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Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and bioinformatic experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor-permissive collagen matrices that drive cell proliferation and suppress apoptosis in non-invasive and invasive breast cancer cell lines. In human triple-negative breast cancer biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in non-invasive compared to invasive regions. Similarly, bioinformatics analysis of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free, and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces the formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective therapeutic modality to limit recurrence in breast cancer patients., (© 2024. The Author(s).)

Cutaneous mastocytosis (CM) is a rare condition in young dogs characterized by multicentric cutaneous proliferation of neoplastic mast cells. Clinical data from 8 dogs that met inclusion criteria (age of onset less than 1.5 years, greater than 3 lesions) were obtained via a standardized survey. Biopsy samples were classified by the Kiupel/Patnaik grading systems and analyzed for c-KIT mutations. The median age of onset was 6 months (range: 2-17 months). Dogs had 5 to more than 50 lesions characterized as nodules, plaques, and papules. Seven dogs were pruritic. Clinical staging in 2 dogs did not reveal visceral involvement. No dogs had systemic illnesses at diagnosis. Histologically, CM was similar to cutaneous mast cell tumor (cMCT). Two dogs had neoplasms classified as high-grade/grade II while 6 dogs had low-grade/grade II neoplasms. No dogs had mutations in c-KIT exons 8 and 11. Treatment included antihistamines (8/8), corticosteroids (7/8), lokivetmab (3/8), and toceranib (1/8). Six dogs were alive with lesions at the end of the study with a median follow-up time of 898 days, while 2 dogs were euthanized. In dogs with high-grade/grade II neoplasms, one continued to develop lesions at 1922 days post-diagnosis, while the other dog was euthanized at 56 days post-diagnosis. One dog was euthanized 621 days post-diagnosis due to rupture of a neoplasm. CM occurs in young dogs and is histologically indistinguishable from cMCT. Current histologic grading systems did not apply uniformly to the dogs of the study and further studies are needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Allergic dermatoses are common in people and domestic animals. Resultant lesions are routinely biopsied and submitted for histological examination to confirm a diagnosis or rule out diseases with overlapping or atypical clinical features. Diagnostic pathologists and clinicians are often faced with the difficult task of determining whether an allergic reaction pattern is present on both the microscopic and macroscopic levels and correlating histopathologic findings with clinical and historical data to achieve a precise clinical diagnosis. The bulk of the current veterinary literature on allergic dermatoses focuses on atopic dermatitis in dogs, distantly followed by cats, horses, and other animals. The objectives of this review are to demonstrate the key histopathologic and clinical diagnostic features of the various allergy-mediated reaction patterns, and to provide diagnosticians with a practical guide for clinicopathological correlations. Current concepts in the pathophysiology of immediate hypersensitivity reactions, with a focus on atopic dermatitis, are discussed. Points of potential histopathologic overlap between the "classic" allergic reaction pattern and less common inflammatory, predominately eosinophilic, conditions that may mimic this pattern will be discussed with the goal of highlighting the critical need for collaboration between pathologists and clinicians in furthering patient care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.O.M. provides consultation services and has received research support from Stallergenes Greer Laboratories, North Carolina, USA.

Background: Dermal arteritis of the nasal philtrum (DANP) has been described in large-breed dogs., Objectives: To characterise clinically distinct, discrete fissures of the dorsolateral nasal alae associated with severe bleeding in German shepherd dogs (GSDs)., Animals: Fourteen privately owned GSDs with linear rostrolateral nasal alar fissures and a histopathological diagnosis of nasal vasculopathy., Materials and Methods: Retrospective analysis of medical records and histological slides., Results: Mean age of onset was 6 years. Before biopsy, episodic arteriolar bleeding was noted in 11 of the 14 (79%) dogs. Slide analysis revealed enlarged nasal arterioles with expanded vascular tunics and luminal stenosis beneath ulcers. Histopathological lesions consistent with mucocutaneous pyoderma and/or facial discoid lupus erythematosus were present in 5 of the 14 (36%) dogs. Enlarged arterioles stained blue with Alcian blue and Masson's trichrome stains, consistent with deposition of mucin and collagen, respectively. Immunohistochemical stains (neutrophil myeloperoxidase, IBA1, CD3) were performed. CD3 was negative for all dogs, whilst neutrophil myeloperoxidase and IBA1 occasionally demonstrated intramural neutrophils (3 of the 14 dogs, 21%) or histiocytes (1 of the 14 dogs, 7%) in altered vessels, respectively. All dogs underwent medical management and/or surgical excision. Treatments included tacrolimus, prednisone, ciclosporin-modified, pentoxifylline, antimicrobials and doxycycline/niacinamide. No dogs were treated with antimicrobials alone. For seven dogs with long-term follow-up, treatment response was complete in five (71%) and partial in two (29%), with six of the seven (86%) receiving immunomodulatory treatments to maintain remission., Conclusion and Clinical Relevance: Nasal alar arteriopathy of GSDs shares histopathological changes with DANP. It has characteristic clinical and histopathological features and appears amenable to immunomodulation., (© 2023 ESVD and ACVD.)

Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals. We investigated two unrelated cats with recurring erosions and ulcers on ear pinnae, oral mucosa, and paw pads that were suggestive of EB. Histopathology confirmed the diagnosis of EB in both cats. Case 1 was severe and had to be euthanized at 5 months of age. Case 2 had a milder course and was alive at 11 years of age at the time of writing. Whole genome sequencing of both affected cats revealed independent homozygous variants in COL17A1 encoding the collagen type XVII alpha 1 chain. Loss of function variants in COL17A1 lead to junctional epidermolysis bullosa (JEB) in human patients. The identified splice site variant in case 1, c.3019+1del, was predicted to lead to a complete deficiency in collagen type XVII. Case 2 had a splice region variant, c.769+5G>A. Assessment of the functional impact of this variant on the transcript level demonstrated partial aberrant splicing with residual expression of wildtype transcript. Thus, the molecular analyses provided a plausible explanation of the difference in clinical severity between the two cases and allowed the refinement of the diagnosis in the affected cats to JEB. This study highlights the complexity of EB in animals and contributes to a better understanding of the genotype-phenotype correlation in COL17A1 -related JEB.

Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca 2+ pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Canine cutaneous epitheliotropic T-cell lymphoma is a neoplasm with heterogeneous clinical and histopathological presentations. Survival times and responses to therapy are variable, and indicators to predict outcomes are lacking. Clinical and histopathological parameters from 176 archival cases from the University of Pennsylvania and University of Bern (2012-2018) were investigated for associations with clinical outcomes. Histopathological evaluation used digitized whole slide images and QuPath software. Cases included 107 female and 69 male dogs from 48 breeds, with a mean age of 10.4 years. Most common clinical signs were erythema ( n = 131), crusting ( n = 108), and scaling ( n = 102). Affected sites were haired skin ( n = 159), lip ( n = 74), nasal planum ( n = 49), and paw pads ( n = 48). The median survival time (MST) was 95 days (1-850). Dogs had 4.26-fold and 2.82-fold longer MST when treated with chemotherapy and prednisone, respectively, than when receiving supportive care. Haired skin involvement (hazard ratio [HR]: 2.039, 95% confidence interval [CI]: 1.180-3.523), erosions/ulcers (HR: 1.871, 95% CI: 1.373-2.548), nodules (HR: 1.496, 95% CI: 1.056-2.118), and crusting (HR: 1.454, 95% CI: 1.061-1.994) were clinical parameters predicting poor outcomes, whereas complete posttherapeutic clinical remission (HR: 0.469, 95% CI: 0.324-0.680) and a stable disease (HR: 0.323, 95% CI: 0.229-0.456) were associated with longer survival. Histopathological features associated with the increased risk of death were extensive infiltration of the panniculus (HR: 2.865, 95% CI: 1.565-4.809), mitotic count ≥7/high-power field (HR: 3.027, 95% CI: 2.065-4.439), cell diameter ≥10.0 µm (HR: 2.078, 95% CI: 1.281-3.372), and nuclear diameter ≥8.3 µm (HR: 3.787, 95% CI: 1.647-8.707).

Epidermolysis bullosa (EB) is a group of blistering disorders that includes several subtypes, classified according to their level of cleavage. Typical clinical signs are blisters and erosions resulting from minimal trauma. The disease has been described in many mammalian species and pathogenic variants in at least 18 different genes have been identified. In the present study, we investigated a Cardigan Welsh Corgi with congenital clinical signs consistent with epidermolysis bullosa. The puppy had blisters and erosions on the paw pads, and the oral mucosa. Histologic examination demonstrated the typical clefting between the dermis and epidermis and confirmed the clinical suspicion. We obtained whole genome sequencing data from the affected puppy and searched for variants in candidate genes known to cause EB. This revealed a heterozygous missense variant, KRT5:p.(E476K), affecting the highly conserved KLLEGE motif of keratin 5. The mutant allele in the affected puppy arose owing to a de novo mutation event as it was absent from both unaffected parents. Knowledge of the functional impact of KRT5 variants in other species together with the demonstration of the de novo mutation event establishes KRT5:p.(E476K) as causative variant for the observed EBS., (© 2022 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Ichthyoses are hereditary skin disorders characterized by the formation of scales and defects in the outermost layer of the epidermis. In dogs, at least six different breed-specific ichthyoses including a relatively common PNPLA1-related autosomal recessive ichthyosis in Golden Retrievers are known. In this study, we investigated 14 Golden Retrievers with scales that were not homozygous for the mutant PNPLA1 allele suggesting a genetically distinct new form of ichthyosis. Histopathological examinations showed lamellar, orthokeratotic hyperkeratosis, and mildly hyperplastic epidermis that led to the diagnosis of a nonepidermolytic ichthyosis. Combined linkage and homozygosity mapping in 14 cases and 30 nonaffected family members delimited a critical interval of ∼12.7 Mb on chromosome 23. Whole-genome sequencing of an affected dog revealed a single protein-changing variant within this region that was not present in 795 control genomes. The identified variant is a 14 bp deletion in the ABHD5 gene (c.1006_1019del), leading to a frameshift and altering the last 14 codons p.(Asp336Serfs*6). The genotypes at this variant showed perfect cosegregation with the ichthyosis phenotype in a large family comprising 14 cases and 72 controls. ABHD5 encodes an acyltransferase required for lipid metabolism. In humans, variants in ABHD5 cause Chanarin-Dorfman syndrome, a neutral lipid storage disease with ichthyosis. Our data in dogs together with the knowledge on the effects of ABHD5 variants in humans strongly suggest ABHD5:c.1006_1019del as candidate causative genetic variant for a new canine form of ichthyosis, which we propose to designate as Golden Retriever ichthyosis type 2 (ICH2)., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

The stratum corneum (SC), the outermost layer of the epidermis, serves a crucial role in maintaining body hydration and protection from environmental insults. When the stratum corneum is injured or when the genetic blueprints are flawed, the body is at risk of dehydration, secondary infections and allergen sensitization. Advancements in veterinary dermatology have revealed a wide gamut of disease from relatively benign to lethal that specifically arise from flawed structural proteins, enzymes or lipids needed to create the corneocytes and lipid bilayers of the SC. Some conditions closely mimic their human counterparts while others are unique to the dog. This review will focus on forms of ichthyosis in the dog., (© 2021 ESVD and ACVD.)

Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration have been clinically termed palisading granuloma in dogs. Study aims were to characterize the cellular infiltrate of canine palisading granuloma and document salient clinical features. Inclusion criteria were met for 36 dogs and encompassed nodular dermal and subcutaneous histiocyte-predominant cellular infiltrates targeting and enveloping collagen fibers/necrotic foci with palisading configurations. Infectious causes were ruled out via standard histochemical stains and/or clinical data. Medical records were reviewed for signalment, clinical features, treatment, outcome, and comorbidities. Immunohistochemistry (IBA1, CD204, E-cadherin) and Masson's trichrome stain were used to assess histiocytic populations and dermal collagen, respectively. The histiocytes had moderate or strong immunolabeling for IBA1 and CD204 in 36/36 dogs (100%) and mild positive immunolabeling for E-cadherin in 3/36 dogs (8%). Alteration of collagen was graded as moderate or strong in 32/36 dogs (89%) and mild in 3/36 dogs (8%). Large breeds predominated with 30/36 dogs (83%) being ≥23 kg. Focal nodules were identified in 31/36 dogs (86%). The head/face were involved in 19/36 dogs (53%) and the extremities in 18/36 dogs (50%). Lesions from the 5/36 dogs (14%) with multiple nodules contained prominent eosinophilic infiltrates. Following excision, there was no evidence of recurrence. In conclusion, palisading granulomas are a distinct, non-neoplastic, histiocyte-predominant inflammatory condition in dogs associated with altered dermal collagen and favorable prognosis.

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3 :c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3 :c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3 -related JEB in domestic animals.

Background: It has long been speculated that sterile granulomatous dermatitis and lymphadenitis (SGDL) occurs in adult dogs. However, only three published case reports exist., Hypothesis/objectives: To describe clinical presentation, identify breed predispositions, and assess treatment and outcomes of adult dogs with the histopathological diagnosis of SGDL., Animals: Included are 90 dogs with biopsies submitted to a veterinary teaching hospital with a histopathological diagnosis consistent with SGDL, from 2004 to 2018, of which 35 had medical records available for review., Methods: Data were analysed retrospectively from histopathology submission forms, medical records, surveys and telephone calls. Scoring systems were created to aid statistical analysis of outcomes., Results: Havanese dog (P < 0.0001), Australian shepherd dog (P < 0.0001), Irish setter (P < 0.0001), Dachshund (P = 0.0002), bichon frise (P = 0.0003) and Maltese dog (P = 0.004) were significantly over-represented breeds. The median age at onset was 1,292 days (3.54 years). Dogs up to five years of age were significantly over-represented (P < 0.01). Of 35 dogs with medical records available for review, the median treatment duration was 60 days and the median time to remission 28 days. Remission status was not established for five dogs but the remaining 30 dogs reached remission. Nineteen dogs remained in complete remission. Recrudescence occurred in 11 dogs (median follow-up 60 days)., Conclusions and Clinical Importance: This study shows a close parallel in clinical appearance, histopathological results and clinical behaviour, of both adult and juvenile onset SGDL; therefore, SGDL should be considered as a differential diagnosis for dogs of all ages., (© 2019 the European Society of Veterinary Dermatology and the American College of Veterinary Dermatology.)

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8-10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1 :c.2541&#95;2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog.

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1 :c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species., Competing Interests: The authors declare no conflict of interest.

Background: Canine acute eosinophilic dermatitis with oedema (CAEDE) and sterile neutrophilic dermatosis have overlapping clinical and histopathological features., Hypothesis/objectives: The objective of this study was to identify features that differentiate these entities., Animals: Forty dogs., Methods and Materials: Retrospective case series. Forty cases with diagnoses of either CAEDE and/or sterile neutrophilic dermatosis were included based on histopathological review. Medical records (29 of 40 dogs) were reviewed for clinical findings and historical data. Commercially available immunohistochemical stains for granulocytes and a Luna stain were performed (40 of 40 dogs) to assess the granulocytic infiltrate., Results: Nineteen cases had been previously diagnosed as CAEDE, seven cases had been designated as sterile neutrophilic dermatosis and 14 cases had overlapping features. Based on review and receiver operating characteristic (ROC) curve analysis, 30 cases with >12% eosinophils, enumerated by Luna staining, were diagnosed as eosinophilic dermatitis and oedema. Ten cases were diagnosed as sterile neutrophilic dermatosis. Dogs with CAEDE frequently had gastrointestinal signs (24 of 30;80%) and pruritus (11 of 30;33%). In dogs with sterile neutrophilic dermatosis, five of 10 (50%) had diagnoses of or histories compatible with immune-mediated polyarthropathy., Conclusions and Clinical Importance: In this case series, CAEDE was encountered more frequently than neutrophilic dermatosis and could be distinguished by the eosinophilic infiltrate, aided by a Luna stain. Concurrent arthralgia was more frequently identified with neutrophilic dermatosis. It remains unclear whether CAEDE and sterile neutrophilic dermatosis are separate disease entities or varied manifestations of the same disease., (© 2019 ESVD and ACVD.)

