Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer's disease mouse models.

Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.

Comparison of selected cytomorphological features of canine pemphigus foliaceus and superficial pyoderma.

BACKGROUND: Cytological detection of acantholytic keratinocytes (acantholytic cells [AC]) helps to identify canine pemphigus foliaceus (cPF) yet AC also occurs in superficial pyoderma (SP), the main differential diagnosis. HYPOTHESIS/OBJECTIVES: To compare selected cytomorphological features of cPF and SP and to establish cytological diagnostic criteria that could differentiate cPF from SP. ANIMALS: 40 and 51 client-owned dogs with PF and SP, respectively. MATERIALS AND METHODS: Impression smears from cPF (64), impetigo (40) and exfoliative superficial pyoderma (ESP) (17) samples were stained with Romanowsky stain, randomised, blinded and evaluated by two investigators independently. The entire sample was screened (×500 or ×1000 magnification) for round (AC1), boat (AC2) and raft AC, eosinophils and bacteria. Interobserver agreements were calculated. RESULTS: The average number of the 10 highest ×500 fields for AC1 and AC2 was significantly higher in PF than SP (p < 0.0001; Kruskal-Wallis test). Rafts and eosinophils were more common in PF than SP (p < 0.0001; chi-square test), while bacteria were rare in PF (5%; p < 0.0001; chi-square test). Observations between the experienced and novice investigators were highly correlated. An ROC analysis identified five AC1/×500-magnification field as a suitable cut-off value for predicting PF diagnosis. This cut-off value was tested by two additional investigators, who identified sensitivity of 84%-100%, specificity of 95%-97% and accuracy of 95%-96% for the diagnosis of cPF. CONCLUSIONS AND CLINICAL RELEVANCE: Criterion-based impression smear cytological evaluation can provide strong evidence to support the clinical diagnosis. Acantholytic cell morphology varies in cPF and SP, and experience can improve accuracy in cytological differentiation.

Retrospective analysis of histologic lesions in captive arachnids.

Invertebrates, including arachnids, are a common taxon in zoological collections. Invertebrate medicine and pathology are emerging subspecialties, but there is limited reference material or published resources describing histologic lesions in arachnids. Histopathology of 26 captive arachnids (20 spiders and 6 scorpions) from institutional collections was reviewed. Most animals were found dead with limited clinical signs. Tissues evaluated included body wall (cuticle and epidermis), skeletal muscle, book lungs, digestive tract (pharynx, esophagus, sucking stomach, midgut tube, midgut diverticula, and stercoral pocket), central and peripheral nervous system, heart, hemolymph vessels and sinuses, Malpighian tubules, coxal glands, and gonads. Inflammation was frequent (24/26, 92%), and seen in multiple organs (18/24, 75%) with the midgut diverticulum most commonly affected (14/24, 58%) followed by the book lungs (13/24 arachnids, 54%), and body wall (8/24 arachnids, 33%). Inflammation comprised hemocyte accumulation, hemocytic coagula, melanization, and nodulation. Infectious agents, including bacteria (11/26, 42%), fungi (10/26, 38%), and parasites (2/26, 8%), were seen within inflammatory aggregates. Coinfection with multiple infectious agents was common (6/24, 25%). No etiologic agent was identified in 7/24 (29%) cases with inflammatory lesions. Lesions suggestive of decreased nutritional status or increased metabolic rate included midgut diverticula atrophy in 11/26 (42%) animals and skeletal muscle atrophy in 6/26 (23%) animals. Atrophic lesions were seen in combination with infection (8/11, 73%), pregnancy (2/11, 18%), male sex (2/11, 18%), or without other lesions (1/11, 9%). Other suspected contributors to death included dysecdysis-associated trauma (2/26, 8%) and uterine intussusception (1/26, 4%). No animals had neoplasia.

Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. METHODS: Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. RESULTS: CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1ß mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. CONCLUSIONS: Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.

Cutaneous epitheliotropic lymphosarcoma in a captive white catfish (Ameiurus catus Linnaeus).

