Transglutaminase 2: a novel autoantigen in canine idiopathic central nervous system inflammatory diseases

Necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE) and granulomatous meningoencephalomyelitis (GME) are common idiopathic inflammatory central nervous system (CNS) diseases with unknown etiology in dogs. We previously showed that IgG autoantibodies in the cerebrospinal fluid (CSF) of NME cases reacted to unknown brain proteins as well as to glial fibrillary acidic protein (GFAP). In the present report, we evaluated the autoantibodies against transglutaminase2 (TG2) in the canine CNS diseases. CSF samples obtained from dogs with NME (n=19), NLE (n=7), GME (n=11) and miscellaneous CNS diseases (n=12) were subjected. CSFs from 20 healthy dogs were used as controls. Indirect fluorescent antibody test on the canine cerebrum revealed astrocyte-binding IgG in the CSF of NME. After absorption of the CSF with bovine GFAP, the CSF still possessed the reactivity to astrocytes. Double-color staining showed clear colocalization of the autoantibodies and anti-human TG2 rabbit polyclonal IgG. An immunoblot assay against human recombinant TG2 revealed anti-TG2 IgG in the CSF from dogs with NME, NLE and GME. The CSF of canine idiopathic encephalitis cases, notably of NME, tended to show high ELISA OD values against human recombinant TG2 compared to healthy controls. The presence of anti-TG2 autoantibodies in the CSF may contribute to the elucidation of the etiology of canine NME, NLE and GME.     

Idiopathic ocular and nasal granulomatous inflammatory disease in a dog

A young female Akita presented for ocular and nasal lesions. Examination showed bilateral 360 degree limbal masses that extended onto the peripheral cornea. In addition, intranasal granulomatous masses were observed by rhinoscopy. Histopathologic examination with immunohistochemical staining showed that these masses were almost identical and were classified as an idiopathic, T-cell rich, granulomatous inflammation. The dog responded well to anti-inflammatory medication and the disease remains in remission 2 years after the initial presentation.     

Granular cell tumor of the canine central nervous system: two cases.

Although pure granular cell tumors have been reported in various sites in the dog, only one tumor has been reported in the central nervous system. Two dogs presented with neurologic signs had brain lesions detected by magnetic resonance imaging in the area of the olfactory bulbs and frontal cortex. In both dogs, a clinical diagnosis of a granular cell tumor was made from tissues obtained from stereotactic biopsies guided by computed tomography. Surgical removal of the tumors was followed by histopathologic, ultrastructural, and immunocytochemical characterization. Although not conclusive, these studies indicated that the granular cells were not of leucocyte origin but may have been derived from the meninges. One dog died 12 months after surgery, and the other was alive 4 months later.     

Spongy degeneration of the central nervous system in two canine littermates

Progressive dysmetria was observed at four months and six months of age in two female Labrador retriever littermates. Neurological examinations indicated a cerebellar disorder. Laboratory analyses were normal. The dogs were studied clinically until they were killed for necropsy at nine months and eleven months of age. Both dogs had normal brain size, shape, and calvarial symmetry; the older dog had body weight loss, reduced brain weight, and muscle atrophy. Microscopically, there were vacuoles, hypertrophied fibrous astrocytes, myelin loss, and prominent blood vessels, distributed symmetrically in the subcortical and deep white matter of all lobes of the cerebrum; in the folial and deep white matter of the cerebellum; in the tracts of some cranial nerves; in the thalamic area, midbrain and brainstem; and in the white matter of the spinal cord. There was no significant myelinolysis, inflammation, or axonal degeneration. Ultrastructurally, there were intramyelinic vacuoles with separation of lamellae at intraperiod lines and larger spaces formed by coalescence of ruptured vacuoles. Hypertrophied fibrous astrocytes had abundant glial filaments, edematous cytosol, membrane-bound crystalline inclusions, dilated cytocavitary systems, and abnormal mitochondria. The clinical, histological, and ultrastructural findings resembled those reported for the juvenile form of Canavan's disease (van Bogaert and Bertrand type) in children.     