The stratum corneum (SC), the top layer of the epidermis, is the functional site of the skin barrier and serves to maintain hydration of the body by preventing water loss and thwarting the entrance of pathogens. The naked mole rat (NMR) (Heterocephalus glaber) is a rodent that resides in hypoxic underground tunnels in arid Africa. NMRs are not only hairless; their skin is devoid of glands and pain sensation. To understand how the skin barrier of the NMR is uniquely adapted to this environment, skin samples from the dorsum and ventral abdomen in one adult and one neonate were examined by transmission electron microscopy using both reduced osmium tetroxide to assess overall structure and ruthenium tetroxide post-fixation to assess lipid organization. These findings were compared with that of hairless mice-a well-defined model for skin barrier studies. The plasticity of the skin was evaluated on 10 NMRs from a colony at the Philadelphia Zoo in humid and dry conditions by measuring cutaneous hydration, transepidermal water loss (TEWL), and pH. The epidermal ultrastructure of the NMR differed from hairless mice by having the following features: decreased content of lamellar bodies (LBs), higher LB pleomorphism, periodic presence of abnormal lipid bilayers, and an unusually thick SC. The NMRs developed significant TEWL and a trend toward decreased hydration when subjected to dry conditions. While these features illustrate an imperfect skin barrier in terrestrial mammals, they likely represent adaptations of the poikilothermic NMRs to their unique natural fossorial climate. Prolonged exposure to decreased humidity could possibly lead to adverse health effects in this species., (© 2019 Wiley Periodicals, Inc.)

Background: Ischaemic dermatopathy encompasses a poorly understood subset of canine diseases that share similar clinical and histological features. Very little information is currently available regarding population characteristics, progression and outcome., Hypothesis/objectives: This study aimed to describe the clinical features and therapeutic outcomes of ischaemia dermatopathy, excluding familial dermatomyositis, using cases diagnosed by histopathological analysis., Animals: One hundred and seventy-seven cases submitted for histopathological analysis between 2005 and 2016 met inclusion criteria, of which 93 had complete medical records available., Methods and Materials: Both records and pointed surveys were used to retrieve information. Scoring systems were created to subjectively evaluate clinical outcomes and likelihood of a vaccine association., Results: Of 177 cases, toy and miniature poodles, Chihuahuas, Maltese, Yorkshire terriers and Jack Russell terriers were significantly over-represented (P < 0.001). Of the 93 cases for which historical data were obtained, median age at skin biopsy was five years (0.42-13 years) and median body weight was 7.3 kg (range 1.32-50.3 kg). The condition in 45 dogs (48.3%) was found likely to be associated with vaccination. Younger ages (P = 0.011) and higher body weights (P = 0.003) were positively correlated with greater likelihood of vaccination. Body weight <10 kg (P = 0.0045) and older ages (P = 0.0048) were significantly associated with worse outcomes., Conclusions and Clinical Importance: This study provides support for breed predispositions and identifies potential prognostic factors. Importantly, over half of the cases were considered unlikely to be vaccine-associated, demonstrating the need to investigate other underlying causes of this condition., (© 2019 ESVD and ACVD.)

The huemul (Hippocamelus bisulcus) is an endangered cervid endemic to southern Argentina and Chile. Here we report foot lesions in 24 huemul from Bernardo O'Higgins National Park, Chile, between 2005 and 2010. Affected deer displayed variably severe clinical signs, including lameness and soft tissue swelling of the limbs proximal to the hoof or in the interdigital space, ulceration of the swollen tissues, and some developed severe proliferative tissue changes that caused various types of abnormal wear, entrapment, and/or displacement of the hooves and/or dewclaws. Animals showed signs of intense pain and reduced mobility followed by loss of body condition and recumbency, which often preceded death. The disease affected both genders and all age categories. Morbidity and mortality reached 80% and 40%, respectively. Diagnostics were restricted to a limited number of cases from which samples were available. Histology revealed severe papillomatous epidermal hyperplasia and superficial dermatitis. Electron microscopy identified viral particles consistent with viruses in the Chordopoxvirinae subfamily. The presence of parapoxvirus DNA was confirmed by a pan-poxvirus PCR assay, showing high identity (98%) with bovine papular stomatitis virus and pseudocowpoxvirus. This is the first report of foot disease in huemul deer in Chile, putatively attributed to poxvirus. Given the high morbidity and mortality observed, this virus might pose a considerable conservation threat to huemul deer in Chilean Patagonia. Moreover, this report highlights a need for improved monitoring of huemul populations and synergistic, rapid response efforts to adequately address disease events that threaten the species., Competing Interests: The authors have declared that no competing interests exist.

