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Case summary A 14-year 3-month-old spayed female mixed-breed cat presented with jaundice, anaemia and thrombocytopenia. Haemophagocytic syndrome associated with lymphoma was suspected after cytological examination of the spleen. Despite treatment with prednisolone, L-asparaginase and nimustine, the cat died 176 days after the initial presentation. Necropsy revealed splenomegaly and hepatomegaly, without lymphadenopathy. Histopathologically, neoplastic lymphoid cells infiltrated the hepatic sinusoid and splenic sinus. The neoplastic lymphoid cells showed marked hepatocytotropism and contained erythrocytes, which was also confirmed by electron microscopy. Immunohistochemically, neoplastic lymphoid cells were positive for CD3, TIA1 (GMP-17) and granzyme B, and negative for CD8, CD20, CD56, CD57, CD79a and Iba1. Based on these findings, the cat was diagnosed with hepatosplenic T-cell lymphoma (HS-TCL) with hepatocytotropism. Relevance and novel information This case shows cytotoxic immunophenotype of HS-TCL in a cat, which has not been demonstrated before. Severe hepatocytotropism and haemophagocytosis of the neoplastic cells were likely to be associated with jaundice and anaemia, respectively, and the poor outcome of the present case.

Case summary A 14-year-old spayed female American Shorthair cat was presented with weight loss and a palpable abdominal mass. Abdominal ultrasound and CT revealed a duodenal mass with suspected perforation and an enlarged jejunal lymph node. Cytological evaluation from a fine-needle aspiration of the abdominal mass displayed many atypical round cells, some with a small amount of light pink material at the cellular edge. The duodenal mass was surgically removed, and was diagnosed as a plasma cell tumour immunohistochemically positive for CD79 alpha, IgA and lambda immunoglobulin light chains. In addition, amyloidosis was detected. PCR to assess the antigen receptor rearrangement of the tumour cells showed a monoclonal rearrangement of the immunoglobulin heavy chain gene. Postoperatively, the cat received chemotherapy with cyclophosphamide and prednisolone. Owing to progressive enlargement of the jejunal lymph node, different chemotherapy protocols were used sequentially, namely chlorambucil, lomustine and L-asparaginase. However, the cat died 96 days after the initial diagnosis. Post-mortem examination confirmed systemic dissemination of tumour cells. The cause of death was considered to be a result of a complication of the tumour itself and associated amyloidosis. Relevance and novel information This patient was diagnosed with a primary duodenal plasmacytoma, and primary (amyloid light-chain) amyloidosis. In cats, intestinal plasmacytoma is rarely reported and associated amyloidosis is an uncommon feature, when compared with humans. To our knowledge, this is the first clinical report of duodenal plasmacytoma in a cat. The present report shows that feline plasmacytomas should be included in the differential diagnosis of a duodenal mass.

The objective of this study was to determine the radiocesium transfer rates of pigs fed haylage contaminated with low levels of cesium at different growth stages. We measured the body weight of juvenile and adult pigs during the treatment period to confirm their health status. We also performed pig blood hematologic and biochemical analyses at both growth stages. To our knowledge, this is the first study to report pig radiocesium transfer coefficient rates after 1 month of chronic oral treatment, which is the period assumed to be required for body equilibrium under a diet of radiocesium-contaminated food. The results showed higher radiocesium retention rates in the kidneys, liver, spleen, genitals, psoas major, bladder, thyroid, and urine than in the blood and bone (tibia and femur) of pigs at both growth stages. The radiocesium retention levels were generally higher in juvenile pigs than in adult pigs, with the highest transfer coefficient ratio in the kidneys (16.2%).