A wild caught white catfish (Ameiurus catus Linnaeus) developed multiple cutaneous masses. Cytology revealed neoplastic lymphocytes and microscopy confirmed dermal infiltration with epitheliotropism in the epidermis, oral mucosa, and cornea, without internal organ involvement. Transmission electron microscopy did not identify viral particles. Histopathology supported cutaneous epitheliotropic lymphosarcoma, a condition most commonly reported in mammals. This is the first reported case of cutaneous epitheliotropic lymphosarcoma in an ictalurid and one of the few published cases of this condition in any fish species.

Trunk-dominant and classic facial pemphigus foliaceus in dogs - comparison of anti-desmocollin-1 and anti-desmoglein-1 autoantibodies and clinical presentations.

BACKGROUND: Canine trunk-dominant pemphigus foliaceus (PF) is mentioned rarely in the literature. HYPOTHESIS/OBJECTIVES: The goal of this study was to provide clinical description of trunk-dominant PF and to demonstrate the prevalence of serum antikeratinocyte, anti-desmocollin-1 (DSC1) and anti-desmoglein-1 (DSG1) antibodies, and determine their diagnostic value in this particular PF phenotype. MATERIALS AND METHODS: Clinically relevant information was collected from 31, 25 and 34 dogs with trunk-dominant and facial PF and superficial pyoderma (SP), respectively. Sera from these dogs were tested for antikeratinocyte, anti-DSC1 and anti-DSG1 antibodies using indirect immunofluorescence on canine tissues and DSC1- and DSG1-transfected cells. Sera from healthy dogs and dogs with clinically irrelevant diseases served as controls. RESULTS: Footpad involvement and grouped/polycyclic lesion organisation were identified as features of both PF phenotypes, and not of SP. Antikeratinocyte immunoglobulin (Ig)G was not specific for canine PF. By contrast, antigen-specific IgG was detected only in PF sera; anti-DSC1 IgG in 100% and 58% of dogs with facial and trunk-dominant PF, respectively, and anti-DSG1 IgG in 7% of dogs with trunk-dominant PF only. CONCLUSIONS: Trunk-dominant PF shares DSC1 as a major autoantigen with facial PF. The ability to detect anti-DSC1 IgG is lower in trunk-dominant PF, yet despite the lower sensitivity, the positive predictive value and accuracy of this particular anti-DSC1 IgG test are high. A negative test result, however, cannot exclude the diagnosis, and characteristic clinical features such as footpad involvement and/or grouped/polycyclic lesions must be considered when distinguishing trunk-dominant PF from its most relevant differential diagnosis: SP.

Contexte - Le pemphigus foliacé (PF) dominant le tronc chez le chien est rarement mentionné dans la littérature. Hypothèse/Objectifs - Le but de cette étude était de fournir une description clinique du PF dominant le tronc et de démontrer la prévalence des anticorps sériques anti-kératinocytes, anti-desmocolline-1 (DSC1) et anti-desmogléine-1 (DSG1), et de déterminer leur valeur diagnostique dans ce phénotype particulier de PF. Matériels et méthodes - Des informations cliniquement pertinentes ont été recueillies auprès de 31, 25 et 34 chiens atteints respectivement de PF à dominante tronculaire et faciale et de pyodermite superficielle (SP). Les sera de ces chiens ont été testés pour les anticorps anti-kératinocytes, anti-DSC1 et anti-DSG1 en utilisant l'immunofluorescence indirecte sur des tissus canins et des cellules transfectées avec DSC1 et DSG1. Des sera de chiens sains et de chiens atteints de maladies cliniquement non pertinentes ont servi de témoins. Résultats - L'implication du coussinet plantaire et l'organisation des lésions groupées / polycycliques ont été identifiées comme des caractéristiques des deux phénotypes PF, et non de SP. L'immunoglobuline antikératinocytaire (Ig)G n'était pas spécifique du PF canin. En revanche, l'IgG spécifique de l'antigène n'a été détectée que dans les sera de PF ; IgG anti-DSC1 chez 100 % et 58 % des chiens atteints de PF faciale et tronc-dominante, respectivement, et anti-DSG1 IgG chez 7 % des chiens avec PF tronc-dominant uniquement. Conclusions - Le PF à dominante tronculaire partage DSC1 comme auto-antigène majeur avec le PF facial. La capacité à détecter les IgG anti-DSC1 est plus faible chez les PF à dominante tronculaire, mais malgré la sensibilité plus faible, la valeur prédictive positive et la précision de ce test IgG anti-DSC1 particulier sont élevées. Cependant, un résultat de test négatif ne peut pas exclure le diagnostic, et les caractéristiques cliniques caractéristiques telles que l'atteinte du coussinet plantaire et/ou les lésions groupées/polycycliques doivent être prises en compte lors de la distinction entre la PF à dominante tronculaire et son diagnostic différentiel le plus pertinent : la SP.