Thrombocytosis and central nervous system involvement in a case of canine acute megakaryoblastic leukemia

This case report presents a 14‐month‐old female Poodle mix with acute megakaryoblastic leukemia based on a marked thrombocytosis, abnormal platelet morphology, circulating dwarf megakaryocytes, and blast cells in the blood. Bone marrow abnormalities included dysmegakaryopoiesis dygranulopoiesis, and an increased number of blast cells was observed in the blood. Extensive leukemic involvement was also found in the liver, spleen, lymph nodes, lungs, kidneys, and brain. The cytopathologic features of the abnormal circulating cells were highly suggestive of being megakaryocytic in origin, which was supported by negative myeloperoxidase staining and positive von Willebrand factor staining on immunocytochemistry (ICC). The neoplastic cells were also CD61 positive and had variable von Willebrand factor expression on ICC. Although there were only 25% blast cells in the bone marrow, which theoretically supported myelodysplastic syndrome, the hypothesis that this case represented acute myeloid leukemia of megakaryoblastic origin was confirmed by the continuous increase in circulating blast cell numbers during follow‐up visits and the extensive leukemic involvement of parenchymal organs.     

Pharmaceutical and nutraceutical management of canine osteoarthritis: present and future perspectives

Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases and causes of lameness in the dogs. The osteoarthritic disease process involves the entire synovial joint, encompassing the synovium, cartilage and underlying bone. Joint failure results from an abnormal mechanical strain causing damage to normal tissue or failure of pathologically impaired articular cartilage and bone under the influence of normal physiological strain or a combination of both. In both cases, the end point is cartilage loss and joint impairment. Osteoarthritic chondrocytes show an altered phenotype characterised by an excess production of catabolic factors, including metalloproteinases and reactive oxygen species. These factors constitute potential therapeutic targets and some new drugs and nutraceuticals have been proposed to promote the return to homeostasis. Until now, the therapeutic management of OA in dogs has been dominated by nonsteroidal anti-inflammatory drugs, but some new compounds, including diacerhein, with potential structure-modifying effects, are already used to treat OA in humans and could be helpful to manage OA in the dog. In addition, novel nutraceuticals, such as avocado/soybean unsaponifiable substances, have shown symptomatic effects in knee OA in humans, and could offer an alternative to prevent OA progression. This paper provides an overview of recent discoveries in the pathophysiology and in the therapeutic management of osteoarthritis in dogs.     

Peptide absorption: a review of current concepts and future perspectives.

Absorption of di- and tripeptides from the gastrointestinal tract is accepted as being an important biological phenomenon. The extent to which peptides are absorbed and the nutritional and metabolic significance of peptide absorption remain unclear. Evidence is strong for the existence of multiple peptide transport systems, including one type that is electrogenic in nature and that requires a protonmotive force and cotransports two H+ for every peptide transported. The rate of absorption of peptides can be responsive to level of dietary intake and level of dietary protein. Peptide absorption seems to be an important physiological process in ruminants, and this process may account for a large portion of absorbed amino acids. An important new observation is that the nonmesenteric portion of the portal-drained viscera of the ruminant is a major site of peptide absorption. These new observations may result in a reshaping of the currently accepted theory concerning protein utilization by ruminants.     

The future of immunotherapy for canine atopic dermatitis: a review

Allergen specific immunotherapy (ASIT) is a foundation treatment for canine atopic dermatitis (CAD), though few critical studies have documented its effectiveness as a disease‐modifying treatment in dogs. The mechanisms by which ASIT works in dogs have not been elucidated, although they are likely to parallel those known for humans. Current ASIT approaches in CAD focus on either subcutaneous or sublingual administration. Greater knowledge of major allergens in dogs, ideal dosage regimes and details of allergen admixture are likely to lead to better efficacy in CAD. Evaluation of biomarkers for successful therapy may also be of benefit. Potentially important advances in human medicine, that have yet to be explored in dogs, include use of modified allergen preparations such as allergoids, recombinant major allergens or allergen peptides; modification with adjuvants; or packaging of the above in virus‐like particles. Co‐administration of immunomodulators such as CpG oligodeoxynucleotides or specific monoclonal antibodies might direct the immune response in the desired direction while calming the “cytokine storm” of active disease. Initial trials of alternative routes of administration such as intralymphatic immunotherapy have yielded exciting results in humans, and continuing study in dogs is underway. Progress in ASIT of human food allergy may provide clues that will assist with improved diagnosis and patient management of CAD. Importantly, further study must be undertaken to clarify the conditions under which ASIT is a valuable treatment modality for dogs.     

