospective case-control study. Animals—707 dogs that underwent general anesthesia for the diagnosis or treatment of IVDD between 1992 and 1996 or between 2002 and 2006. Procedures—Postoperative pneumonia was diagnosed if compatible clinical signs (cough or hypoxemia) and radiographic abnormalities (alveolar infiltrates) developed within 48 hours after anesthesia. To identify risk factors for postoperative pneumonia, findings for dogs that developed postoperative pneumonia between 2002 and 2006 were compared with findings for a randomly selected control group of unaffected dogs from the same population. Results—There were no significant differences in age, breed, body weight, sex, location of IVDD, or survival rate between the 2 time periods, but there were significant differences in the use of magnetic resonance imaging, computed tomography, and hemilaminectomy and in the percentage of dogs that developed postoperative pneumonia in the later (4.6%) versus the earlier (0.6%) years. Significant risk factors for postoperative pneumonia included preanesthetic tetraparesis, cervical lesions, undergoing magnetic resonance imaging, undergoing > 1 anesthetic procedure, longer duration of anesthesia, and postanesthetic vomiting or regurgitation. Conclusions and Clinical Relevance—Results suggested that at this institution, the incidence of postoperative pneumonia in dogs anesthetized for diagnosis or treatment of IVDD had increased in recent years.

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12917-015-0466-x) contains supplementary material, which is available to authorized users.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12917-015-0467-9) contains supplementary material, which is available to authorized users.

A 16-year-old female spayed English Staffordshire terrier was presented for evaluation of a 10-month history of intermittent myoclonic episodes, and a one weeks history of short episodes of altered mentation, ataxia and collapse. Magnetic resonance imaging identified subcortical oedema, predominately in the parietal and temporal lobes and multiple cerebral microbleeds. Serum biochemistry, indirect blood pressure measurements and magnetic resonance imaging abnormalities were consistent with hypertensive encephalopathy secondary to chronic kidney disease.

Background A retrospective study of the clinicopathological features of presumed and confirmed cases of idiopathic inflammatory polymyopathy in the Hungarian Vizsla dog and guidelines for breeding. Results 369 medical records were reviewed (1992–2013) and 77 Hungarian Vizslas were identified with a case history consistent with idiopathic inflammatory polymyopathy. Inclusion criteria were: group 1 (confirmed diagnosis); histopathology and clinical findings compatible with an inflammatory polymyopathy and group 2 (probable diagnosis); clinical findings compatible with a polymyopathy including dysphagia, sialorrhea, temporal muscle atrophy, elevated serum creatine kinase (CK) activity, and sufficient clinical history to suggest that other neuromuscular disorders could be ruled out. Some group 2 dogs had muscle biopsy, which suggested muscle disease but did not reveal an inflammatory process. The mean age of onset was 2.4 years; male dogs were slightly overrepresented. Common presenting signs were dysphagia, sialorrhea, masticatory muscle atrophy, and regurgitation. Common muscle histopathological findings included degenerative and regenerative changes, with multifocal mononuclear cell infiltration with lymphoplasmacytic myositis of variable severity. A positive response to immunosuppressive treatment supported an immune-mediated aetiology. The mean age at death and survival time were 6.4 and 3.9 years, respectively. Recurrence of clinical signs and aspiration pneumonia were common reasons for euthanasia. Conclusions Diagnosis of Vizsla idiopathic inflammatory polymyopathy can be challenging due to lack of specific tests, however the presence of dysphagia, regurgitation and masticatory muscle atrophy in this breed with negative serological tests for masticatory muscle myositis and myasthenia gravis, along with muscle biopsies suggesting an inflammatory process, support the diagnosis. However, there is an urgent need for a more specific diagnostic test. The average of inbreeding coefficient (CoI) of 16.3% suggests an increased expression of a Dog Leukocyte Antigen Class II haplotype, leading to an increased disease risk. The prognosis remains guarded, as treatment can only manage the disease. Recurrence of clinical signs and perceived poor quality of life are the most common reasons for humane euthanasia. Electronic supplementary material The online version of this article (doi:10.1186/s12917-015-0408-7) contains supplementary material, which is available to authorized users.