Introducción- el pénfigo foliáceo (PF) de distribución truncal predominante se describe raramente n la literatura. Hipótesis/Objetivos- el objetivo de este estudio fue proporcionar una descripción clínica del PF truncal y demostrar la prevalencia de anticuerpos séricos antiqueratinocitos, antidesmocolina-1 (DSC1) y antidesmogleína-1 (DSG1), y determinar su valor diagnóstico en este fenotipo PF particular. Materiales y métodos- se recopiló información clínicamente relevante de 31, 25 y 34 perros con PF dominante truncal, PF dominante facial y pioderma superficial (PS), respectivamente. Los sueros de estos perros se analizaron en busca de anticuerpos antiqueratinocitos, anti-DSC1 y anti-DSG1 mediante inmunofluorescencia indirecta en tejidos caninos y células transfectadas con DSC1 y DSG1. Sueros de perros sanos y perros con enfermedades clínicamente irrelevantes sirvieron como controles. Resultados- la afectación de la almohadilla plantar y la organización de lesiones agrupadas/policíclicas se identificaron como características de ambos fenotipos de PF y no de SP. La inmunoglobulina (Ig)G antiqueratinocitos no fue específica para la PF canina. Por el contrario, la IgG específica de antígeno se detectó solo en sueros PF; IgG anti-DSC1 en el 100 % y el 58 % de los perros con PF predominante en la cara y el tronco, respectivamente, y IgG anti-DSG1 en el 7 % de los perros con PF predominante en el tronco solamente. Conclusiones- el PF dominante truncal comparte DSC1 como un autoantígeno importante con el PF facial. La capacidad para detectar IgG anti-DSC1 es menor en la PF dominante truncal; sin embargo, a pesar de la menor sensibilidad, el valor predictivo positivo y la precisión de esta prueba de IgG anti-DSC1 en particular son altos. Sin embargo, un resultado negativo de la prueba no puede excluir el diagnóstico, y deben tenerse en cuenta las características clínicas, como la afectación de las almohadillas plantares y/o las lesiones agrupadas/policíclicas, al distinguir la PF dominante truncal de su diagnóstico diferencial más relevante: SP.

Contexto - O pênfigo foliáceo (PF) canino predominante no tronco é raramente relatado na literatura. Hipótese/Objetivos - O objetivo deste estudo foi apresentar a descrição clínica do PF predominante no tronco e demonstrar a prevalência de anticorpos anti-queratinócitos, anti-desmocolina-1 (DSC1) e anti-desmogleína-1 (DSG1), e determinar o seu potencial diagnóstico neste tipo particular de PF. Materiais e métodos - Informações clinicamente relevantes foram coletadas de 31, 25 e 34 cães com PF predominante no tronco, PF facial e piodermite superficial (PS), respectivamente. Os soros destes cães foram testados para anticorpos anti-queratinócitos, anti-DSC1 e anti-DSG1 utilizando imunofluorescência indireta em tecidos caninos e em células DSC1 e DSG1 transfectadas. Os soros de cães saudáveis e cães com doenças clinicamente irrelevantes serviram de controle. Resultados - O acometimento dos coxins e a organização agrupada/policíclica das lesões foram identificadas como características de ambos os fenótipos de PF, não de PS. A imunoglobulina (Ig)G anti-queratinócitos não foi específica para PF. Em contraste, IgG antígeno-específica foi detectada apenas no soro de PF; IgG anti-DSC1 em 100% e 58% dos cães com PF facial e predominante no tronco, respectivamente, e IgG anti-DSG1 em 7% dos cães somente acometidos pelo PF predominante no tronco. Conclusões - O PF predominante no tronco compartilha DSC1 como um autoantígeno principal com PF facial. A capacidade de detectar IgG anti-DSC1 é menor no PF predominante no tronco, mas apesar da sensibilidade mais baixa, o valor preditivo positivo e a precisão do teste IgG anti-DSC1 específico são altos. Um resultado de teste negativo, no entanto, não pode excluir o diagnóstico, e características clínicas típicas, como envolvimento do coxim plantar e/ou lesões agrupadas/policíclicas, devem ser consideradas ao distinguir PF predominante no tronco de seu diagnóstico diferencial mais relevante: PS.

