@article{sai_nakanishi_scofield_tokarz_linder_cohen_ninomiya-tsuji_2023, title={Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer?s disease mouse models}, volume={136}, ISSN={["1477-9137"]}, DOI={10.1242/jcs.260102}, abstractNote={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.}, number={6}, journal={JOURNAL OF CELL SCIENCE}, author={Sai, Kazuhito and Nakanishi, Aoi and Scofield, Kimberly M. and Tokarz, Debra A. and Linder, Keith E. and Cohen, Todd J. and Ninomiya-Tsuji, Jun}, year={2023}, month={Mar} }
 @article{bizikova_linder_anderson_2023, title={Erosive and ulcerative stomatitis in dogs and cats: which immune-mediated diseases to consider?}, volume={261}, ISSN={["1943-569X"]}, DOI={10.2460/javma.22.12.0573}, abstractNote={Abstract Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Bizikova, Petra and Linder, Keith E. and Anderson, Jamie G.}, year={2023}, month={Jun}, pages={S48–S57} }
 @article{gedon_bizikova_olivry_mendoza-kuznetsova_oberkirchner_robertson_linder_2023, title={Histopathological characterisation of trunk-dominant canine pemphigus foliaceus, and comparison with classic facial and insecticide-triggered forms}, volume={6}, ISSN={["1365-3164"]}, DOI={10.1111/vde.13174}, abstractNote={While the clinical features were described recently, the histopathological characterisation of trunk-dominant canine pemphigus foliaceus (PF) is lacking, and whether it differs from classic facial or insecticide-triggered PF is unknown. This study describes the histopathological findings of trunk-dominant PF, and compares the results to classic facial and insecticide-triggered PF. Skin biopsies from 103 dogs with clinically characterised trunk-dominant (n = 33), classic facial (n = 26) and insecticide-triggered PF (n = 44) were included. Histological sections, randomised and blinded, were scored for over 50 morphological parameters of pustules, epidermis, dermis, adnexa and crusts. Intact pustule area and width were measured by digital microscopy. In trunk-dominant PF, 77 intact pustules were predominantly subcorneal (0.0019–1.940 mm2 area, 0.0470–4.2532 mm wide), and contained from one to over 100 acantholytic keratinocytes. Pustules had boat acantholytic cells, corneocytes, perinuclear eosinophilic rings, neutrophil rosettes, acantholytic cell necrosis, rafts, cling-ons and/or eosinophils. Peripustular epidermal spongiosis, necrosis and lymphocyte exocytosis occurred, as did follicular pustules. Mixed dermal inflammation often contained eosinophils. Trunk-dominant PF did not differ from the other PF groups except for few parameters, such as having fewer rafts (p = 0.003). Additional autoimmune inflammatory patterns occurred in all PF groups. Trunk-dominant PF and other canine PF variants are histologically similar, which indicates shared pathomechanisms. The identification of common boat acantholytic cells and corneocyte separation has implications for the mechanisms of acantholysis. The diversity of histopathological and polyautoimmunity features support complicated immune mechanisms. Finally, results indicate that diagnostic biopsies cannot differentiate between these PF variants in dogs. 虽然最近对其临床特征进行了描述，但缺乏躯干显性犬落叶型天疱疮(PF)的组织病理学特征，也不知道它是否与经典的面部或杀虫剂引发的PF不同。 本研究描述了躯干显性PF的组织病理学发现，并将其结果与经典的面部和杀虫剂触发PF进行了比较。 包括103只具有临床特征的躯干显性(n=33)、典型面部(n=26)和杀虫剂触发PF(n=44)的犬的皮肤活检。 组织学切片，随机和盲法，对脓疱、表皮、真皮、毛囊附件和结痂的50多个形态学参数进行评分。通过数字显微镜测量完整的脓疱面积和宽度。 在躯干显性的PF中，77个完整的脓疱主要位于角质层下(面积0.0019–1.940 mm2，宽度0.0470–4.2532 mm)，包含1至100多个棘层松懈性角质细胞。脓疱有连片的棘层松懈细胞、角化细胞、核周嗜酸性粒细胞环、中性粒细胞花环、棘层松懈细胞坏死、筏状排列、紧靠和/或嗜酸性粒细胞。出现脓疱周围表皮海绵状水肿、坏死和淋巴细胞外排，毛囊性脓疱也是如此。混合性真皮炎症通常含有嗜酸性粒细胞。躯干显性PF与其他PF组没有差异，除了一些参数，例如筏状排列更少(p=0.003)。所有PF组都出现了额外的自身免疫炎症模式。 躯干显性PF和其他犬PF变体在组织学上相似，这表明共同的病理机制。常见连片棘层松懈细胞和分离角化细胞的鉴定，牵连出棘层松懈的机制。组织病理学和多重自身免疫特征的多样性支持复杂的免疫机制。最后，结果表明，诊断性活组织检查无法区分犬的这些PF变体。 Bien que les caractéristiques cliniques aient été décrites récemment, la caractérisation histopathologique du pemphigus foliacé (PF) canin à dominant tronculaire fait défaut, et on ne sait pas s'il diffère du PF facial classique ou induit par un insecticide. Cette étude décrit les résultats histopathologiques provenant de PF à dominante tronculaire et les compare à ceux de PF faciaux classiques et induits par un insecticide. les biopsies cutanées de 103 chiens présentant une PF à dominante tronculaire (n = 33), faciale classique (n = 26) et déclenchée par un insecticide (n = 44) sont étudiées. Des coupes histologiques, randomisées et en aveugle, sont évaluées pour plus de 50 paramètres morphologiques relatifs aux pustules, à l'épiderme, au derme, aux annexes et aux croûtes. La surface et la largeur des pustules intactes sont mesurées par microscopie numérique. Concernant les PF à dominante tronculaire, 77 pustules intactes sont principalement sous-cornéennes (surface de 0,0019 à 1,940 mm2, largeur de 0,0470 à 4,2532 mm) et contiennent de un à plus de 100 kératinocytes acantholytiques. Les pustules contiennent des cellules acantholytiques en radeau, des cornéocytes, des halos éosinophiles périnucléaires, des rosettes de neutrophiles, une nécrose des cellules acantholytiques, des radeaux, des amas et/ou des éosinophiles. Une spongiose épidermique péripustuleuse, une nécrose et une exocytose lymphocytaire sont observées, ainsi que des pustules folliculaires. L'inflammation cutanée mixte contient souvent des éosinophiles. Le PF à dominante tronculaire ne différe pas des autres groupes de PF, à l’exception de quelques paramètres, comme le fait de présenter moins de radeaux (p = 0,003). D’autres patterns inflammatoires auto-immuns ont été observés dans tous les groupes de PF. le PF à dominante tronculaire et les autres variants canins de PF sont histologiquement similaires, ce qui indique des mécanismes pathologiques communs. L'identification commune de cellules acantholytiques en radeau associée à la disruption des cornéocytes a des implications en termes de mécanisme acantholytique. La diversité des caractéristiques histopathologiques et de polyauto-immunité argue en faveur de mécanismes immunitaires complexes. Enfin, les résultats indiquent que l’examen des biopsies ne permet pas de différencier ces variants de PF chez le chien. Während die klinischen Merkmale jüngst beschrieben wurden, fehlt eine histopathologische Charakterisierung des Rumpf-dominierten Pemphigus foliaceus (PF) des Hundes, ebenso ist die Unterscheidung zum klassischen Gesichts- oder Insektizid-ausgelöstem PF unbekannt. Diese Studie beschreibt die histopathologischen Befunde des Rumpf-dominierten PF, und vergleicht die Ergebnisse zum klassischen Gesichts- und Insektizid-ausgelösten PF. Hautbiopsien von 103 Hunden mit klinisch beschriebenem Rumpf-dominierten PF (n = 33), klassischem Gesichts- (n = 26) und Insektizid-ausgelöstem PF (n = 44) wurden inkludiert. Histologische Schnitte, zufällig ausgewählt und geblindet, wurden auf über 50 morphologische Parameter wie Pusteln, Epidermis, Dermis, Adnexe und Krusten untersucht. Bei intakten Pusteln wurde die Stelle und der Durchmesser mittels Digitalmikroskopie gemessen. Beim Rumpf-dominierten PF traten intakte Pusteln vor allem subcorneal auf (0,0019-1,949 mm2; 0,0470-4,2532 mm Durchmesser) und enthielten zwischen einem und über 100 akantholytische Keratinozyten. Die Pusteln hatten Boot-ähnliche akantholytische Zellen, Korneozyten, perinukleäre eosinophile Ringe, neutrophile Rosetten, akantholytische Zellnekrosen, zusammenhängende Zellen, einzeln anhängende Zellen und/oder Eosinophile. Es trat eine peripustulöse epidermale Spongiose, Nekrose und Lymphozyten Exozytose auf, sowie follikuläre Pusteln. In der gemischten dermalen Entzündung traten auch häufig Eosinophile auf. Der Rumpf-dominierte PF unterschied sich nicht vom PF der anderen Gruppen außer in einigen wenigen Parametern, wie weniger zusammenhängende Zellen (p = 0,003). Zusätzliche autoimmune entzündliche Merkmale traten in allen PF-Gruppen auf. Der Rumpf-dominierte PF und andere PF-Varianten des Hundes sind histologisch ähnlich, was einen gemeinsamen Pathomechanismus deutlich macht. Die Identifizierung sogenannter akantholytischer Zellen in Boot-Form und eine Korneozyten Separierung hat auch eine Bedeutung im Bezug auf die Mechanismen der Akantholyse. Die Vielfalt der histopathologischen und polyautoimmunen Merkmale weist auf komplizierte immune Mechanismen hin. Letztendlich zeigen diese Ergebnisse, dass die diagnostischen Biopsien nicht zwischen den PF-Varianten des Hundes unterscheiden können. 体幹優位型犬落葉状天疱瘡(PF)の病理組織学的特徴は最近報告されているが、古典的な顔面型や駆虫薬誘発型PFと異なるかどうかは不明である。 本研究では、体幹優位型PFの病理組織学的所見を述べ、古典的顔面型PFおよび駆虫薬誘発型PFと比較することであった。 体幹優位型PF(n = 33)、古典的顔面型PF(n = 26)、駆虫薬誘発型PF(n = 44)の臨床的特徴を有する犬103頭の皮膚生検が対象となった。 組織切片を無作為に盲検化し、膿疱、表皮、真皮、付属器、痂皮の50以上の形態学的パラメータについてスコア化した。膿疱の面積と幅は、デジタル顕微鏡で測定した。 体幹優位型PFでは、77個の膿疱は主に角層下(面積0.0019-1.940mm2、幅0.0470-4.2532mm)で、1~100個以上の角化細胞が含まれていた。膿疱は、ボート状の棘融解細胞、角質細胞、核周囲の好酸性リング、好中球ロゼット、棘融解細胞壊死、ラフト、クリングオン、好酸球を有していた。毛包の膿疱と同様に、膿疱周囲表皮の海綿状変化、壊死、リンパ球のエクソサイトーシスが起こった。真皮の混合性炎症はしばしば好酸球を含んでいた。体幹優位型PFは、ラフトが少ない(p = 0.003)といったいくつかのパラメータを除いて、他のPFグループと差がなかった。自己免疫性炎症パターンは、すべてのPF群で発生した。 体幹優位型PFと他の犬PF変種は組織学的に類似しており、これは病態メカニズムを共有していることを示した。共通のボート状棘融解細胞および角質細胞の分離の特定は、棘融解のメカニズムを示唆していた。病理組織学的および多自己免疫学的特徴の多様性は、複雑な免疫機構を支持した。最後に、診断用生検では、犬におけるこれらのPF変種を区別することができないことが示された。 Enquanto as características clínicas foram descritas recentemente, ainda falta a caracterização histopatológica do pênfigo foliáceo (PF) canino predominante no tronco e não se sabe se ele difere do PF foliáceo facial clássico e do desencadeado por inseticida. Este estudo descreve os achados histopatológicos do PF predominante no tronco e compara os resultados com o PF clássico e com o desencadeado por inseticidas. Foram incluídas biópsias cutâneas de 103 cães com PF caracterizado clinicamente como predominante no tronco (n = 33), facial clássico (n = 26) e desencadeado por inseticidas (n = 44). Cortes histológicos randomizados e cegos foram classificados por mais de 50 parâmetros morfológicos de pústulas, epiderme, derme, anexos e crostas. A área e a largura das pústulas intactas foram mensuradas por microscopia digital. No PF predominante no tronco, as pústulas intactas foram principalmente subcórneas (0,0019–1,940 mm2 de área, 0,0470–4,2532 mm de largura), e continham de um a mais de cem queratinócitos acantolíticos. As pústulas apresentavam células acantolíticas em formato de barco, corneócitos, anéis eosinofílicos perinucleares, rosetas neutrofílicas, necrose de células acantolíticas, aglomerados de células acantolíticas, grupos de células do estrato granuloso aderidas ao estrato córneo (cling-on) e/ou eosinófilos. Ocorreram espongiose epidérmica peripustular, necrose e exocitose de linfócitos, bem como pústulas foliculares. No infiltrado inflamatório dérmico misto frequentemente continha eosinófilos. O PF predominante no tronco não diferiu dos outros grupos de PF exceto para poucos parâmetros, como por exemplo apresentar menos aglomerados de células acantolíticas (p = 0.003). Os outros padrões inflamatórios autoimunes ocorreram em todos os grupos de PF. O PF predominante no tronco e as outras variantes do PF canino são histologicamente similares, o que indica a existência de patomecanismos comuns. A identificação frequente de células acantolíticas em formato de barco e separação de corneócitos tem implicações nos mecanismos de acantólise. A diversidade as características histopatológicas e poliautoimunes corroboram com os mecanismos imunológicos complexos. Finalmente, os resultados indicam que as biópsias diagnósticas não são capazes de diferenciar essas variantes de PF em cães. si bien las características clínicas se describieron recientemente, falta la caracterización histopatológica del pénfigo foliáceo (PF) canino dominante en el tronco, y se desconoce si difiere del PF facial clásico o desencadenado por insecticidas. Este estudio describe los hallazgos histopatológicos de la PF predominante en el tronco y compara los resultados con PF facial clásico y el PF desencadenado por insecticidas. Se incluyeron biopsias de piel de 103 perros con PF predominante en el tronco clínicamente caracterizado (n = 33), PF facial clásico (n = 26) y el desencadenado por insecticida (n = 44). Las secciones histológicas se puntuaron para más de 50 parámetros morfológicos al azar y de forma ciega para las características de pústulas, epidermis, dermis, anejos y costras. El área y el ancho de la pústula intacta se midieron mediante microscopía digital. En la PF dominante de tronco 77 pústulas intactas fueron predominantemente subcorneales (0,0019–1,940 mm2 de área, 0,0470–4,2532 mm de ancho) y contenían de uno a más de 100 queratinocitos acantolíticos. Las pústulas tenían células acantolíticas agrupadas, corneocitos, anillos eosinófilos perinucleares, rosetas de neutrófilos, necrosis de células acantolíticas, acantolisis en línea, células acantoliticsas adheridas y/o eosinófilos. Se produjo espongiosis epidérmica peripustulosa, necrosis y exocitosis de linfocitos, así como pústulas foliculares. La inflamación dérmica mixta a menudo contenía eosinófilos. La PF de tronco dominante no se diferenció de los otros grupos de PF excepto por algunos parámetros, como tener menos células en línea (p = 0,003). Se produjeron patrones inflamatorios autoinmunitarios adicionales en todos los grupos de PF. El PF dominante en el tronco y otras variantes del PF canino son histológicamente similares, lo que indica mecanismos patogénicos compartidos. La identificación de células acantolíticas en grupos y la separación de corneocitos tiene implicaciones para los mecanismos de acantólisis. La diversidad de características histopatológicas y de poliautoinmunidad respalda mecanismos inmunitarios complicados. Finalmente, los resultados indican que las biopsias de diagnóstico no pueden diferenciar entre estas variantes de PF en perros. Trunk-dominant pemphigus foliaceus (tPF) is a clinical variant of canine pemphigus foliaceus (PF) that presents without dorsal muzzle/nasal planum involvement and, sometimes, without footpad involvement typically seen in classic facial PF (fPF).1 The trunk-dominant patterning of skin lesions and the acantholytic pustular reactions seen on cytological and histological evaluation also occur in canine superficial bacterial pyoderma, thus making this variant of PF more difficult, time-consuming and expensive to diagnose.1 Although the clinical and immunological features of tPF were recently described and compared with fPF,1 little is known about its histological features. Additionally, it is unclear if there are histopathological differences between tPF and the other clinical PF variants recognised in dogs that could suggest potential pathomechanisms of the lesion formation, explain the clinical variation, or help in differentiating these conditions. Therefore, the purpose of this study was to (i) describe the histopathological features of canine tPF and (ii) compare the histopathological features of tPF with those of classic fPF and insecticide-triggered PF (iPF). Skin biopsy specimens from client-owned dogs with active tPF and fPF collected for standard-of-care, routine diagnostic assessment between January 2004 and March 2022 were selected for the study (North Carolina State University and Cummings School of Veterinary Medicine at Tufts University). Client consent to use the diagnostic samples for study purposes was obtained. Case inclusion criteria and the majority of PF patients were clinically described in a previously published study.1 Briefly, patients had a pustular skin disease with cytological confirmation of keratinocyte acantholysis and lesion distributions of tPF or fPF.1 No potential drug or other trigger was identified. For fPF, symmetrical lesions affected the dorsal muzzle/nasal planum, with or without other body areas involved. For tPF, skin lesions affected the body, and not the dorsal muzzle/nasal planum. Dogs had a negative bacterial culture and/or clinical signs did not respond to oral antibiotics, complete remission was achieved with immunosuppressive therapy, and 3-month follow-up information was available. The type and dose of immunomodulatory drugs received during the 2-week period before biopsy collection were recorded and statistically assessed for impact on results. Previously published cases of iPF were included.2-4 Haematoxylin and eosin-stained biopsy sections were pre-screened to establish histological descriptive criteria and a scoring system, before being randomised (https://www.random.org), blinded and digitally scanned (Aperio AT2 microscope slide scanner; Leica Biosystems). Whole-slide image files were viewed with Aperio ImageScope (v.12.4.6; Leica Biosystems) and glass slides were viewed with an Olympus BX40 microscope. Pustules had to contain acantholytic cells, while granulocyte accumulations in the epidermis without acantholytic cells were classified as micropustules. Pustules with more than 50% of healing at the base by parakeratosis were classified as crusts. Using image files, each histological section and every pustule was individually identified and numbered for each case, and pustules were recorded as intact or ruptured (more than 15% disrupted or partially dried). Pustule descriptors were tracked to each pustule uniquely. The cross-sectional area of each intact pustule was calculated from manual morphometric tracings and the greatest pustule width was measured using Aperio ImageScope. Morphological descriptors are provided in Table 1, including the related scoring scheme used for each criterion. For parameters scored per case, the histological section with the most developed lesion was selected. Boat acantholytic cells were defined as separated keratinocytes in pustules that retained a flattened or ellipsoidal shape. These cells were further subcategorised into granulated boat cells and boat-like cells without keratohyalin granules. All slides were reviewed by two authors (Natalie Gedon and Keith Linder). Hyperplasia Hyperkeratosis Perivascular fibrina Fibrosis severitya Statistical analyses were carried out using Prism 9.5.0 (GraphPad). All multiple association statistics were performed in R Core Team (A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, 2022). Statistical details are provided in Appendix S1 in the Supporting information. The histopathological description of 33 tPF cases is provided below and comparison to the most relevant findings of 26 fPF and 44 iPF cases is summarised in Table 2. Additional descriptive data and statistical analysis of the three groups can be found in Tables S1–S10 and Appendix S2. Thirty-three cases of tPF had 232 unique histological sections with a median number of seven unique sections per case (range: 2–12); 226 were from haired skin and six from footpad/margin. A total of 147 intact and ruptured pustules were evaluated in the epidermis. Seventy-seven intact pustules (Figure 1a) in the epidermis had a median width of 0.37 mm (range: 0.05–4.25 mm) and a median cross-sectional area of 0.04 mm2 (range: 0.002–1.94 mm2). While controlling for area of the intact pustules, there were no significant differences between groups in any of the pustule descriptive parameters (p = 0.37). Ruptured pustules spanned significantly higher number of hair follicles (median: 2, range: 0–12) than intact pustules (median: 0, range: 0–4; p < 0.0001; Wilcoxon–Mann–Whitney U-test); however, the follicle density varied greatly in biopsy samples. The epidermal level of pustules was identifiable in 130 pustules and was most often located from the stratum corneum (SC) to the stratum spinosum (SS; 94; Figure 1a); a few pustules extended from the SC to the stratum granulosum (SG) (four), the SG to the SS (five) or were within the SS (12). In some pustules, there was extension from the SC to the stratum basale (SB; 11), from the SG to the SB (three) or from the SS to the SB (one). Ruptured pustules contained a significantly higher number of acantholytic cells (median score 3) than intact pustules (median 1; p < 0.0001; Wilcoxon–Mann–Whitney U-test). Acantholytic cells contained keratohyalin granules (Figure 2d) in 59% of pustules (82 of 138). Rafts were present (Figure 3a) in 25% of pustules (36 of 143) and their size varied from three to 74 keratinocytes (median 5). Perinuclear eosinophilic rings (Figure 3a) occurred in 57% of pustules (81 of 142). These occurred specifically in acantholytic cells (72 of 142; 51%), in nondetached peripustular keratinocytes in the epidermal margin of pustules (57 of 142; 40%) and/or in rafts. In nondetached keratinocytes with perinuclear rings, cells were not always rounded or separated (Figure 3a) and occurred with or without adjacent neutrophil exocytosis. Boat acantholytic cells (Figures 2 and 3) occurred in most pustules (122 of 145; 84%) and were granulated boat cells (85 of 145; 59%) and/or nongranulated boat-like cells (112 of 145; 77%). Flatter boat cells with granules did not have perinuclear rings, or collapse of keratohyalin granules to around the nucleus, and formed just below the SC (Figures 2a–c and 3b). Wider boat cells sometimes had collapse of perinuclear rings only on the faces of the cell and not from the tapered periphery, granules were not collapsed towards the nucleus from the tapered periphery, and these cells formed deeper in the SG (Figure 2a–c). Corneocytes occurred often in pustules (99 of 145; 68%; Figure 2a,e) and were significantly more common in ruptured pustules (p < 0.0001; Fisher's exact test). Corneocytes delaminated from the inner surface of the stratum compactum (Figure 2a), sometimes with segmental complete loss of the stratum compactum and additional delamination of cells from the stratum disjunctum. Roof cling-on acantholytic cells were present in 30 of 105 (29%) pustules. Pustules always contained neutrophils and, often, eosinophils (92 of 146 [63%]; median severity score 1, range: 0–3). In some instances, eosinophils outnumbered neutrophils (19 of 146; 13%). Macrophages were common in pustules (126 of 146; 86%) and were usually in very low numbers (<5 macrophages); occasional cases had pustules with higher numbers of macrophages (Figure 2d). Degenerate granulocytes occurred in intact pustules (37 of 77; 48%), although the score was usually low (median 0.5; range: 1–3). Neutrophil rosettes of at least two acantholytic cells were present in around half of the pustules (74 of 144; 51%; Figure 3b). Neutrophil rosettes also occurred on free or partly detached boat acantholytic cells and corneocytes (Figures 2e and 3b). Lymphocytic exocytosis into the epidermis was always present, usually mild (median severity score 1, range: 1–3), and more often peripustular (28 of 32; 88%) with lymphocytes below or next to pustules (Table S3). A few micropustules, usually one to three, were present in the epidermis (Figure 1d) in the majority of cases (27 of 33; 82%), were peripustular and/or nonperipustular and were more often in the SS (24 of 27; 89%) than the subcorneal location (11 of 27; 41%). Micropustules contained neutrophils and often eosinophils (14 of 27; 52%) and macrophages (15 of 27; 56%). Eosinophils outnumbered neutrophils in micropustules in nine of 27 (33%) cases. Macrophage microaggregates, one to three, also occurred in the epidermis, yet were uncommon (5 of 33; 15%). Extension of epidermal pustules into hair follicle infundibula occurred in 48 of 134 (36%) pustules. Pustules in hair follicle infundibula (Figures 1c and 2d) occurred in 15 of 33 (45%) cases, although the numbers were low (median: 0; range: 0–17). Micropustules were present in follicles in 14 of 32 (44%) cases. The number of micropustules per case was generally low, one to two only, and thus micropustules were not enumerated per case. Crusts were present in infundibula (evidence of resolved pustule) in 12 of 33 (36%) cases. Pustules with hair follicle extension, follicular pustules and micropustules had similar morphological features to those in the epidermis, including the presence of eosinophils, and occasional macrophages. The total number of cases with evidence of any of the four features of follicular involvement was 27 of 33 (82%), indicating that some form of follicular involvement was common in tPF. Epidermal hyperplasia occurred in all cases (Figure 1a,b), ranged from mild to marked and was regular or