Visceral leishmaniasis (VL) is caused by parasitic protozoa of the genus Leishmania and is characterized by clinical manifestations such as fever, hepatosplenomegaly and anemia. Hemophagocytosis, the phenomenon of phagocytosis of blood cells by macrophages, is found in VL patients. In a previous study we established an experimental model of VL, reproducing anemia in mice for the first time, and identified hemophagocytosis by heavily infected macrophages in the spleen as a possible cause of anemia. However, the mechanism for parasite-induced hemophagocytosis or its role in parasite survival remained unclear. Here, we established an in vitro model of Leishmania-induced hemophagocytosis to explore the molecules involved in this process. In contrast to naïve RAW264.7 cells (mouse macrophage cell line) which did not uptake freshly isolated erythrocytes, RAW264.7 cells infected with L. donovani showed enhanced phagocytosis of erythrocytes. Additionally, for hemophagocytes found both in vitro and in vivo, the expression of signal regulatory protein α (SIRPα), one of the receptors responsible for the 'don't-eat-me' signal was suppressed by post-transcriptional control. Furthermore, the overlapped phagocytosis of erythrocytes and Leishmania parasites within a given macrophage appeared to be beneficial to the parasites; the in vitro experiments showed a higher number of parasites within macrophages that had been induced to engulf erythrocytes. Together, these results suggest that Leishmania parasites may actively induce hemophagocytosis by manipulating the expression of SIRPα in macrophages/hemophagocytes, in order to secure their parasitism.

Case summary A 7-year-old mixed-breed cat presented with subcutaneous oedema and erythema extending from the right axilla to the abdomen. Fine-needle aspiration of the subcutaneous lesion revealed large, atypical, round cells. A clonality analysis for the T-cell receptor-gamma and immunoglobulin heavy chain genes showed no clonal rearrangement. The presumed diagnosis was lymphoma and the cat was treated with prednisolone and L-asparaginase but died 78 days after initial treatment. At necropsy, an oedematous subcutaneous mass in the right axilla, hepatomegaly, splenomegaly and lymphadenopathy of the mediastinum and left axilla were observed. Histopathological examination revealed diffuse infiltration of large atypical round cells in the subcutaneous mass, liver, spleen, lymph nodes and bone marrow. Immunohistochemically, the tumour cells were strongly positive for CD56, and negative for CD3, CD20, CD79a, CD57, granzyme B and perforin. Based on these findings, the cat was diagnosed with blastic natural killer (NK) cell lymphoma/leukaemia. Relevance and novel information Here, we report the pathological and clinical findings of NK cell lymphoma/leukaemia in a cat. The antibody for human CD56, a diagnostic marker for human NK cell neoplasms, showed cross-reactivity with feline CD56 by immunohistochemistry and Western blotting analysis. The antibody could be a useful diagnostic marker for feline NK cell neoplasms.

Abstract Background Gallbladder mucocele (GBM) is a common disease in the canine gallbladder. Although the pathogenesis of GBM remains unclear, we recently reported that the excessive accumulation of mucin in the gallbladder is not a result of overproduction by gallbladder epithelial cells (GBECs). Hypothesis/Objectives Changes in the function of GBECs other than the production of mucin are associated with the pathogenesis of GBM. We performed an RNA sequencing (RNA‐seq) analysis to comprehensively search for abnormalities in gene expression profiles of GBECs in dogs with GBM. Animals Fifteen dogs with GBM and 8 dogs euthanized for reasons other than gallbladder disease were included. Methods The GBECs were isolated from gallbladder tissues to extract RNA. The RNA‐seq analysis was performed using the samples from 3 GBM cases and 3 dogs with normal gallbladders, and the gene expression profiles were compared between the 2 groups. Differences in mRNA expression levels of the extracted differentially expressed genes (DEGs) were validated by quantitative reverse transcription polymerase chain reaction (RT‐qPCR) using samples of 15 GBM cases and 8 dogs with normal gallbladders. Results Comparison of gene expression profiles by RNA‐seq extracted 367 DEGs, including ANO1, a chloride channel associated with changes in mucin morphology, and HTR4, which regulates the function of chloride channels. The ANO1 and HTR4 genes were confirmed to be downregulated in the GBM group by RT‐qPCR. Conclusions and Clinical Importance Our results suggest that GBM may be associated with decreased function of chloride channels expressed in GBECs.