Case report A 6-year-old neutered male Australian Kelpie presented with a 2-year history of seizures. Neurological examination was consistent with a generalised prosencephalic lesion. Serum biochemical testing was performed in addition to magnetic resonance imaging of the brain and cerebrospinal fluid analysis. Magnetic resonance imaging revealed a reduction in the number of sulci and gyri in addition to cortical thickening, resulting in a diagnosis of lissencephaly. The dog was treated with anticonvulsants and follow-up information obtained from the referring veterinarian 11 months after diagnosis indicated that the dog had good seizure control. Conclusion This is the first report of lissencephaly in the Australian Kelpie and would suggest that some dogs with the condition can be managed with long-term anticonvulsant medication.

The influence of dietary and citrus flavonoids on health and mental well-being has been increasingly attractive. They exert antioxidative, antiinflammatory, and neuroprotective effects. Aging, oxidative stress, and neuroinflammation increase the risk of degeneration of the central nervous system. Citrus flavonoids can traverse the blood–brain barrier and hence are promising candidates for intervening in age-related neurodegenerative disorders, dementias, and cognitive declines. Pharmacological activities of flavonoids can be attributed to their antioxidant, antiinflammatory, and signaling properties. In brains, flavonoids are more likely to act as signaling molecules than antioxidants. In this chapter, we briefly demonstrate dietary and citrus flavonoids and their effects in neuroprotection and improvements in neurodegenerative disease-associated dementias and cognitive declines. Distinct beneficial bioactivities of flavonoids on neurological processes, ameliorating effects of citrus flavonoids in Alzheimer’s disease-related memory impairments, multiple mechanisms (including those controlled at molecular level) underlying neuroprotection, and memory improvements of citrus flavonoids are discussed. Additionally, the application of the flavonoids to other dementias and practical concerns for therapeutic use are also mentioned.

Objective—To evaluate 4 rapid supravital stains and 3 preparation techniques for use in the intraoperative diagnosis of intracranial lesions. Animals—10 dogs and 1 cat euthanatized for intracranial lesions. Procedure—Specimens were taken from lesions and slides prepared, using 3 techniques: touch impression, medium-pressure impression, or smear preparation. Preparations were then stained with 4 stains: modified Wright stain, May-Grünwald-Giemsa, toluidine blue, and zynostain and examined in a blinded randomized fashion. Cytologic diagnosis was compared with histopathologic diagnosis and classified on the basis of identification of the pathologic process and specific diagnosis into the following categories: complete correlation, partial correlation, or no correlation. Results—An overall diagnostic accuracy of 81% (107/132) was achieved on the basis of a combination of partial and complete correlation. Of the stains examined, modified Wright stain appeared to be most accurate, with complete correlation in 17 of 33 (52%) specimens and partial correlation in 12 of 33 (36%) specimens. Of the preparation methods, touch preparation and smear preparation provided the most accurate results, with an overall diagnostic accuracy of 82% (36/44) for both methods. However, smear preparations appeared to be of greater diagnostic value, with fewer nondiagnostic specimens, compared with touch preparations. Conclusions and Clinical Relevance—Cytologic preparations provide a useful diagnostic tool for the intraoperative diagnosis of intracranial lesions. All stains examined yielded promising results, the most accurate of which appeared to be the modified Wright stain. The smear preparation appeared to be the preparation method of greatest diagnostic value. (Am J Vet Res 2002;63:381–386)

Primary T-cell lymphoma is a rare form of CNS neoplasia. Diagnosis may be aided by use of cytologic examination of CSF. Primary CNS T-cell lymphoma should be considered in a patient with multiple cranial nerve abnormalities, even if results of imaging studies are considered normal.