Microarray analysis of differentially expressed genes of primary tumors in the canine central nervous system

The pathophysiologic similarities of many human and canine cancers support the role of the domestic dog as a model for brain tumor research. Here we report the construction of a custom canine brain-specific cDNA microarray and the analysis of gene expression patterns of several different types of canine brain tumor. The microarray contained 4000 clones from a canine brain specific cDNA library including 2161 clones that matched known genes or expressed sequence tags (ESTs) and 25 cancer-related genes. Our study included 16 brain tumors (seven meningiomas, five glial tumors, two ependymomas, and two choroid plexus papillomas) from a variety of different dog breeds. We identified several genes previously found to be differentially expressed in human brain tumors. This suggests that human and canine brain tumors share a common pathogenesis. In addition, we also found differentially expressed genes unique to either meningiomas or the glial tumors. This report represents the first global gene expression analysis of different types of canine brain tumors by cDNA microarrays and might aid in the identification of potential candidate genes involved in tumor formation and progression.     

Recent findings and future perspectives of digestive physiology in rabbits: a review

The rabbit is one of the most common laboratory animals. Consequently, there is an enormous number of publications concerning its physiology. The present review is restricted to a special field and deals with the new findings of the rabbit's digestive physiology. For the sake of better intelligibility the most important antecedents are also given. First the particularities of feed intake regulation are demonstrated. The strong control mechanism can be disturbed by feed antinutritives, mycotoxins and high environmental temperature. Caecotrophy depends on three main factors: stimulation of rectal mechanoreceptors, perception of the specific odour of the soft faeces, and the inner motive determined by the blood level of metabolites and hormones. The species characteristics of proportions, pH conditions, microflora and -fauna of the rabbit's digestive tract are given. The digestion and absorption of dietary nutrients are discussed. Special sections deal with the sorption of electrolytes and VFAs in the gut, the caecal digestive process, the formation of hard and soft faeces and the role of the caecotrophy in stomachal carbohydrate degradation. A relatively new area, i.e. the development and maturation of the gastrointestinal tract, is also shown. The postnatal evolution of digestive enzyme activity is also summarized. The main endogenic factors (breed, sex, age, stress, caecotrophy, presence of hairball in the stomach) influencing the digestion of dietary nutrients are also described. The probable future trends are given, too.     

The role of glutamate in central nervous system health and disease--a review

Glutamate is the principal excitatory neurotransmitter in the brain. Knowledge of the glutamatergic synapse has advanced enormously over the last 10 years, primarily through application of cellular electrophysiological and molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic glutamate receptors with intrinsic cation permeable channels. There are also three groups of metabotropic, G-protein-coupled glutamate receptors that can modify neuronal excitability. There are also two glial glutamate transporters and three neuronal transporters in the brain. Endogenous glutamate may contribute to the brain damage occurring acutely after traumatic brain injury as well as having a role in the excitatory imbalance present in epileptic conditions and contributing to the pathophysiology of hepatic encephalopathy in animals. Understanding the role of glutamate in these neurological diseases may highlight treatment potentials of antagonists to glutamatergic transmission. This paper presents a review of the literature of glutamate and its role in neurological function and disease.     