Abstract Dogs diagnosed with chronic enteropathy (CE) or small-cell lymphoma (SCL) exhibit marked differences in faecal microbiota and organic acid profiles compared with healthy dogs, as well as immune abnormalities in intestinal mucosal tissue. However, few studies have analysed trace organic acids, such as succinic acid, which have been suggested to be associated with IBD in humans. Therefore, in this study, we compared the faecal microbiota and organic acid profiles as well as serum inflammatory markers between dogs with disease (n = 11; 6 with CE and 5 with SCL) and healthy controls (n = 16). We also performed machine learning and correlation analysis to obtain more detailed insights into the characteristics of affected dogs. These results revealed that dogs with CE and SCL had lower levels of Erysipelotrichaceae (e.g. Turicibacter and Allobaculum), exhibited abnormalities in the succinic acid metabolism (i.e. succinic acid accumulation and decreased levels of Phascolarctobacterium as succinic acid-utilising bacteria) and increased levels of pathobiont bacteria such as Escherichia-Shigella. Additionally, the presence of Dubosiella was significantly negatively correlated with Canine Inflammatory Bowel Disease Activity Index scores. These findings are expected to aid the development of microbiome-based medications and/or supplements, although further verification is needed.

Abstract Prior to the formation of amyloid fibrils, the pathological hallmark in tau-related neurodegenerative disease, tau monomers aggregate into a diverse range of oligomers. Granular tau oligomers, consisting of approximately 40 tau protein molecules, are present in the prefrontal cortex of patients at Braak stages I-II, preclinical stages of Alzheimer’s disease (AD). Antibodies to granular tau oligomers as antigens have not been reported. Therefore, we generated new rat monoclonal antibodies by immunization with granular tau oligomers. Three antibodies from different hybridoma clones showed stronger immunoreactivity to granular tau oligomers and tau fibrils compared with monomeric tau. Of the three antibodies, 2D6-2C6 showed 3000-fold greater immunoreactivity in P301L-tau transgenic (rTg4510) mice than in non-transgenic mice, while MC1 antibody, which detects pathological conformations of tau, showed a 5.5-fold increase. These results suggest that 2D6-2C6 recognizes aggregates more specifically than MC1. In AD subjects, 2D6-2C6 recognized neurofibrillary tangles and pretangles, and co-localized within AT8-positive cells containing phosphorylated tau aggregates. The epitope of 2D6-2C6 is the 423–430 amino acid (AA) sequence of C-terminal regions. Taken together, a novel monoclonal antibody, 2D6-2C6, generated by immunization with granular tau oligomers binds to tau aggregates at the 423–430 AA sequence.

Hemophagocytosis is a phenomenon in which macrophages phagocytose blood cells. There are reports on up-regulated hemophagocytosis in patients with infectious diseases including typhoid fever, tuberculosis, influenza and visceral leishmaniasis (VL). However, mechanisms of infection-associated hemophagocytosis remained elusive due to a lack of appropriate animal models. Here, we have established a mouse model of VL with hemophagocytosis. At 24 weeks after infection with 1 x 10(7) Leishmania donovani promastigotes, BALB/cA mice exhibited splenomegaly with an average tissue weight per body weight of 2.96%. In the tissues, 28.6% of macrophages contained phagocytosed erythrocytes. All of the hemophagocytosing macrophages were parasitized by L. donovani, and higher levels of hemophagocytosis was observed in heavily infected cells. Furthermore, more than half of these hemophagocytes had two or more macrophage-derived nuclei, whereas only 15.0% of splenic macrophages were bi- or multi-nuclear. These results suggest that direct infection by L. donovani causes hyper-activation of host macrophages to engulf blood cells. To our knowledge, this is the first report on hemophagocytosis in experimental Leishmania infections and may be useful for further understanding of the pathogenesis.

Abstract X‐linked muscular dystrophy in cats (FXMD) is an uncommon disease, with few reports describing its pathogenic genetic variants. A 9‐year‐old castrated male domestic shorthair cat was presented with persistent muscle swelling and breathing difficulty from 3 years of age. Serum activity of alanine aminotransferase, aspartate transaminase, and creatine kinase were abnormally high. Physical and neurological examinations showed muscle swelling in the neck and proximal limb, slow gait, and occasional breathing difficulties. Electromyography showed pseudomyotonic discharges and complex repetitive discharges with a “dive‐bomber” sound. Histopathology revealed muscle necrosis and regeneration. Whole‐genome sequencing identified a novel and unique hemizygous nonsense genetic variant, c.8333G > A in dystrophin (DMD), potentially causing a premature termination codon (p.Trp2778Ter). Based on a combination of clinical and histological findings and the presence of the DMD nonsense genetic variant, this case was considered FXMD, which showed mild clinical signs and long‐term survival, even though immunohistochemical characterization was lacking.