irregular. Neither pseudocarcinomatous, papillary nor psoriasiform-like hyperplasia patterns occurred. Hyperkeratosis away from pustules and attached crusts was uncommon (six of 33; 18%), always mild, orthokeratotic and basket-weave to laminated. One or several ulcers occurred in a third of the cases. Ulcers were generally small (less than the width of 50 keratinocytes) and usually were associated with the base or margin of a pustule (92% of ulcers). Most cases (31 of 33; 94%) exhibited moderate epidermal spongiosis (median: 2, range: 0–3), which was predominantly peripustular (Figure 1b). Peripustular spongiosis did not affect all pustules in cases where it occurred. Spongiosis occurred along the base of pustules, below acantholysis and not above it. Spongiotic pustules (no acantholytic cells) were uncommon (four of 33; 12%), small and few in number (one to two per case). Mild laminar hydropic change of the epidermis was present in a few cases. Necrotic acantholytic keratinocytes (Figure 3a,c) with retained shape and nuclear profiles occurred in 39 of 75 (52%) of intact pustules. They were hypereosinophilic and lacked differential staining (coagulative necrosis). Nuclei were sometimes pyknotic. Low numbers of necrotic acantholytic keratinocytes were usually observed (median: 1, range: 0–3). Necrosis was occasionally observed in nondetached peripustular keratinocytes (13 of 75; 17%) within intact pustules. A few cases had similar, rounded, individual necrotic keratinocytes in the epidermis next to pustules and were satellited by neutrophils. Moderate numbers (11–25) of apoptotic keratinocytes were seen in the epidermis of most cases (31 of 33; 94%; median: 2, range: 0–3). They were more often away from pustules (29 of 30; 97%) than near pustules (14 of 30; 47%). Basal layer apoptosis (29 of 31; 94%) occurred more commonly (Figure 3d) than suprabasal apoptosis (20 of 31;65%) and basal layer apoptosis was usually more numerous (26 of 31; 84%) than suprabasal (five of 31; 16%) apoptosis. The basal layer of hair follicle infundibula often had apoptosis, which was not associated with pustules. Lymphocytic satellitosis of apoptotic keratinocytes was seen in nine of 31 (29%) cases and usually only on rare cells in the epidermis. Additional inflammatory patterns occurred in all three PF clinical phenotypes. Lymphocytic bulbitis (tPF; Figure 4a), subepidermal vesicular dermatitis (iPF; Figure S1b) and suprabasal clefting (iPF; Figure S1a) were all seen in one case each. Lymphocytic interface dermatitis was mild-to-marked in four fPF cases (Figure S1c), and mild in one iPF and in one tPF case. Vasculitis in the panniculus was neutrophilic, eosinophilic and/or fibrinous and moderate in one tPF case (Figure 4b), and mild in one iPF case (Figure S1d). Multifocal, neutrophilic to pyogranulomatous sebaceous gland (or duct) adenitis was mild in five tPF cases (Figure 4c), mild-to-marked in two fPF cases (Figure S1e) and mild in four iPF cases. Furunculosis was mild to marked and found in six tPF cases (Figure 4d and Figure S1f) and in one case each of fPF and iPF. Nodular pyogranulomatous dermatitis was mild-to-marked and occurred in two cases of tPF and one case each of fPF and iPF, which were likely to have been secondary to furunculosis in some cases. The histomorphological features of canine tPF are characterised for the first time and are similar to fPF and iPF. Some morphological features were statistically different, yet their incidence was relatively high in all PF groups and histological features were not identified that could confidently differentiate PF phenotypes. The shared morphological features support common molecular mechanisms in canine PF phenotypes, despite—presumably—different disease triggers. Indeed, PF phenotypes are thought to share desmocollin-1(DSC1) as a major autoantigen.1, 3, 5 Beyond this commonality, in-depth investigations of the molecular mechanisms of canine PF are lacking and the reason for clinical variations is still unknown. Likewise, clinical variations in human PF and pemphigus vulgaris (PV) are well-recognised.6 Differences in circulating autoantibodies (anti-DSG1 versus anti-DSG3) have been associated with clinical lesion location and epidermal depth of acantholysis.6, 7 In dogs, anti-desmoglein-1(DSG1) antibodies were demonstrated in only 5%–7% of fPF and tPF patients, and antibodies to other DSGs and DSCs have not been investigated.1, 5, 8, 9 In proteomics-based and protein-array investigations of human PF and PV, a much larger number of autoantibody targets and autoreactive B cell clones have been identified; which also might relate to clinical phenotypes.10 Potentially, the clinical differences in tPF versus fPF are partly to the result of differences in target tissues, nasal planum and footpad being more similar anatomically and less targeted in tPF than haired skin.1 In fact, some canine PF patients present only with nasal planum or footpad lesions.11, 12 Based on keratinocyte morphology, different mechanisms of keratinocyte acantholysis are likely to occur in canine PF variants. Perinuclear eosinophilic rings occurred in acantholytic and peripustular keratinocytes, and these rings are thought to indicate active mechanisms of cell separation.13, 14 Ultrastructurally, desmosomes are reduced in number and size, and keratin intermediate filaments retract towards the nucleus to form the ring.14 Mechanistically, it is thought that autoantibodies induce cell separation by depletion of the membrane pool of cadherins, thus limiting desmosome formation, and by desmosome dismantling and internalisation, mediated partly by active cell signalling via calcium, protein kinase-C and phospholipase-C.15, 16 In this study, pustule margin keratinocytes formed rings before cell detachment, with or without adjacent neutrophils, suggesting neutrophil proximity is not needed to initiate this process. A role for secreted neutrophil enzymes/mediators from distant neutrophils in pustules is not excluded, however. Our study identified boat acantholytic cells and individualised corneocytes in pustules which indicate that nonactive mechanisms of cell separation also occur. Active acantholysis cannot separate corneocytes because of terminal differentiation and covalent cross-linking of corneodesmosomes and intermediate filaments by transglutaminases.17 Boat acantholytic cells formed in the SG and have intermediate features. These cells remain partially flattened, retain tapered edges, contain a nucleus and fail to fully round when separated, suggesting that the cytoskeleton is partly stabilised, possibly by transglutaminase activity and/or by interactions with tight junctions that occur at the cell periphery in SG2 and SG1 layer cells.17, 18 Tight junction interactions could explain collapse of inte}, journal={VETERINARY DERMATOLOGY}, author={Gedon, Natalie Katharina Yvonne and Bizikova, Petra and Olivry, Thierry and Mendoza-Kuznetsova, Ekaterina and Oberkirchner, Ursula and Robertson, James Benjamin and Linder, Keith Emerson}, year={2023}, month={Jun} }
 @article{phelps_palekar_conley_ferrero_driggers_linder_kullman_reif_sheats_dewitt_et al._2023, title={Legacy and emerging per- and polyfluoroalkyl substances suppress the neutrophil respiratory burst}, volume={20}, ISSN={["1547-6901"]}, url={https://doi.org/10.1080/1547691X.2023.2176953}, DOI={10.1080/1547691X.2023.2176953}, abstractNote={Per- and polyfluoroalkyl substances (PFASs) are used in a multitude of processes and products, including nonstick coatings, food wrappers, and fire-fighting foams. These chemicals are environmentally-persistent, ubiquitous, and can be detected in the serum of 98% of Americans. Despite evidence that PFASs alter adaptive immunity, few studies have investigated their effects on innate immunity. The report here presents results of studies that investigated the impact of nine environmentally-relevant PFASs [e.g. perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid potassium salt (PFOS-K), perfluorononanoic acid (PFNA), perfluorohexanoic acid (PFHxA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), 7H-perfluoro-4-methyl-3,6-dioxa-octane sulfonic acid (Nafion byproduct 2), and perfluoromethoxyacetic acid sodium salt (PFMOAA-Na)] on one component of the innate immune response, the neutrophil respiratory burst. The respiratory burst is a key innate immune process by which microbicidal reactive oxygen species (ROS) are rapidly induced by neutrophils in response to pathogens; defects in the respiratory burst can increase susceptibility to infection. The study here utilized larval zebrafish, a human neutrophil-like cell line, and primary human neutrophils to ascertain whether PFAS exposure inhibits ROS production in the respiratory burst. It was observed that exposure to PFHxA and GenX suppresses the respiratory burst in zebrafish larvae and a human neutrophil-like cell line. GenX also suppressed the respiratory burst in primary human neutrophils. This report is the first to demonstrate that these PFASs suppress neutrophil function and support the utility of employing zebrafish larvae and a human cell line as screening tools to identify chemicals that may suppress human immune function.}, number={1}, journal={JOURNAL OF IMMUNOTOXICOLOGY}, author={Phelps, Drake W. and Palekar, Anika I. and Conley, Haleigh E. and Ferrero, Giuliano and Driggers, Jacob H. and Linder, Keith E. and Kullman, Seth W. and Reif, David M. and Sheats, M. Katie and DeWitt, Jamie C. and et al.}, year={2023}, month={Dec} }
 @article{gaudette_ladouceur_troan_whitehurst_dombrowski_lewbart_linder_passingham_christian_schreeg_2023, title={Retrospective analysis of histologic lesions in captive arachnids}, volume={4}, ISSN={["1544-2217"]}, DOI={10.1177/03009858231162948}, abstractNote={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.}, journal={VETERINARY PATHOLOGY}, author={Gaudette, Chris and LaDouceur, Elise E. B. and Troan, Brigid V. and Whitehurst, Nathan and Dombrowski, Daniel S. and Lewbart, Gregory A. and Linder, Keith E. and Passingham, Kent and Christian, Larry S. and Schreeg, Megan E.}, year={2023}, month={Apr} }
 @misc{bizikova_olivry_linder_rybnicek_2023, title={Spontaneous autoimmune subepidermal blistering diseases in animals: a comprehensive review}, volume={19}, ISSN={["1746-6148"]}, url={https://doi.org/10.1186/s12917-023-03597-1}, DOI={10.1186/s12917-023-03597-1}, abstractNote={Abstract Autoimmune subepidermal blistering diseases (AISBDs) are rare skin disorders of animals that were first identified in dogs but several AISBDs are now recognised in other companion animal species. Most AISBDs in animals are homologues of the human diseases and are thought to share similar pathomechanisms of epidermal and/or mucosal blister formation caused by autoantibodies targeting structural proteins of the basement membrane zone (BMZ). Disruption of their structural function by the autoantibodies and/or recruited inflammation leads to BMZ fragility, which presents clinically as vesicles, bullae and, later, deep erosions and ulcers. Canine AISBDs are the best characterised, particularly the more common variants such as mucous membrane pemphigoid (48%), epidermolysis bullosa acquisita (EBA) (26%), and bullous pemphigoid (10%). Exceedingly rare AISBDs in the dog are junctional EBA, mixed AISBD, type-1 bullous systemic lupus erythematosus, linear IgA dermatosis, and pemphigus gestationis. The diagnosis of a specific AISBD is made by combining the clinical features (breed, age, lesion distribution) with histological evidence of subepithelial clefting, but not all AISBDs can be differentiated in this manner and specialised immunological testing is required. This latter, unfortunately, is not readily available and, therefore, the specific AISBD diagnosis often remains unconfirmed. While this limits further understanding of these diseases, it does not prevent clinicians from treating their patients, as the treatment approaches are similar for the different AISBDs in dogs. This review primarily focuses on canine AISBDs, the species for which these diseases have been best characterised, and shorter descriptions of variants in other species are also provided.}, number={1}, journal={BMC VETERINARY RESEARCH}, author={Bizikova, Petra and Olivry, Thierry and Linder, Keith and Rybnicek, Jan}, year={2023}, month={Feb} }
 @article{schreeg_radkin_haugland_murphy_rushton_linder_2022, title={Ameloblastic carcinoma in horses: case report and literature review}, ISSN={["1943-4936"]}, DOI={10.1177/10406387211068459}, abstractNote={Ameloblastic carcinoma is a malignant odontogenic neoplasm that has been reported only rarely in veterinary species. A 16-y-old Arabian crossbred mare was presented for evaluation of a hard mass on the body of the mandible, with evidence of osteolysis on radiographs. Incisional biopsies revealed an invasive neoplasm comprised of spindloid epithelial cells with a high mitotic count and partial dual cytokeratin–vimentin immunoreactivity. The horse was euthanized because of rapid tumor progression 3 mo after presentation. Postmortem evaluation revealed partial obliteration of the mandible by a large, firm-to-hard, tan, locally destructive and invasive mass with no gross or histologic evidence of metastasis. Postmortem histology revealed a poorly differentiated epithelial neoplasm with variably prominent features suggestive of odontogenic histogenesis: a plexiform ribbon architecture, infrequent basilar palisading with antibasilar nuclei, rare basilar cytoplasmic clearing, subepithelial matrix hyalinization, and partial dual cytokeratin–vimentin immunoreactivity. Features of malignancy included regions of necrosis, pronounced cellular atypia, a high mitotic count, extensive tissue invasion and local tissue destruction, and extension of neoplastic cells beyond the margins of the mandibular bone. Collectively, these features are most consistent with mandibular ameloblastic carcinoma. Including our case described here, ameloblastic carcinoma has been reported in only 5 horses. The microscopic features reported most consistently are dual cytokeratin–vimentin immunoreactivity, a high mitotic count, and basilar palisading. Ameloblastic carcinoma should be considered as a differential diagnosis for rapidly growing, locally invasive masses arising from the dentate jaw of horses.}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Schreeg, Megan E. and Radkin, Megan and Haugland, Jennifer and Murphy, Brian G. and Rushton, Steve and Linder, Keith E.}, year={2022}, month={Jan} }
 @article{heniff_chen_christiansen_harms_law_legner_linder_2022, title={Cutaneous epitheliotropic lymphosarcoma in a captive white catfish (Ameiurus catus Linnaeus)}, volume={4}, ISSN={["1365-2761"]}, url={https://doi.org/10.1111/jfd.13625}, DOI={10.1111/jfd.13625}, abstractNote={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.}, journal={JOURNAL OF FISH DISEASES}, author={Heniff, Ashlyn C. and Chen, Laura R. and Christiansen, Emily F. and Harms, Craig A. and Law, Jerry M. and Legner, Christian and Linder, Keith E.}, year={2022}, month={Apr} }
 @article{rasche_mozzachio_linder_2022, title={Cutaneous mast cell tumors in 11 miniature pigs: a retrospective study}, ISSN={["1943-4936"]}, DOI={10.1177/10406387221079255}, abstractNote={Better understanding of mast cell tumors (MCTs) in miniature pigs is needed to guide diagnosis and establish clinical significance. We characterized the gross pathology, histopathology, histochemical staining, and KIT immunoreactivity of cutaneous MCTs in a retrospective descriptive study of 11 miniature pigs (Sus scrofa domesticus). Tumors were single or multiple papules, small nodules, or plaques. In one pig, lymph nodes and internal organs were affected. Histologically, all MCTs involved the dermis, and some extended to the subcutis (4 of 11) and skeletal muscle (1 of 11). Most tumors were well-demarcated, unencapsulated, nodular or multinodular masses (8 of 11) and fewer were poorly demarcated plaques (3 of 11). Neoplastic cells were often well-differentiated with pale amphophilic-to-eosinophilic faintly granular cytoplasm, occasional binucleation, rare multinucleation, and a low mitotic count (<7 per 10 hpf; 10 of 11). Eosinophils were present in tumors in all cases. Cytoplasmic granules stained most consistently with high-pH (2.5-3) toluidine blue (9 of 10) compared to low-pH (0.5-1) toluidine blue (6 of 9) or Giemsa (7 of 10). KIT immunoreactivity patterns were strong perimembranous (4 of 8), focal perinuclear and stippled cytoplasmic (1 of 8), and diffuse cytoplasmic (3 of 8), and included 1 case that was negative for histochemical stains; hence, KIT is a promising diagnostic marker for MCTs in miniature pigs.}, journal={JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION}, author={Rasche, Brittany L. and Mozzachio, Kristie and Linder, Keith E.}, year={2022}, month={Feb} }
 @article{banovic_olivry_artlet_rothstein_beco_linek_zabel_peters-kennedy_welle_wilkes_et al._2022, title={Hyperkeratotic erythema multiforme variant in 17 dogs}, volume={12}, ISSN={["1365-3164"]}, url={https://doi.org/10.1111/vde.13141}, DOI={10.1111/vde.13141}, abstractNote={A new canine subgroup defined as 'old-dog' or 'hyperkeratotic' erythema multiforme (HKEM) with marked hyperkeratosis and parakeratosis has been proposed without any detailed description of larger case series.We report herein the signalment, clinical signs, treatment outcome, and histopathological and immunological findings in 17 dogs with HKEM.Inclusion criteria were the presence of (i) scaly skin lesions with or without crusting; and (ii) microscopic lesions typical of EM (i.e. a panepidermal cytotoxic lymphocytic dermatitis with or without basal keratinocyte apoptosis); and (iii) microscopic ortho- and/or parakeratotic hyperkeratosis affecting the interfollicular epidermis.Clinical questionnaires and skin biopsies were reviewed. Polymerase chain reactions for epidermotropic viruses and direct immunofluorescence were performed.Various breeds were affected with an over-representation of males in their mid-to-late adulthood (median age 9 years). Generalised skin lesions included multifocal-to-coalescing, linear and annular macules and plaques with erythema and adherent firm crusting. Microscopic lesions were specific for EM and featured prominent superficial epidermal apoptosis with lymphocytic satellitosis and parakeratosis. No drug triggers were identified. Polymerase chain reactions for canine herpesvirus polymerase gene, canine parvovirus and canine distemper virus were negative in all HKEM and canine erosive EM (15 dogs) biopsies. Lesions failed to respond to oral and/or topical antimicrobials. Complete remission of signs was achieved in 9 of 17 dogs (53%) using immunosuppressive regimens.Hyperkeratotic erythema multiforme (HKEM) is a chronic, persistent and clinically distinctive erythema multiforme (EM) variant that differs from 'classic' vesiculobullous erosive-to-ulcerative EM in dogs.De nouveaux sous-groupes canins définis comme des érythèmes polymorphes « vieux chiens » et « hyperkératosiques » (HKEM) avec une hyperkératose et une parakératose marquées ont été proposés sans aucune description détaillée de séries de cas plus importantes.Nous rapportons ici le signalement, les signes cliniques, les résultats du traitement et les résultats histopathologiques et immunologiques chez 17 chiens atteints de HKEM.Les critères d'inclusion étaient la présence de : (i) lésions cutanées squameuses avec ou sans croûtes; et (ii) des lésions microscopiques typiques de l'EM (c'est-à-dire une dermatite lymphocytaire cytotoxique panépidermique avec ou sans apoptose basale des kératinocytes); et (iii) une hyperkératose microscopique ortho- et/ou parakératosique affectant l'épiderme interfolliculaire. MATÉRIELS ET MÉTHODES: Des questionnaires cliniques et des biopsies cutanées ont été examinés. Des réactions en chaîne par polymérase pour les virus épidermotropes et une immunofluorescence directe ont été réalisées. RÉSULTATS: Diverses races étaient touchées avec une surreprésentation des mâles dans leur âge moyen à tardif (âge médian neuf ans). Les lésions cutanées généralisées comprenaient des macules et des plaques multifocales à coalescentes, linéaires et annulaires avec un érythème et des croûtes fermes adhérentes. Les lésions microscopiques étaient spécifiques de l'EM et comportaient une apoptose épidermique superficielle proéminente avec une satellitose lymphocytaire et une parakératose. Aucun déclencheur médicamenteux n'a été identifié. Les réactions en chaîne de la polymérase pour le gène de la polymérase de l'herpèsvirus canin, le parvovirus canin et le virus de la maladie de Carré étaient négatives dans toutes les biopsies HKEM et EM érosive canine (15 chiens). Les lésions n'ont pas répondu aux antimicrobiens oraux et/ou topiques. Une rémission complète des signes a été obtenue chez neuf des 17 chiens (53 %) en utilisant des traitements immunosuppresseurs.HKEM est une variante EM chronique, persistante et cliniquement distincte qui diffère de l'EM vésiculobulleuse « classique » érosive à ulcérative chez le chien.INTRODUCCIÓN: Se han propuesto nuevos subgrupos caninos de eritema multiforme definidos como "de perro viejo" e "hiperqueratósico" (HKEM) con hiperqueratosis y paraqueratosis marcadas sin ninguna descripción detallada de series de casos más grandes.En este documento describimos la presentación, los signos clínicos, el resultado del tratamiento y los hallazgos histopatológicos e inmunológicos en 17 perros con HKEM.Los criterios de inclusión fueron la presencia de: (i) lesiones cutáneas escamosas con o sin formación de costras; y (ii) lesiones microscópicas típicas de EM (es decir, una dermatitis linfocítica citotóxica panepidérmica con o sin apoptosis de queratinocitos basales); y (iii) hiperqueratosis microscópica orto y/o paraqueratósica que afecta la epidermis interfolicular. MATERIALES Y MÉTODOS: Se revisaron cuestionarios clínicos y biopsias de piel. Se realizaron reacciones en cadena de la polimerasa (PCR) para virus epidermotrópicos e inmunofluorescencia directa.Varias razas se vieron afectadas con una sobrerrepresentación de machos en su edad adulta media o tardía (edad media de nueve años). Las lesiones cutáneas generalizadas incluyeron máculas y placas lineales y anulares, multifocales a coalescentes, con eritema y formación de costras firmes y adherentes. Las lesiones microscópicas fueron específicas para EM y presentaban apoptosis epidérmica superficial prominente con satelitosis linfocítica y paraqueratosis. No se identificaron desencadenantes farmacológicosmm. Las reacciones en cadena de la polimerasa para el gen de la polimerasa del herpesvirus canino, el parvovirus canino y el virus del moquillo canino fueron negativas en todas las biopsias HKEM y EM erosiva canina (15 perros). Las lesiones no respondieron a los antimicrobianos orales y/o tópicos. Se logró la remisión completa de los signos en nueve de 17 perros (53 %) usando regímenes inmunosupresores. CONCLUSIONES Y RELEVANCIA CLÍNICA: HKEM es una variante de EM crónica, persistente y clínicamente distintiva que difiere de la EM vesiculoampollosa "clásica" erosiva a ulcerosa en perros.Neue canine Untergruppen, die definiert wurden als „alter-Hund“ und „hyperkeratotisches Erythema multiforme (HKEM) mit deutlicher Hyperkeratose und Parakeratose wurden ohne detaillierte Beschreibung größerer Fallserien vorgeschlagen.Hierin beschreiben wir das Signalement, die klinischen Zeichen, den Behandlungsausgang, und die histopathologischen und immunologischen Befunde bei 17 Hunden mit HKEM.Inklusionskriterien waren das Vorhandensein von: (i) schuppigen Hautveränderungen mit oder ohne Krustenbildung; und (ii) mikroskopischen Läsionen von EM (i.e. eine panepidermale zytotoxische lymphozytäre Dermatitis mit und ohne Apoptose der basalen Keratinozyten); und (iii) mikroskopischer ortho- und/oder parakeratotischer Hyperkeratose, die die interfollikuläre Epidermis betrifft.Klinische Fragebögen und Hautbiopsien wurden reviewed. Es wurden Polymerasekettenreaktionen auf epidermotropisches Virus und direkte Immunfluoreszenz durchgeführt.Es waren verschiedene Rassen betroffen, wobei männliche Tiere in mittlerem bis späterem Erwachsenenalter (das mediane Alter betrug neun Jahre) überrepräsentiert waren. Generalisierte Hautveränderungen bestanden aus multifokalen-bis koaleszierenden, linearen und annularen Maculae und Plaques mit Erythem und anhaftenden festen Krusten. Die mikroskopischen Veränderungen waren spezifisch für EM und zeigten eine prominente superfizielle epidermale Apoptose mit lymphzytärer Satellitose und Parakeratose. Es wurden keine eindeutigen Auslöser identifiziert. Polymerasekettenreaktionen auf canines Herpesvirus Polymerase Gen, canines Parvovirus und canines Staupevirus waren in allen HKEM und den caninen erosiven EM-Biopsien (15 Hunde) negativ. Die Veränderungen reagierten nicht auf orale und/oder topische Antibiotika. Eine komplette Remission der Zeichen wurde bei neun von 17 Hunden (53%) mittels Immunsupressiva erzielt.HKEM ist eine chronische, persistierende und klinisch eindeutige EM-Variante, die sich von der „klassischen“ vesikulobullösen erosiv-bis-ulzerativen EM der Hunde unterscheidet.