Localised erythema multiforme-like reaction confined to a region of clipper burn in a dog.

Localised erythema multiforme (LEM) is only reported to occur in humans and not in domestic species. This case report describes the clinical and histopathological features of LEM-like reaction in a dog, confined to a region of clipper burn.

L'érythème polymorphe localisé (LEM) n'est signalé que chez l'homme et non chez les animaux domestiques. Ce cas clinique décrit les caractéristiques cliniques et histopathologiques d'une réaction de type LEM chez un chien, localisé sur une région de brûlure de tondeuse.

El eritema multiforme localizado (LEM) sólo se ha descrito en seres humanos y no en especies domésticas. Este artículo describe un caso de un perro con una lesión confinada a una zona de quemadura por un rasurador cuyas características clínicas e histopatológicas fueron similares a LEM.

O eritema multiforme localizado (EML) é relatado apenas em humanos e não em animais domésticos. Este relato de caso descreve as características clínicas e histopatológicas de uma reação EML-símile em um cão, limitada a uma região de queimadura por lâmina de tosa.

Three-dimensional (3D) imaging of lipids in skin tissues with infrared matrix-assisted laser desorption electrospray ionization (MALDESI) mass spectrometry.

Three-dimensional (3D) mass spectrometry imaging (MSI) has become a growing frontier as it has the potential to provide a 3D representation of analytes in a label-free, untargeted, and chemically specific manner. The most common 3D MSI is accomplished by the reconstruction of 2D MSI from serial cryosections; however, this presents significant challenges in image alignment and registration. An alternative method would be to sequentially image a sample by consecutive ablation events to create a 3D image. In this study, we describe the use of infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) in ablation-based 3D MSI for analyses of lipids within fresh frozen skin tissue. Depth resolution using different laser energy levels was explored with a confocal laser scanning microscope to establish the imaging parameters for skin. The lowest and highest laser energy level resulted in a depth resolution of 7 µm and 18 µm, respectively. A total of 594 lipids were putatively detected and detailed lipid profiles across different skin layers were revealed in a 56-layer 3D imaging experiment. Correlated with histological information, the skin structure was characterized with differential lipid distributions with a lateral resolution of 50 µm and a z resolution of 7 µm.

Bullous amyloidosis in a horse: first description in veterinary medicine.

BACKGROUND: Bullous amyloidosis is a rare disease in humans that has not been described in a veterinary species in the peer-reviewed literature. The human disease is characterised by haemorrhagic vesicles and bullae on the skin and mucosae, which form due to amyloid deposition. HYPOTHESIS/OBJECTIVES: To describe the clinical features, laboratory analysis and histopathological features of an unique presentation of bullous disease in a horse. ANIMALS: A 17-year-old thoroughbred mare presented for weight loss and severe oral cavity ulcers. METHODS AND MATERIALS: Investigations involved haematological evaluation, chemistry profiles, gastroscopy and serum protein electrophoresis, and, postmortem, histopathological evaluation, Congo-red staining and transmission electron microscopy (TEM). RESULTS: Haemorrhagic vesicles and bullae occurred on the mucosa of the oral cavity, lips, oesophagus and stomach, and much less the muzzle, face and mucocutaneous areas of the perineum, where scarring was evident. Histopathological evaluation and Congo-red staining confirmed the presence of amyloid deposits in dermis and submucosa, in association with vesicle and bulla formation, consistent with bullous amyloidosis. TEM confirmed amyloid fibril deposition in the dermis and along the basement membrane zone. Clefts occurred in the superficial dermis and submucosa, which explained haemorrhage and scarring. The presence of a polyclonal gammopathy and the rapid abolishment of Congo-red staining with performate pretreatment supported serum amyloid A and secondary amyloidosis. CONCLUSION AND CLINICAL IMPORTANCE: Bullous amyloidosis is a novel disease of the horse and a newly recognised differential for bullous disease, for which the haemorrhagic nature of bullae, scarring and deep secondary ulcers are considered clinical clues to the condition.