Beta amyloid (Aβ) deposits are seen in aged individuals in many of the mammalian species that possess the same Aβ amino acid sequence as humans. Conversely, neurofibrillary tangles (NFT), the other hallmark lesion of Alzheimer's disease (AD), are extremely rare in these animals. We detected Aβ deposits in the brains of Tsushima leopard cats (Prionailurus bengalensis euptilurus) that live exclusively on Tsushima Island, Japan. Aβ42 was deposited in a granular pattern in the neuropil of the pyramidal cell layer, but did not form argyrophilic senile plaques. These Aβ deposits were not immunolabeled with antibodies to the N-terminal of human Aβ. Sequence analysis of the amyloid precursor protein revealed an amino acid substitution at the 7th residue of the Aβ peptide. In a comparison with other mammalian animals that do develop argyrophilic senile plaques, we concluded that the alternative Aβ amino acid sequence displayed by leopard cats is likely to be related to its distinctive deposition pattern. Interestingly, most of the animals with these Aβ deposits also developed NFTs. The distributions of hyperphosphorylated tau-positive cells and the two major isoforms of aggregated tau proteins were quite similar to those seen in Alzheimer's disease. In addition, the unphosphorylated form of GSK-3β colocalized with hyperphosphorylated tau within the affected neurons. In conclusion, this animal species develops AD-type NFTs without argyrophilic senile plaques.

Using 0.5% and 1.0% MGM-P, the objective of the present study was to determine a more appropriate additive level for early-weaned piglets as an alternative to the use of antibiotics. Thirty-six weaned piglets were allotted to one of four groups and given a basal diet (NC), with the basal diet containing either 0.5% (LT) or 1.0% (HT) MGM-P or antibiotics (PC). Diarrhea incidence, growth performance, hematology, blood biochemistry, and blood amino acid concentrations were monitored during the experimental period. Three piglets per group with a body weight nearest to the average level were slaughtered after the experiment to assess their organ index. The results showed that no diarrhea was observed either in the treatment groups or in the control group. The 0.5% group showed an upward trend in body weight and average daily gain at all stages. The WBC counts at 21 days of age were higher (p > 0.05) both in the MGM-P addition groups and the LT and HT groups. For some of the plasma amino acids, such as arginine, phenylalanine concentrations were significantly lower (p < 0.05) in the HT group at the end of the trial. The pathological examination of all organs confirmed no differences. Consequently, the 0.5% MGM-P addition level may be suggested as a potential alternative to the use of antibiotic additives. Even with additives as high as 1%, there is no negative effect on ADG and FCR.

Abstract Histiocytic sarcoma (HS) is an incurable aggressive tumor, and no consensus has been made on the treatment due to its rare occurrence. Since dogs spontaneously develop the disease and several cell lines are available, they have been advocated as translational animal models. In the present study, therefore, we explored gene mutations and aberrant molecular pathways in canine HS by next generation sequencing to identify molecular targets for treatment. Whole exome sequencing and RNA-sequencing revealed gene mutations related to receptor tyrosine kinase pathways and activation of ERK1/2, PI3K-AKT, and STAT3 pathways. Analysis by quantitative PCR and immunohistochemistry revealed that fibroblast growth factor receptor 1 (FGFR1) is over-expressed. Moreover, activation of ERK and Akt signaling were confirmed in all HS cell lines, and FGFR1 inhibitors showed dose-dependent growth inhibitory effects in two of the twelve canine HS cell lines. The findings obtained in the present study indicated that ERK and Akt signaling were activated in canine HS and drugs targeting FGFR1 might be effective in part of the cases. The present study provides translational evidence that leads to establishment of novel therapeutic strategies targeting ERK and Akt signaling in HS patients.

The Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has a wide host range, extending from pigs and ardeid birds to opportunistic dead-end hosts, such as humans and horses. However, JEV encephalitis infections in aquatic mammals are rare, with only two cases in seals reported to date. Here, we report a lethal case of JEV and Schizophyllum commune co-infection in an aquarium-housed harbor seal in Japan. We isolated JEV from the brain of the dead seal and characterized its phylogeny and pathogenicity in mice. The virus isolate from the seal was classified as genotype GIb, which aligns with recent Japanese human and mosquito isolates as well as other seal viruses detected in China and Korea, and does not exhibit a unique sequence trait distinct from that of human and mosquito strains. We demonstrated that the seal isolate is pathogenic to mice and causes neuronal symptoms. These data suggest that seals should be considered a susceptible dead-end host for circulating JEV in natural settings.