This paper introduces a new method for estimating the excitability of brain networks. The motivation for this research was to develop a system that can track pathological changes in excitability, in diseases such as epilepsy. The ability to track excitability may provide a method for anticipating seizures and intervening therapeutically. Four normally healthy canines were implanted with the Medtronic Activia PC+S deep brain stimulation and sensing system. The devices were used to probe the circuit of Papez, with electrical stimulation in the anterior nucleus of the thalamus to measure evoked potentials in the hippocampus. The canines were given three different dosage levels of anti-convulsant medication in an attempt to manipulate the excitability of the network. The results showed changes in the morphology of the evoked potentials, following a circadian profile and reflecting times of drug delivery.

This report describes the clinical, histopathologic, and imaging findings of multifocal oligodendrogliomas from three canine patients. Clinical history varied but included seizure activity and behavior changes. Neurologic examination abnormalities included ataxia, proprioceptive deficits, cranial nerve deficits, and changes in mentation. MRI in one patient revealed multifocal brain lesions; however, the MRI was normal in another one of the patients. Histopathologic evaluation identified multifocal neoplastic infiltrates in all three patients involving the cerebral cortex, brainstem, and spinal cord, with leptomeningeal extension in two of the three patients. All three patients were euthanized due to progression of their neurologic condition and/or complications due to aspiration pneumonia. Oligodendrogliomas should be considered a differential diagnosis for patients with multifocal brain disease.

Telomere shortening in normal somatic cells has been proposed as a major barrier to unlimited cellular proliferation. Telomerase is an enzyme capable of maintaining telomere length, and thus bypassing this barrier. In human beings, telomerase activity is restricted to cancer cells and cells of stem or germ cell lineages. Dogs represent a potentially useful clinical model for the development of telomerase-based therapies because telomerase activity is also restricted to cancer cells and stem cells in this species. We examined the ability of telomestatin to inhibit telomerase activity in telomerase-positive D17 and CMT7 canine cancer cell lines. At a concentration of 2 microM, telomestatin treatment resulted in a decrease in telomerase activity, telomere shortening, growth inhibition and apoptosis in telomerase-positive cancer cells. These effects were not seen in telomerase-negative skin fibroblasts or negative controls. These results confirm that telomestatin specifically inhibits telomerase activity in canine cancer cells and strengthens the usefulness of dogs as a model for testing telomerase-based therapies.

Increased telomerase activity (TA) has been found in human and canine solid tumours, stem cells and somatic tissues with enhanced proliferative potential. The relationship between TA in normal and malignant lymphoid tissues remains unclear. The TA and the expression of canine telomerase reverse transcriptase catalytic subunit (dogTERT) messenger RNA (mRNA) were analyzed in malignant lymph nodes from 30 dogs with lymphoma, from two dogs with non-neoplastic illness and from two clinically normal dogs, demonstrating a statistically significant difference between TA in lymphoma lymph nodes (n = 30) and normal nodes (n = 4) but no significant difference in dogTERT mRNA expression. In addition, the expression of telomerase reverse transcriptase catalytic subunit (TERT) protein and Ki67 was analyzed in malignant lymph nodes from 10 dogs with lymphoma and from two clinically normal dogs by immunohistochemistry. TERT expression was associated with Ki67 in all lymphoma nodes (n = 10), and differences were illustrated between TERT and Ki67 expression between lymphoma (n = 10) and non-lymphoma (n = 2) nodes. This data support further investigation of telomerase in canine haematopoietic neoplasia through large-scale prospective studies.