Canine junctional epidermolysis bullosa due to a novel mutation in LAMA3 with severe upper respiratory involvement.

BACKGROUND: Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone. OBJECTIVES: To characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of puppies with severe upper respiratory involvement, and to identify an associated genetic variant. ANIMALS: Five of eight puppies in an Australian cattle dog cross-bred litter showed signs of skin fragility. Three were stillborn and one died at one month of age. The two surviving puppies were presented with blistering skin disease and severe respiratory distress. Additionally, one unaffected sibling was examined and blood was obtained for genetic testing. METHODS AND MATERIALS: Post-mortem examination, histopathological evaluation and electron microscopy were performed. Whole genome sequencing (WGS) of one affected puppy was compared to a database of 522 dogs of 55 different breeds for variant analysis. Sanger sequencing of one additional affected and one unaffected sibling confirmed the variant. RESULTS: Clinically, severe mucocutaneous ulcers occurred in frictional areas with claw sloughing. Histopathological results revealed subepidermal clefts and electron microscopy confirmed the split in the lamina lucida. Post-mortem examination documented extensive pharyngeal and laryngeal lesions with granulation tissue and fibrinous exudate obscuring the airway. Moderate tracheal hypoplasia contributed. The WGS revealed a novel missense variant in the laminin α3-chain XP_537297.2p(Asp2867Val), with an autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL RELEVANCE: A novel variant in LAMA3 caused a generalized and severe phenotype of JEB with an unique clinical presentation of upper airway obstruction.

Deep pemphigus (pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus) in dogs, cats and horses: a comprehensive review.

Pemphigus is the term used to describe a group of rare mucocutaneous autoimmune bullous diseases characterized by flaccid blisters and erosions of the mucous membranes and/or skin. When the autoantibodies target desmosomes in the deep layers of the epidermis, deep pemphigus variants such as pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus develop. In this article, we will review the signalment, clinical signs, histopathology and treatment outcome of pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus in dogs, cats and horses; where pertinent, we compare the animal diseases to their human homologue. Canine, feline and equine pemphigus vulgaris, pemphigus vegetans and paraneoplastic pemphigus have many features similar to the human counterpart. These chronic and often relapsing autoimmune dermatoses require aggressive immunosuppressive therapy. In animals, the partial-to-complete remission of pemphigus vulgaris and pemphigus vegetans has been achieved with high dose glucocorticoid therapy, with or without adjunct immunosuppressants; the prognosis is grave for paraneoplastic pemphigus.

Cutaneous polyautoimmunity in two unrelated dogs: pemphigus foliaceus and generalized discoid lupus erythematosus.

BACKGROUND: Polyautoimmunity, the concurrent expression of two or more distinct autoimmune diseases (ADs) in a single individual, is a known phenomenon in humans and has been rarely reported in dogs. To the best of the authors' knowledge, comorbid pemphigus foliaceus (PF) and generalized discoid lupus erythematosus (GDLE) has not been reported in dogs. HYPOTHESIS/OBJECTIVES: To describe the clinical, histological and immunological features and treatment outcome of two unrelated dogs with comorbid PF and GDLE. ANIMALS: One 10-year-old, spayed German shepherd dog and one 8-year-old, castrated American Staffordshire terrier presented for evaluation of a symmetrical, facial- and/or pedal-dominant pustular dermatitis with concurrent, truncal scaly plaques. METHODS: For each dog, clinicopathological characterization included physical examination, lesion cytological evaluation, bacterial culture and sensitivity testing, skin histopathological investigation and direct and indirect immunofluorescence testing. Additional diagnostic imaging and haematological testing was performed to exclude extracutaneous disease. RESULTS: Both dogs exhibited lesions clinically and histologically compatible with PF and GDLE. Moreover, one dog exhibited generalized leucotrichia and chronic superficial keratitis. Remission was achieved with immunosuppressive dosages of prednisolone [high-dose pulse (Case 1) or standard immunosuppressive dosage (Case 2)] and ciclosporin (5-6 mg/kg/day). Tissue-bound antikeratinocyte immunoglobulin (Ig)G and IgM were detected in both dogs. A weak basement membrane zone deposit of C3 was seen in one dog. Circulating antikeratinocyte and anti-desmocollin-1 IgG were detected in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Cutaneous polyautoimmunity can occur in the dog. Depending on the specific disease combinations, overlapping clinical features may present diagnostic and/or therapeutic challenges. Moreover, these cases should be monitored for development of additional cutaneous or extra-cutaneous AD(s).