Abstract Background Lymphoma with Mott cell change, or Mott cell lymphoma (MCL), is an uncommon variant of canine lymphoma. Because of its rare occurrence, there has been no comprehensive study describing the disease so far. Miniature dachshunds, a popular breed in Japan, sometimes experience MCL. Objectives To investigate the clinical characteristics and outcomes of MCL in miniature dachshunds. Methods Medical records were retrospectively reviewed to identify miniature dachshunds diagnosed with MCL and other types of lymphoma. Data on clinical and laboratory findings, treatments and outcomes were collected. Survival times were compared between miniature dachshunds with MCL and other types of lymphoma. Results Of the 87 miniature dachshunds diagnosed with lymphoma, 9 (10%) had cytological characteristics of MCL. All 9 miniature dachshunds with MCL were categorised as having alimentary lymphoma (small and/or large intestine, 6 dogs; mesenteric lymph node, 3 dogs). The median age was 3.1 years (range, 2.0–9.4 years). All nine dogs were treated with chemotherapeutic protocols used for large cell lymphoma or alkylating agents such as melphalan or chlorambucil. The overall response rate to initial chemotherapy was 78%, and the median progression‐free survival was 105 days. Overall survival in these nine dogs ranged from 6 to >1513 days (median, 240 days), which was significantly longer than in 29 miniature dachshunds with alimentary large cell lymphoma other than MCL (median, 57 days; p = 0.0491). Conclusions MCL in miniature dachshunds can be recognised as a peculiar type of B‐cell lymphoma occurring in relatively young dogs as an alimentary form and has a longer survival compared with typical alimentary large cell lymphoma.

Background: Feline large granular lymphocyte lymphoma (LGLL) is a grave prognosis. However, the effectiveness of concurrent treatment with chemotherapy and activated lymphocyte therapy for feline LGLL has not been evaluated. Case Description: A 7-year-old, castrated male, domestic cat presented with gastrointestinal symptoms and an abdominal mass. A Tru-Cut biopsy of the mass revealed LGLL. The cat responded well to chemotherapy regimens of cyclophosphamide, vincristine, prednisolone, and L-asparaginase. Further, activated lymphocyte therapy was added as an adjuvant treatment. The cat survived 982 days from the first presentation and experienced few adverse events. Necropsy was performed and immunohistochemistry revealed that the neoplastic lymphocytes were CD3−/CD20− cells. The final diagnosis was non-T/B LGLL. Conclusion: Minimal physical burden and a good initial response to chemotherapy might have contributed to long-term survival in the present case. Moreover, activated lymphocyte therapy could be performed safely and may be a feasible treatment for feline non-T/B LGLL.

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Visceral leishmaniasis (VL) is the most severe form of leishmaniasis caused by protozoan parasites of the genus Leishmania. Hepatomegaly is one of the most frequent clinical manifestations of VL, whereas immunopathology of the symptom has not been well investigated. Using our chronic model of experimental VL, we examined the influence of Leishmania donovani infection on the liver by clinical, histological, and biochemical analyses. The infected mice showed increased liver weight 24 weeks post-infection. Although an increase in serum ALT and inflammatory cell accumulation were observed in the livers of infected mice, no apparent parenchymal necrosis or fibrosis was observed. Tissue water content analyses demonstrated that increased liver weight was predominantly due to an increase in water weight. Together with the finding of hepatic sinusoidal dilation, these results suggested that edema associated with sinusoidal dilation causes hepatomegaly in L. donovani infection. Immunostaining of platelets and erythrocytes showed no thrombus formation or damage to the sinusoidal endothelium in the liver of infected mice. Taken together, these results suggest that hepatomegaly during experimental VL is caused by non-obstructive sinusoidal dilation.