Cryptococcosis of the central nervous system in a dog

A 3-year-old female German Shepherd Dog was evaluated for progressive mental obtundation and vestibular signs. Central nervous system cryptococcosis was diagnosed on the basis of growth of Cryptococcus neoformans in fungal culture of CSF, as well as detection of the organism in CSF via microscopy. Cryptococcal capsular latex antigen agglutination titer was 1:262,144 in CSF and 1:1,048,576 in serum samples. Imaging with magnetic resonance augmented diagnosis. The dog improved after long-term treatment with fluconazole. Fluconazole is useful in the treatment of CNS cryptococcosis, because it attains high concentration in the CNS. Long-term therapy is often required for resolution of clinical signs, and affected animals may require long-term follow-up with periodic evaluation of CSF via fungal culture and latex agglutination tests. Monitoring serum latex agglutination test results may provide a safe, less invasive means of monitoring response to treatment.     

A review of coronavirus infection in the central nervous system of cats and mice

Feline infectious peritonitis (FIP) is a common cause of death in cats. Management of this disease has been hampered by difficulties identifying the infection and determining the immunological status of affected cats and by high variability in the clinical, pathological, and immunological characteristics of affected cats. Neurological FIP, which is much more homogeneous than systemic effusive or noneffusive FIP, appears to be a good model for establishing the basic features of FIP immunopathogenesis. Very little information is available about the immunopathogenesis of neurologic FIP, and it is reasonable to use research from the well-characterized mouse hepatitis virus (MHV) immune-mediated encephalitis system, as a template for FIP investigation, and to contrast findings from the MHV model with those of FIP. It is expected that the immunopathogenic mechanisms will have important similarities. Such comparative research may lead to better understanding of FIP immunopathogenesis and rational prospects for management of this frustrating disease.     

Cryptococcosis involving the eye and central nervous system of a dog

Cryptococcus neoformans meningoencephalitis was diagnosed as the cause of stupor and generalized seizures in a 2-year-old Cocker Spaniel. Unilateral granulomatous chorioretinitis was observed ophthalmoscopically, and isolation of C neoformans from CSF confirmed the antemortem diagnosis. The dog was euthanatized and necropsied. Multifocal lesions were seen throughout the lungs, nasal turbinates, cerebral cortex, and the optic nerve of each eye. Microscopically, the multifocal lesions were granulomas consisting of lymphocytes, macrophages, plasma cells, and cryptococcal organisms. Infection may have originated in the nasal passages and extended directly through the ethmoid plate into the meninges of the CNS and optic nerves. Although the prognosis is poor in dogs with CNS involvement, various chemotherapeutic agents are available for use by clinicians.     

Significance of surface epithelial cells in canine cerebrospinal fluid and relationship to central nervous system disease

Background: The term “surface epithelium” is used to describe cells, including meningeal, choroid plexus, ependymal, and endothelial cells, that are found in human cerebrospinal fluid (CSF) and are difficult to distinguish cytologically. We hypothesized that the presence of surface epithelial cells in canine CSF was associated with specific diseases of the central nervous system (CNS). Objectives: In this retrospective study the frequency of surface epithelial cells in CSF from dogs with neurologic disease was investigated along with the potential association with age, specific type of CNS disease, and CSF total nucleated cell count (TNCC) and protein concentration. Methods: The frequency of surface epithelial cells in 359 canine CSF samples was analyzed for 5 disease groups: CNS neoplasia, CNS compression, CNS inflammation, idiopathic epilepsy, and miscellaneous diseases. Groups were also combined into those with and without expected meningeal involvement. Association of the presence of surface epithelial cells in CSF with age, disease type, and CSF TNCC and protein concentration was investigated. Results: Surface epithelial cells were found in 27 of 359 (7.5%) CSF samples: CNS neoplasia 2/30 (6.7%), CNS compression 7/64 (10.9%), CNS inflammation 1/39 (2.6%), idiopathic epilepsy 8/124 (6.5%), and miscellaneous diseases 9/102 (8.8%). Significant associations between surface epithelial cell presence in CSF and age, disease type, CSF TNCC, and CSF protein concentration were not found. Conclusions: The presence of surface epithelial cells was not related to a specific disease group or CSF changes in the studied population. Thus, the presence of surface epithelial cells should be interpreted carefully, as it could represent an incidental finding in CSF specimens.