Rapid response of hyperkeratotic erythema multiforme to oclacitinib in two dogs.

BACKGROUND: Hyperkeratotic erythema multiforme (HKEM) is a clinically distinct dermatosis and poorly characterized syndrome, comprised of hyperkeratotic plaques with variable symmetry and apoptosis similar to "classic" erosive canine EM. Hyperkeratotic EM has a protracted clinical course and, although treatments with glucocorticoids, azathioprine and/or ciclosporin have been tried, rates of remission are low. OBJECTIVES: To describe successful treatment of HKEM in two dogs using oclacitinib. ANIMALS: A 7-year-old, spayed Havanese dog (Case 1) and a 1-year-old, intact cryptorchid Dachshund dog (Case 2). METHODS: Case characterization and clinical diagnoses were based on lesion character, surgical biopsy, cytological evaluation, culture, direct immunofluorescence (DIF) and expected responses to treatments. RESULTS: Both cases exhibited multifocal, often symmetrical hyperkeratotic plaques with adherent scale. Histological findings revealed prominent epidermal hyperplasia, parakeratotic hyperkeratosis, lymphocytic dermatitis and transepidermal apoptosis with lymphocytic satellitosis. DIF revealed fine, patchy IgG, IgM and IgA basement membrane deposits (Case 2). Both dogs exhibited rapid improvement with oral oclacitinib (0.6-0.9 mg/kg twice daily) with a complete remission of clinical signs observed in 12 and seven weeks in cases 1 and 2, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Oclacitinib could be considered as a fast-acting and effective treatment option for HKEM in dogs.

Autoimmune diseases affecting skin melanocytes in dogs, cats and horses: vitiligo and the uveodermatological syndrome: a comprehensive review.

Autoimmune dermatoses targeting melanocytes have gained attention in human medicine due to their progressive nature and the social impact suffered by affected individuals. In veterinary medicine, vitiligo and the uveodermatological syndrome are the two autoimmune diseases that are known to affect skin melanocytes.In the first part of this article, we will review the signalment, clinical signs, histopathology and the treatment outcome of vitiligo in dogs, cats and horses; where pertinent, we compare the animal diseases to their human homologue. In a similar fashion, the information on the uveodermatological syndrome in dogs is reviewed and, where relevant, it is compared to the Vogt-Koyanagi-Harada (VKH) syndrome in humans.Canine, feline and equine vitiligo have many features that mirror their human counterparts. The most effective treatment and outcome of vitiligo in animals remain unclear. The canine uveodermatological syndrome resembles the incomplete VKH variant in humans; for affected individuals, an immediate diagnosis and aggressive treatment are crucial to prevent the development of blindness.

Endothelial alterations in a canine model of immune thrombocytopenia.

Bleeding heterogeneity amongst patients with immune thrombocytopenia (ITP) is poorly understood. Platelets play a role in maintaining endothelial integrity, and variable thrombocytopenia-induced endothelial changes may influence bleeding severity. Platelet-derived endothelial stabilizers and markers of endothelial integrity in ITP are largely underexplored. We hypothesized that, in a canine ITP model, thrombocytopenia would lead to alterations in the endothelial ultrastructure and that the Von Willebrand factor (vWF) would serve as a marker of endothelial injury associated with thrombocytopenia. Thrombocytopenia was induced in healthy dogs with an antiplatelet antibody infusion; control dogs received an isotype control antibody. Cutaneous biopsies were obtained prior to thrombocytopenia induction, at platelet nadir, 24 hours after nadir, and on platelet recovery. Cutaneous capillaries were assessed by electron microscopy for vessel thickness, the number of pinocytotic vesicles, the number of large vacuoles, and the number of gaps between cells. Pinocytotic vesicles are thought to represent an endothelial membrane reserve that can be used for repair of damaged endothelial cells. Plasma samples were assessed for vWF. ITP dogs had significantly decreased pinocytotic vesicle numbers compared to control dogs (P = 0.0357) and the increase in plasma vWF from baseline to 24 hours correlated directly with the endothelial large vacuole score (R = 0.99103; P < 0.0001). This direct correlation between plasma vWF and the number of large vacuoles, representing the vesiculo-vacuolar organelle (VVO), a permeability structure, suggests that circulating vWF could serve as a biomarker for endothelial alterations and potentially a predictor of thrombocytopenic bleeding. Overall, our results indicate that endothelial damage occurs in the canine ITP model and variability in the degree of endothelial damage may account for differences in the bleeding phenotype among patients with ITP.