Gallbladder mucocele (GBM) is one of the most common gallbladder diseases in dogs. Its pathogenesis has not yet been clarified, but excessive accumulation of a secretory gel–forming mucin, MUC5AC in the gallbladder has been reported. This study aimed to ascertain if MUC5AC overproduction resulted in mucus accumulation in the gallbladder during GBM development. Eleven dogs undergoing cholecystectomy who were pathologically diagnosed with GBM were included, and the expression level of mucins, particularly MUC5AC and MUC5B, in their gallbladder epithelial cells was compared with those in normal gallbladder epithelial cells. On reverse transcriptionquantitative polymerase chain reaction screening, there was a significant difference (P<0.05) in the mRNA expression level of MUC1, but not of other mucins including MUC5AC and MUC5B, between mucocele and normal gallbladder epithelial cells. Protein expression levels were also evaluated for MUC5AC and MUC5B using immunohistochemistry. There was little immunoreactivity for MUC5AC, whereas MUC5B showed definitive staining in gallbladder epithelial cells. There was no difference in MUC5AC and MUC5B protein expression levels between mucocele and normal gallbladder epithelial cells. These data suggest that excessive production of mucin, especially MUC5AC and MUC5B, does not occur in canine GBM, and that abnormal mucus excretion, rather than excessive mucus production, may be the cause of GBM development. [ABSTRACT FROM AUTHOR]

Cerebral amyloid β (Aβ) deposition is a pathological hallmark of Alzheimer’s disease (AD). There are several molecular species of Aβ, including Aβ40, Aβ42, and Aβ43, and the pathological roles of Aβ43 have attracted particular attention in recent years. Aβ43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aβ42 and Aβ40. Aβ40 and Aβ42 deposition have been demonstrated in several animal species, while Aβ43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aβ pathologies. In the present study, the deposition patterns of Aβ40, Aβ42, and Aβ43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aβ42, Aβ43, and Aβ40. However, diffuse SPs and capillary CAA lesions were negative for Aβ40. In sea lions, all SPs and most CAA lesions were positive for Aβ42, Aβ43, and Aβ40, while capillary CAA lesions were negative for Aβ40. In cats, Aβ42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aβ43, but negative for Aβ40. Double-labelling immunohistochemistry revealed the co-localization of Aβ42 and Aβ43. These findings suggest that Aβ43 and Aβ42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aβ pathology. [ABSTRACT FROM AUTHOR]

A 10-year-old mixed breed dog was presented with a 0.8 cm diameter mass below the left eye region. The mass was surgically removed and processed for histopathological examination. Microscopically, tumor cells proliferated in small lobules, nests and cords, and the tumor parenchyma was separated by desmoplastic stroma. Majority of the tumor cells were periodic acid-Schiff (PAS)-positive, and the desmoplastic stroma was densely collagenous and mucinous. Immunohistochemical results showed that the tumor cells were diffusely positive for cytokeratin 15, cytokeratin 19 and CD 34, while cytokeratin 8 reactivity was limited to the tumor cells proliferating in cords. Few tumor cells were positive for nestin. Based on the histopathological findings, the tumor was diagnosed as desmoplastic tricholemmoma. [ABSTRACT FROM AUTHOR]

The article presents the case of a new-born male marmoset that was found dead in a zoo. No history of clinical abnormalities were found on the littermate and parents. Moderate to sever multiple necrotic foci in liver and heart were found during gross observations at necropsy. Further examinations revealed Tyzzer's disease.

The article discusses research being done on mammary lipid-rich carcinoma with extensive amyloid deposition in a dog. It references several studies including "Classification and Grading of Canine Mammary Tumors" by M. Goldschmidt, L. Pena, R. Rasotto and V. Zappulli in a 2011 issue of "Veterinary Pathology" and "Biochemical Properties of Regulatory Peptides Derived from Milk Proteins" by H. Meisel in a 1997 issue of "Biopolymers."