背景: 犬の多形紅斑には、「老犬型」「過角化型(HKEM)」という新しいサブグループが提案されているが、大規模な症例に関する詳細な記述はない。 目的: 本研究の目的は、過角化型多形紅斑を発症した17頭の犬について、シグナルメント、臨床症状、治療成績、病理組織学的および免疫学的所見を報告することであった。 対象動物: (1) 痂皮を伴うか否かの鱗屑性皮膚病変、(2) EMに典型的な顕微鏡的病変(すなわち、基底細胞のアポトーシスを伴うか否かの汎上皮細胞障害性リンパ球性皮膚炎)、(3) 毛包間表皮を冒す顕微鏡的正角化性および/または不全角化性角化亢進が認められることを登録条件とした。 材料と方法: 臨床アンケートおよび皮膚生検のレビューを行った。上皮向性ウイルスに対するポリメラーゼ連鎖反応および直接免疫蛍光検査を行った。 結果: 様々な犬種が罹患し、成犬中期から後期(中央値9歳)の雄に過剰発現していた。全身の皮膚病変は、紅斑および付着性の固い痂皮を伴う、多巣性〜癒合性の線状および環状の斑およびプラークを含んでいた。顕微鏡所見では、EMに特異的で、リンパ球性衛生現象を伴う表皮表面のアポトーシスおよび錯角化が顕著であった。薬物による誘発は確認されなかった。犬ヘルペスウイルスポリメラーゼ遺伝子、犬パルボウイルス、犬ジステンパーウイルスに対するポリメラーゼ連鎖反応は、HKEMおよび犬びらん性EM(15頭)のすべての生検で陰性であった。病変は経口および外用抗菌薬に反応しなかった。免疫抑制療法により17頭中9頭(53%)で症状の完全寛解が得られた。 結論と臨床的意義: HKEMは，"古典的 "な小水疱性びらん-潰瘍性EMとは異なる、慢性で持続的で臨床的に特徴的なEMの一形態である。.背景: 提出了定义为“老年犬”和“角化过度”多形红斑 (HKEM) 伴明显角化过度和角化不全的新亚组，未对更大的犬病例系列进行任何详细描述。 目的: 我们在此报告了17只HKEM犬的病征、临床症状、治疗结果以及组织病理学和免疫学结果。 动物: 入选标准为存在:(i) 皮屑性病变伴或不伴结痂；和 (ii)EM 的典型显微镜下病变(即全表皮细胞毒性淋巴细胞性皮炎伴或不伴基底角质细胞凋亡)；和 (iii) 影响毛囊间表皮的显微镜下角化过度和/或角化不全。 材料和方法: 审查临床问卷和皮肤活检。对亲表皮病毒进行聚合酶链反应和直接免疫荧光检测。 结果: 不同品种发病，成年中后期(中位年龄9岁)公犬比例过高。全身性皮肤病变包括多灶性至融合、线性和环形的斑疹和斑块，伴红斑和粘连性结痂。显微镜下具有EM特异性病变，以突出的浅表表皮凋亡，伴淋巴细胞卫星现象和角化不全为特征。未发现药物触发因素。犬疱疹病毒聚合酶基因、犬细小病毒和犬瘟热病毒的聚合酶链反应在所有 HKEM 和犬糜烂性EM(15只犬)活检中均为阴性。病变经口服和(或)外用抗菌药治疗无效。使用免疫抑制方案时，9/17只犬 (53%) 的症状完全缓解。 结论和临床相关性: HKEM是一种慢性、持续性和临床上独特的 EM 变体，不同于犬的“经典”水疱大疱性糜烂至溃疡性EM。.Novos subgrupos caninos definidos como eritema multiforme do “cão idoso” e “hiperqueratótico” (HKEM) apresentando hiperqueratose e paraqueratose acentuadas têm sido propostos sem qualquer descrição detalhada em uma série de casos maior.Nós relatamos aqui os sinais clínicos, resposta ao tratamento, e achados histopatológicos imunológicos em 17 cães com (HKEM).Os critérios de inclusão foram a presença de: (i) lesões cutâneas descamativas com ou sem crostas;(ii) lesões microscópicas típicas EM (exemplo: dermatite citotóxica linfocítica panepidermal com ou sem apoptose dos queratinócitos da camada basal); e (iii) hiperqueratose orto e/ou paraqueratótica afetando a epidermie interfolicular. MATERIAIS E MÉTODOS: Questionários clínicos e biópsias cutâneas foram revisados. Realizou-se PCR de vírus epidermotrópicos.Diversas raças foram afetadas e houve uma super-representação de machos de meia idade (idade média de nove anos). As lesões cutâneas generalizadas incluíram máculas e placas multifocais a coalescentes, lineares e anulares com eritema e crostas firmes aderentes. As lesões microscópicas eram específicas para EM e apresentavam apoptose epidérmica superficial proeminente com satelitose linfocítica e paraqueratose. Nenhum medicamento foi identificado como agente incitane. As reações em cadeia da polimerase para o gene da polimerase do herpesvírus canino, parvovírus canino e vírus da cinomose foram negativas em todas as biópsias HKEM e EM erosiva canina (15 cães). As lesões não responderam aos antimicrobianos orais e/ou tópicos. A remissão completa dos sinais ocorreu em nove dos 17 cães (53%) usando imunossupressores. CONCLUSÕES E RELEVÂNCIA CLÍNICA: HKEM é uma variante crônica, persistente e clinicamente distinta do EM que difere do EM vesiculobolhoso erosivo-ulcerativo “clássico” em cães.}, journal={VETERINARY DERMATOLOGY}, author={Banovic, Frane and Olivry, Thierry and Artlet, Barbara and Rothstein, Emily and Beco, Luc and Linek, Monika and Zabel, Sonja and Peters-Kennedy, Jeanine and Welle, Monika and Wilkes, Rebecca and et al.}, year={2022}, month={Dec} }
 @article{tham_lanz_linder_2022, title={Localised erythema multiforme-like reaction confined to a region of clipper burn in a dog}, ISSN={["1365-3164"]}, DOI={10.1111/vde.13058}, abstractNote={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.Das Auftreten einer lokalisierten Form von Erythema multiforme (LEM) ist nur bei Menschen und nicht bei Haustieren beschrieben. Dieser Fallbericht beschreibt die klinischen und histopathologischen Merkmale einer LEM-ähnlichen Reaktion bei einem Hund, die auf eine rasierte Stelle beschränkt war.限局性多形紅斑 (LEM) は、ヒトにのみ発症することが報告されており、家畜には発症しない。本症例は，バリカン焼けの部位に限局した犬における LEM 様反応の臨床的，病理組織学的特徴について述べたものである。.局部多形红斑 (LEM) 仅发生于人类，而家养物种未见报道。本病例报告描述了犬 LEM 样反应的临床和组织病理学特征，病变局限于电剪灼烧区域。.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.}, journal={VETERINARY DERMATOLOGY}, author={Tham, Heng L. and Lanz, Otto I and Linder, Keith E.}, year={2022}, month={Jan} }
 @article{lee_you_taylor-just_linder_atkins_ralph_cruz_bonner_2022, title={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}, ISSN={["1091-7691"]}, DOI={10.1080/08958378.2022.2086651}, abstractNote={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.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.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-1β 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.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.}, journal={INHALATION TOXICOLOGY}, author={Lee, Ho Young and You, Dorothy J. and Taylor-Just, Alexia J. and Linder, Keith E. and Atkins, Hannah M. and Ralph, Lauren M. and Cruz, Gabriela and Bonner, James C.}, year={2022}, month={Jun} }
 @article{bizikova_linder_mamo_2022, title={Trunk-dominant and classic facial pemphigus foliaceus in dogs - comparison of anti-desmocollin-1 and anti-desmoglein-1 autoantibodies and clinical presentations}, ISSN={["1365-3164"]}, DOI={10.1111/vde.13094}, abstractNote={Canine trunk-dominant pemphigus foliaceus (PF) is mentioned rarely in the literature. 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. 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. 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. 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. Hintergrund – Pemphigus foliaceus (PF), der dominant am Rumpf des Hundes vorkommt wird in der Literatur selten erwähnt. Hypothese/Ziele – Das Ziel dieser Studie war es, eine klinische Beschreibung des Pemphigus foliaceus (PF), der dominant am Rumpf des Hundes vorkommt, zu liefern und die Prävalenz von Serum Antikeratinozyten, Anti-Desmocollin-1 (DSC1) und Anti-Desmoglein-1 (DSG1) Antikörper zu demonstrieren und ihren diagnostischen Wert bei diesem, speziellen PF Phänotyp festzustellen. Materialien und Methoden – Es wurden klinisch relevante Informationen von 31, 25 und 34 Hunden mit Pemphigus foliaceus (PF), der dominant am Rumpf vorkommt, sowie von Gesichts PF und oberflächlicher Pyodermie (SP) gesammelt. Sera dieser Hunde wurden mittels indirekter Immunfluoreszenz in caninem Gewebe und in DSC-1 und DSG1-transfizierten Zellen auf Antikeratinozyten, Anti-DSC1 und Anti-DSG1 Antikörper getestet. Sera von gesunden Hunden und Hunden mit klinisch irrelevanten Krankheiten dienten als Kontrollen. Ergebnisse – Eine Beteiligung der Fußballen und eine gruppierte/polyzyklische Organisation der Veränderungen wurden als Merkmale beider PF Phänotypen identifiziert, jedoch nicht für SP. Antikeratinozyten Immunglobulin (Ig) G war nicht spezifisch für caninen PF. Im Gegenteil Antigen-spezifisches IgG wurde nur in PF Sera; anti-DSC1 IgG in 100% bzw. 58% der Hunde mit Gesichts- bzw. Rumpf-dominantem PF und anti-DSG1 IgG in 7% der Hunde mit ausschließlich Rumpf-dominantem PF gefunden. Schlussfolgerungen – Der PF, welcher dominant am Rumpf des Hundes vorkommt, teilt sich DSC1 als Major Autoantigen mit dem Gesichts PF. Die Fähigkeit anti-DSC1 IgG zu finden ist beim Rumpf-dominanten PF niedriger, dennoch ist trotz der niedrigeren Sensibilität, der positive prädiktive Wert und die Genauigkeit dieses speziellen anti-DSC1 IgG Tests hoch. Ein negatives Testergebnis kann jedoch die Diagnose nicht ausschließen und die charakteristischen klinischen Merkmale wie Beteiligung der Fußballen und/oder gruppierte/polyzyklische Veränderungen müssen beachtet werden, wenn eine Rumpf-dominate PF Form von seiner wesentlichsten Differentialdiagnose, der SP, unterschieden werden soll. 背景 - 犬の体幹優位型落葉状天疱瘡(PF)は、文献上ほとんど言及されていない。 仮説/目的 - 本研究の目的は、体幹優位型落葉状天疱瘡の臨床情報を提供し、血清中の抗ケラチノサイト抗体、抗デスモコリン-1(DSC1)抗体および抗デスモグレイン-1(DSG1)抗体の陽性率を明らかにし、この特殊なPF表現型における診断的価値を決定することであった。 材料と方法 - 体幹優位型、顔面優位型のPFおよび表在性膿皮症(SP)の犬31頭、25頭および34頭からそれぞれ臨床的に関連する情報を収集した。これらの犬の血清を、犬組織とDSC1-およびDSG1-トランスフェクト細胞に対する間接免疫蛍光法を用いて、抗ケラチノサイト抗体、抗DSC1抗体および抗DSG1抗体について検査した。健常犬および臨床的に無関係な病気の犬の血清を対照とした。 結果 - 足蹠の浸潤と群発性/多発性病変の編成が両PF表現型の特徴として確認され、SPの特徴とはならなかった。抗ケラチノサイト免疫グロブリン(Ig)Gは、犬のPFに特異的ではなかった。一方、抗原特異的IgGはPFの血清にのみ検出された。顔面および体幹優位のPF犬では、それぞれ100%および58%に抗DSC1 IgGが、体幹優位のPFの犬のみでは7%に抗DSG1 IgGが検出された。 結論 - 体幹優位型PFは、顔面優位型PFと同様にDSC1が主要な自己抗原である。体幹優位型PFでは抗DSC1 IgGの検出能力は低いが、感度が低いにもかかわらず、この特殊な抗DSC1 IgG検査の陽性適中率と精度は高い。しかし、検査結果が陰性でも診断を除外することはできず、体幹優位型PFをその最も関連性の高い鑑別診断であるSPから鑑別する際には、足蹠病変および/または群発/多発性病変などの特徴的な臨床症状を考慮しなければならない。 背景-文献中很少提及犬躯干显性落叶型天疱疮(PF)。 假设/目的-本研究的目的是提供躯干显性PF的临床描述，并证明血清抗角质细胞、抗桥粒芯糖蛋白-1(DSC1)和抗桥粒芯糖蛋白-1(DSG1)抗体的流行率，并确定其在该特定PF表型中的诊断价值。 材料和方法-分别从31、25和34只躯干显性和面部PF以及浅表性脓皮病(SP)犬中收集临床相关信息。使用犬组织以及DSC1和DSG1转染细胞的间接免疫荧光法，检测这些犬血清中的抗角质形成细胞、抗DSC1和抗DSG1抗体。健康犬和临床无关疾病犬的血清作为对照。 结果-爪垫受累和分组/多环病变组织被确定为PF表型的特征，而不是SP的特征。抗角质细胞免疫球蛋白(Ig)G对犬PF无特异性。相比之下，仅在PF血清中检测到抗原特异性IgG；面部和躯干显性PF犬中抗DSC1 IgG分别占100%和58%，仅躯干显性PF犬中抗DSG1 IgG占7%。 结论-躯干显性PF与面部PF共享DSC1作为主要的自身抗原。在躯干显性PF中检测抗DSC1 IgG的能力较低，然而尽管敏感性较低，但这种特殊的抗DSC1 IgG检测的阳性预测值和准确性较高。然而，阴性检测结果不能排除诊断，在区分躯干显性PF与其最相关的鉴别诊断:SP时，必须考虑爪垫受累和(或)成群/多环病变等特征性临床特征。 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. APPENDIX S1 Indirect immunofluorescence methods TABLE S1 Secondary antibodies used in the indirect immunofluorescence experiments FIGURE S1 Indirect immunofluorescence examples (a) Green, intercellular, web-like pattern confirming the presence of antikeratinocyte IgG using healthy canine footpad tissue and serum from a dog with pemphigus foliaceus; (b) green, stippled fluorescence confirming the presence of anti-DSC1 IgG using DSC1-transfected 293 T cells and serum from a dog with pemphigus foliaceus; (c) negative control using nontransfected 293 T cells and serum from a dog with pemphigus foliaceus. Blue staining depicts the nuclei (Vectashield-DAPI, Vector Laboratories; Burlingame, CA, USA) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.}, journal={VETERINARY DERMATOLOGY}, author={Bizikova, Petra and Linder, Keith E. and Mamo, Lisa B.}, year={2022}, month={Jun} }
 @article{fussell_bizikova_breuhaus_harris_moore_chen_linder_2021, title={Bullous amyloidosis in a horse: first description in veterinary medicine}, volume={6}, ISSN={["1365-3164"]}, DOI={10.1111/vde.12982}, abstractNote={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.To describe the clinical features, laboratory analysis and histopathological features of an unique presentation of bullous disease in a horse.A 17-year-old thoroughbred mare presented for weight loss and severe oral cavity ulcers.Investigations involved haematological evaluation, chemistry profiles, gastroscopy and serum protein electrophoresis, and, postmortem, histopathological evaluation, Congo-red staining and transmission electron microscopy (TEM).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.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.L’amyloïdose bulleuse est une maladie rare chez l’homme qui n’a pas encore été décrite dans une espèce vétérinaire dans la littérature avec comité de lecture. La maladie de l’homme est caractérisée par des vésicules et bulles hémorragiques de la peau et des muqueuses qui se forment après dépôt d’amyloïde. HYPOTHÈSES/OBJECTIFS: Décrire les données cliniques, les analyses de laboratoires et les critères histopathologiques d’une présentation unique de maladie bulleuse chez un cheval.Une jument de race de 17 ans présentée pour perte de poids et ulcères sévères de la cavité buccale. MÉTHODES: Les investigations comprenaient une évaluation hématologique, des profils biochimiques, une gastroscopie et une électrophorèse des protéines sériques et, post mortem, un examen histopathologique, une coloration au rouge Congo et une microscopie à transmission électronique (TEM). RÉSULTATS: Les vésicules et bulles hémorragiques se sont développées sur les muqueuses de la cavité orale, les lèvres, l’œsophage et l’estomac et moins au niveau des narines, de la face et des jonctions cutanéo-muqueuses du périnée où des cicatrices étaient évidentes. Une évaluation histopathologique et une coloration au rouge Congo ont confirmé la présence d’amyloïde dans le derme et les muqueuses, en association avec la formation des vésicules et des bulles, compatible avec l’amyloïdose bulleuse. La TEM a confirmé le dépôt de fibrilles d’amyloïdes dans le derme et au niveau de la membrane basale. Un clivage était présent dans le derme superficiel et les sous muqueuses, expliquant l’hémorragie et les cicatrices. La présence d’une gammapathie polyconale et du rapide disparition de la coloration au rouge Congo avec réalisation d’un prétraitement, soutenaient une amyloïde A sérique et une amyloïdose secondaire.L’amyloïdose bulleuse est une nouvelle maladie du cheval et un nouveau différentiel dans les dermatoses bulleuses pour laquelle la nature hémorragique des bulles, des cicatrices et des ulcères secondaires profonds est considérée comme une donnée clinique évocatrice de l’atteinte.INTRODUCCIÓN: la amiloidosis bullosa es una enfermedad rara en humanos que no se ha descrito en ninguna especie veterinaria en la literatura revisada. La enfermedad humana se caracteriza por vesículas y ampollas hemorrágicas en la piel y las mucosas, que se forman debido al depósito de amiloide. HIPÓTESIS/OBJETIVOS: describir las características clínicas, análisis de laboratorio y características histopatológicas de una presentación única de enfermedad bullosa en un caballo. ANIMALES: una yegua pura sangre de 17 años que se presentó por pérdida de peso y úlceras severas en la cavidad oral. MÉTODOS: Las investigaciones incluyeron evaluación hematológica, perfiles químicos, gastroscopia y electroforesis de proteínas séricas y, post mortem, evaluación histopatológica, tinción con rojo Congo y microscopía electrónica de transmisión (TEM). RESULTADOS: Se observaron vesículas y ampollas hemorrágicas en la mucosa de la cavidad oral, labios, esófago y estómago, y mucho menos en el hocico, la cara y las áreas mucocutáneas del perineo, donde las cicatrices eran evidentes. La evaluación histopatológica y la tinción con rojo Congo confirmaron la presencia de depósitos de amiloide en dermis y submucosa, en asociación con formación de vesículas y ampollas, compatibles con amiloidosis bullosa. TEM confirmó el depósito de fibrillas de amiloide en la dermis y a lo largo de la zona de la membrana basal. Se produjeron hendiduras en la dermis superficial y la submucosa, lo que explica la hemorragia y la cicatrización. La presencia de una gammapatía policlonal y la rápida desaparición de la tinción con rojo Congo con el pretratamiento con permanganato potásico confirmaron amiloide A sérico y la amiloidosis secundaria. CONCLUSIÓN E IMPORTANCIA CLÍNICA: la amiloidosis bullosa es una enfermedad nueva del caballo y un diferencial recientemente reconocido de enfermedades bullosas. La naturaleza hemorrágica de las ampollas, la presencia de cicatrices y de úlceras secundarias profundas se consideran indicios clínicos de esta enfermedad.Die bullöse Amyloidose ist eine seltene Erkrankung beim Menschen, die noch bei keiner tierischen Spezies in Peer-Review Literatur beschrieben wurde. Die Erkrankung ist beim Menschen durch hämorrhagische Bläschen und Blasen auf der Haut und den Schleimhäuten gekennzeichnet, die sich aufgrund von Amyloid Ablagerung bilden.Die Beschreibung der klinischen Merkmale, der Laboranalyse und der histopathologischen Merkmale einer einzigartigen Präsentation einer bullösen Erkrankung bei einem Pferd.Eine 17 Jahre alte Vollblutaraberstute wurde wegen Gewichtsverlust und hochgradigen Ulzera in der Mundhöhle vorgestellt.Die Untersuchungen beinhalteten Hämatologie, Biochemie, Gastroskopie und eine Serumelektrophorese, sowie post mortem eine histopathologische Evaluierung, Kongorotfärbung und Transmissionselektronenmikroskopie (TEM).Hämorrhagische Bläschen und Blasen traten an der Mundschleimhaut, an den Lippen, der Speiseröhre und im Magen auf, sowie etwas weniger ausgeprägt an der Nase, dem Gesicht und den mucokutanen Übergängen des Perneums, wo Narbenbildung evident war. Die histopathologische Evaluierung und die Kongorotfärbung bestätigten das Vorkommen von Amyloidablagerungen in der Dermis und Submukosa, im Zusammenhang mit Bläschen- und Blasenbildung, was mit einer bullösen Amyloidose übereinstimmte. Die TEM bestätigte Amyloidfasernablagerungen in der Dermis und entlang der Basalmembranzone. In der oberflächlichen Dermis und Submukosa bestand eine Spaltenbildung, die die Blutung und die Narbenbildung erklärten. Das Auftreten eine polyklonalen Gammopathie sowie das rasche Verschwinden der Kongorotfärbung nach performativer Vorbehandlung stützte die Diagnose einer Serum Amyloid A und einer sekundären Amyloidose.Die bullöse Amyloidose ist eine neue Erkrankung des Pferdes und eine neu erkannte Differentialdiagnose für bullöse Erkrankungen, bei der die hämorrhagische Natur der Blasen, die Narbenbildung und die tiefen sekundären Ulzera als klinische Hinweise für diesen Zustand gelten.背景: 水疱性アミロイドーシスは、ヒトではまれな疾患で、獣医学的にはまだ報告されていない。本疾患は、アミロイド沈着により皮膚や粘膜に形成される出血性の小水疱や水疱が特徴である。 仮説/目的: 本研究の目的は、1頭の馬に認められた水疱疾患のユニークな症状の臨床的特徴、実験室解析および病理組織学的特徴を説明することであった。 供試動物: 17歳のサラブレッドの雌馬が体重減少および重度の口腔内潰瘍のために来院した。 方法: 血液学的評価、化学的プロファイル、胃内視鏡検査、血清タンパク質電気泳動を行い、死後、組織学的評価、コンゴレッド染色、透過型電子顕微鏡 (TEM) を行った。 結果: 出血性小水疱および水疱は口腔、口唇、食道、胃の粘膜に発生し、鼻口部、顔面、会陰粘膜皮膚領域にはほとんど発生せず、瘢痕が認められた。病理組織学的評価およびコンゴレッド染色により、水疱性アミロイドーシスと一致した、小水疱や水疱の形成と関連する真皮および粘膜下層のアミロイド沈着の存在が確認された。TEMでは、真皮および基底膜帯に沿ってアミロイド線維の沈着が確認された。表層の真皮および粘膜下層に裂け目が生じており, 出血および瘢痕化が説明できた。ポリクローナルガンモパシーの存在と、前治療の実施によるコンゴレッド染色の急速な廃絶は、血清アミロイド A および続発性アミロイドーシスを支持した。 結論と臨床的重要性: 水疱性アミロイドーシスは馬の新しい病気であり、水疱症の鑑別として新たに認識された。水疱の出血性の性質、瘢痕、深い二次的な潰瘍がこの病気の臨床的な手がかりと考えられる。.背景: 大疱性淀粉样变性是一种人类罕见疾病, 动物发病尚未在兽医同行评审文献中描述过。人类疾病的特征是皮肤和粘膜上的出血性水疱和大疱, 其由淀粉样蛋白沉积形成。 假设/目的: 描述马大疱性疾病独特表现的临床特征、实验室分析和组织病理学特征。 动物: 只17岁的纯种母马因体重减轻和严重的口腔溃疡而就诊。 方法: 研究涉及血液学评价、化学特征、胃镜检查和血清蛋白电泳, 以及尸检、组织病理学评价、刚果红染色和透射电子显微镜(TEM)。 结果: 口腔、嘴唇、食管和胃的粘膜上发生出血性水疱和大疱, 更少发生在有明显瘢痕的口鼻、面部和会阴皮肤粘膜区域。组织病理学评价和刚果红染色证实真皮和粘膜下层存在淀粉样沉积物, 与水泡和大疱形成相关, 与大疱性淀粉样变性一致。TEM证实淀粉样纤维沉积于真皮, 并沿基底膜区沉积。裂隙发生在真皮浅层和粘膜下层, 这解释了出血和瘢痕形成。多克隆丙种球蛋白病的存在和进行预处理后刚果红染色的快速消除,支持了血清淀粉样蛋白a和继发性淀粉样变性。 结论和临床意义: 大疱性淀粉样变性是马的一种新型疾病, 并发现与大疱性疾病存在差异, 大疱的出血性质、瘢痕和深部继发性溃疡被认为是该疾病的临床线索。.A amiloidose bolhosa é uma doença rara em humanos que não foi descrita em espécies veterinárias na literatura com sistema de revisão por pares. A doença humana é caracterizada por vesículas e bolhas hemorrágicas na pele e mucosas, que se formam devido à deposição de substância amiloide. HIPÓTESE/OBJETIVOS: Descrever as características clínicas, exames laboratoriais e histopatológicos de uma doença bolhosa com apresentação singular em um cavalo.Uma égua da raça puro-sangue inglês de 17 anos de idade foi apresentada devido a um quadro de perda de peso e úlceras graves da cavidade oral. MÉTODOS: As investigações consistiram de avaliação hematológica, perfil bioquímico, gastroscopia e eletroforese de proteínas séricas e, postmortem, avaliação histopatológica, coloração com vermelho do Congo e microscopia eletrônica de transmissão (TEM).Vesículas e bolhas hemorrágicas estavam presentes na mucosa da cavidade oral, lábios, esôfago e estômago, e, em menor quantidade, no focinho, face e regiões mucocutâneas do períneo, onde a presença de tecido cicatricial era evidente. A avaliação histopatológica e a coloração com vermelho do Congo confirmaram a presença de depósitos de substância amiloide na derme e submucosa, associados à formação de vesículas e bolhas, compatível com amiloidose bolhosa. A TEM confirmou a deposição de fibrila amiloide na derme e ao longo da zona da membrana basal. Observou-se a presença de fissuras na derme superficial e submucosa, justificando a hemorragia e as cicatrizes. A presença de uma gamopatia policlonal e a rápida descoloração do vermelho do Congo após pré-tratamento corroboraram com a amiloide A sérica e a amiloidose secundária. CONCLUSÃO E IMPORTÂNCIA CLÍNICA: A amiloidose bolhosa é uma nova doença descrita em equinos e representa um diagnóstico diferencial recentemente reconhecido para quadros bolhosos, sendo que a natureza hemorrágica das bolhas, presença de cicatrizes e úlceras profundas secundárias são consideradas indícios clínicos da condição.}, journal={VETERINARY DERMATOLOGY}, author={Fussell, Devin and Bizikova, Petra and Breuhaus, Babetta and Harris, R. Adam and Moore, A. Russell and Chen, Laura and Linder, Keith E.}, year={2021}, month={Jun} }