The role of oclacitinib in the management of ischaemic dermatopathy in four dogs.

BACKGROUND: Ischaemic dermatopathy represents a heterogenous and poorly-characterized canine syndrome that is often refractory to conventional immunosuppression. Janus-kinase inhibitors (JAKinibs) are used for the treatment of various human autoimmune diseases, including dermatomyositis. Oclacitinib is a generally well-tolerated, veterinary-approved, nonselective JAKinib that has therapeutic potential as an immunosuppressant. HYPOTHESIS/OBJECTIVES: To describe four cases of treatment refractory juvenile-onset ischaemic dermatopathy that rapidly and durably responded to oclacitinib administration. ANIMALS: Four mixed-breed dogs, three 9-month-old male littermates and one 6-month-old female, were presented for generalized patchy alopecia, scarring and ulcerative dermatitis. Microscopic skin lesions were consistent with a severe ischaemic dermatopathy. METHODS AND MATERIALS: A complete remission of skin lesions could not be achieved in any dog with glucocorticoids alone, nor when these were combined with adjuvant immunosuppressants. Oclacitinib treatment was then initiated at the dosage of 0.4-0.7 mg/kg twice daily, along with a tapering regimen of oral prednisolone. RESULTS: A full clinical remission was achieved within four weeks of starting this combination therapy, with prednisolone being stopped within eight weeks thereof. Remission was maintained in two dogs with lower doses or dosing frequencies of oclacitinib, whereas the two others required persistent twice daily administration of this JAKinib. CONCLUSIONS AND CLINICAL IMPORTANCE: Oclacitinib was a useful immunosuppressive adjuvant to oral glucocorticoids for the treatment of refractory or severe cases of ischaemic dermatopathy in these four dogs. Such observation warrants further studies of the safety, efficacy and mechanism of action of oclacitinib as an immunosuppressant.

Cutaneous lupus erythematosus in dogs: a comprehensive review.

Since the first description of discoid lupus erythematosus (LE) in two dogs in 1979, the spectrum of canine cutaneous lupus erythematosus (CLE) variants has expanded markedly.In this review, we first propose an adaptation of the Gilliam-Sontheimer classification of CLE for dogs. We then review the signalment, clinical signs, laboratory and histopathology and treatment outcome of the currently recognized variants of canine CLE, which are vesicular CLE, exfoliative CLE, mucocutaneous LE and facial or generalized discoid LE. We end with a short description of the rare cutaneous manifestations of systemic LE in dogs.Canine CLE variants are heterogeneous, some of them mirror their human counterparts while others appear-thus far-unique to the dog. As most CLE subtypes seem to have a good prognosis after diagnosis, veterinarians are encouraged to become familiar with the spectrum of often-characteristic and unique clinical signs that would permit an early diagnosis and the rapid implementation of an effective treatment.

Generalized papillomatosis in three horses associated with a novel equine papillomavirus (EcPV8).