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) as senile plaques and cerebral amyloid angiopathy, and hyperphosphorylated tau (hp-tau) as neurofibrillary tangles in the brain. The AD-related pathology has been reported in several non-human animals, and most animals develop only the Aβ or tau pathology. We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species (seal, sea lion, and walrus). Molecular analyses revealed that the sequence of pinniped Aβ was identical to that of human Aβ. Histopathological examinations detected argyrophilic plaques composed of Aβ associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aβ plaques. Aβ deposits were observed in the blood vessel walls of the meninges and cerebrum. Pinniped tau protein was physiologically subjected to alternative splicing at exons 2, 3, and 10, and presented as five isoforms: two 3-repeat tau isoforms (1N3R, 2N3R) and three 4-repeat tau isoforms (0N4R, 1N4R, 2N4R); 0N3R tau isoform was absent. Histopathological examinations revealed argyrophilic fibrillar aggregates composed of hp-tau in the neuronal somata and neurites of aged pinniped brains. Few hp-tau aggregates were found in oligodendrocytes and microglia. Biochemically, hp-tau of the 3-repeat and 4-repeat isoforms was detected in brain sarkosyl-insoluble fractions. Aβ and hp-tau both predominantly accumulated in the neocortex, particularly the frontal cortex. Furthermore, the activation of GSK-3β was detected within cells containing hp-tau aggregates, and activated GSK-3β was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aβ deposition, the activation of GSK-3β contributes to hp-tau accumulation in pinniped brains. Here, we report that pinniped species naturally accumulate Aβ and tau with aging, similar to the human AD pathology.

Abstract Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.

A 2-year-old spayed female Shiba Inu was presented with progressive non-ambulatory bilateral paraparesis, back pain, and urinary incontinence. CT and MRI revealed multiple vertebral malformations and type IV dermoid sinus. Hemilaminectomy was performed in T1–T5 to remove the dermoid sinus and granulomatous lesion that infiltrated into the spinal cord parenchyma. Histopathological examination of the excised tissue revealed type IV dermoid sinus with granulomatous meningomyelitis. After surgery, back pain was resolved, and the dog recovered ambulation and voluntary urination at the time of follow-up 4 months after surgery.

Equus caballus papillomavirus type 2 (EcPV2) infection has been associated with genital squamous cell carcinoma (SCC) development in horses. However, very few reports on EcPV2-associated disease in Asia exist. Our study characterizes pathological and virological features of an EcPV2-associated vulvar SCC from a Japanese mare. Conventional PCR, in situ hybridization, reverse-transcriptase PCR and immunohistochemistry confirmed the presence and distribution of EcPV2 within the lesion and suggested that p53 degradation may not be the mechanism by which this virus induces neoplastic transformation. The complete viral sequence in this Japanese case shows near perfect sequence homology with European reference strains of EcPV2, which may be useful when considering the target for future EcPV2 vaccine development. This report also serves to highlight the importance of EcPV2 in female (vulvar) neoplasia, which is less commonly recognized than EcPV2-induced male (penile or preputial) neoplasia. Finally, the SCC described in this mare was an unusual acantholytic variant that has not been reported previously in horses. It is the first report of EcPV2 identified from genital SCC in Asia and underscores the likely worldwide distribution of this virus and its consistent association with equine genital neoplasia.

Epilepsy surgery is a common therapeutic option in humans with drug-resistant epilepsy. However, there are few reports of intracranial epilepsy surgery for naturally occurring epilepsy in veterinary medicine. A 12-year-old neutered male domestic shorthair cat with presumed congenital cortical abnormalities (atrophy) in the right temporo-occipital cortex and hippocampus had been affected with epilepsy from 3 months of age. In addition to recurrent epileptic seizures, the cat exhibited cognitive dysfunction, bilateral blindness, and right forebrain signs. Seizures had been partially controlled (approximately 0.3–0.7 seizures per month) by phenobarbital, zonisamide, diazepam, and gabapentin until 10 years of age; however, they gradually became uncontrollable (approximately 2–3 seizures per month). In order to plan epilepsy surgery, presurgical evaluations including advanced structural magnetic resonance imaging and long-term intracranial video-electroencephalography monitoring were conducted to identify the epileptogenic zone. The epileptogenic zone was suspected in the right atrophied temporo-occipital cortex and hippocampus. Two-step surgery was planned, and a focal cortical resection of that area was performed initially. After the first surgery, seizures were not observed for 2 months, but they then recurred. The second surgery was performed to remove the right atrophic hippocampus and extended area of the right cortex, which showed spikes on intraoperative electrocorticography. After the second operation, although epileptogenic spikes remained in the contralateral occipital lobe, which was suspected as the second epileptogenic focus, seizure frequency decreased to