 @article{herrmann_linder_meurs_friedenberg_cullen_olby_bizikova_2021, title={Canine junctional epidermolysis bullosa due to a novel mutation in LAMA3 with severe upper respiratory involvement}, volume={32}, ISSN={["1365-3164"]}, url={https://doi.org/10.1111/vde.12972}, DOI={10.1111/vde.12972}, abstractNote={Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone.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.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.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.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.A novel variant in LAMA3 caused a generalized and severe phenotype of JEB with an unique clinical presentation of upper airway obstruction.L’épidermolyse bulleuse jonctionnelle (JEB) est un groupe de dermatoses cutanées congénitales vésiculeuses caractérisées par un clivage au niveau de la lamina lucida de la membrane basale.Caractériser les critères cliniques et morphologiques de maladies bulleuses congénitales dans une portée de chiots avec troubles respiratoires sévères et identifier un variant génétique associé.Cinq des huit chiots d’une portée de chiens croisés bouvier australien ont montré des signes de fragilité cutanée. Trois étaient mort-nés et un est mort à l’âge d’un mois. Les deux chiots survivants ont été présentés avec une dermatose vésiculeuse et des troubles respiratoires sévères. En outre, un chiot sain a été examiné et du sang a été prélevé pour tests génétiques. MATÉRIELS ET MÉTHODES: Un examen post-mortem, une évaluation histopathologique et electro-microscopique ont été réalisés. Le séquençage complet du génome (WGS) d’un chiot atteint a été comparé à une base de données de 522 chiens de 55 races différentes pour une analyse de variant. Le séquençage de Sanger d’un autre chiot atteint et un chiot sain a confirmé le variant. RÉSULTATS: Cliniquement, les ulcères cutanéo-muqueux sévères étaient observés aux zones de friction avec pertes des griffes. Les résultats histopathologiques révélèrent des séparations sous épidermiques et l’électro-microscopie a confirmé le clivage au sein de la lamina lucida. L’examen post mortem a documenté des lésions laryngées et pharyngées extensives avec tissue de granulation et exsudat fibrineux dissimulant les voies aériennes. Une hypoplasie trachéale modérée y contribuait. Le WGS a révélé un nouveau variant contre-sens dans la chaine α3 de laminine XP_537297.2p(Asp2867Val), avec un mode autosomal récessif de transmission.Un nouveau variant cause un phénotype de JEB sévère et généralisé avec une présentation clinique unique d’obstruction des voies respiratoires supérieures.INTRODUCCIÓN: la epidermólisis bullosa de la unión (JEB) es un grupo de enfermedades cutáneas congénitas con formación de ampollas caracterizadas por una hendidura a lo largo de la lámina lúcida de la zona de la membrana basal. OBJETIVOS: establecer las características clínicas y morfológicas de una enfermedad mecanobullosa congénita en una camada de cachorros con afectación respiratoria superior grave e identificar una variante genética asociada. ANIMALES: cinco de los ocho cachorros en una camada mestiza de perros de ganado australiano mostraron signos de fragilidad de la piel. Tres nacieron muertos y uno murió al mes de edad. Los dos cachorros supervivientes presentaron una enfermedad cutánea con ampollas y dificultad respiratoria grave. Además, se examinó a un hermano no afectado y se extrajo sangre para realizar pruebas genéticas. MÉTODOS Y MATERIALES: Se realizó examen post-mortem, evaluación histopatológica y microscopía electrónica. La secuenciación del genoma completo (WGS) de un cachorro afectado se comparó con una base de datos de 522 perros de 55 razas diferentes para el análisis de variantes. La secuenciación de Sanger de un hermano afectado adicional y un hermano no afectado confirmó la variante. RESULTADOS: Clínicamente, se produjeron úlceras mucocutáneas graves en áreas de fricción con desprendimiento de garras. Los resultados histopatológicos revelaron hendiduras subepidérmicas y la microscopía electrónica confirmó la escisión en la lámina lúcida. El examen post-mortem documentó extensas lesiones faríngeas y laríngeas con tejido de granulación y exudado fibrinoso que oscurecía las vías respiratorias. A las lesions también se añadía una hipoplasia traqueal moderada. El WGS reveló una nueva variante sin sentido en la cadena α3 de laminina XP_537297.2p (Asp2867Val), con un modo de herencia autosómico recesivo. CONCLUSIÓN Y RELEVANCIA CLÍNICA: una nueva variante genética causó un fenotipo generalizado y severo de JEB con una presentación clínica única de obstrucción de las vías respiratorias superiores.Die Junctional Epidermolysis Bullosa (JEB) umfasst eine Gruppe kongenitaler blasenbildender Hauterkrankungen, die durch eine Spaltbildung durch die Lamina lucida der Basalmembranzone charakterisiert sind. ZIEL: Die Charakterisierung klinischer und morphologischer Merkmale einer kongenitalen mechanobullösen Erkrankung bei einem Wurf von Welpen mit hochgradiger respiratorischer Beteiligung sowie eine Identifizierung der damit zusammenhängenden genetischen Variante.Fünf von acht Welpen eines Australian cattle Dog Mischlingswurfes zeigten Zeichen von Hautfragilität. Drei waren totgeboren und ein Welpe starb mit einem Monat. Die zwei überlebenden Welpen wurden mit einer blasenbildenden Hauterkrankung und hochgradiger respiratorischer Not vorgestellt. Zusätzlich wurde ein nicht betroffenes Geschwister untersucht und Blut zur genetischen Analyse genommen.Eine Post Mortem Untersuchung, eine histopathologische Evaluierung und Elektronenmikroskopie wurden durchgeführt. Eine Ganz-Genom Sequenzierung (WGS) eines erkrankten Welpen wurde mit der Datenbank von 522 Hunden 55 verschiedener Rassen zur Varianzanalyse verglichen. Mittels Sanger Sequenzierung eines der weiteren betroffenen und eines nicht erkrankten Geschwisters wurde die Variante bestätigt.Klinisch traten hochgradige mukokutane Ulzera an Reibungsstellen auf, wobei sich die Krallen ablösten. Die histopathologische Untersuchung ergab subepidermale Spalten und mittels Elektronenmikroskopie wurde der Spalt in der Lamina lucida bestätigt. Die Post mortem Untersuchung dokumentierte ausgedehnte Läsionen in Pharynx und Larynx, wobei Granulationsgewebe und fibrinöses Exsudat die Luftwege behinderten. Eine moderate tracheale Hypoplasie trug zu dem Problem bei. Die WGS zeigte eine neue Missense Mutation in der Laminin α3-Kette XP_537297.2p(Asp2867Val), bei autosomal rezessiver Vererbung.Eine neue Variante bedingte eine generalisierte Form einer JEB mit einem stark betroffenen Phänotyp und einer einzigartigen klinischen Präsentation der Obstruktion der oberen Atemwege.背景: Junctional epidermolysis bullosa（JEB）は，基底膜領域のlamina lucidaを介した間隙を特徴とする先天性水疱性皮膚疾患の一群である。 目的: 本研究の目的は、重度の上気道病変を有する子犬集団における先天性機械的水疱性疾患の臨床的および形態学的特徴を明らかにし，関連する遺伝子変異を同定することであった。 供試動物: オーストラリアン・キャトル・ドッグとの交配で生まれた子犬8頭のうち、5頭に皮膚脆弱性の兆候が見られた。3頭は死産し、1頭は生後1ヶ月で死亡した。生き残った2頭の子犬は、水ぶくれのある皮膚病と重度の呼吸困難を呈していた。さらに、罹患していない1頭の同腹仔を診察し、遺伝子検査のために血液を採取した。 材料と方法: 死後検査、病理組織学的評価および電子顕微鏡検査を行った。罹患子犬1頭の全ゲノム塩基配列（WGS）を、55種の犬522頭のデータベースと比較し、バリアント解析を行った。さらに罹患した1頭の同腹仔と罹患していない1頭の同腹仔のサンガーシークエンス法により、変異が確認された。 結果: 臨床的には、重度の粘膜皮膚潰瘍が摩擦部位に発生し、爪が剥がれた。病理組織学的には表皮下の間隙を認め、電子顕微鏡ではlamina lucidaの間隙が確認された。死後検査では、肉芽組織および線維性滲出液が気道を塞いでいる広範囲の咽頭および喉頭の病変が記録された。中等度の気管低形成が認められた。WGSの結果、ラミニンα3鎖のXP_537297.2p(Asp2867Val)という新規ミスセンス変異が見つかり、常染色体劣性遺伝であることが判明した。 結論と臨床的妥当性: 新規変異は、上気道閉塞というユニークな臨床症状を伴うJEBの全般的で重篤な表現型の原因となった。.背景: 交界性大疱性表皮松解症(Junctional epidermolysis bullosa，JEB)是一组先天性水疱性皮肤病，以基底膜区透明层裂隙为特征。 目的: 描述一窝严重上呼吸道发病幼犬先天性机械大疱病的临床和形态学特征，并确定相关的遗传变异。 动物: 澳大利亚杂交牛犬8只同窝幼犬中的5只显示出皮肤脆弱症状。3只为死胎，1例在1月龄时死亡。2只存活幼犬表现为水疱性皮肤病和严重呼吸窘迫。此外，检查了1只未发病的同窝犬，并采集血液用于基因检测。 方法和材料: 进行尸检、组织病理学评价和电子显微镜检查。将1只发病幼犬的全基因组测序(WGS)与55个不同品种的522只犬的数据库进行比较，进行变异分析。对另外一个发病和一个未发病的同窝犬进行Sanger测序，证实了该变异。 结果: 临床上，重度皮肤粘膜溃疡发生在摩擦区域，伴爪脱落。组织病理学结果显示表皮下裂隙，电子显微镜检查证实透明层开裂。尸检记录了广泛的咽部和喉部病变，伴有肉芽组织和纤维蛋白性渗出物阻塞气道。导致中度气管发育不全。WGS揭示了层粘连蛋白α3-链XP_537297.2p(Asp2867Val)的一个新的错义变体，具有常染色体隐性遗传模式。 结论和临床相关性: 种新变体引起JEB的广泛和严重表型，具有上呼吸道阻塞的独特临床表现。.A epidermólise bolhosa juncional (EBJ) é um grupo de doenças cutâneas congênitas apresentando lesões bolhosas caracterizadas por fissuras ao longo da lâmina lúcida da zona da membrana basal.Detalhar as características clínicas e morfológicas de uma doença mecanobolhosa congênita em uma ninhada de filhotes de cães com comprometimento respiratório superior grave e identificar uma variante genética associada.Cinco dos oito filhotes em uma ninhada com cães boideieros australianos mestiços apresentaram sinais de fragilidade da pele. Três nasceram mortos e um morreu com um mês de idade. Os dois cachorros sobreviventes apresentaram dermatopatia bolhosa e dificuldade respiratória grave. Além disso, um irmão não afetado foi examinado e o sangue foi obtido para teste genético. MÉTODOS E MATERIAIS: Foram realizados exame post-mortem, avaliação histopatológica e microscopia eletrônica. O sequenciamento do genoma completo (WGS) de um filhote afetado foi comparado a um banco de dados de 522 cães de 55 raças diferentes para análise de variantes. O sequenciamento de Sanger de um irmão afetado adicional e um irmão não afetado confirmou a variante.Clinicamente, úlceras mucocutâneas graves ocorreram em áreas de fricção com arranhadura pelas unhas. Os resultados histopatológicos revelaram fissuras subepidérmicas e a microscopia eletrônica confirmou a fissura na lâmina lúcida. O exame post-mortem documentou lesões laríngeas e faríngeas extensas com tecido de granulação e exsudato fibrinoso obscurecendo as vias aéreas. Hipoplasia traqueal moderada contribuiu. O WGS revelou uma nova variante missense na cadeia α3 da laminina XP_537297.2p (Asp2867Val), com um modo de herança autossômico recessivo. CONCLUSÃO E RELEVÂNCIA CLÍNICA: Uma nova variante causou um fenótipo generalizado e grave de EBJ com uma apresentação clínica única de obstrução das vias aéreas superiores.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Herrmann, Ina and Linder, Keith E. and Meurs, Kathryn M. and Friedenberg, Steven G. and Cullen, Jonah and Olby, Natasha and Bizikova, Petra}, year={2021}, month={Aug}, pages={379-+} }
 @article{rasche_tucker_linder_harrison_negrao watanabe_2021, title={Case Report: Pulmonary Conidiobolomycosis in a Vietnamese Pot-Bellied Pig}, volume={8}, ISSN={["2297-1769"]}, DOI={10.3389/fvets.2021.799641}, abstractNote={An adult castrated male Vietnamese pot-bellied pig had a 1-week history of acute dyspnea and lethargy. Minimal diagnostic testing was authorized by the owner, resulting in treatment with a third-generation cephalosporin and a non-steroidal anti-inflammatory drug. Partial improvement was observed after a week; however, the pig died 2 weeks after the initial onset of clinical signs. Macroscopically, ~90% of the left lung was effaced by large masses with a caseonecrotic center. Histologic examination revealed eosinophilic granulomas with myriad, intralesional, negatively staining hyphae highlighted by "sleeves" of hypereosinophilic material (Splendore-Hoeppli material). Infection with an oomycete or "zygomycete" (i.e., organisms of the order Entomophthorales or Mucorales) was initially considered. Pan-fungal PCR and sequencing performed on formalin-fixed, paraffin-embedded lung tissue identified Conidiobolus spp., consistent with a diagnosis of primary pulmonary conidiobolomycosis. There are only a few reports of infections with Conidiobolus spp. (and other members of the order Entomophthorales) in swine. Unlike humans and other animal species, conidiobolomycosis in pigs presents more commonly as a primary pulmonary disease rather than rhinofacial or nasopharyngeal disease.}, journal={FRONTIERS IN VETERINARY SCIENCE}, author={Rasche, Brittany L. and Tucker, Samuel M. and Linder, Keith and Harrison, Tara M. and Negrao Watanabe, Tatiane Terumi}, year={2021}, month={Dec} }
 @article{sims_nagle_tolbert_anderson_linder_neel_2021, title={Correlation of cytology to histology in a case of canine granulomatous colitis in a Boxer dog}, volume={10}, ISSN={["1939-165X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85117248282&partnerID=MN8TOARS}, DOI={10.1111/vcp.13058}, abstractNote={A 2-year-old castrated male mixed breed dog presented to the North Carolina State Veterinary Teaching Hospital for chronic diarrhea with hematochezia and weight loss. Cytology performed on a rectal scraping revealed macrophages containing magenta, light pink, and variably blue granular inclusions, and phagocytosed material concerning for infectious organisms. Histopathology was consistent with granulomatous colitis and identified intra-histiocytic bacterial organisms, confirmed by fluorescent in situ hybridization (FISH)-tissue culture-confirmed Escherichia coli. Based on these findings, a diagnosis of granulomatous colitis was made. The patient was successfully treated with oral enrofloxacin, and near-complete remission of signs was achieved within 6 weeks. This report describes a case of granulomatous colitis in a mixed breed dog, and is the first published description of the cytologic features of this uncommon disease, offering a valuable cytologic-histologic correlation. In this case, the cytology was helpful in identifying features consistent with granulomatous colitis and prioritizing the differential diagnoses and diagnostic plan.}, number={S1}, journal={VETERINARY CLINICAL PATHOLOGY}, author={Sims, Cory S. and Nagle, Jonathan and Tolbert, M. Katherine and Anderson, Katie and Linder, Keith and Neel, Jennifer}, year={2021}, month={Oct} }
 @article{meuten_moore_donovan_bertram_klopfleisch_foster_smedley_dark_milovancev_stromberg_et al._2021, title={International Guidelines for Veterinary Tumor Pathology: A Call to Action}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211013712}, abstractNote={Standardization of tumor assessment lays the foundation for validation of grading systems, permits reproducibility of oncologic studies among investigators, and increases confidence in the significance of study results. Currently, there is minimal methodological standardization for assessing tumors in veterinary medicine, with few attempts to validate published protocols and grading schemes. The current article attempts to address these shortcomings by providing standard guidelines for tumor assessment parameters and protocols for evaluating specific tumor types. More detailed information is available in the Supplemental Files, the intention of which is 2-fold: publication as part of this commentary, but more importantly, these will be available as "living documents" on a website (www.vetcancerprotocols.org), which will be updated as new information is presented in the peer-reviewed literature. Our hope is that veterinary pathologists will agree that this initiative is needed, and will contribute to and utilize this information for routine diagnostic work and oncologic studies. Journal editors and reviewers can utilize checklists to ensure publications include sufficient detail and standardized methods of tumor assessment. To maintain the relevance of the guidelines and protocols, it is critical that the information is periodically updated and revised as new studies are published and validated with the intent of providing a repository of this information. Our hope is that this initiative (a continuation of efforts published in this journal in 2011) will facilitate collaboration and reproducibility between pathologists and institutions, increase case numbers, and strengthen clinical research findings, thus ensuring continued progress in veterinary oncologic pathology and improving patient care.}, journal={VETERINARY PATHOLOGY}, author={Meuten, Donald J. and Moore, Frances M. and Donovan, Taryn A. and Bertram, Christof A. and Klopfleisch, Robert and Foster, Robert A. and Smedley, Rebecca C. and Dark, Michael J. and Milovancev, Milan and Stromberg, Paul and et al.}, year={2021}, month={Jul} }
 @article{mones_schreeg_sommer_linder_lewbart_2021, title={Surgical management and histopathology of wen overgrowth and neoplasia in four oranda goldfish (Carassius auratus)}, volume={9}, ISSN={["2052-6121"]}, DOI={10.1002/vrc2.27}, abstractNote={Abstract The wen is a cap of gelatinous soft tissue that extends over the head and face of many varieties of fancy goldfish ( Carassius auratus ). Here, we describe the surgical management and histopathology of four fish with proliferative wen lesions. All fish were anesthetized for debulking or biopsy of the affected wen. One fish was diagnosed with wen hyperplasia, one fish was diagnosed with wen hyperplasia with a concurrent spindle cell neoplasm, and two fish were diagnosed with epithelial neoplasms of the wen, including a carcinoma arising within a papilloma and an epidermal papilloma with spindle cell and hyalinized matrix proliferation. This is the first published report of neoplasia in the wen of fancy goldfish. Regular evaluation of the wen during routine physical examinations may allow for biopsy of wen lesions, leading to early diagnosis and treatment interventions.}, number={1}, journal={VETERINARY RECORD CASE REPORTS}, author={Mones, Alissa and Schreeg, Megan and Sommer, Samantha and Linder, Keith and Lewbart, Gregory}, year={2021}, month={Mar} }
 @article{bai_linder_muddiman_2021, title={Three-dimensional (3D) imaging of lipids in skin tissues with infrared matrix-assisted laser desorption electrospray ionization (MALDESI) mass spectrometry}, volume={413}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-020-03105-6}, abstractNote={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.}, number={10}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Bai, Hongxia and Linder, Keith E. and Muddiman, David C.}, year={2021}, month={Apr}, pages={2793–2801} }
 @article{alloway_linder_may_rose_delay_bender_tucker_luff_2020, title={A Subset of Equine Gastric Squamous Cell Carcinomas Is Associated With Equus Caballus Papillomavirus-2 Infection}, volume={57}, ISSN={["1544-2217"]}, DOI={10.1177/0300985820908797}, abstractNote={Squamous cell carcinoma (SCC) is the most common neoplasm of the equine stomach. However, the mechanisms underlying malignant transformation are unknown. As Equus caballus papillomavirus–2 (EcPV-2) is a likely cause of some genital SCCs, we hypothesized that EcPV-2 is associated with a subset of equine gastric SCCs. To this aim, we performed polymerase chain reaction (PCR) and in situ hybridization (ISH) for EcPV-2 E6/ E7 oncogenes on 11 gastric SCCs and on gastric samples from 15 control horses with no SCC. PCR for EcPV-2 was positive in 7/11 (64%) gastric SCCs; non-SCC gastric samples were all negative. Intense hybridization signals for EcPV-2 E6/E7 nucleic acid were detected by ISH within tumor cells in 5/11 (45%) gastric SCCs, including distant metastases. No hybridization signals were detected within any of the non-SCC gastric cases. This study provides support for a potential association between EcPV-2 infection and a subset of equine gastric SCC.}, number={3}, journal={VETERINARY PATHOLOGY}, author={Alloway, Elizabeth and Linder, Keith and May, Susan and Rose, Trevor and DeLay, Josepha and Bender, Susan and Tucker, Alison and Luff, Jennifer}, year={2020}, month={May}, pages={427–431} }
 @article{levy_linder_mamo_herrmann_bizikova_2020, title={Cutaneous polyautoimmunity in two unrelated dogs: pemphigus foliaceus and generalized discoid lupus erythematosus}, volume={31}, ISSN={["1365-3164"]}, DOI={10.1111/vde.12851}, abstractNote={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.To describe the clinical, histological and immunological features and treatment outcome of two unrelated dogs with comorbid PF and GDLE.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.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.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.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).La poly-auto-immunité, l’expression concomitante de deux ou plus de maladies auto-immunes (ADs) chez un même individu est un phénomène connu chez l’homme ; c’est rarement décrit chez le chien. A la connaissance des auteurs, l’association d’un pemphigus foliacé (PF) et d’un lupus érythémateux discoïde (GDLE) n’a pas été décrit chez le chien. HYPOTHÈSES/OBJECTIFS: Décrire les données clinques, histologiques et immunologiques ainsi que l’évolution de deux chiens non liés atteints de PF et GDLE.Une chienne berger allemand stérilisée de 10 ans et un american staffordshire terrier castré de 8 ans présentés en consultation pour une dermatite pustuleuse à dominante faciale/podale symétrique associée à des plaques squameuses tronculaires. MÉTHODES: Pour chaque chien, un examen physique incluait une caractérisation clinicopathologique, une évaluation cytologique, une culture bactériologique et des tests de sensibilité, un examen histopathologique et des tests d’immunofluorescence directes et indirectes. Des test d’imagerie et hématologiques supplémentaires ont été réalisés pour exclure des maladies extra-cutanées. RÉSULTATS: Les deux chiens ont montré des lésions cliniques et histologiques compatibles avec PF et GDLE. En outre, un chien a montré une leucotrichie généralisée et une kératite superficielle chronique. Une rémission a été obtenue avec des doses immunosuppressives de prednisolone [doses élevées pulsées (Cas 1) ou dose immunosuppressive standard (Cas 2)] et ciclosporine (5-6 mg/kg/jour). Des immunoglobulines (Ig)M et IgG antikératinocytes ont été détectées chez les deux chiens. Un dépot faible de C3 au niveau de la membrane basale a été observé chez un chien. Les antikératinocytes circulants et IgG anti-desmocolline 1 ont été détectés chez un chien.La poly-auto-immunité cutanée peut se produite chez le chien. En fonction des combinaisons spécifiques des maladies, un recoupement des lésions cliniques peut représenter un défit diagnostic et/ou thérapeutique. En outre, ces cas devraient être suivis pour le développement d’autres atteintes cutanées ou extracutanées.INTRODUCCIÓN: la poliautoinmunidad, la expresión conjunta de dos o más enfermedades autoinmunes (ADs) distintas en un solo individuo, es un fenómeno conocido en humanos; rara vez se ha reportado en perros. A entender de los autores, pénfigo foliáceo (PF) y lupus eritematoso discoide generalizado (GDLE) no se han reportado en perros en aparición conjunta. HIPÓTESIS/OBJETIVOS: describir las características clínicas, histológicas e inmunológicas y el resultado del tratamiento de dos perros no relacionados con PF y GDLE de aparición conjunta. ANIMALES: un perro pastor alemán castrado de 10 años de edad y un American Staffordshire terrier castrado de 8 años de edad presentados para evaluación de una dermatitis predominantemente pustular simétrica, facial y/o podal y placas escamosas truncales concomitantes. MÉTODOS: en cada perro, la caracterización clínico-patológica incluyó examen físico, evaluación citológica de la lesión, cultivo bacteriano y pruebas de sensibilidad, investigación histopatológica de la piel y pruebas de inmunofluorescencia directa e indirecta. Se realizó un diagnóstico por imagen adicional y una investigación hematológica para excluir enfermedades extracutáneas. RESULTADOS: Ambos perros exhibieron lesiones clínicamente e histológicamente compatibles con PF y GDLE. Además, un perro presentó leucotrichia generalizada y queratitis superficial crónica. La remisión se logró con dosis inmunosupresoras de prednisolona [pulso de dosis alta (caso 1) o dosis inmunosupresora estándar (caso 2)] y ciclosporina (5-6 mg/kg /día). Se detectaron inmunoglobulinas (Ig) G e IgM antiqueratinocitos unidas a tejidos en ambos perros. Se observó un depósito débil de C3 en la membrana basal epidermal en un perro. Se detectaron IgG antiqueratinocitos y anti-desmocollin-1 circulantes en un perro. CONCLUSIONES E IMPORTANCIA CLÍNICA: la poliautoinmunidad cutánea puede ocurrir en el perro. Dependiendo de las combinaciones de enfermedades específicas, las características clínicas superpuestas pueden presentar dificultades diagnósticas y/o terapéuticas. Además, estos casos deben ser controlados por el posible desarrollo de AD(s) cutáneas o extracutáneas adicionales.Die Polyautoimmunität, der momentane Ausdruck für zwei oder mehr unterschiedliche Autoimmunerkrankungen (ADs) in einem einzigen Individuum ist ein bekanntes Phänomen beim Menschen; es wird bei Hunden nur selten beschrieben. Nach bestem Wissen der Autoren, wurde bisher eine Komorbidität von Pemphigus foliaceus (PF) und generalisiertem discoiden Lupus Erythematosus (GDLE) bei Hunden nicht beschrieben.Die Beschreibung der klinischen, histologischen und immunologischen Merkmale und Behandlungserfolge zweier nicht verwandter Hunde mit Komorbidität von PF und GDLE.Eine 10 Jahre alte kastrierte Deutsche Schäferhündin und ein 8 Jahre alter kastrierter American Staffordshire Terrier wurden zur Evaluierung einer symmetrischen, Gesichts und/oder die Füsse-dominierender pustulöser Dermatitis mit gleichzeitigen schuppigen Plaques am Rumpf vorgestellt.Für jeden Hund beinhaltete die klinisch-pathologische Charakterisierung eine physische Untersuchung, eine zytologische Evaluierung der Läsionen, eine Bakterienkultur und Antibiogramm, eine histopathologische Untersuchung der Haut und direkte und indirekte Immunfluoreszenz. Zusätzliche Bildgebende Diagnostik und hämatologische Untersuchungen wurden durchgeführt, um Erkrankungen, die nicht mit der Haut im Zusammenhang standen, auszuschließen.Beide Hunde zeigten Hautveränderungen, die klinisch und histologisch mit PF und GDLE vergleichbar waren. Zusätzlich zeigte ein Hund eine generalisierte Leukotrichie und eine chronische superfizielle Keratitis. Eine Remission wurde mit immunsuppressiven Dosen von Prednisolon [hochdosierte Pulstherapie (Fall 1) oder eine Standard immunsuppressive Dosis (Fall 2)] und Ciclosporin (5-6 mg/kg/Tag) erzielt. An Gewebe gebundene Antikeratinozyten Immunglobulin (Ig) G und IgM wurden bei beiden Hunden gefunden. Eine schwache Ablagerung in der Basalmembran von C3 wurde bei einem Hund gefunden. Bei einem Hund wurden zirkulierende Antikeratinozyten und Anti-Desmocollin-1 IgG festgestellt.Eine kutane Polyautoimmunität kann beim Hund auftreten. Abhängig von den spezifischen Krankheitskombinationen, könnten überlappende klinische Merkmale diagnostische und/oder therapeutische Herausforderungen darstellen. Darüber hinaus sollten diese Erkrankungen auf die Entwicklung zusätzlicher kutaner oder extra-kutaner AD(s) untersucht werden.背景: 単一個体における2つ以上の異なる自己免疫疾患（AD）を同時発現する多発性自己免疫性疾患は、人医療においては既知の現象である。犬ではほとんど報告されていない。著者の知る限り、落葉性天疱瘡（PF）および全身性円板状エリテマトーデス（GDLE）を併発した犬は報告されていない。 仮説/目的: 本研究の目的は、PFとGDLEが併発した血縁のない2頭の犬の臨床的、組織学的、免疫学的特徴と治療成績を説明することであった。 供試動物: 1頭の10歳避妊雌ジャーマン・シェパード・ドッグおよび1頭の8歳去勢雄アメリカン・スタッフォードシャー・テリアが、左右対称性の顔面および/または肢を主要病変とする膿疱性皮膚炎と同時発生した体幹の鱗状局面の評価のため来院した。 方法: 各犬の臨床病理学的特性の評価には、身体検査、病変細胞学的評価、細菌培養および薬剤感受性検査、皮膚組織病理学的検査、直接および間接免疫蛍光検査を含んだ。皮膚以外の疾患を除外するため、追加画像診断および血液学的調査を実施した。 結果: どちらの犬においても、PFおよびGDLEと臨床的および組織学的に適合した病変を示した。さらに、1頭の犬は、全身性白毛症および慢性表在性角膜炎を呈した。免疫抑制量のプレドニゾロン[高用量パルス（症例1）または標準免疫抑制量（症例2）]およびシクロス​​ポリン（5-6 mg / kg /日）によって寛解に至った。組織結合抗ケラチノサイト免疫グロブリン（Ig）GおよびIgMがどちらの犬でも検出された。 C3の基底膜領域における弱い沈着が1頭の犬に認められた。循環抗角化細胞および抗デスモコリン-1 IgGが1頭の犬で検出された。 結論と臨床的重要性: 犬では皮膚自己免疫疾患が起こる。特定の疾患の組み合わせに応じて、重複する臨床的特徴は診断および/または治療上の課題が認められる場合がある。さらに、本症例は皮膚または皮膚以外のADの追加の発生を監視する必要がある。.背景: 多发性自身免疫是已知的人类疾病，一个病患同时表现两种或两种以上不同的自体免疫病 (ADs)；在犬鲜有报道。据作者所知，尚未有过关于犬并发落叶型天疱疮 (PF) 和全身性盘状红斑狼疮 (GDLE) 的报告 。 假设/目的: 描述两只无血缘关系、并发PF和GDLE的犬，报告其临床、组织学和免疫学特征以及治疗效果。 动物: 一只10岁切除卵巢的德国牧羊犬和一只8岁去势的美国斯塔福德郡㹴犬，评估其对称性面部和/或爪部脓疱性皮炎，以及并发的躯干鳞屑性斑块。 方法: 对于每只犬，临床病理学表征包括体格检查、病变细胞学评估、细菌培养和药敏试验、皮肤组织病理学研究以及直接和间接免疫荧光试验。另外进行影像学诊断和血液学检查，以排除皮肤系统外疾病。 结果: 两只犬均表现出与PF和GDLE临床和组织学相符的病变。此外，一只犬表现出全身性白毛病和慢性浅表性角膜炎。使用免疫抑制剂量的泼尼松龙 [高剂量脉冲（病例 1），或标准免疫抑制剂量（病例 2）] 和环孢素（5-6 mg/kg/天）达到缓解。在两只犬身上均检测到组织结合的抗角质细胞免疫球蛋白 (Ig) G 和 IgM。在一只犬身上观察到C3的弱基底膜带沉积。在一只犬身上检测到循环抗角质细胞和抗桥粒糖蛋白-1 IgG。 结论和临床重要性: 皮肤多发性自体免疫可发生在犬身上。根据特定的疾病组合、重叠的临床特征可能带来诊断和/或治疗挑战。此外，应监测这些病例是否发生其他皮肤或皮肤系统外ADs。.A poliautoimunidade, expressão simultânea de duas ou mais doenças autoimunes (DAs) distintas em um único indivíduo, é um fenômeno conhecido em humanos; este raramente é relatado em cães. De acordo com o conhecimento dos autores, ainda não há relatos em cães de pênfigo foliáceo (PF) e o lúpus eritematoso discóide generalizado (GDLE) em comorbidade. HIPÓTESE/OBJETIVOS: Descrever as características clínicas, histológicas e imunológicas e o resultado do tratamento de dois cães não relacionados com PF e GDLE em comorbidade.Um cão pastor alemão de 10 anos, castrado e um American Staffordshire terrier castrado de 8 anos de idade foram apresentados para avaliação de uma dermatite pustular simétrica, predominantemente facial e/ou a podal com placas descamativas concomitantes no dorso. MÉTODOS: Para cada cão, a caracterização clínico-patológica incluiu exame físico, avaliação citológica lesional, cultura bacteriana e teste de sensibilidade, investigação histopatológica da pele e teste direto e indireto de imunofluorescência. Diagnóstico por imagem adicional e investigação hematológica foram realizadas para excluir doença extracutânea.Ambos os cães apresentaram lesões clinica e histologicamente compatíveis com PF e GDLE. Além disso, um cão exibiu leucotriquia generalizada e ceratite superficial crônica. A remissão foi alcançada com dosagens imunossupressoras de prednisolona [pulso de alta dose (Caso 1) ou dosagem imunossupressora padrão (Caso 2)] e ciclosporina (5-6 mg / kg / dia). Detectou-se a presença de imunoglobulina (Ig) anti-queratinócito G e a IgM ligadas ao tecido em ambos os cães. Um depósito fraco de C3 na zona da membrana basal foi observado em um cão. Anticorpos IgG anti-queratinócitos e anti-desmocolina-1 circulantes foram detectados em um cão. CONCLUSÕES E IMPORTÂNCIA CLÍNICA: A poliautoimunidade cutânea pode ocorrer no cão. Dependendo das combinações específicas de doenças, as características clínicas sobrepostas podem apresentar desafios diagnósticos e/ou terapêuticos. Além disso, esses casos devem ser monitorados quanto ao desenvolvimento de Das cutâneas ou extra-cutâneas adicionais.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Levy, Britt J. and Linder, Keith E. and Mamo, Lisa B. and Herrmann, Ina and Bizikova, Petra}, year={2020}, month={Aug}, pages={325-+} }