Canine acute eosinophilic dermatitis with edema is an uncommon syndromic disorder in dogs with a unique clinical presentation. Most but not all dogs have a history of gastrointestinal upset preceding or concomitant with skin lesion onset. Affected dogs present with macular to generalized erythema that is most evident on the glabrous skin of the abdomen. Although the etiology is not known, an adverse drug reaction or a systemic type I hypersensitivity reaction may play a role. Some cases can be difficult to distinguish from canine sterile neutrophilic dermatosis due to overlapping clinical criteria and eosinophil degranulation in tissue section., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE To describe the clinical and histologic features of acute erythroderma in dogs with gastrointestinal disease. DESIGN Retrospective case series. ANIMALS 18 dogs with erythroderma and gastrointestinal disease. PROCEDURES Medical records and biopsy specimens were reviewed. Information collected from medical records included signalment, clinical signs, physical examination and diagnostic test results, treatment, and outcome. The Naranjo algorithm was used to estimate the probability of an adverse drug reaction for each dog. RESULTS All dogs had an acute onset of erythematous macules or generalized erythroderma. Histologic features of skin biopsy specimens had 3 patterns representing a progressive spectrum of inflammation. Most dogs had vomiting (n = 17) and hematochezia (10). Signs of gastrointestinal disease became evident before, after, or concurrent with the onset of skin lesions in 10, 3, and 5 dogs, respectively. Inflammatory bowel disease, pancreatitis, and adverse food reaction were diagnosed in 5, 3, and 3 dogs, respectively. The cause of the gastrointestinal signs was not identified for 8 dogs. Eight dogs had a Naranjo score consistent with a possible adverse drug reaction. Treatment of skin lesions included drug withdrawal (n = 15), antihistamines (16), and corticosteroids (14). Signs of gastrointestinal disease and skin lesions resolved at a mean of 4.6 days and 20.8 days, respectively, after onset. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated acute erythroderma may be associated with > 1 gastrointestinal disease or an adverse drug reaction in some dogs. Recognition of the clinical and histologic features of this syndrome is essential for accurate diagnosis.

Background: Plectin, a large linker protein found in many tissues, acts to connect components of the cytoskeleton to each other. In the epidermis, plectin binds keratin intermediate filaments to hemidesmosomes. A deficiency of plectin in the skin leads to blister formation in the basal layer and the disease epidermolysis bullosa simplex (EBS)., Hypothesis/objectives: To describe a novel blistering disease that arose spontaneously in a litter of puppies., Animals: Two female and one male 20-day-old Eurasier puppies, from a litter of six, were presented for evaluation of failure to thrive and then euthanized due to poor prognosis. The puppies had ulcers on the lips, tongue, nasal planum, paw pads and abdomen., Results: Immunolabelling on frozen skin for basement membrane proteins revealed patchy and weak to absent staining for plectin as compared with strong linear staining in normal dogs. Ultrastructurally, hemidesmosomes were irregularly shaped and had loss of distinction between inner and outer plaques. Pedigree analysis supported an autosomal recessive mode of inheritance. A premature stop codon was discovered in exon 27 of PLEC that resulted in the production of a severely truncated protein., Conclusion: The study describes the first documented spontaneous EBS associated with a PLEC variant in domestic animals., (© 2016 ESVD and ACVD.)

Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC&#95;06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species., Competing Interests: The authors have declared that no competing interests exist.

Background: Although zinc responsive dermatosis is typically a disorder of Arctic breed dogs, this study identifies similar cutaneous lesions on the face and pressure points of Boston terrier dogs., Hypothesis/objectives: To document the clinical and histological features of localized parakeratotic hyperkeratosis of Boston terrier dogs, to determine if the lesions respond to zinc supplementation and to determine whether tissue zinc levels were decreased in affected versus unaffected dogs., Material and Methods: Sixteen Boston terrier dogs with similar gross and histological findings were identified retrospectively from two institutions. Follow-up information for nine dogs from one institution was obtained from referring veterinarians using a questionnaire. Tissue zinc levels were measured from formalin-fixed paraffin-embedded skin biopsy samples of affected and unaffected dogs using inductively coupled plasma mass spectrometry., Results: Mild to severe parakeratotic hyperkeratosis with follicular involvement was present in all 16 cases. Of the nine dogs for which follow-up information was available, five dogs received oral zinc supplementation and four dogs had documented clinical improvement or resolution of dermatological lesions. The median skin zinc levels were not significantly different between affected and unaffected dogs., Conclusions and Clinical Importance: To the best of the authors' knowledge this is the first report of localized parakeratotic hyperkeratosis in Boston terrier dogs, some of which improved with oral zinc supplementation. Prospective studies in Boston terrier dogs are warranted to document potential zinc deficiency (serum and/or tissue levels, pre- and post-treatment) and to objectively assess response to zinc supplementation and other therapies., (© 2016 ESVD and ACVD.)