Abstract A 7‐year‐old neutered female domestic shorthaired cat born in Poland and then moved to Japan presented to the local clinic with recent onset of convulsive cluster seizures and status epilepticus. Magnetic resonance imaging revealed bilateral swelling of the hippocampus with T2 hyperintensity and contrast enhancing image, suggesting hippocampal necrosis. The cat completely recovered after treatment with antiepileptic drugs (AED) and administration of prednisolone (1 mg/kg PO q24h for 4 days and tapered). However, cluster seizures reoccurred and developed into status epilepticus despite increasing doses of AED. Although the convulsions were resolved by other AEDs, stupor and renal failure developed, and the cat was euthanized. Pathological findings were consistent with hippocampal necrosis. Immunological analysis for leucine‐rich glioma inactivated 1 (LGI1) autoantibodies was negative, but antibodies against DCC (deleted in colorectal carcinoma) known as netrin‐1 receptor were found. This report describes a case of feline autoimmune limbic encephalitis and hippocampal necrosis that were presumably associated with DCC autoantibodies.

Neonatal encephalopathy with seizures (NEwS) is an epileptic encephalopathy with an autosomal recessive inheritance pattern found in Standard Poodle puppies. The causal genetic variant for NEwS has been identified as a homozygous missense mutation in ATF2 (c.152T>G, p.Met51Arg), and a pathological cerebellar change has been reported. Magnetic resonance imaging showed reduced whole-brain size, dilated ventricles, developmental abnormalities of the white matter of the cerebrum, white matter signal abnormalities in the occipital lobe, and abnormal morphology of the cerebellum. Histopathology included previously unrecognized irregular neuronal migration in the subventricular zone around the lateral ventricles in the frontal lobe and white matter rarefaction especially at the level of the occipital lobe in the cerebrum in addition to the cerebellar cortical dysplasia that has been previously described. The findings of this case may highlight the critical role of ATF2 in neurodevelopmental processes in the canine brain.

Abstract Background Invasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC. Methods Total RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks. Results Differential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E2 receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property. Conclusions Our data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC.

This study assessed the feasibility of using a vegetable extract, MGM-P (quebracho tannin product), as an alternative to antibiotics for weaned piglets; it investigated MGM-P effects on growth performance, diarrhea, and overall health in early-weaned piglets. In total, 24 piglets were allocated to three treatment groups fed basal diets supplemented with 0, 0.2%, or 0.3% MGM-P for 20 days. The addition of 0.3% MGM-P to the diet of early-weaned piglets improved diarrhea incidence, hematological parameters, and intestinal mucosa structure. Furthermore, the addition of 0.2% or 0.3% MGM-P to the diet of early-weaned piglets did not affect their overall health. Importantly, MGM-P had no effects on average daily gain (ADG), average daily feed intake (ADFI), or feed conversion ratio (FCR). Gut morphology analysis showed that treatment with 0.3% MGM-P enhanced the jejunal villus height (p < 0.05) while reducing the ileal crypt depth (p < 0.05) and colon mucosal thickness (p < 0.05). Collectively, the findings suggested that the use of MGM-P as an alternative to dietary antibiotics could improve diarrhea incidence in early-weaned piglets without negative effects on growth performance or overall health.

In July 2004, an outbreak of influenza A (H3N2) was detected at 3 Bhutanese refugee camps in southeastern Nepal. Hemagglutination inhibition showed that ≈40% of the viruses from this outbreak were antigenically distinct from the A/Wyoming/3/03 vaccine strain. Four amino acid differences were observed in most of the 26 isolates compared with the A/Wyoming/3/2003 vaccine strain. All 4 substitutions are located within or adjacent to known antibody-binding sites. Several isolates showed a lysine-to-asparagine substitution at position 145 (K145N) in the hemagglutinin molecule, which may be noteworthy since position 145 is located within a glycosylation site and adjacent to an antibody-binding site. H3N2 viruses continue to drift from the vaccine strain and may remain as the dominant strains during the 2005–2006 influenza season. Thus, the 2005–2006 Northern Hemisphere vaccine strain was changed to A/California/7/2004, a virus with all 4 amino acid substitutions observed in these Nepalese isolates.