 @article{elliott_linder_nolan_2020, title={Feasibility study evaluating arrhythmogenesis and cardiac damage after heart-base irradiation in mice: A brief communication}, volume={6}, ISSN={["2053-1095"]}, DOI={10.1002/vms3.303}, abstractNote={Abstract Radiation‐induced heart disease (RIHD) is a potential cause of morbidity and mortality in dogs undergoing thoracic irradiation. Arrhythmias and sudden death have been documented in dogs undergoing stereotactic body radiation therapy for heart base tumours. A study was proposed to interrogate the effect of different stereotactic‐like radiation prescriptions on RIHD development, including arrhythmogenesis and classical histological endpoints in a mouse model. A pilot study was performed initially. The heart base of CD1 ( n = 3) and C57Bl/6J ( n = 3) female mice were irradiated (12 Gy × 3, daily) with a clinical linear accelerator. No significant adverse effects were noted and each mouse survived the entire subsequent 3‐month observation period. At various time points, no arrhythmias were identified on ECG analysis. Cardiac histology (haematoxylin and eosin, and picrosirius red staining) was performed at 3 months. In a single CD1 mouse and two C57BI/6J mice, multifocal, minimal, peri‐vascular lymphoplasmacytic inflammation was noted within the irradiated proximal heart. In one mouse of each strain, a small, single focus of fibrinoid vascular necrosis was observed. Overall, there was no significant myocardial necrosis, atrophy or inflammation. Picrosirius red staining revealed no evidence of fibrosis in any mouse. Dosimetric verification indicated that the irradiation was successful and delivered as planned, with an average predicted‐to‐measured dose‐difference within 5%. While this study did not demonstrate significant arrhythmogenesis, certain modifications of the experimental mouse irradiation procedures are discussed which may enable more translationally relevant modelling of the canine cardiac response to SBRT‐like irradiation.}, number={4}, journal={VETERINARY MEDICINE AND SCIENCE}, author={Elliott, James and Linder, Keith and Nolan, Michael W.}, year={2020}, month={Nov}, pages={1009–1016} }
 @article{eisemann_ashwell_devine_poole_poore_linder_2020, title={Physiological response, function of sweat glands, and hair follicle cycling in cattle in response to fescue toxicosis and hair genotype}, volume={98}, ISSN={0021-8812 1525-3163}, url={http://dx.doi.org/10.1093/jas/skaa013}, DOI={10.1093/jas/skaa013}, abstractNote={Abstract Fescue toxicosis is a syndrome that results when cattle consume toxic endophyte-infected tall fescue. The objective of this study was to compare the response in physiological variables, sweat gland function, hair follicle cycling, and gene expression to feeding a total mixed ration that included tall fescue haylage and tall fescue seed containing a toxic endophyte (EI) or tall fescue haylage containing a nontoxic novel endophyte (EN) in beef heifers (Angus × Senepol heifers, n = 31) with 2 different hair genotypes. Numbers in each subgroup were as follows: novel endophyte, heterozygous slick (EN-S; n = 8), novel endophyte, homozygous hairy (wild type, EN-W; n = 7), endophyte-infected, heterozygous slick (EI-S; n = 10), and endophyte-infected, homozygous hairy (wild type, EI-W; n = 6). Physiological measurements were taken weekly for 7 wk. Data were analyzed using the MIXED procedure of SAS including dietary fescue treatment (EN vs. EI) and hair genotype (S vs. W) as main effects, day as a repeated measure, and temperature–humidity index (THI) as a covariate. Skin biopsies were taken before treatment initiation and on day 37 of treatment. Average surface temperature (ST) increased as the THI increased (P < 0.0001). Average ST was greater (P < 0.01) for animals fed EI than for animals fed the EN fescue diet, and greater (P < 0.01) for animals with the W genotype compared with animals with the S genotype. The difference between heifers with the S and W genotype was greater at greater THI (genotype × day interaction, P < 0.01). Transepidermal water loss (TEWL) was greater (P < 0.05) for animals with the S genotype compared with the W genotype and greater (P < 0.05) for heifers with the S genotype than for heifers with the W genotype when fed EI (36.7, 38.5, 30.0, and 38.7 g/m2 per hour for EN-W, EN-S, EI-W, and EI-S, respectively). The fraction of follicles in telogen in plucked hair samples for heifers fed EI was greater for animals with the S genotype than the W genotype (fraction in telogen: 0.456, 0.565, 0.297, 0.702 for EN-W, EN-S, EI-W, and EI-S, respectively; diet × genotype interaction, P < 0.05). Fraction of follicles in anagen was the opposite. EI fescue resulted in increased ST, changes in hair follicle cycling that support greater hair growth, and decreased TEWL for heifers with the W genotype compared with S genotype, suggesting greater heat stress in response to EI.}, number={3}, journal={Journal of Animal Science}, publisher={Oxford University Press (OUP)}, author={Eisemann, J.H. and Ashwell, M.S. and Devine, T.L. and Poole, D.H. and Poore, M.H. and Linder, K.}, year={2020}, month={Mar} }
 @article{high_linder_mamo_levy_herrmann_bizikova_2020, title={Rapid response of hyperkeratotic erythema multiforme to oclacitinib in two dogs}, volume={31}, ISSN={["1365-3164"]}, DOI={10.1111/vde.12852}, abstractNote={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.To describe successful treatment of HKEM in two dogs using oclacitinib.A 7-year-old, spayed Havanese dog (Case 1) and a 1-year-old, intact cryptorchid Dachshund dog (Case 2).Case characterization and clinical diagnoses were based on lesion character, surgical biopsy, cytological evaluation, culture, direct immunofluorescence (DIF) and expected responses to treatments.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.Oclacitinib could be considered as a fast-acting and effective treatment option for HKEM in dogs.L’érythème polymorphe hyperkératosique (HKEM) est une dermatose cliniquement distincte et un syndrome peu caractérisé, comprenant des plaques hyperkératosiques de symétrie variable et de l'apoptose semblable à l’EM canine érosive « classique ». L’EM hyperkératosique a une évolution clinique au long cours et bien que des traitements avec corticoïdes, azathioprine et/ou ciclosporine aient été essayés, les taux de rémission sont faibles.Décrire un traitement efficace de l’HKEM chez deux chiens à l'aide d'oclacitinib.Un chien bichon havanais de 7 ans (Cas 1) et un teckel cryptorchide entier de 1 an (Cas 2). MÉTHODES: La caractérisation du cas et le diagnostic clinique ont été basés sur les lésions, les biopsies, la cytologie, la culture, l'immunofluorescence directe (DIF) et les réponses attendues aux traitements. RÉSULTATS: Les deux cas ont montré des plaques hyperkératosiques, souvent symétriques, multifocales avec squames adhérentes. Les données histologiques ont montré une hyperplasie épidermique proéminente, de l'hyperkératose parakératosique, une dermatite lymphocytaire et de l'apoptose transépidermique avec satellitose lymphocytaire. Le DIF a révélé des dépôts en patch d'IgG, IgM et IgA sur la membrane basale (Cas 2). Les deux chiens ont montré une amélioration rapide avec de l'oclacitinib oral (0.6-0.9 mg/kg deux fois par jour) avec rémission complète des signes cliniques observés en 12 et sept semaines respectivement dans les cas 1 et 2.L'oclacitinib pourrait être considéré comme une option thérapeutique rapide et efficace pour l’HKEM chez le chien.INTRODUCCIÓN: el eritema multiforme hiperqueratótico (HKEM) es una dermatosis clínicamente distinta y un síndrome mal caracterizado, compuesto por placas hiperqueratóticas con simetría variable y apoptosis similar a la EM canina erosiva “clásica”. La EM hiperqueratótica tiene un curso clínico prolongado y, aunque se han intentado tratamientos con glucocorticoides, azatioprina y/o ciclosporina, las tasas de remisión son bajas. OBJETIVOS: describir el tratamiento exitoso de HKEM en dos perros tratados con oclacitinib. ANIMALES: un perro Havanés esterilizado de 7 años de edad (caso 1) y un perro Dachshund criptórquido intacto de 1 año de edad (caso 2). MÉTODOS: la caracterización de casos y los diagnósticos clínicos se basaron en el carácter de la lesión, la biopsia quirúrgica, la evaluación citológica, el cultivo, la inmunofluorescencia directa (DIF) y las respuestas esperadas a los tratamientos. RESULTADOS: ambos casos exhibieron placas hiperqueratóticas multifocales, a menudo simétricas, con escamas adherentes. Los hallazgos histológicos revelaron hiperplasia epidérmica prominente, hiperqueratosis paraqueratótica, dermatitis linfocítica y apoptosis transepidérmica con satelitósis linfocítica. DIF reveló depósitos de membrana basal IgG, IgM e IgA finas y discontinuas (Caso 2). Ambos perros mostraron una mejoría rápida con oclacitinib oral (0,6-0,9 mg/kg dos veces al día) con una remisión completa de los signos clínicos observados en 12 y siete semanas en los casos 1 y 2, respectivamente. CONCLUSIÓN E IMPORTANCIA CLÍNICA: Oclacitinib podría considerarse como una opción de tratamiento de acción rápida y eficaz para HKEM en perros.Das hyperkeratotische Erythema multiforme (HKEM) ist eine klinisch deutlich abgegrenzte Dermatose, aber ein schlecht beschriebenes Syndrom, welches aus hyperkeratotischen Plaques mit unterschiedlicher Symmetrie und Apoptose, ähnlich dem „klassischen“ erosiven EM des Hundes, besteht. Das hyperkeratotische EM zeigt einen langwierigen klinischen Verlauf und, obwohl Behandlungen mit Glukokortikoiden, Azathioprin und/oder Ciclosporin versucht worden sind, sind die Remissionsraten niedrig.Die Beschreibung einer erfolgreichen Behandlung von HKEM bei zwei Hunden mittels Oclacitinib.Eine 7 Jahre alte kastrierte Havaneserhündin (Fall 1) und ein 1 Jahre alter intakter kryptorchider Dackelrüde (Fall 2).Die Fallbeschreibung sowie die Beschreibung der klinischen Diagnosen basierte auf dem Aussehen der Läsionen, der chirurgischen Biopsie, der zytologischen Evaluierung, der Kultur, der direkten Immunfluoreszenz (DIF) und der erwarteten Behandlungserfolge.Beide Fälle zeigten multifokale, oft symmetrische hyperkeratotische Plaques mit anhaftenden Schuppen. Die histologischen Befunde zeigten eine prominente epidermale Hyperplasie, eine parakeratotische Hyperkeratose, eine lymphozytäre Dermatitis und eine transepidermale Apoptose mit lymphozytärer Satellitenbildung. Die DIF zeigte feine, fleckige Ablagerungen von IgG, IgM und IgA in der Basalmembran (Fall 2). Beide Hunde zeigten eine schnelle Verbesserung mit Oclacitinib per os (0,6-0,9 mg/kg zweimal täglich), wobei eine völlige Remission der klinischen Zeichen innerhalb von 12 bzw sieben Wochen in den Fällen 1 bzw 2 gesehen wurden.Oclacitinib könnte als schnell-wirkende und wirksame Behandlungsoption für HKEM bei Hunden in Frage kommen.背景: 過角化性多形紅斑(HKEM)は、臨床的に異なる皮膚疾患であり、対称性で可変的な過角化性性局面および「古典的な」犬のびらん性EMに類似したアポトーシスで構成される、特徴が不十分な症候群である。過角化性EMは長期にわたる臨床経過をたどり、グルココルチコイド、アザチオプリン、および/またはシクロスポリンによる治療が試みられているが、寛解率は低い。 目的: 本研究の目的は、オクラシチニブ使用による2頭の犬のHKEMの成功した治療について説明することであった。 供試動物: 7歳、避妊雌、ハバニーズ(症例1)と1歳、停留精巣の雄、ダックスフンド(症例2)。 方法: 症例の特徴付けおよび臨床診断は、病変の特徴、外科的生検、細胞学的評価、培養、直接免疫蛍光法(DIF)、および治療に対する期待される反応に基づいた。 結果: どちらの症例も、付着性の鱗屑を伴う多巣性で、しばしば対称性の過角化性局面を示した。組織学的所見は、顕著な表皮過形成、不全角化性角化症、リンパ球性皮膚炎、およびリンパ球性サテライトーシスを伴う経皮アポトーシスを明らかにした。 DIFにより、細かいパッチ状のIgG、IgM、IgAの基底膜の沈着が明らかになった(症例2)。どちらの症例も経口オクラシチニブ(0.6-0.9 mg / kg 1日2回)で急速な改善を示し、症例1および2ではそれぞれ12週間および7週間で臨床症状の完全寛解が観察された。 結論と臨床的重要性: オクラシチニブは、犬のHKEMに即効性があり効果的な治療オプションと考えることができる。.背景: 过度角化性多形红斑 (HKEM) 是一种临床上独特的皮肤病,这种综合征的特征较少,包括可能对称发生的过度角化性斑块,以及类似于“典型”糜烂性犬EM的细胞凋亡。过度角化性 EM 的临床病程持久,尽管已尝试使用糖皮质激素、硫唑嘌呤和/或环孢素治疗,但缓解率较低。 目的: 报告使用奥拉替尼成功治疗的两只HKEM患犬。 动物: 一只 7 岁、切除卵巢的哈瓦犬(病例 1)和一只 1 岁、未去势隐睾腊肠犬(病例 2)。 方法: 病例特征和临床诊断基于病变特征、外科活检、细胞学评价、培养、直接免疫荧光 (DIF) 和预期的治疗反应。 结果: 两个病例均表现出多灶性、通常对称的过度角化性斑块,伴粘附性鳞屑。组织学的调查结果揭示了突出的表皮增生,角化不全性过度角化病,淋巴细胞性皮炎,以及伴随淋巴细胞性卫星现象的跨表皮细胞凋亡。DIF 显示点、片状 IgG、IgM 和 IgA 基底膜沉积(病例 2)。口服给予奥拉替尼(0.6-0.9 mg/kg,每日两次)后,两只犬均表现出快速改善,在病例 1 和 2 中,分别在 12 周和 7 周内观察到临床体征完全缓解。 结论和临床意义: 奥拉替尼可被认为是犬 HKEM 的一种速效和有效的治疗选择。.O eritema multiforme hiperqueratótico (HKEM) é uma dermatose clinicamente distinta e uma síndrome pouco caracterizada, composta por placas hiperqueratóticas com simetria e apoptose variáveis ​​semelhantes ao EM canino erosivo “clássico”. O EM hiperqueratótico apresenta um quadro clínico prolongado e, apesar de tratamentos com glicocorticóides, azatioprina e/ou ciclosporina tenham sido tentados, as taxas de remissão são baixas.Descrever o tratamento bem-sucedido do HKEM em dois cães usando oclacitinib.Um cão Havanese de 7 anos, castrado (Caso 1), e um cachorro Dachshund com criptorquidia intacto de 1 ano (Caso 2). MÉTODOS: A descrição do caso e o diagnóstico clínico foram baseados nas características da lesão, biópsia cirúrgica, avaliação citológica, cultura, imunofluorescência direta (IFD) e respostas esperadas aos tratamentos.Ambos os casos apresentaram placas hiperqueratóticas multifocais, muitas vezes simétricas, com escama aderida. Os achados histológicos revelaram hiperplasia epidérmica proeminente, hiperqueratose paraqueratótica, dermatite linfocítica e apoptose transepidérmica com satelitose linfocítica. A IFD revelou depósitos finos e irregulares de IgG, IgM e IgA na membrana basal (Caso 2). Ambos os cães apresentaram melhora rápida com oclacitinib oral (0,6-0,9 mg / kg duas vezes ao dia) com remissão completa dos sinais clínicos observados em 12 e sete semanas nos casos 1 e 2, respectivamente. CONCLUSÃO E IMPORTÂNCIA CLÍNICA: Oclacitinib pode ser considerado uma opção de tratamento de ação rápida e eficaz para HKEM em cães.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={High, Endya J. and Linder, Keith E. and Mamo, Lisa B. and Levy, Britt J. and Herrmann, Ina and Bizikova, Petra}, year={2020}, month={Aug}, pages={330-+} }
 @article{you_lee_taylor-just_linder_bonner_2020, title={Sex differences in the acute and subchronic lung inflammatory responses of mice to nickel nanoparticles}, volume={14}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2020.1808105}, abstractNote={Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.}, number={8}, journal={NANOTOXICOLOGY}, author={You, Dorothy J. and Lee, Ho Young and Taylor-Just, Alexia J. and Linder, Keith E. and Bonner, James C.}, year={2020}, month={Sep}, pages={1058–1081} }
 @article{tham_linder_olivry_2019, title={Autoimmune diseases affecting skin melanocytes in dogs, cats and horses: vitiligo and the uveodermatological syndrome: a comprehensive review}, volume={15}, ISSN={1746-6148}, url={http://dx.doi.org/10.1186/s12917-019-2003-9}, DOI={10.1186/s12917-019-2003-9}, abstractNote={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.}, number={1}, journal={BMC Veterinary Research}, publisher={Springer Science and Business Media LLC}, author={Tham, Heng L. and Linder, Keith E. and Olivry, Thierry}, year={2019}, month={Jul} }
 @article{tam_hall_messenger_jima_house_linder_smart_2019, title={C/EBP beta suppresses keratinocyte autonomous type 1 IFN response and p53 to increase cell survival and susceptibility to UVB-induced skin cancer}, volume={40}, ISSN={["1460-2180"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85083447649&partnerID=MN8TOARS}, DOI={10.1093/carcin/bgz012}, abstractNote={p53 is activated by DNA damage and oncogenic stimuli to regulate senescence, apoptosis and cell-cycle arrest, which are essential to prevent cancer. Here, we utilized UVB radiation, a potent inducer of DNA damage, p53, apoptosis and skin cancer to investigate the mechanism of CCAAT/enhancer binding protein-β (C/EBPβ) in regulating p53-mediated apoptosis in keratinocytes and to test whether the deletion of C/EBPβ in epidermis can protect mice from UVB-induced skin cancer. UVB-treatment of C/EBPβ skin conditional knockout (CKOβ) mice increased p53 protein levels in epidermis and enhanced p53-dependent apoptotic activity 3-fold compared with UVB-treated control mice. UVB increased C/EBPβ levels through a p53-dependent pathway and stimulated the formation of a C/EBPβ-p53 protein complex; knockdown of C/EBPβ increased p53 protein stability in keratinocytes. These results suggest a p53-C/EBPβ feedback loop, whereby C/EBPβ, a transcriptional target of a p53 pathway, functions as a survival factor by negatively regulating p53 apoptotic activity in response to DNA damage. RNAseq analysis of UVB-treated CKOβ epidermis unexpectedly revealed that type 1 interferon (IFN) pathway was the most highly enriched pathway. Numerous pro-apoptotic interferon stimulated genes were upregulated including some known to enhance p53 apoptosis. Our results indicate that p53 and IFN pathways function together in response to DNA damage to result in the activation of extrinsic apoptosis pathways and caspase 8 cleavage. Last, we observed CKOβ mice were resistant to UVB-induced skin cancer. Our results suggest that C/EBPβ represses apoptosis through keratinocyte autonomous suppression of the type 1 IFN response and p53 to increase cell survival and susceptibility to UVB-induced skin cancer.}, number={9}, journal={CARCINOGENESIS}, author={Tam, Hann W. and Hall, Jonathan R. and Messenger, Zachary J. and Jima, Dereje D. and House, John S. and Linder, Keith and Smart, Robert C.}, year={2019}, month={Sep}, pages={1099–1109} }
 @article{levy_linder_olivry_2019, title={The role of oclacitinib in the management of ischaemic dermatopathy in four dogs}, volume={30}, ISBN={1365-3164}, ISSN={0959-4493 1365-3164}, url={http://dx.doi.org/10.1111/vde.12743}, DOI={10.1111/vde.12743}, abstractNote={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. To describe four cases of treatment refractory juvenile-onset ischaemic dermatopathy that rapidly and durably responded to oclacitinib administration. 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. 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. 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. 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. La dermatopathie ischémique représente un syndrome canin hétérogène faiblement caractérisé souvent réfractaire aux immunosuppresseurs classiques. Les inhibiteurs de Janus-kinase (JAKinibs) sont utilisés pour le traitement de maladies auto-immunes de l'homme y compris la dermatomyosite. L'oclacitinib est généralement bien supporté, disponible en médecine vétérinaire, inhibiteur de JAK non sélectif qui peut avoir des propriétés immunosuppressives potentielles. Décrire quatre cas réfractaires aux traitements de dermatopathie ischémique juvénile qui répondent rapidement et durablement à l'oclacitinib. Quatre chiens croisés, trois mâles de 9 mois et une femelle de 6 mois, ont été présentés pour dermatite généralisée ulcérative et cicatricielle et alopécique en patch. Les lésions cutanées microscopiques étaient compatibles avec une dermatite ischémique sévère. Une rémission complète des lésions cutanées n'a pas pu être obtenue avec des corticoïdes seuls ni avec en association à un immunosuppresseur adjuvant. Le traitement à l'oclacitinib a été initié à la dose de 0,4-0,7 mg/kg deux fois par jour associé à un traitement dégressif de prednisolone oral. Une rémission clinique complète a été atteinte en quatre semaines avec la prednisolone stoppée au bout de huit semaines. La rémission a été maintenue pour deux chiens avec de faibles doses d'oclacitinib tandis que les deux autres ont nécessité une administration de l'inhibiteur de JAK deux fois par jour. L'oclacitinib semble être un immunosuppresseur adjuvant utile aux corticoïdes oraux pour le traitement des cas sévères de dermatopathie ischémique pour ces quatre chiens. D'autres études sont nécessaires pour compléter ces observations pour l'innocuité, l'efficacité et le mécanisme d'action de l'oclacitinib en tant qu'immunosuppresseur. la dermatopatía isquémica representa un síndrome canino heterogéneo y mal caracterizado que a menudo es refractario a la inmunosupresión convencional. Los inhibidores de Janus-kinase (JAKinibs) se utilizan para el tratamiento de diversas enfermedades autoinmunes humanas, incluida la dermatomiositis. Oclacitinib es un JAKinib no selectivo, bien tolerado, aprobado para uso veterinario, que tiene un potencial terapéutico como inmunosupresor. Describir cuatro casos de presumible dermatopatía isquémica juvenil refractarios a tratamiento que respondieron de forma rápida y duradera a la administración de oclacitinib. se presentaron cuatro perros de raza mestiza, tres de ellos de la misma camada de 9 meses de edad y una hembra de 6 meses de edad con una alopecia multifocal generalizada, cicatrización y dermatitis ulcerativa. Las lesiones microscópicas de la piel fueron compatibles con una dermatopatía isquémica intensa. no se pudo lograr una remisión completa de las lesiones cutáneas en ningún perro solo con glucocorticoides, ni cuando se combinaron con inmunosupresores adyuvantes. Se inicio entonces el tratamiento con oclacitinib a una dosis de 0,4-0,7 mg/kg dos veces al día, junto con un régimen de reducción gradual de prednisolona oral. se logró una remisión clínica completa dentro de las cuatro semanas posteriores al inicio de esta terapia de combinación, deteniéndose la prednisolona dentro de las ocho semanas posteriores. La remisión se mantuvo en dos perros con dosis más bajas o menores frecuencias de dosificación de oclacitinib, mientras que los otros dos requirieron la administración persistente dos veces al día de este JAKinib. el oclacitinib parece ser un adyuvante inmunosupresor útil con los glucocorticoides orales para el tratamiento de casos refractarios o graves de dermatopatía isquémica en estos cuatro perros. Esta observación indica la necesidad de estudios adicionales sobre seguridad, eficacia y mecanismo de acción del oclacitinib como inmunosupresor. Eine ischämische Dermatopathie repräsentiert ein heterogenes und schlecht charakterisiertes Syndrom beim Hund, welches oft refraktär auf konventionelle Immunsuppression reagiert. Für die Behandlung verschiedener humaner Autoimmunerkrankungen wie auch für die Dermatomyositis werden Janus-Kinase Inhibitoren (JAKinibs) eingesetzt. Oclacitinib ist ein generell gut verträglicher, veterinärmedizinisch zugelassener, nichtselektiver JAKinib, welcher therapeutisches Potential als ein Immunsuppressivum aufweist. Die Beschreibung von vier Fällen einer refraktären vermeintlichen, beim Jugendlichen auftretenden, ischämischen Dermatopathie, die rasch und dauerhaft auf eine Oclacitinib Verabreichung reagierte. Vier Mischlingshunde, drei 9 Monate alte männliche Geschwister und eine 6 Monate alte Hündin wurden mit einer generalisierten fleckigen Alopezie, Narbenbildung und einer ulzerativen Dermatitis vorgestellt. Die mikroskopischen Hautveränderungen waren vereinbar mit einer hochgradigen ischämischen Dermatopathie. Eine völlige Remission der Hautveränderungen konnte bei keinem der Hunde ausschließlich mit Glukokortikoiden erzielt werden, dies gelang nur, wenn diese mit zusätzlichen Immunsuppressiva kombiniert wurden. Daraufhin wurde Oclacitinib bei einer Dosierung von 0,4-0,7 mg/kg zweimal täglich eingesetzt, gleichzeitig wurde Prednisolon per os ausgeschlichen. Eine völlige klinische Remission wurde innerhalb von vier Wochen nach Beginn der Kombinationstherapie erzielt, wobei Prednisolon innerhalb von acht Wochen gestoppt wurde. Eine Remission konnte bei zwei Hunden mit einer niedrigeren Dosierung oder einer Verringerung der Verabreichungsfrequenz von Oclacitinib erzielt werden, während die beiden anderen Hunde eine andauernde zweimal tägliche Verabreichung dieses JAKinib benötigten. Oclacitinib schien ein nützliches Immunsuppressivum als Adjuvant zu oralen Glukokortikoiden für die Behandlung von hartnäckigen oder schweren Fällen von ischämischer Dermatopathie zu sein. Eine derartige Beobachtung rechtfertigt weitere Studien über die Sicherheit, Wirksamkeit und den Wirkungsmechanismus von Oclacitinib als Immunsuppressivum. 