Host-microbe interactions may play a fundamental role in the pathogenesis of atopic dermatitis, a chronic relapsing inflammatory skin disorder characterized by universal colonization with Staphylococcus species. To examine the relationship between epidermal barrier function and the cutaneous microbiota in atopic dermatitis, this study used a spontaneous model of canine atopic dermatitis. In a cohort of 14 dogs with canine atopic dermatitis, the skin microbiota were longitudinally evaluated with parallel assessment of skin barrier function at disease flare, during antimicrobial therapy, and post-therapy. Sequencing of the bacterial 16S ribosomal RNA gene showed decreased bacterial diversity and increased proportions of Staphylococcus (S. pseudintermedius in particular) and Corynebacterium species compared with a cohort of healthy control dogs (n = 16). Treatment restored bacterial diversity with decreased proportions of Staphylococcus species, concurrent with decreased canine atopic dermatitis severity. Skin barrier function, as measured by corneometry, pH, and transepidermal water loss also normalized with treatment. Bacterial diversity correlated with transepidermal water loss and pH level but not with corneometry results. These findings provide insights into the relationship between the cutaneous microbiome and skin barrier function in atopic dermatitis, show the impact of antimicrobial therapy on the skin microbiome, and highlight the utility of canine atopic dermatitis as a spontaneous nonrodent model of atopic dermatitis., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Noninflammatory alopecia is a frequent problem in dogs. Estrogen-induced alopecia is well described in dogs, with estrogen producing testicular tumors and canine female hyperestrogenism., Objectives: To increase awareness that extensive alopecia in dogs can be caused by exposure to estradiol gel used by owners to treat their postmenopausal symptoms., Animals: Skin biopsies from five dogs with extensive alopecia were examined., Methods: Owners were asked for a thorough case history, including possible exposure to an estradiol gel. Complete blood work and serum chemistry panel analysis were performed to investigate possible underlying causes. Formalin-fixed skin biopsy samples were obtained from lesional skin and histopathology was performed., Results: All owners confirmed the use of a transdermal estradiol gel and close contact with the affected dogs before development of alopecia. Histopathologic examination showed a similar picture in all five dogs. Most hair follicles were predominantly either in kenogen or telogen and hair follicle infundibula showed mild to moderate dilation. Hair regrowth was present in all five dogs after the exposure to the estradiol gel was stopped or minimized. Blood work and serum chemistry panel were within normal limits in all cases. One dog had elevated estradiol concentrations, whereas in another dog estradiol concentrations were within normal limits., Conclusion and Clinical Importance: Alopecia can occur after contact with a transdermal gel used as treatment for postmenopausal symptoms in women. Estradiol gel used by female owners therefore represents a possible cause for noninflammatory alopecia in dogs. Estradiol concentrations are not necessarily elevated in affected dogs., (© 2015 ESVD and ACVD.)

A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species., (© The Author(s) 2014.)

Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) littermates. By using murine (4T1) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromal organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To describe clinical and histopathologic features of furunculosis in dogs following water immersion or exposure to grooming products., Design: Retrospective case series., Animals: 22 dogs with skin lesions consistent with furunculosis and a history of water immersion or grooming prior to onset. Procedures-Information collected from the medical records of affected dogs included signalment, clinical signs, bathing or grooming procedure, diagnostic tests, treatment, and outcome., Results: German Shepherd Dogs (4/22 [18%]) and Labrador Retrievers (4/22 [18%]) were most commonly affected. Skin lesions, particularly hemorrhagic pustules and crusts, were dorsally located in all dogs and occurred a median of 2 days (range, 1 to 7 days) following water immersion or exposure to grooming products. Twenty (91%) dogs were bathed at home or at a commercial grooming facility prior to lesion onset; 1 dog developed skin lesions following hydrotherapy on an underwater treadmill, and 1 dog developed peri-incisional skin lesions after surgery. Lethargy, signs of neck or back pain, and fever were common clinical signs. Pseudomonas aeruginosa was the most common bacterial isolate from dogs with bacteriologic culture performed on skin samples (10/14). The main histologic feature was acute follicular rupture in the superficial dermis with suppurative inflammation and dermal hemorrhage. Systemic antimicrobial treatment, particularly oral administration of fluoroquinolones, resulted in excellent clinical response in 16 of 22 (73%) dogs., Conclusions and Clinical Relevance: Acute-onset furunculosis with characteristic clinical and histopathologic features in dogs following water immersion or exposure to grooming products was described. Knowledge of the historical and clinical features of this syndrome is essential for accurate diagnosis and appropriate treatment of affected dogs.

Toll-like receptor signaling and subsequent activation of NF-κB- and MAPK-dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-κB and MAPK signaling, resulting in blockade of NF-κB-dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti-Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas-associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia-induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8-mediated cell death overrides blockade of immune signaling by YopJ to promote anti-Yersinia immune defense.

Background: Seborrhoeic keratoses (SKs) are common benign epidermal neoplasms in humans and are rarely diagnosed in the dog. These circumscribed, raised, variably pigmented plaques arise in middle aged to older humans, with a focal or multicentric distribution; although common, the underlying cause of these lesions is not known. Although less common in the dog, the lesions are similar and have features that overlap with papillomavirus-associated pigmented viral plaques., Hypothesis/objectives: Seborrhoeic keratoses in the dog are negative for canine papillomavirus., Animals: Eleven cases of SK from a 12 year period were reviewed., Methods: This was a retrospective study of the histopathological findings and case histories. Complete clinical records following collection of the skin biopsy were available in five of 11 cases. Immunohistochemistry was performed for all cases; PCR analysis was carried out for papillomavirus in six cases., Results: Histologically, SKs had an exophytic to mildly endophytic epidermal proliferation, creating a papillomatous to acanthotic, hyperkeratotic, frequently pigmented plaque. There was an absence of hypergranulosis or viral cytopathic effect; PCRs for canine papillomavirus within the formalin-fixed paraffin-embedded skin biopsies were negative. No breed, sex or site predilection was recognized. The mean age at biopsy of the lesions was 8.8 years (range 5-14 years)., Conclusions and Clinical Importance: Histopathological features and negative papillomavirus status distinguish SK as an important differential diagnosis for pigmented viral plaques in dogs., (© 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.)