BACKGROUND: Currently, seven equine papillomaviruses (PV) are known and are associated with one of three different and distinct clinical presentations. HYPOTHESIS/OBJECTIVES: To report the clinical, histopathological and immunohistochemical findings in horses with generalized papillomatosis associated with a novel equine PV, Equus caballus papillomavirus 8 (EcPV8). ANIMALS: Three client-owned quarter horses. METHODS: Case report, retrospective. RESULTS: Dozens to thousands of papillomas involved the axilla, inguinal area and proximal limbs as well as the ventral and lateral neck, thorax and abdomen. Lesions were sometimes confluent in ventral areas. Fewer lesions were on the face, ears, distal limbs and genitalia. Plaque-type papillomas were small, 0.5 to 1.5 cm in diameter and hyperkeratotic. Histologically, plaque-type papillomas prominently involved follicular infundibula. Immunohistochemical findings demonstrated PV antigen in superficial keratinocyte nuclei. PCR using degenerate primers for the PV L1 gene and sequencing of amplicons revealed PV DNA sequences that were 98% identical for all three cases, but shared <70% identity to other PVs. Horses were otherwise healthy; serum immunoglobulin levels and peripheral blood lymphocyte phenotyping did not identify a known immunodeficiency syndrome. Lesions nearly completely resolved after 1.5 years in one horse and persisted for two years in another, despite intralesional human IFN-alpha treatment. The oldest horse was lost to follow-up. CONCLUSION AND CLINICAL IMPORTANCE: A novel equine papillomavirus (EcPV8) is associated with a distinct, plaque-type, generalized papillomatosis. Papillomas persisted for months to years, with or without treatment.

Bartonella henselae in a dog with ear tip vasculitis.

BACKGROUND: Bartonella henselae, a Gram-negative, zoonotic, alpha-proteobacteria has been previously implicated in association with cutaneous vasoproliferative lesions (bacillary angiomatosis), nodular panniculitis and multifocal erythema (erythema multiforme) in dogs. OBJECTIVE: Describe clinical, microbiological and histological lesions in a dog with ear margin vasculitis and B. henselae infection. ANIMALS: A 12-month-old, specific pathogen-free intact female beagle dog maintained in a vector-free laboratory animal resource facility. METHODS AND MATERIALS: Bartonella and Rickettsia serological evaluation, Bartonella and Rickettsia PCR, Bartonella alpha-proteobacteria growth medium (BAPGM) enrichment blood culture/PCR, histopathological investigation and confocal immunohistochemical evaluation. RESULTS: Serological investigation (seroreversion) and PCR testing of aural tissue biopsies failed to support Rickettsia rickettsii as a cause of the aural vasculitis; however, B. henselae, genotype San Antonio 2 DNA was amplified and sequenced from both ear tip margins and from normal-appearing abdominal skin. Seroconversion to B. henselae was documented retrospectively by IFA testing. Bartonella henselae organisms were visualized by confocal immunostaining within all three biopsies. Histopathology revealed small vessel necrotizing vasculitis and dermal necrosis. Bartonella henselae seroreversion and complete resolution of skin lesions occurred in conjunction with administration of oral doxycycline and enrofloxacin for six weeks. CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella henselae is an emerging zoonotic pathogen that has been associated with leucocytoclastic vasculitis in humans and may have had a contributing or causative role in the development of the cutaneous aural margin vasculitis in this beagle.

Scleromyxoedema in a dog.

BACKGROUND: In humans, scleromyxoedema is a chronic progressive skin condition traditionally characterized by deposits of mucin, increased number of fibroblasts and fibrosis in the skin, and by systemic disease. Thyroid disease is typically absent. A monoclonal gammopathy is usually present, as are other comorbidities. Descriptions of scleromyxoedema in the veterinary literature are limited to a single feline case. One dog, previously reported as having papular mucinosis, exhibited features that matched the more current diagnostic criteria of scleromyxoedema. OBJECTIVES: To describe generalized papular mucinosis in a dog with systemic illness and to compare the signs with those of human lichen myxoedematosus conditions, specifically scleromyxoedema. RESULTS: A nine-year-old female, spayed English springer spaniel dog presented with generalized papules and nodules (0.5-5 cm) on the body and proximal fore and hind limbs, sparing the face and distal limbs distal to carpi/tarsi. Larger nodules were erythematous. Nodules occurred in proximal limb muscles. The dog had concurrent osteoarthritis of the elbows and coxofemoral joints, developed generalized weakness, declined in health and was euthanized. Thyroid disease was lacking and a monoclonal gammopathy was not present. Histopathological evaluation revealed the classic triad of mucin, fibroblast proliferation and fibrosis with very mild inflammation, as described for humans. CONCLUSION AND CLINICAL IMPORTANCE: We document scleromyxoedema in a dog with significant morbidity and features of the human disease. Recognizing the typical histopathology is important for identifying cases and to establish a diagnosis. Systemic evaluation is important to identify evidence of internal disease and associated comorbidities, which are common, variable, and impact classification and prognosis in humans.