虚血性皮膚症は、従来の免疫抑制にはしばしば抵抗性で、異質性で特徴が乏しい犬の症候群である。ヤヌスキナーゼ阻害剤(JAKinib)は、皮膚筋炎を含む様々な人の自己免疫疾患の治療に使用されている。オクラシチニブは、免疫抑制剤としての治療可能性を有した、一般的に忍容性が高く、獣医学的に承認された、非選択的なJAKinibである. 本研究の目的は、オクラシチニブ投与に迅速かつ持続的に反応した、治療難治性と推定される若年発症虚血性皮膚症の4症例を記述することである. 汎発性に斑状脱毛、瘢痕および潰瘍性皮膚炎を認めた4頭のMIX犬(9ヶ月齢の同腹仔の雄3頭および6ヶ月齢の雌1頭)。顕微鏡的皮膚病変は重度の虚血性皮膚症と一致していた. どの犬でも、グルココルチコイド単独あるいはアジュバント免疫抑制薬との組み合わせでは、皮膚病変の完全寛解は達成できなかった。次いで、オクラシチニブ治療を経口プレドニゾロンの漸減投与計画と共に、1日2回、0.4〜0.7 mg/kgの用量で開始した. この併用療法を開始してから4週間以内に完全な臨床的寛解を達成し、プレドニゾロンは8週間以内に中止した。オクラシチニブの用量または投与頻度の減少させた2頭の犬で寛解を維持したが、他の2頭はこのJAKinibの1日2回の持続投与を必要とした. オクラシチニブは、本研究の犬4頭における難治性または重度の虚血性皮膚症治療に対し、経口グルココルチコイドの有用な免疫抑制アジュバントであるように思われた。そのような結果は、免疫抑制剤としてのオラシチニブの安全性、有効性および作用機序のさらなる研究を保証するものである. 缺血性皮肤病是一种异质且缺乏特征的犬综合征,通常用传统的免疫抑制难以治愈。Janus-激酶抑制剂(JAKinibs)用于治疗多种人类自身免疫疾病,包括皮肌炎。奥克拉克替尼是一种耐受性良好、兽医认可的非选择性JAKinib,可以作为免疫抑制剂治疗. 描述四个推定性幼年发病的缺血性皮肤病的顽固病例,奥克拉克替尼治疗效果快速且持久. 四只呈现全身性脱毛斑、瘢痕和溃疡性皮炎的混血犬,其中三只为9月龄同窝公犬,以及一只6月龄母犬。镜检发现其皮肤病变为严重的缺血性皮肤病. 任何犬单独使用糖皮质激素,或与免疫抑制剂联合使用,都不能完全缓解皮肤病变。随后,开始给予奥克拉克替尼,剂量0.4-0.7mg/kg,每日两次,伴随逐渐减量的泼尼松龙口服. 在开始这种联合治疗的四周内,临床症状完全缓解,其中泼尼松龙在八周内停用。两只犬用低剂量或低频率的奥克拉克替尼维持,而另两只犬则需要持续每日两次给予这种JAKinib. 奥克拉克替尼对口服糖皮质激素来说,显然是一种有效的辅助免疫抑制剂,用于治疗这四只犬的顽固或严重缺血性皮肤病。根据这一观察结果,奥克拉克替尼作为免疫抑制剂的安全性、有效性和作用机制,需进一步研究. A dermatopatia isquêmica representa uma síndrome canina heterógena e pouco caracterizada que é refratária à imunossupressão convencional. Os inibidores da Janus-quinase (JAKinibs) são utilizados para o tratamento de diversas doenças autoimunes em humanos, incluindo a dermatomiosite. O oclacitinib é um JAKinib não seletivo geralmente bem tolerado, de uso veterinário que possui um potencial terapêutico como imunossupressor. Descrever quatro casos presuntivos de dermatopatia isquêmica juvenil refratária ao tratamento convencional que responderam rapidamente e duradouramente à administração de oclacitinib. Quatro cães mestiços, três machos de nove meses de idade, irmãos da mesma ninhada, e uma fêmea de seis meses de idade, foram apresentados com alopecia multifocal, fibrose e dermatite ulcerativa. As lesões cutâneas microscópicas foram compatíveis com dermatopatia isquêmica grave. Não foi possível se obter remissão completa das lesões cutâneas em nenhum dos cães somente com corticoterapia, nem mesmo em associação com imunossupressores adjuvantes. O tratamento com oclacitinib foi iniciado em uma dose de 0,4-0,7 mg/kg duas vezes ao dia, juntamente com o protocolo de redução gradativa da prednisolona. Resolução clínica completa foi alcançada dentro de quatro semanas após o início da terapia combinada, com a interrupção da prednisolona em oito semanas. A remissão foi mantida em dois cães com baixas doses ou menor frequência de administração de oclacitinib, enquanto os outros dois cães necessitaram de administração contínua de deste JAKinib duas vezes ao dia. O oclacitinib parece ser um imunossupressor útil como adjuvante aos glicocorticoides orais no tratamento de casos de casos graves de dermatopatia isquêmica refratária nesses quatro cães. Tal observação justifica novos estudos sobre segurança, eficácia e mecanismos de ação do oclacitinib como imunossupressor.}, number={3}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Levy, Britt J. and Linder, Keith E. and Olivry, Thierry}, year={2019}, month={Apr}, pages={201–e63} }
 @article{southern_neupane_ericson_dencklau_linder_bradley_mckeon_long_breitschwerdt_2018, title={Bartonella henselae
 in a dog with ear tip vasculitis}, volume={29}, ISSN={0959-4493}, url={http://dx.doi.org/10.1111/vde.12695}, DOI={10.1111/vde.12695}, abstractNote={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.Describe clinical, microbiological and histological lesions in a dog with ear margin vasculitis and B. henselae infection.A 12-month-old, specific pathogen-free intact female beagle dog maintained in a vector-free laboratory animal resource facility.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.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.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.}, number={6}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Southern, Brittany L. and Neupane, Pradeep and Ericson, Marna E. and Dencklau, Jamie C. and Linder, Keith E. and Bradley, Julie M. and McKeon, Gabriel P. and Long, Charles T. and Breitschwerdt, Edward B.}, year={2018}, month={Oct}, pages={537–e180} }
 @article{linder_bizikova_luff_zhou_yuan_breuhaus_nelson_mackay_2018, title={Generalized papillomatosis in three horses associated with a novel equine papillomavirus (EcPV8)}, volume={29}, number={1}, journal={Veterinary Dermatology}, author={Linder, K. E. and Bizikova, P. and Luff, J. and Zhou, D. and Yuan, H. and Breuhaus, B. and Nelson, E. and Mackay, R.}, year={2018} }
 @article{fukuyama_martel_linder_ehling_ganchingco_baeumer_2018, title={Hypochlorous acid is antipruritic and anti-inflammatory in a mouse model of atopic dermatitis}, volume={48}, ISSN={["1365-2222"]}, DOI={10.1111/cea.13045}, abstractNote={Background It has been reported that topical hypochlorous acid (HOCl) formulations lead to relief of itch in human patients with atopic dermatitis; however, the specific antipruritic mechanism of action remains unclear. Objective To confirm itch relief and reduction of lesions in a mouse model of atopic dermatitis and to elucidate possible HOCl's mode of action. Methods In this study, the effects of topical administration of HOCl hydrogel (0.05%) on atopic dermatitis-like lesions in NC/Nga mice model as well as in vitro effects of HOCl on dorsal root ganglia neurons and mouse bone marrow-derived dendritic cells (mBMDCs) were investigated. NC/Nga mice were sensitized with house dust mite allergen and treated topically with HOCl hydrogel both preventively and therapeutically against established lesions. Allergen challenge was continued during HOCl hydrogel application. Results Treatment with HOCl hydrogel prevented the development of lesions and scratching bouts during the whole observation period. When administered after full development of lesions, HOCl reduced lesions and scratching behaviour to a similar extent as a positive control 0.1% betamethasone dipropionate ointment. The reduced inflammatory response by HOCl treatment was demonstrated by reduced secretion of inflammatory cytokines in affected skin tissue from NC/Nga mice. In addition, HOCl significantly reduced IL-12 production in mBMDC. The diminished scratching behaviour was confirmed by impaired response to several pruritogens in dorsal root ganglia neurons excised from NC/Nga mice after termination of the studies. The response to the stimuli was also reduced by pre-incubation of sensory neurons from untreated BALB/c mice with 0.0001% HOCl. Conclusions and Clinical Relevance These data indicate a direct reduction in sensory response by HOCl, leading to significantly reduced itch and inflammation in vivo.}, number={1}, journal={CLINICAL AND EXPERIMENTAL ALLERGY}, author={Fukuyama, T. and Martel, B. C. and Linder, K. E. and Ehling, S. and Ganchingco, J. R. and Baeumer, W.}, year={2018}, month={Jan}, pages={78–88} }
 @article{levine_cianciolo_linder_bizikova_birkenheuer_brooks_salous_nordone_bellinger_marr_et al._2017, title={Endothelial alterations in a canine model of immune thrombocytopenia}, volume={30}, ISSN={0953-7104 1369-1635}, url={http://dx.doi.org/10.1080/09537104.2017.1378807}, DOI={10.1080/09537104.2017.1378807}, abstractNote={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.}, number={1}, journal={Platelets}, publisher={Informa UK Limited}, author={LeVine, Dana N. and Cianciolo, Rachel E. and Linder, Keith E. and Bizikova, Petra and Birkenheuer, Adam J. and Brooks, Marjory B. and Salous, Abdelghaffar K. and Nordone, Shila K. and Bellinger, Dwight A. and Marr, Henry and et al.}, year={2017}, month={Nov}, pages={88–97} }
 @article{draughn_allen_routh_stone_kirker_boegli_schuchman_linder_baynes_james_et al._2017, title={Evaluation of a 2-aminoimidazole variant as adjuvant treatment for dermal bacterial infections}, volume={11}, journal={Drug Design Development and Therapy}, author={Draughn, G. L. and Allen, C. L. and Routh, P. A. and Stone, M. R. and Kirker, K. R. and Boegli, A. and Schuchman, R. M. and Linder, K. E. and Baynes, R. E. and James, G. and et al.}, year={2017}, pages={153–162} }
 @article{risselada_linder_griffith_roberts_davidson_zamboni_messenger_2017, title={Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study}, volume={12}, number={10}, journal={PLoS One}, author={Risselada, M. and Linder, K. E. and Griffith, E. and Roberts, B. V. and Davidson, G. and Zamboni, W. C. and Messenger, K. M.}, year={2017} }
 @article{banovic_linder_uri_rossi_olivry_2016, title={Clinical and microscopic features of generalized discoid lupus erythematosus in dogs (10 cases)}, volume={27}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84991447094&partnerID=MN8TOARS}, DOI={10.1111/vde.12389}, abstractNote={Generalized discoid lupus erythematosus (GDLE) is a newly recognized canine variant of chronic cutaneous lupus erythematosus (CLE) that is not well characterized. We report herein the signalment, clinical signs, treatment outcome, histopathology and immunological findings of 10 dogs with GDLE. Inclusion criteria were: (i) a >3 month history of generalized skin lesions indicating a chronic or recurrent nature; (ii) skin lesions resembling those of human GDLE; (iii) histopathology of CLE (lymphocyte-rich interface dermatitis). Direct immunofluorescence (IF) and antinuclear antibody serology were investigated whenever possible. Various breeds were affected in their mid- to late adulthood. Selection criteria of generalized multifocal, annular (“discoid”) to polycyclic plaques with pigment changes, erythematous margin, adherent scaling, follicular plugging and central alopecia were shown in all dogs. In nine dogs, plaques contained mild to moderate central scarring with depigmentation and/or hyperpigmentation. There were no dogs in which the disease progressed to systemic lupus erythematosus within a median follow-up of 2.5 years. Per inclusion criteria, interface dermatitis occurred with basement membrane zone (BMZ) thickening, suprabasal apoptosis and/or dermal fibrosis in some dogs. Infundibular interface folliculitis was common; it sometimes transitioned to mural folliculitis in lower follicle segments, and occurred with follicular and sebaceous gland atrophy. The direct IF revealed patchy deposition of immunoglobulin IgG and IgM at the BMZ. Lesions responded to a variety of treatments, including ciclosporin, hydroxychloroquine, topical tacrolimus and tetracycline/niacinamide. Relapses were common after medications were tapered. These observations support the existence of a canine homologue of human GDLE. Le lupus érythémateux discoïde généralisé (GDLE) est un variant canin nouvellement reconnu du lupus cutané chronique (CLE) qui n'est pas bien défini. Nous rapportons ici le signalement, les signes cliniques, l'efficacité des traitements, l'histopathologie et les données immunologiques de 10 chiens atteints de GDLE. Les critères d'inclusion étaient (i) a>3 mois de commémoratifs de lésions cutanées généralisées correspondant à une atteinte chronique ou récidivante; (ii) des lésions cutanées ressemblant à celles de la GDLE de l'homme; (iii) l'histopathologie de CLE (dermatite d'interface riche en lymphocytes). L'immunofluorescence directe (IF) et la sérologie anticorps antinucléaires ont été étudiées si possible. Des races variées ont été atteintes à l’âge adulte à adulte-avancé. Les critères de sélection des plaques annulaires (« discoïdes) à polycycliques multifocales généralisées avec modification de pigmentation, marges érythémateuses, squames adhérentes, obstruction folliculaire et alopécie centrale ont été observés chez tous les chiens. Pour neuf chiens, les plaques contenaient un squamosis central faible à modéré avec dépigmentation et/ou hyperpigmentation. Pour aucun chien il n'y a eu de progression de la maladie en lupus érythémateux systémique sur une période moyenne de suivi de 2.5 ans. Par les critères d'inclusion, la dermatite d'interface avec épaississement de la zone de la membrane basale (BMZ), de l'apoptose suprabasale et/ou une fibrose dermique étaient observés chez certains chiens. Une folliculite d'interface infundibulaire était fréquente; celle-ci évoluait parfois en folliculite murale dans les portions basses des follicules et se développait en association avec une atrophie folliculaire ou sébacée. L’IF directe révélait une disposition en patch d'immunoglobuline IgG et IgM sur la BMZ. Les lésions répondaient à une variété de traitements, comprenant la ciclosporine, l'hydroxychloroquine, la tacrolimus topique et la tétracycline/niacinamide. Les récidives étaient fréquentes après diminution de doses des traitements. Ces observations supportent l'existence d'un homologue canin du GDLE de l'homme. el lupus eritematoso discoide generalizado (GDLE) es una variante recientemente reconocida de lupus eritematoso cutáneo crónico canino (CLE) que no está bien caracterizada. en este artículo se presenta la anamnesis, signos clínicos, resultados del tratamiento, histopatología y hallazgos inmunológicos de 10 perros con GDLE. Los criterios de inclusión fueron: (i) una historia> 3 meses de lesiones cutáneas generalizadas que indicaban una naturaleza crónica o recurrente; (ii) lesiones de la piel similares a las de GDLE humana; (iii) histopatología de CLE (dermatitis de interfase rica en linfocitos). Se investigaron por inmunofluorescencia directa (IF) y serología los anticuerpos antinucleares siempre que fue posible. Diversas razas fueron afectadas con perros de mediana a avanzada edad. Criterios de selección presentes en todos los perros fueron la presencia de lesiones multifocales, anulares (“discoides”) a placas policíclicas con cambios en la pigmentación, margen eritematoso, costras adherentes, taponamiento folicular y alopecia central. En nueve perros, las placas contenían leve a moderada cicatrización central con depigmentación y / o hiperpigmentación. No hubo perros en los que la enfermedad progresara a lupus eritematoso sistémico con un tiempo medio de de seguimiento de 2,5 años. Por los criterios de inclusión, hubo dermatitis de interfase con engrosamiento de la membrana basal (BMZ), apoptosis suprabasal y / o fibrosis dérmica en algunos perros. La inflamación de interfase infundibular fue común y a veces progresaba a foliculitis mural en los segmentos más bajos del folículo, y se producía con atrofia de las glándulas sebáceas y foliculos. El IF directa reveló deposición irregular de inmunoglobulina IgG e IgM en la BMZ. Las lesiones respondieron a una variedad de tratamientos, incluyendo ciclosporina, hidroxicloroquina, tacrolimus y tetraciclina / niacinamida. Las recaídas fueron frecuentes con la disminución de la dosis de medicamentos. Estas observaciones confirman la existencia de un homólogo canino de GDLE humana. Der generalisierte Diskoide Lupus Erythematosus (GDLE) ist eine neu erkannte canine Variante des chronischen kutanen Lupus Erythematosus (CLE), der noch nicht gut beschrieben wurde. Wir berichten hiermit vom Signalement, den klinischen Zeichen, dem Behandlungserfolg, der Histopathologie und den immunologischen Befunden von 10 Hunden mit GDLE. Inklusionskriterien waren: (i) a > 3 monatiger Vorbericht einer generalisierten Hautveränderung, die auf eine chronische oder wiederkehrende Natur schließen lässt; (ii) Hautveränderungen, die jenen der Menschen mit GDLE ähneln; (iii) eine mit CLE kompatible Histopathologie (Lymphozyten-reiche Interface Dermatitis). Direkte Immunfluoreszenz (IF) und Antikörperserologie wurden wenn möglich untersucht. Verschiedene Rassen waren im mittleren bis höherem Alter betroffen. Die Auswahlkriterien von generalisierten multifokalen, annularen bis polycyclischen Plaques mit Pigmentveränderungen, erythematösen Rändern, anhaftenden Schuppen, folliculärem Plugging und einer zentralen Alopezie wurden bei allen Hunden gefunden. Bei neun Hunden enthielten die Plaques milde bis moderate zentrale Narben mit einer Depigmentierung und/oder Hyperpigmentierung. Es gab keine Hunde bei denen sich die Krankheit innerhalb von einem medianen Follow-up von 2,5 Jahren zu einem systemischen Lupus Erythematosus weiterentwickelte. Nach den Aufnahmekriterien trat die Interface Dermatitis gemeinsam mit einer Verdickung der Basalmembran (BMZ), einer suprabasalen Apoptose und/oder einer dermalen Fibrose bei einigen Hunden auf. Eine Interface Dermatitis des Infundibulums war häufig; diese entwickelte sich gelegentlich in den unteren Follikelabschnitten zu einer muralen Follikulitis, gleichzeitig trat sie mit einer follikulären und sebaziösen Drüsenatrophie auf. Die direkte IF zeigte fleckige Ablagerungen von Immunglobulin IgG und IgM an der BMZ. Die Veränderungen wurden auf eine Reihe von Behandlungen besser; diese bestanden aus Ciclosporin, Hydroxychloroquinolon, topischem Takrolimus und Tetrazykline/Niacinamid. Sobald die Medikamente ausgeschlichen wurden, war ein Wiederauftreten häufig. Diese Beobachtungen unterstützen die Tatsache, dass ein canines Homolog zum humanen GDLE existiert. 全身性円板状紅斑性狼瘡(GDLE)は、慢性皮膚紅斑性狼瘡(CLE)の犬の1亜型として新たに認知されているが、その特徴はよくわかっていない。 10頭のGDLEの犬における、シグナルメント、臨床所見、治療反応性、病理学的所見および免疫学的所見をここに報告する。 組み入れ基準は以下のものとした:(i)3ヶ月以上の慢性あるいは再発性の全身性皮膚病変を持つこと; (ii)皮膚病変が人のGDLEと類似していること; (iii)病理組織学的にCLE(リンパ球を主体とする境界部皮膚炎)の所見を持つこと。直接免疫蛍光染色(IF)および抗核抗体血清検査は可能な限り実施した。 中年齢から高齢の様々な犬種が罹患していた。組み入れ基準である、全身多発性の環状(”円板状”)から多環状の色素変化を伴う局面、紅斑性の縁、固着性の鱗屑、毛嚢性栓および中心性の脱毛が、全ての症例で認められた。9頭では、局面は色素脱失および/あるいは色素沈着を伴う軽度から中程度の中心性の瘢痕を伴っていた。中央値2.5年の追跡調査の間に、全身性エリテマトーデスに進行した症例はいなかった。組み入れ基準である境界部皮膚炎は、表皮基底膜領域(BMZ)の肥厚、基底層上細胞のアポトーシスおよび/あるいは真皮の線維化をいくつかの症例で伴っていた。毛漏斗部の境界部毛包炎が一般的に認められ、時折、毛包下部の壁内毛包炎へと移行し、毛包および皮脂腺の萎縮を伴っていた。直接IFでは、免疫グロブリンIgGおよびIgMの斑状の沈着がBMZに認められた。病変は、シクロスポリン、ヒドロキシクロロン、タクロリムス塗布、テトラサイクリン/ナイアシンアミドなどの様々な治療に反応した。薬剤を漸減するとほとんどの症例で再発した。 これらの所見は、人のGDLEに相同する犬の疾患の存在を支持するものである。 泛发性盘状红斑狼疮(GDLE),最近被认为是犬慢性皮肤型红斑狼疮(CLE)的一种变异,目前未能对其充分定义。 本文报道了10只GDLE患犬的病征、临床症状、治疗效果、组织病理学和免疫学发现。 入选标准为:(i)慢性或复发性全身性皮肤病,病史超过3个月;(ii)皮肤病变类似于人类GDLE;(iii) CLE(淋巴细胞丰富的界面皮炎)组织病理学特征。尽可能通过直接免疫荧光法(IF)和抗核抗体血清学检查。 患犬为不同品种、成年中期至后期。所有犬表现为全身多灶性、环状(盘状)或多环状斑块,伴随色素改变、边缘红斑、粘附皮屑、毛囊角栓和中心脱毛。9只犬的斑块伴有轻度或中度色素减退和/或色素过度沉着。在中值回访时间2.5年内,没有犬发展为全身性红斑狼疮。每一个入选病例均伴有基底膜区(BMZ)增厚、基底上层细胞凋亡和/或部分犬皮肤纤维化。常见漏斗区的界面毛囊炎;有时可能在毛囊末端发展为毛囊壁炎,同时伴有毛囊和皮脂腺的萎缩。直接IF显示,BMZ的免疫球蛋白IgG和IgM缀块性沉积。多种治疗对病变有效,包括环孢素、羟化氯喹、外用他克莫斯和四环素/烟酰胺。药物逐渐减量后常见复发。 这些发现表明,存在与人类GDLE同源的犬GDLE。 Lúpus eritematoso discoide generalizado (LEDG) é uma variante canina do lúpus eritematoso cutâneo crônico (LECC) reconhecida recentemente e pouco caracterizada. Relatar os sinais clínicos, tratamentos empregados, histopatologia e achados imunológicos de dez cães com LEDG. Os critérios de inclusão foram: (i) histórico de lesões cutâneas generalizados por três ou mais meses, indicando natureza crônica ou recorrente; (ii) lesões cutâneas semelhantes às do LEDG humano; (iii) histopatologia sugestiva de LECC (dermatite de interface com infiltrado linfocitário). Imunofluorescência direta (IFD) e sorologia para anticorpo antinuclear foram investigadas sempre que possível. Diversas raças foram afetadas em uma faixa etária média entre a metade ao fim da vida adulta. O critério de seleção de lesões anulares (“discoide”) a placas policíclicas com alterações pigmentares , margem eritematosa, escamas aderidas, cilindros foliculares e alopecia central foram observados em todos os cães. Em nove, as placas apresentavam área cicatricial central discreta a moderada com despigmentação e/ou hiperpigmentação. Nenhum dos cães apresentou progressão para lúpus eritematoso sistêmico em dois anos e meio, em média, de acompanhamento. Por critério de inclusão, dermatite de interface ocorreu com espessamento da membrana basal (MB), apoptose suprabasal e/ou fibrose dérmica, em alguns animais. Foliculite de interface foi comum, esta algumas vezes evoluiu para foliculite mural em segmentos foliculares profundos, e ocorreu com atrofia folicular e de glândulas sebáceas. IFD revelou deposição irregular de imunoglobulina do tipo IgG e IgM na MB. As lesões responderam positivamente a diversos tratamentos, incluindo ciclosporina, hidroxicloroquina, tacrolimus tópico e tetraciclina com niacinamida. Recidivas foram comuns após a descontinuação da medicação. Estas observações suportam a existência da forma homóloga canina de LDG humana.}, number={6}, journal={VETERINARY DERMATOLOGY}, publisher={Wiley-Blackwell}, author={Banovic, Frane and Linder, Keith E. and Uri, Maarja and Rossi, Michael A. and Olivry, Thierry}, year={2016}, month={Dec}, pages={488-+} }