The stratum corneum acts as a permability barrier to keep the body hydrated while preventing environmental damage and exposure to pathogens and noxious substances. Disorders of cornification (DOC) arise from an inability to form a normal stratum corneum. Most DOC arise secondary to skin allergies, ectoparasitism, endocrine and metabolic diseases. Primary DOC typically arise from single gene mutations. As there is no cure for primary DOC (ichthyoses), a stepwise diagnostic approach is fundamental to establishing a correct diagnosis. Treatment involves a regimen of topical therapy as well as medical scrutiny to address secondary bacterial and yeast infections., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Cats with feline herpesvirus (FeHV-1)-associated dermatitis typically present with ulcerative lesions on the rostral muzzle and nasal planum. This report describes FeHV-1 dermatitis in the flank region, in the absence of facial lesions., Hypothesis/objectives: Clinicians should be aware of this unusual manifestation of FeHV-1 dermatitis to prevent potential misdiagnosis., Animals: A 12-year-old male castrated Bengal cat and a 3-year-old male castrated Siamese cat with plaques and ulcers in the flank region are described., Methods: Formalin-fixed biopsy samples were obtained from lesional skin. Histopathology and FeHV-1 immunohistochemistry were performed., Results: Each sample had epidermal and follicular necrosis with a dense dermal infiltrate of eosinophils. Few to moderate numbers of intranuclear inclusion bodies were present in keratinocytes. The presence of FeHV-1 in the lesions was confirmed with immunohistochemistry., Conclusions and Clinical Importance: Feline herpesvirus-associated dermatitis should not be ruled out based on the location of the lesion, because a correct diagnosis is imperative for proper treatment. Future studies to assess the cause of lesions at this unusual site are warranted., (© 2012 The Authors. Veterinary Dermatology. © 2012 ESVD and ACVD.)

The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments.

A familial form of lupus, termed exfoliative cutaneous lupus erythematosus (ECLE) has been recognized for decades in German shorthaired pointer dogs (GSP). Previous studies were suggestive of autosomal recessive inheritance. The disease presents as a severe dermatitis with age of onset between 16 and 40 weeks, and mirrors cutaneous lupus erythematosus (CLE) in humans. Lameness and, in advanced cases, renal disease may be present. Most affected dogs are euthanized before reaching the age of 4 years. The diagnosis is made by clinical observations and microscopic examination of skin biopsies. In humans, many different forms of CLE exist and various genes and chromosomal locations have been implicated. The large number of potential candidate loci combined with often weak association prevented in depth screening of the dog population thus far. During the course of our studies, we developed a colony of dogs with ECLE as a model for human CLE and the genetic analysis of these dogs confirmed the autosomal recessive mode of inheritance of CLE in GSPs. Using canine patient material, we performed a genome-wide association study (GWAS) to identify the genomic region harboring the gene involved in the development of the disease in GSPs. We identified a SNP allele on canine chromosome 18 that segregated with the disease in the 267 dogs tested. The data generated should allow identification of the mutant gene responsible for this form of cutaneous lupus erythematosus in dogs and assist in the understanding of the development of similar disease in humans.

Cowpox virus (CPXV) infections are a sporadic cause of localized or disseminated skin disease in domestic animals and humans in Europe. Rodents are considered the primary reservoir host for CPXV. Cats can become infected by close contact with rodents and are the most important source of human infections. Recently, public awareness has also been drawn to CPXV infections by an outbreak of rat to human infections in central Europe. In dogs, CPXV infections are rare. Here we report a case of a 5-month-old Rottweiler with a focal nodule on the muzzle. The lesion was fully excised, and recovery was uneventful. The preliminary diagnosis of a CPXV infection was established by the characteristic inclusion bodies on histopathological examination. The diagnosis was confirmed by electron microscopy and polymerase chain reaction (PCR). Sequencing of the PCR product led to a 231 bp sequence of the orthopoxvirus HA gene that was identical to a CPXV strain previously isolated from a cat. This is the third documented case of a canine CPXV infection., (© 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.)

The repair of cutaneous wounds in the postnatal animal is associated with the development of scar tissue. Directing cell activities to efficiently heal wounds while minimizing the development of scar tissue is a major goal of wound management and the focus of intensive research efforts. Type III collagen (Col3), expressed in early granulation tissue, has been proposed to play a prominent role in cutaneous wound repair, although little is known about its role in this process. To establish the role of Col3 in cutaneous wound repair, we examined the healing of excisional wounds in a previously described murine model of Col3 deficiency. Col3 deficiency (Col3+/-) in aged mice resulted in accelerated wound closure with increased wound contraction. In addition, Col3-deficient mice had increased myofibroblast density in the wound granulation tissue as evidenced by an increased expression of the myofibroblast marker, α-smooth muscle actin. In vitro, dermal fibroblasts obtained from Col3-deficient embryos (Col3+/- and -/-) were more efficient at collagen gel contraction and also displayed increased myofibroblast differentiation compared to those harvested from wild-type (Col3+/+) embryos. Finally, wounds from Col3-deficient mice also had significantly more scar tissue area on day 21 post-wounding compared to wild-type mice. The effect of Col3 expression on myofibroblast differentiation and scar formation in this model suggests a previously undefined role for this ECM protein in tissue regeneration and repair., (Copyright © 2011 S. Karger AG, Basel.)