Background: Tumor proliferation in human intracranial meningiomas can be defined by the reactivity of the monoclonal antibody MIB-1 to the Ki-67 antigen. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, is a predictive marker for survival of dogs with intracranial meningiomas. Hypothesis: Ki-67 is expressed in canine intracranial meningiomas and is associated with VEGF expression. Ki-67 expression is a prognostic marker for patient outcome. Animals: Seventy client-owned dogs with WHO grade I intracranial meningiomas. Methods: Retrospective study assessing the degree of immunostaining for Ki-67 by MIB-1 and VEGF expression in intracranial meningioma tissue from dogs. MIB-1 Labeling Index (LI) was calculated with Image J NIH-software. Extent, intensity, and distribution of VEGF-expression was assessed semiquantitatively. Cross tabulations with Fisher's exact tests and nonparametric Spearman's rank correlations were performed to identify associations between VEGF expression and MIB-1 LI. Fifteen dogs underwent postsurgical radiotherapy and were included in survival analysis. The effect of MIB-1 LI on survival was examined by Kaplan-Meier and Cox proportional hazards regression procedures. Results: Ki-67 staining was positive in 91% (64/70) and VEGF expression was detected in 96% (67/70). There was no significant association between VEGF expression and MIB-1 LI. MIB-1 LI was not associated with survival. Conclusions and Clinical Importance: MIB-1 antibody can be used to document cell proliferation in intracranial meningiomas in dogs, but does not predict outcome. No association between VEGF as a marker of angiogenesis and tumor proliferation was found. Angiogenesis might be a more important predictor of meningioma activity in dogs than is Ki-67.

Telomerase is a ribonucleoprotein enzyme complex that synthesizes telomere DNA. It is detected in 85‐90% of malignant tumours in humans, but not in most somatic cells. Because telomerase plays a critical role in cell immortality, it represents an important target for anticancer therapies. We have previously shown that the dog is a potentially useful model for evaluating telomerase-based therapeutics. In this present study we analysed 93 canine brain tumours for telomerase reverse transcriptase (TERT) expression by immunohistochemistry. TERT immunoreactivity was detected in 16 of 50 grade 1 (32%) and 29 of 43 grade 2 tumours (67.4%), demonstrating a statistically significant association with histological grade ( P = 0.00012). A subset of 51 tumours was also assessed for MIB-1 expression. The MIB-1 labelling index (LI) was found to correlate significantly with tumour grade, with a mean MIB-1 LI of 1.5% for grade 1 tumours, as compared with a mean MIB-1 LI of 21.7% for grade 2 tumours ( P << 0.001). The MIB-1 LI was also significantly associated with TERT expression in all brain tumours ( P << 0.001). These data further support the dog as a model for the preclinical development of telomerase-based therapeutics in brain tumours.

Pituitary apoplexy is a syndrome which has been described in humans caused by acute haemorrhage or infarction within a pituitary tumour or a non-tumorous pituitary gland. This report describes the authors' observations of a dog in which vomiting, visual disturbances, seizures, altered consciousness and diencephalic dysfunction occurred in association with haemorrhage originating from a pituitary macroadenoma. The clinical signs were thought to be consistent with disruption of the hypothalamus and brainstem, together with raised intracranial pressure due to intraventricular haemorrhage. These signs, and the pathological findings, bear a striking resemblance to those associated with the syndrome of pituitary apoplexy, seen in humans.

A 7-year-old castrated male Rottweiler was evaluated for an 18-month history of bilateral hind limb lameness, signs of pain on rising, and mild ataxia. A gas-filled lumbosacral disk space (vacuum disk phenomenon) was revealed by use of computed tomography. Additional smaller gas bubbles were in the periphery of the disk and between the degenerated L5-L6 dorsal articular facets (vacuum facet phenomenon). Vacuum disk and facet phenomena have been described in humans with degenerative disk and vertebral articular facet joint disease; gas attracted from surrounding tissues accumulates within clefts of the degenerated disk or in unstable facet joints. Vacuum disk phenomenon has been reported in dogs and indicates degenerative disk disease. The phenomenon is more commonly observed by use of computed tomography, compared with conventional radiography, and can be elicited by hyperextension of the vertebral column.