 @article{olivry_mayhew_paps_linder_peredo_rajpal_hofland_cote-sierra_2016, title={Early Activation of Th2/Th22 Inflammatory and Pruritogenic Pathways in Acute Canine Atopic Dermatitis Skin Lesions}, volume={136}, ISSN={["1523-1747"]}, url={https://doi.org/10.1016/j.jid.2016.05.117}, DOI={10.1016/j.jid.2016.05.117}, abstractNote={Determining inflammation and itch pathway activation in patients with atopic dermatitis (AD) is fraught with the inability to precisely assess the age of skin lesions, thus affecting the analysis of time-dependent mediators. To characterize inflammatory events occurring during early experimental acute AD lesions, biopsy samples were collected 6, 24, and 48 hours after epicutaneous application of Dermatophagoides farinae house dust mites to sensitized atopic dogs. The skin transcriptome was assessed using a dog-specific microarray and quantitative PCR. Acute canine AD skin lesions had a significant up-regulation of genes encoding T helper (Th) 2 (e.g., IL4, IL5, IL13, IL31, and IL33), Th9 (IL9), and Th22 (IL22) cytokines as well as Th2-promoting chemokines such as CCL5 and CCL17. Proinflammatory (e.g., IL6, LTB, and IL18) cytokines were also up-regulated. Other known pruritogenic pathways were also activated: there was significant up-regulation of genes encoding proteases cathepsin S (CTSS), mast cell chymase (CMA1), tryptase (TPS1) and mastin, neuromedin-B (NMB), nerve growth factor (NGF), and leukotriene-synthesis enzymes (ALOX5, ALOX5AP, and LTA4H). Experimental acute canine house dust mite-induced AD lesions exhibit an activation of innate and adaptive immune responses and pruritogenic pathways similar to those seen in humans with acute AD, thereby validating this model to test innovative therapeutics modalities for this disease.}, number={10}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, publisher={Elsevier BV}, author={Olivry, Thierry and Mayhew, David and Paps, Judy S. and Linder, Keith E. and Peredo, Carlos and Rajpal, Deepak and Hofland, Hans and Cote-Sierra, Javier}, year={2016}, month={Oct}, pages={1961–1969} }
 @article{palerme_jones_ward_balakrishnan_linder_breitschwerdt_keene_2016, title={Infective endocarditis in 13 cats}, volume={18}, ISSN={1760-2734}, url={http://dx.doi.org/10.1016/j.jvc.2016.04.003}, DOI={10.1016/j.jvc.2016.04.003}, abstractNote={To describe the clinical presentation, clinicopathological abnormalities and outcomes of a series of cats diagnosed with infective endocarditis (IE) at two tertiary care referral institutions.Thirteen client-owned cats presenting to the cardiology or emergency services of tertiary referral institutions with a diagnosis of endocarditis based on the modified Duke criteria.Retrospective case series. Medical records were reviewed to extract relevant data. In addition, cases that had cardiac tissue available were evaluated by polymerase chain reaction for the presence of Bartonella DNA.Prevalence of feline IE was 0.007%. Cats with endocarditis tended to be older (median age: 9 years, range: 2-12 years) and no sex or breed was overrepresented. Commonly encountered clinical signs included respiratory distress (n = 5) and locomotor abnormalities of varying severity (n = 5). Echocardiographic examination detected valvular lesions consistent with endocarditis on the aortic (n = 8) or mitral (n = 5) valves. Nine cats were diagnosed with congestive heart failure at the time of endocarditis diagnosis. Overall, prognosis was grave with a median survival time of 31 days.In contrast to dogs, cats with IE typically present with clinical signs consistent with cardiac decompensation and locomotor abnormalities suggestive of either thromboembolic disease or inflammatory arthritis. Given the advanced state of disease when diagnosis typically occurs, prognosis is grave.}, number={3}, journal={Journal of Veterinary Cardiology}, publisher={Elsevier BV}, author={Palerme, Jean-Sébastien and Jones, Ashley E. and Ward, Jessica L. and Balakrishnan, Nandhakumar and Linder, Keith E. and Breitschwerdt, Edward B. and Keene, Bruce W.}, year={2016}, month={Sep}, pages={213–225} }
 @article{doelle_linder_boche_jagannathan_leeb_linek_2016, title={Initial characterization of stiff skin-like syndrome in West Highland white terriers}, volume={27}, ISSN={["1365-3164"]}, DOI={10.1111/vde.12316}, abstractNote={Stiff skin syndrome and systemic or localized scleroderma are cutaneous disorders characterized by dermal fibrosis and present clinically with induration of the skin, with or without joint, internal organ or vascular involvement.To provide clinical, histological and preliminary genetic analysis of two West Highland white terrier siblings presenting with indurated skin resembling stiff skin syndrome in humans.Two client owned full sibling West Highland white terriers from two different litters.Clinical examination, histopathological examination and whole genome sequencing analysis of affected and unaffected West Highland white terriers.Affected dogs exhibited markedly indurated skin that was attached firmly to the underlying tissue and incomplete closure of the mouth and eyes. No abnormalities were found by neurological or orthopaedic examination, radiographs of the head or whole body computed tomography. Histologically, the dermis and pannicular septa were thickened by a marked increase in coarse collagen fibres and a mild to moderate increase in collagen fibre diameter. The syndrome most likely follows an autosomal recessive mode of inheritance. The sequence analysis did not reveal any obvious causative variant in the investigated candidate genes ADAMTSL2 and FBN1.The clinical phenotype and histopathological features of two West Highland white terrier siblings resembled stiff skin syndrome in humans. Unlike in humans, or previously described beagles with stiff skin, there was no restriction of joint mobility. Genetic analysis did not detect a candidate causative variant and warrants further research.}, number={3}, journal={VETERINARY DERMATOLOGY}, author={Doelle, Maren and Linder, Keith E. and Boche, Janna and Jagannathan, Vidhya and Leeb, Tosso and Linek, Monika}, year={2016}, month={Jun}, pages={210-+} }
 @article{tham_olivry_linder_bizikova_2016, title={Mucous membrane pemphigoid in dogs: A retrospective study of 16 new cases}, volume={27}, number={5}, journal={Veterinary Dermatology}, author={Tham, H. L. and Olivry, T. and Linder, K. E. and Bizikova, P.}, year={2016}, pages={376-} }
 @article{alpi_brown_neel_grindem_linder_harper_2016, title={Scanning technology selection impacts acceptability and usefulness of image-rich content}, volume={104}, ISSN={["1536-5050"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84955278757&partnerID=MN8TOARS}, DOI={10.3163/1536-5050.104.1.003}, abstractNote={Clinical and research usefulness of articles can depend on image quality. This study addressed whether scans of figures in black and white (B&W), grayscale, or color, or portable document format (PDF) to tagged image file format (TIFF) conversions as provided by interlibrary loan or document delivery were viewed as acceptable or useful by radiologists or pathologists.Residency coordinators selected eighteen figures from studies from radiology, clinical pathology, and anatomic pathology journals. With original PDF controls, each figure was prepared in three or four experimental conditions: PDF conversion to TIFF, and scans from print in B&W, grayscale, and color. Twelve independent observers indicated whether they could identify the features and whether the image quality was acceptable. They also ranked all the experimental conditions of each figure in terms of usefulness.Of 982 assessments of 87 anatomic pathology, 83 clinical pathology, and 77 radiology images, 471 (48%) were unidentifiable. Unidentifiability of originals (4%) and conversions (10%) was low. For scans, unidentifiability ranged from 53% for color, to 74% for grayscale, to 97% for B&W. Of 987 responses about acceptability (n=405), 41% were said to be unacceptable, 97% of B&W, 66% of grayscale, 41% of color, and 1% of conversions. Hypothesized order (original, conversion, color, grayscale, B&W) matched 67% of rankings (n=215).PDF to TIFF conversion provided acceptable content. Color images are rarely useful in grayscale (12%) or B&W (less than 1%). Acceptability of grayscale scans of noncolor originals was 52%. Digital originals are needed for most images. Print images in color or grayscale should be scanned using those modalities.}, number={1}, journal={JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION}, author={Alpi, Kristine M. and Brown, James C., Jr. and Neel, Jennifer A. and Grindem, Carol B. and Linder, Keith E. and Harper, James B.}, year={2016}, month={Jan}, pages={15–23} }
 @article{bizikova_linder_wofford_mamo_dunston_olivry_2015, title={Canine epidermolysis bullosa acquisita: A retrospective study of 20 cases}, volume={26}, number={6}, journal={Veterinary Dermatology}, author={Bizikova, P. and Linder, K. E. and Wofford, J. A. and Mamo, L. B. and Dunston, S. M. and Olivry, T.}, year={2015}, pages={441-} }
 @article{pinto_mcmullen_linder_cullen_gilger_2015, title={Clinical, histopathological and immunohistochemical characterization of a novel equine ocular disorder: heterochromic iridocyclitis with secondary keratitis in adult horses}, volume={18}, ISSN={["1463-5224"]}, DOI={10.1111/vop.12234}, abstractNote={Objective To describe the clinical, histopathologic and immunohistochemical characteristics of an equine ocular inflammatory disease resulting in anterior uveitis and corneal endothelial inflammation associated with iris pigment dispersion and retrocorneal fibrous membrane (RFM) formation. Design Retrospective study. Animals studied Sixteen horses with evidence of pigmented keratic precipitates (KPs), corneal edema, and/or iris depigmentation. Information collected from the medical records included signalment, clinical signs, prereferral treatment duration and response to therapy, ophthalmic examination findings, postreferral treatment, response to therapy, and outcome. Results Twenty-one eyes from 16 horses were affected. Age ranged between 9 and 25 years (Average 16.1 years). Blepharospasm, epiphora, and/or corneal opacification were the first clinical signs noted. At the time of referral pigmented KPs, corneal edema, iridal depigmentation, and retrocorneal membranes were commonly seen. Treatment included topical and/or systemic anti-inflammatories and antibiotics with variable response. Reduction or cessation of anti-inflammatory therapy resulted in worsening of clinical signs and disease progression. Eight eyes ultimately required enucleation. Histopathology changes include iridal pigment loss and dispersion, RFM formation, and keratitis. Variable degrees of lymphoplasmacytic inflammation were dominated by T-cells within the corneal stroma, RFM, iris, and ciliary body with occasional multinucleated giant cells. Conclusions Heterochromic iridocyclitis with secondary keratitis (HIK) is characterized by uveal inflammation with pigment dispersion and suspected corneal endothelial dysfunction. Horses being treated for HIK require diligent and frequent follow-up examinations in combination with aggressive local immune suppression to control the disease. However, HIK may not respond to therapy and enucleation may ultimately be required to ensure the horse's comfort.}, number={6}, journal={VETERINARY OPHTHALMOLOGY}, author={Pinto, Nelson I. and McMullen, Richard J., Jr. and Linder, Keith E. and Cullen, John M. and Gilger, Brian C.}, year={2015}, month={Nov}, pages={443–456} }
 @article{bizikova_moriello_linder_sauber_2015, title={Dinotefuran/pyriproxyfen/permethrin pemphigus-like drug reaction in three dogs}, volume={26}, number={3}, journal={Veterinary Dermatology}, author={Bizikova, P. and Moriello, K. A. and Linder, K. E. and Sauber, L.}, year={2015}, pages={206-} }
 @article{rossi_messenger_linder_olivry_2015, title={Generalized Canine Discoid Lupus Erythematosus Responsive to Tetracycline and Niacinamide Therapy}, volume={51}, ISSN={["1547-3317"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84943745108&partnerID=MN8TOARS}, DOI={10.5326/jaaha-ms-6116}, abstractNote={Discoid lupus erythematosus (DLE) is a commonly reported canine autoimmune disease that normally presents with a phenotype consisting of erythema, depigmentation, scaling, erosions/ulcers, and scarring over the nasal planum and the proximal dorsal muzzle. Recently, two cases of a generalized variant of this disease have been reported, whose lesions responded to either systemic glucocorticoids or a combination of topical corticosteroids, topical tacrolimus, and the oral antimalarial hydroxychloroquine. The purpose of this report is to describe an 11 yr old shih tzu that presented with skin lesions consisting of multiple annular, erythematous papules and plaques, hyperpigmentation, adherent scaling, and atrophic scars over the caudal dorsum, flanks, craniodorsal thorax, and lateroproximal extremities. A diagnosis of generalized DLE was made based on the clinical presentation, histopathology, laboratory values, and direct immunofluorescence findings. Treatment consisted of oral tetracycline and oral niacinamide, which resulted in complete remission of clinical signs. This is the first documented report of generalized canine DLE responding to the described immunomodulating regimen. Such a combination might therefore be considered as a glucocorticoid and/or antimalarial alternative for the management of generalized DLE.}, number={3}, journal={JOURNAL OF THE AMERICAN ANIMAL HOSPITAL ASSOCIATION}, author={Rossi, Michael A. and Messenger, Linda M. and Linder, Keith E. and Olivry, Thierry}, year={2015}, pages={171–175} }
 @article{olivry_rossi_banovic_linder_2015, title={Mucocutaneous lupus erythematosus in dogs (21 cases)}, volume={26}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84955657545&partnerID=MN8TOARS}, DOI={10.1111/vde.12217}, abstractNote={The diagnosis of dogs with chronic juxtamucosal erosive lesions and histopathology typical of cutaneous lupus erythematosus (CLE) is unclear. We report herein 21 dogs with mucocutaneous erosive lesions and lupus-specific histopathology that we propose to be affected with mucocutaneous lupus erythematosus (MCLE), another variant of chronic CLE. Inclusion criteria were the presence of the following: (i) a >2 month history of chronic or recurrent skin lesions; (ii) erosions or ulcers predominating at mucosae or mucocutaneous junctions; (iii) microscopic lesions of CLE (i.e. a lymphocyte-rich interface dermatitis with basal keratinocyte damage); and (iv) a lack of complete remission following antimicrobials. Clinical questionnaires and skin biopsies were reviewed. Direct immunofluorescence and antinuclear antibody serology were performed whenever possible. More than half of the 21 dogs were German shepherds or their crosses. The disease affected mostly dogs in their mid-adulthood and there was an over-representation of females. Erosions and ulcers predominated at genital/perigenital and anal/perianal areas, with a lower frequency of involvement of periocular, perioral and perinasal regions. In these dogs, there were no clinical signs suggestive of an associated systemic lupus erythematosus. Microscopic lesions were specific for CLE, but they were patchy and often infected with bacteria. The most common immunological finding was focal IgG deposition at the basement membrane zone. Lesions responded to varying interventions, but oral glucocorticoids led to a shorter time to complete remission. Relapses were common upon treatment tapering. These observations support MCLE being another variant of canine CLE. el diagnóstico de perros con lesiones erosivas crónicas cercanas a la mucosa y con histopatología típica de cutáneos lupus eritematoso (CLE) no está muy claro. en este artículo estudiamos 21 casos de perros con lesiones erosivas mucocutáneas y patología específica de lupus que proponemos están afectados con lupus eritematoso mucocutáneo (MCLE), otra variante CLE crónico. los criterios de inclusión fueron la presencia de los siguientes elementos: i) una historia de más de dos meses de lesiones recurrentes de la piel crónicas; ii) erosiones y ulceración predominantemente en las mucosas y uniones mucocutáneas; iii) lesiones microscópicas de cutáneos lupus eritematoso (dermatitis de interfase rica en linfocitos con daño a los queratinocitos basales); y iv) falta de remisión completa tras el tratamiento antimicrobiano. Los cuestionarios clínicos y las biopsias de piel fueron revisadas. Se realizó inmunofluorescencia directa y serología para anticuerpos antinucleares cuando fue posible. más de la mitad de los 21 perros fueron Pastores Alemanes o sus cruces. Las enfermedad afectó mayormente a perros de edad adulta media y hubo mayor representación de hembras. Erosiones y úlceras predominaron en la zona genital/perigenital y zonas anal/perianal, con menor frecuencia en las zonas perioculares, perianales y perinasales. En estos perros no hubo signos clínicos indicativos de lupus eritematoso sistémico. Las lesiones microscópicas fueron específicas para CLE, pero fueron discontínuas y a menudo infectadas con bacterias. El hallazgo inmunológico más común fue deposición focal de IgG en la zona basal. La lesiones respondieron a varias intervenciones, pero la administración de corticoides por vía oral produjo un intervalo más corto para alcanzar remisión completa. Las recidiva fueron frecuentes tras la disminución progresiva del tratamiento. estas observaciones apoyan la existencia de MCLE como otra variante de CLE canino. Le diagnostic des chiens atteints de lésions érosives cutanéo-muqueuses chroniques et l'histopathologie typique de lupus cutané érythémateux (CLE) n'est pas clair. Nous décrivons ici 21 chiens atteints de lésions érosives cutanéo-muqueuses avec histopathologie spécifique de lupus. Nous proposons un diagnostic de lupus érythémateux cutanéo-muqueux (MCLE), un autre variant du CLE chronique. Les critères d'inclusion étaient la présence (i) plus de 2 mois de lésions cutanées chroniques ou récidivantes; (ii) érosions ou ulcères majoritairement localisés aux muqueuses ou aux jonctions cutanéo-muqueuses; (iii) des lésions microscopiques de CLE (i.e. une dermatite d'interface riche en lymphocytes avec atteinte des kératinocytes basaux); et (iv) une absence de rémission complète après antibiothérapie. Les dossiers cliniques et les biopsies cutanées ont été relus. Une immunofluorescence directe et une sérologie anticorps antinucléaires ont été réalisés si possible. Plus de la moitié des 21 chiens étaient des bergers allemands de race ou croisés. La maladie concernait principalement des chiens adultes et les femelles étaient sur-représentées. Les érosions et ulcères prédominaient aux zones génitales/périgénitales et anales/périanales, avec une plus faible fréquence d'atteinte périocculaire, périorale et périnasale. Chez ces chiens, il n'y avait aucun symptôme évocateur d'un lupus systémique associé. Les lésions microscopiques étaient spécifiques du CLE mais étaient localisées et souvent infectées par des bactéries. Les données immunologiques les plus fréquentes étaient un dépôt focal d'IgG au niveau de la membrane basale. Les lésions ont répondu à différents traitements mais les corticoïdes oraux menaient à une rémission complète dans un temps plus court. Les récidives étaient fréquentes au cours de la baisse des traitements. Ces observations supportent le MCLE en tant qu'autre variant de CLE canin. Die Diagnose von Hunden mit chronischen juxtamukosalen erosiven Veränderungen und die typische Histopathologie des kutanen Lupus erythematosus (CLE) sind unklar. Wir berichten hier von 21 Hunden mit mukokutanen erosiven Veränderungen und einer Lupus-spezifischen Histopathologie, die wir einem mucocutanen Lupus erythematosus (MCLE), einer weiteren Variante von chronischem CLE, zuschreiben. Einschlusskriterien waren das Vorkommen von Folgendem: (i) eine > 2 monatige Anamnese chronischer oder wiederkehrender Hautveränderungen; (ii) Erosionen oder Ulzera, die vor allem an der Mukosa oder den mukokutanen Übergängen auftraten; (iii) mikroskopische Veränderungen von CLE (i.e. eine Lymphozyten-reiche Interface Dermatitis mit basaler Keratinozytenzerstörung); und (iv) das Ausbleiben einer völligen Remission nach Anwendung von Antibiotika. Es wurden klinische Fragebögen und Hautbiopsien reviewed. Eine direkte Immunfluoreszenz und eine Antinukleäre Antikörperserologie wurde, wo immer möglich, durchgeführt. Mehr als die Hälfte der 21 Hunde waren Deutsche Schäferhunde oder ihre Mischlinge. Die Krankheit betraf hauptsächlich Hunde mittleren Alters, wobei weibliche Tiere überrepräsentiert waren. Erosionen und Ulzera kamen hauptsächlich genital/perigenital und anal/perianal vor, wobei periokuläre, periorale und perinasale Regionen weniger häufig betroffen waren. Bei diesen Hunden gab es keine klinischen Anzeichen, die auf einen Zusammenhang mit einem systemischen Lupus erythematosus hingewiesen hätten. Die mikroskopischen Veränderungen waren typisch für CLE, kamen aber nur stellenweise vor und waren mit Bakterien infiziert. Der häufigste immunologische Befund war eine fokale Ablagerung von IgG an der Basalmembran. Die Veränderungen reagierten auf die unterschiedlichsten Behandlungen, aber Glukokortikoide per os führten in der kürzesten Zeit zur völligen Remission. Rezidive traten bei ausschleichender Behandlung häufig auf. Diese Beobachtungen unterstützen die Meinung, dass MCLE eine weitere Variante des caninen CLE darstellt.}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Olivry, Thierry and Rossi, Michael A. and Banovic, Frane and Linder, Keith E.}, year={2015}, month={Aug}, pages={256-+} }
 @article{pultorak_linder_maggi_balakrishnan_breitschwerdt_2015, title={Prevalence of Bartonella spp. in Canine Cutaneous Histiocytoma}, volume={153}, ISSN={0021-9975}, url={http://dx.doi.org/10.1016/j.jcpa.2015.04.001}, DOI={10.1016/j.jcpa.2015.04.001}, abstractNote={Canine cutaneous histiocytoma (CCH) is a common, benign neoplastic proliferation of histiocytes of Langerhans cell origin that often ulcerate, become secondarily infected and regress spontaneously. Bartonella is a fastidious genus of facultative intracellular pathogens that can be transmitted through arthropod bites and epidermal animal scratches and has been identified previously in the cytoplasm of histiocytes within granulomatous lesions and in skin biopsy samples of inflammatory pustules and papules. Based on the established inflammatory and oncogenic properties of Bartonella, we hypothesized that Bartonella spp. DNA could be amplified from CCH more often than from non-lesional skin and bacteria could be localized within skin tumours using indirect immunofluorescence (IIF). Paraffin wax-embedded surgical biopsy samples from dogs with CCH and non-neoplastic skin adjacent to osteosarcomas (control group selected due to wide surgical margins) were retrieved from the archive of the pathology service of North Carolina State University College of Veterinary Medicine. DNA was extracted and regions of the 16S-23S rRNA intergenic transcribed spacer (ITS) region and the pap31 and gltA genes were amplified by polymerase chain reaction (PCR) using Bartonella-specific primers. IIF was performed using a primary Bartonella henselae monoclonal antibody to localize B. henselae in tissues of PCR-positive dogs. Bartonella vinsonii subsp. berkhoffii was amplified from 1/17 (5.8%) control tissues and B. henselae was amplified from 4/29 (13.8%) CCH tissues. The prevalence of B. vinsonii subsp. berkhoffii (P = 0.37) or B. henselae (P = 0.28) did not vary statistically between study groups. B. henselae could be visualized in 2/4 (50.0%) CCH tissues using IIF. Based on this study, Bartonella spp. are unlikely to cause CCH.}, number={1}, journal={Journal of Comparative Pathology}, publisher={Elsevier BV}, author={Pultorak, E.L. and Linder, K. and Maggi, R.G. and Balakrishnan, N. and Breitschwerdt, E.B.}, year={2015}, month={Jul}, pages={14–21} }