Six German shorthaired pointer dogs (two females, four males) with exfoliative cutaneous lupus erythematosus (ECLE) were studied in a controlled setting until disease progression necessitated euthanasia. During investigations into the heredity of disease, five dogs received immunomodulatory drugs to alleviate clinical signs (lameness, erythema, scaling, erosions/ulcers). One dog served as a control and received only baths and oral fatty acids. Four dogs received ciclosporin (5-10 mg/kg once daily) for 4.5 months to 2 years. Ciclosporin decreased erythema and arthralgia, but did not halt worsening of lesions. Three dogs received hydroxychloroquine (5-10 mg/kg once daily) for 8 weeks, 7 months, and 9 months, respectively, with no side effects. Hydroxychloroquine appeared to slow clinical progression in two dogs on extended treatment and normalized globulin levels in all three dogs while receiving the drug. Four dogs, including the control dog, were euthanized between 1 and 4.5 years of age. Two remaining male dogs received a tumour necrosis factor (TNF)-α antagonist, adalimumab, at 0.5 mg/kg every 2 weeks for 8 weeks then weekly for 8 weeks. Serum TNF-α levels were not significantly altered nor were quantifiable changes seen in skin lesions or lameness. Subsequently, the dogs were maintained on hydroxychloroquine for another year. This is the first study to evaluate the use of a TNF-α inhibitor for canine lupus and the first to address the safety of long-term administration of hydroxychloroquine, albeit in a small number of dogs. The study documents the progression of ECLE and generally poor response to therapy., (© 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.)

Patients with defective ectodysplasin A (EDA) have X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition comprising hypotrichosis, inability to sweat, abnormal teeth, and frequent pulmonary infections. The XLHED dogs show the same clinical signs as humans with the disorder, including frequent respiratory infections that can be fatal. The respiratory disease in humans and dogs is thought to be due to the absence of tracheal and bronchial glands which are a vital part of the mucociliary clearance mechanism. In our XLHED model, the genetically missing EDA was replaced by postnatal intravenous administration of recombinant EDA resulting in long-term, durable corrective effect on adult, permanent dentition. After treatment with EDA, significant correction of the missing tracheal and bronchial glands was achieved in those dogs that received higher doses of EDA. Moreover, successful treatment resulted in the presence of esophageal glands, improved mucociliary clearance, and the absence of respiratory infection. These results demonstrate that a short-term treatment at a neonatal age with a recombinant protein can reverse a developmental disease and result in vastly improved quality of life., ((c) 2009 Wiley-Liss, Inc.)

A scaling disorder specific to Golden Retriever dogs has been recognized by both dermatologists and pathologists, but to date has not been well characterized. At the University of Pennsylvania's Laboratory of Toxicology and Pathology, 46 cases of ichthyosis were diagnosed histologically in Golden Retriever dogs from January 2004 to January 2007. A total of 22 dogs had skin lesions documented at younger than 1 year of age; 3 dogs between 1 and 2 years of age; 13 dogs developed lesions at older than 2 years; and the time of onset was unknown for 8 dogs. A total of 25 dogs were female, and 21 were male. All dogs had strikingly similar histopathologic changes that consisted of mild to moderate laminar orthokeratotic hyperkeratosis with an absence of epidermal hyperplasia and dermal inflammation. Ultrastructural analysis using a ruthenium tetroxide fixation method was performed on punch biopsy samples from 5 dogs and compared with 2 control dogs (1 clinically and histologically normal sibling of an affected dog and 1 Cairn Terrier). All affected dogs had retained and convoluted membranes with crystalline structures in the stratum corneum. Scattered keratinocytes in the granular cell layer had prominent, clear, membrane-bound, cytoplasmic vacuoles. Pedigree analysis of 14 dogs was compatible with autosomal recessive inheritance, but incomplete dominance could not be ruled out. This unique hyperkeratotic/scaling disorder in Golden Retrievers has distinctive clinical, histologic, and ultrastructural features, which are consistent with a primary cornification defect.

Lethal acrodermatitis (LAD) is a genetic disease affecting bull terrier dogs. The phenotype is similar to that for acrodermatitis enteropathica in humans, but is currently without treatment. The purpose of the research presented here is to determine the biochemical defects associated with LAD using proteomic methodologies. Two affected (male and female) and one unaffected (male) bull terrier pups were euthanized at 14 weeks of age, their livers dissected and prepared for two-dimensional gel electrophoresis (2DE) and densitometry. Approximately 200 protein spots were observed. The density of the spots within each gel was normalized to the total spot volume of the gel; only those soluble liver protein spots that were consistently different in both of the livers of the affected pups compared to the unaffected pup were excised manually and submitted for MALDI mass spectrometry. Thirteen proteins were identified as differentially expressed in the affected, compared to the unaffected, pups. The proteins were involved in numerous cellular physiological functions, including chaperones, calcium binding, and energy metabolism, as well as being associated with the inflammatory response. Of note were haptoglobin, glutamine synthetase, prohibitin and keratin 10 which exhibited at least a fourfold level of differential expression. These data represent the first proteomic analysis of this mutation. The differentially expressed proteins that were identified may be key in understanding the etiology of LAD, and may lead to diagnostic tools for its identification within the bull terrier population.