 @article{tham_linder_tucker_maggi_bizikova_2015, title={Protozoal nodular dermatitis and panniculitis in a Rottweiler puppy caused by Caryospora bigenetica}, volume={27}, ISSN={0959-4493}, url={http://dx.doi.org/10.1111/vde.12271}, DOI={10.1111/vde.12271}, abstractNote={Caryospora bigenetica is an intracellular protozoan parasite in snakes and raptors (primary hosts) and rodents (secondary host). Experimental infection has been documented in mice, pigs and goats; natural infection in dogs is rare.To describe the clinical presentation, histological features, treatment and outcome of a case of protozoal nodular dermatitis and panniculitis in a Rottweiler puppy caused by C. bigenetica.The puppy presented with generalized subcutaneous nodules measuring up to 2 cm in diameter. Histopathology revealed marked suppurative to pyogranulomatous dermatitis and panniculitis with intralesional protozoal organism. PCR and DNA sequencing confirmed infection with C. bigenetica. Treatment with a combination of oral trimethoprim-sulfamethoxazole (TMS), pyrimethamine and high-dose clindamycin (20 mg/kg twice daily) resulted in resolution of lesions in 6 weeks. Discontinuation of the treatment 2 weeks later was followed by a rapid relapse of skin lesions. Clindamycin and TMS were restarted and all lesions resolved within 2 weeks; TMS was discontinued 4 weeks later due to adverse effects. The lesions remained in remission for 2 months while the puppy received clindamycin monotherapy before a second relapse of skin lesions occurred.To the best of the authors' knowledge, this is the first documentation of the treatment and outcome of C. bigenetica cutaneous infection in a dog. Although remission of clinical signs can be achieved with combination therapy of clindamycin and TMS, long-term management is challenging and relapses should be anticipated.}, number={1}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Tham, Heng L. and Linder, Keith E. and Tucker, Alison and Maggi, Ricardo and Bizikova, Petra}, year={2015}, month={Nov}, pages={44–e12} }
 @article{agler_nielsen_urkasemsin_singleton_tonomura_sigurdsson_tang_linder_arepalli_hernandez_et al._2014, title={Canine hereditary ataxia in Old English Sheepdogs and Gordon Setters is associated with a defect in the autophagy gene encoding RAB24}, volume={10}, number={2}, journal={PLoS Genetics}, author={Agler, C. and Nielsen, D. M. and Urkasemsin, G. and Singleton, A. and Tonomura, N. and Sigurdsson, S. and Tang, R. Q. and Linder, K. and Arepalli, S. and Hernandez, D. and et al.}, year={2014} }
 @article{banovic_olivry_linder_2014, title={Ciclosporin therapy for canine generalized discoid lupus erythematosus refractory to doxycycline and niacinamide}, volume={25}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84911380668&partnerID=MN8TOARS}, DOI={10.1111/vde.12139}, abstractNote={Generalized discoid lupus erythematosus (DLE) is an autoimmune skin disease variant rarely reported in dogs. The antimalarial immunomodulator hydroxychloroquine has been suggested as maintenance therapy for generalized DLE in one dog, but several recurrences were noted in the 1 year follow-up of that patient. To describe the effective treatment of generalized DLE with ciclosporin in one dog. A 6-year-old, castrated male crossbred dog was presented with pruritic, well-demarcated annular to polycyclic, hyperpigmented plaques with marginal erythema on the dorsal head, neck, trunk and medial extremities; these had been nonresponsive to treatment with doxycycline and niacinamide. Investigation included complete blood count, serum chemistry profile, urinalysis, serum antinuclear antibody test, histopathological examination and direct immunofluorescence testing of skin biopsies. The presence of lymphocyte-rich interface dermatitis on histology, together with generalized chronic recurrent hyperpigmented plaques, was consistent with the diagnosis of a generalized variant of DLE. The absence of systemic signs and unremarkable laboratory tests excluded concurrent systemic lupus erythematosus. Treatment was initiated with oral dexamethasone and ciclosporin. After 1 month, dexamethasone was discontinued and oral ketoconazole was added to the therapeutic regimen. Four months later, pruritus and erythema resolved, with most skin lesions becoming impalpable. Over the last 6 months, the patient's DLE was maintained in remission with oral ciclosporin and ketoconazole in combination every 3 days. The combination of ciclosporin and ketoconazole appeared effective to induce and maintain lesion remission in this dog with generalized DLE. Le lupus discoïde érythémateux généralisé (DLE) est une dermatite auto-immune rarement rapportée chez le chien. L'hydroxychloroquine, immunomodulateur antimalarien, a été testée comme un traitement d'entretien pour la DLE généralisée chez un chien mais plusieurs récidives ont été observées dans l'année suivant chez ce patient. Décrire le traitement efficace de DLE généralisée avec de la ciclosporine chez un chien. Un chien croisé, mâle castré, de 6 ans, a été présenté avec des plaques prurigineuses hyperpigmentées circulaires à polycycliques bien délimitées avec des bords érythémateux sur le dessus de la tête, du cou, du tronc et sur la face médiale des extrémités; ces lésions n'ont pas répondu à la doxycycline et à la niacinamide. Les examens ont compris une numération formule complète, un profil biochimique, une analyse urinaire, un dosage des anticorps antinucléaires, un examen histopathologique et une immunofluorescence directe de biopsies cutanées. La présence d'une dermatite d'interface riche en lymphocytes à l'histopathologie associée à des plaques hyperpigmentées récidivantes chroniques généralisées est compatible avec le diagnostic d'un variant de DLE généralisée. L'absence de signes systémiques et d'anomalie dans les tests de laboratoire excluent un lupus érythémateux systémique concurrent. Le traitement a été initié avec de la dexaméthasone orale et de la ciclosporine. Après 1 mois, la dexaméthasone a été arrêtée et du kétoconazole oral a été ajoutée au traitement. Quatre mois plus tard, le prurit et l'érythème avaient disparu, la plupart des lésions devenant imperceptibles. Sur les 6 derniers mois, la rémission a été maintenue avec de la ciclosporine et du kétoconazole oral en association tous les 3 jours. L'association de la ciclosporine et du kétoconazole semble efficace pour induire et maintenir la rémission des lésions chez ce chien avec une DLE généralisée. el lupus eritematoso discoide generalizado (DLE) es una enfermedad autoinmune de la piel raramente descrita en perros. Se ha sugerido que el inmunomodulador antimalaria hidroxicloroquina puede utilizarse como terapia de mantenimiento para DLE generalizado en un perro, pero se observaron recidivas en el año de seguimiento del paciente. describir el tratamiento efectivo de disco DLE generalizado en un perro. un macho castrado de seis años de raza mixta se presentó con lesiones tipo placas anulares, a policíclicas, bien demarcadas e hiperpigmentadas que presentaban eritema marginal y que estaban localizadas en la parte dorsal de la cabeza, cuello, tronco, y parte media de las extremidades. Éstas habían respondido al tratamiento con doxiciclina y niacinamida. la investigación incluyó hematología, bioquímica sanguínea, urianálisis, la prueba de anticuerpos antinucleares en el suero, el examen histopatológico, y la inmunofluorescencia directa de la piel. la presencia de dermatitis en interfase con numerosos linfocitos en las preparaciones histológicas, junto con la presencia de placas hiperpigmentadas crónicas recidivantes, fue consistente con un diagnóstico de la variante generalizada de DEL. La ausencia de signos sistémicos y la ausencia de pruebas anormales de laboratorio excluyeron la posibilidad de lupus eritematoso sistémico. El tratamiento se inició con dexametasona oral y ciclosporina. Tras un mes de tratamiento, se discontinuó la dexametasona y se añadió quetoconazol por vía oral al régimen terapéutico, cuatro meses más tarde, el prurito y el eritema habían resuelto y la mayoría de las lesiones de la piel no se detectaron por palpación. En los seis meses siguientes al paciente se mantuvo en remisión con ciclosporina oral y quetoconazol en combinación administrados cada tres días. la combinación de ciclosporina y quetoconazol parece ser efectiva para inducir y mantener la remisión de las lesiones en este perro con DLE generalizado. Der generalisierte diskoide Lupus erythematosus (DLE) ist eine Variante der autoimmunen Hauterkrankung, die bei Hunden selten beschrieben wird. Der antimalarische Immunmodulator Hydrxychloroquin wurde als Erhaltungstherapie für einen generalisierten DLE bei einem Hund vorgeschlagen, wobei es aber innerhalb des Follow-Ups von einem Jahr zum mehrmaligen Wiederauftreten der Krankheit kam. Die Beschreibung einer wirksamen Behandlung eines generalisierten DLE bei einem Hund mit Ciclosporin. Ein sechs Jahre alter kastrierter Mischlingsrüde wurde mit juckenden, gut abgegrenzten annulären bis polyzyklischen, hyperpigmentierten Plaques mit erythematösem Rand am dorsalen Kopf, Nacken, Rumpf und den medialen Extremitäten vorgestellt; diese Veränderungen hatten sich durch die Behandlung mit Doxycyclin und Niacinamid nicht verbessert. Die Untersuchung beinhaltete ein Blutbild, eine Serumbiochemie, eine Urinanalyse, einen Antinukleären Antikörpertest im Serum, eine histopathologische Untersuchung und einen direkten Immunfluoreszenztest der Hautbiopsien. Das histologische Auftreten einer Lymphozyten-reichen Interface Dermatitis zusammen mit generalisierten chronisch wiederkehrenden hyperpigmentierten Plaques war mit der Diagnose einer generalisierten Variante des DLE im Einklang. Durch die Abwesenheit systemischer Symptomatik und den unergiebigen Labortests konnte ein begleitender systemischer Lupus erythematosus ausgeschlossen werden. Es wurde eine Behandlung mit Dexamethason und Ciclosporin per os eingeleitet. Nach einem Monat wurde das Dexamethason abgesetzt und Ketokonazol per os wurde zum Therapieplan hinzugefügt. Vier Monate später waren Juckreiz und Erythem verschwunden, die meisten Hautveränderungen konnte man nicht mehr ertasten. Im Verlauf der letzten sechs Monate konnte der DLE dieses Patienten mit der kombinierten Verabreichung von Ciclosporin und Ketokonazol alle drei Tage in Remission gehalten werden. Die Kombination von Ciclosporin und Ketokonazol zeigte bei diesem Hund mit generalisiertem DLE sowohl bei der Behandlung der Hautveränderungen wie auch bei Erhaltung in Remission ihre Wirksamkeit.}, number={5}, journal={VETERINARY DERMATOLOGY}, author={Banovic, Frane and Olivry, Thierry and Linder, Keith E.}, year={2014}, month={Oct}, pages={483–E79} }
 @article{banovic_olivry_bazzle_tobias_atlee_zabel_hensel_linder_2014, title={Clinical and Microscopic Characteristics of Canine Toxic Epidermal Necrolysis}, volume={52}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985814537530}, DOI={10.1177/0300985814537530}, abstractNote={Canine toxic epidermal necrosis (TEN), a rare and life-threatening cutaneous drug reaction, traditionally has been described as full-thickness devitalization of the epidermis with minimal dermal inflammation; however, few reports detail the histologic findings. We characterize the clinical features and histologic variations of 3 canine TEN patients. Clinically, irregular erythematous and purpuric macules evolved into widespread and severely painful erosions. The number of eroded mucosae varied; however, periocular and perilabial mucocutaneous junctions frequently were affected. Thirteen of 17 biopsies were evaluated. Apoptosis at multiple epidermal levels was the most common pattern of epidermal necrosis (12/13 biopsies, 92%). In contrast, full-thickness coagulation necrosis was present less often (7/13 biopsies, 52%). Lymphocytic interface dermatitis was the predominant inflammatory pattern, and intraepidermal lymphocytes, along with fewer histiocytes, were present to some degree in all samples along with lymphocytic satellitosis of apoptotic keratinocytes. The sequence of changes points to lymphocyte-mediated keratinocyte apoptosis as an early step in lesion development with subsequent variation in progression to coagulation necrosis among patients. Histopathologic changes overlapped with those reported for erythema multiforme, in contrast to traditional histologic descriptions of canine TEN. A specific algorithm for assessment of drug causality in epidermal necrolysis (ALDEN) was applied for each patient; carprofen was associated with a probable score for causality in 1 dog. Clinicians should be encouraged to take multiple biopsies in TEN suspect cases as nearly 25% of all biopsies lacked epithelium and were not diagnostic.}, number={2}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Banovic, F. and Olivry, T. and Bazzle, L. and Tobias, J. R. and Atlee, B. and Zabel, S. and Hensel, N. and Linder, K. E.}, year={2014}, month={Jun}, pages={321–330} }
 @article{rossi_balakrishnan_linder_messa_breitschwerdt_2014, title={ConcurrentBartonella henselaeinfection in a dog with panniculitis and owner with ulcerated nodular skin lesions}, volume={26}, ISSN={0959-4493}, url={http://dx.doi.org/10.1111/vde.12174}, DOI={10.1111/vde.12174}, abstractNote={Bartonella henselae, a Gram-negative, zoonotic Alphaproteobacteria that infects erythrocytes, endothelial cells and dendritic cells, has previously been implicated as a cause of panniculitis in dogs and a human.An 8-year-old, spayed female Labrador retriever and its 78-year-old male owner living in the same household.When preliminary and advanced testing failed to identify the cause of near-simultaneous-onset dermatological lesions, Bartonella serology, Bartonella Alphaproteobacteria growth medium (BAPGM) enrichment blood culture/PCR and immunohistochemistry were used to test specimens from the dog and owner. Bartonella henselae, genotype San Antonio 2 DNA was amplified and sequenced from the man's BAPGM enrichment blood culture and the dog's panniculitis lesion. The bacterium was visualized by immunohistochemistry in the dog's panniculitis lesion; however, neither the dog nor the owner was B. henselae seroreactive. Antibiotic therapy elicited dermatological improvement in both dog and owner.Bartonella henselae is an emerging zoonotic pathogen that induces granulomatous inflammatory lesions in various tissues of animals, including humans. We conclude that this bacterium had a contributory or causative role in the development of the dermatological lesions in the dog and owner.}, number={1}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Rossi, Michael A. and Balakrishnan, Nandhakumar and Linder, Keith E. and Messa, Jacqueline B. and Breitschwerdt, Edward B.}, year={2014}, month={Oct}, pages={60–e22} }
 @article{bizikova_linder_olivry_2014, title={Fipronil-amitraz-S-methoprene-triggered pemphigus foliaceus in 21 dogs: clinical, histological and immunological characteristics}, volume={25}, ISSN={0959-4493}, url={http://dx.doi.org/10.1111/vde.12117}, DOI={10.1111/vde.12117}, abstractNote={A recently launched topical ectoparasiticide containing fipronil, amitraz and S-methoprene has been associated with the development of an acantholytic pustular dermatitis similar to that of Promeris-triggered pemphigus foliaceus (PF).Our objectives were to describe the clinical, histological and immunological features of this PF-like cutaneous adverse drug reaction.Twenty-one dogs with a probable or definitive diagnosis of PF-like cutaneous adverse drug reaction were identified between May 2012 and February 2013.Histology, direct and indirect immunofluorescence were employed to address the study objectives.Most dogs were middle-aged or older (median, 9 years) and of large size (median, 23 kg). In six dogs (29%), the PF-like lesions remained confined to the site of application, while 15 dogs (71%) exhibited lesions at distant sites. One or two applications of the ectoparasiticide were sufficient to trigger PF-like lesions in seven (33%) and six (29%) dogs, respectively. Systemic signs were reported in nine dogs (43%), all with lesions extending to sites distant from application areas. Tissue-bound antikeratinocyte IgG was detected in the lesional epidermis of eight of 19 (42%) cases by direct immunofluorescence, while serum antikeratinocyte IgG was detected in 10 of 14 (71%) cases by indirect immunofluorescence. Autoantibodies were found to target canine desmocollin-1 in 11 of 14 dogs (79%), but not canine desmoglein-1, by indirect immunofluorescence on transfected cells. These immunological findings were similar in cases with localized and distant disease.This new topical ectoparasiticide containing fipronil, amitraz and S-methoprene is capable of triggering the development of an acantholytic pustular dermatosis that is a clinical, histological and immunological close match for Promeris-triggered PF and naturally occurring autoimmune PF in dogs.}, number={2}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Bizikova, Petra and Linder, Keith E. and Olivry, Thierry}, year={2014}, month={Mar}, pages={103–e30} }
 @article{banovic_olivry_linder_tobias_2014, title={Pathology in Practice}, volume={245}, ISSN={["1943-569X"]}, DOI={10.2460/javma.245.11.1237}, number={11}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Banovic, Frane and Olivry, Thierry and Linder, Keith E. and Tobias, Jeremy R.}, year={2014}, month={Dec}, pages={1237–1239} }
 @article{rowe_mathews_linder_tate_2014, title={The Effect of Photodynamic Therapy on Cisterna Chyli Patency in Rats}, volume={43}, ISSN={["1532-950X"]}, DOI={10.1111/j.1532-950x.2014.12222.x}, abstractNote={Objective To radiographically and histologically evaluate the effects of photodynamic therapy on the cisterna chyli in rats. Study Design Experimental study. Animals Adult male Sprague-Dawley rats (n = 60). Methods Cecal lymph nodes were injected with the photodynamic compound verteporfin. A 690 nm, 500 mW diode laser was then directed at the area of the cisterna chyli for either 0, 1.5, or 3 minutes. Cisterna chyli patency was evaluated using lymphography, and histologic changes were evaluated on postoperative Days 1, 3, 5, 7, and 14. Results Histologically, minimal to marked injury to the cisternal and/or pericisternal tissues was present in all treated rats at all time periods. Radiographically, 8/20 cisternae were occluded in the 1.5-minute treatment group (including 1/4 on Day 1, 2/4 on Day 3, 3/4 on Day 5, 0/4 on Day 7, and 2/4 on Day 14), and 9/20 cisternae were occluded in the 3-minute treatment group (including 0/4 on Day 1, 1/4 on Day 3, 3/4 on Day 5, 3/4 on Day 7, and 2/4 on Day 14). There was minimal to no histologic evidence of tissue injury in control rats. All control cisternae were radiographically open. Conclusions Further investigations into the timing of laser application and light dose, or alternative photodynamic agents are required to limit injury to adjacent tissues and to improve the effectiveness of cisternal photoablation.}, number={6}, journal={VETERINARY SURGERY}, author={Rowe, Eric A. and Mathews, Kyle G. and Linder, Keith E. and Tate, Lloyd P.}, year={2014}, month={Aug}, pages={642–649} }
 @article{banovic_linder_boone_jennings_murphy_2013, title={Cat scratch-induced Pasteurella multocida necrotizing cellulitis in a dog}, volume={24}, ISSN={0959-4493}, url={http://dx.doi.org/10.1111/vde.12038}, DOI={10.1111/vde.12038}, abstractNote={In humans, rapidly developing Pasteurella multocida cellulitis after a cat scratch or bite is a well-known entity that sometimes progresses to necrotizing fasciitis and can be fatal.A 3-year-old female spayed whippet dog developed ecchymosis, swelling and pain within 24 h of being scratched by a cat on the ventral thorax. Over the following days, while being treated only with pain medications, the lesions rapidly progressed into haemorrhagic bullae with expanding skin necrosis. A heavy growth of P. multocida was seen on bacterial cultures, and histological examination showed marked, suppurative panniculitis with necrosis of the epidermis, dermis and panniculus. Special histological stains highlighted a moderate amount of Gram-negative coccobacilli admixed with inflammatory cells. Complete resolution was achieved with surgical debridement, skin grafting and intravenous antibiotic treatment. Positive bacterial culture for P. multocida, in conjunction with the history, clinical findings, histology results and the rapid response to therapy, strongly supports a diagnosis of P. multocida necrotizing cellulitis.Complications of cat bite-associated P. multocida infections in humans are well known. To the authors' knowledge, this is the first documentation of P. multocida necrotizing cellulitis in a dog following a cat scratch wound. This case highlights the rapidity and severity of P. multocida cellulitis, if not recognized and treated early. Veterinarians should include P. multocida in the differential diagnosis of any local wound infection following a cat scratch.}, number={4}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Banovic, Frane and Linder, Keith and Boone, Alison and Jennings, Sam and Murphy, K. Marcia}, year={2013}, month={Jun}, pages={463–e108} }
 @article{balakrishnan_cherry_linder_pierce_sontakke_hegarty_bradley_maggi_breitschwerdt_2013, title={Experimental infection of dogs with Bartonella henselae and Bartonella vinsonii subsp. berkhoffii}, volume={156}, ISSN={0165-2427}, url={http://dx.doi.org/10.1016/j.vetimm.2013.09.007}, DOI={10.1016/j.vetimm.2013.09.007}, abstractNote={The lack of a suitable infection model remains an important obstacle for the pathophysiological understanding of Bartonella spp. The following pilot study was designed to determine whether cell culture-grown Bartonella henselae SA2 and Bartonella vinsonii subsp. berkhoffii genotype III would cause persistent bacteremia in dogs. Pre-inoculation screening established that two laboratory-raised Golden retrievers were naturally-infected with Bartonella koehlerae. Despite prior infection, one dog each was inoculated subcutaneously with 5 × 10(4)B. henselae (SA2 strain) or 3 × 10(4)B. vinsonii subsp. berkhoffii genotype III. Dogs were bled weekly for serological testing and culture using Bartonella alpha proteobacteria growth medium (BAPGM) diagnostic platform. Dog 1 seroconverted to B. henselae and Dog 2 seroconverted to B. vinsonii subsp. berkhoffii genotype III. Throughout the study period, Bartonella spp. DNA was neither amplified nor isolated in ante-mortem BAPGM enrichment blood cultures. B. henselae SA2 was isolated from a postmortem bone marrow from Dog 1 and B. koehlerae DNA was amplified from postmortem lung from Dog 2 following BAPGM enrichment culture. Limitations include lack of uninfected controls, a potentially suboptimal B. vinsonii subsp. berkhoffii inoculum and a relatively short duration of study. We conclude that following intradermal infection, sequestration of Bartonella spp. in tissues may limit diagnostic detection of these bacteria in dog blood samples.}, number={1-2}, journal={Veterinary Immunology and Immunopathology}, publisher={Elsevier BV}, author={Balakrishnan, Nandhakumar and Cherry, Natalie A. and Linder, Keith E. and Pierce, Eric and Sontakke, Neal and Hegarty, Barbara C. and Bradley, Julie M. and Maggi, Ricardo G. and Breitschwerdt, Edward B.}, year={2013}, month={Nov}, pages={153–158} }
 @article{breitschwerdt_linder_day_maggi_chomel_kempf_2013, title={Koch's Postulates and the Pathogenesis of Comparative Infectious Disease Causation Associated with Bartonella species}, volume={148}, ISSN={0021-9975}, url={http://dx.doi.org/10.1016/j.jcpa.2012.12.003}, DOI={10.1016/j.jcpa.2012.12.003}, abstractNote={In his homage to Lucretius (‘Georgica’), Vergil is credited with stating: ‘Felix qui potuit rerum cognoscere causas’ (‘Fortunate is he who knows the causes of things’). Based on numerous commentaries and publications it is obvious that clinicians, diagnosticians and biomedical research scientists continue to struggle with disease causation, particularly in the assessment of the pathogenic role of ‘stealth pathogens’ that produce persistent infections in the host. Bartonella species, because of their evolutionary ability to induce persistent intravascular infections, present substantial challenges for researchers attempting to clarify the ability of these stealth bacteria to cause disease. By studying the comparative biological and pathological behaviour of microbes across mammalian genera, researchers might be able more rapidly to advance medical science and, subsequently, patient care by undertaking focused research efforts involving a single mammalian species or by attempting to recapitulate a complex disease in an rodent model. Therefore, in an effort to further assist in the establishment of disease causation by stealth pathogens, we use recent research observations involving the genus Bartonella to propose an additional postulate of comparative infectious disease causation to Koch's postulates.}, number={2-3}, journal={Journal of Comparative Pathology}, publisher={Elsevier BV}, author={Breitschwerdt, E.B. and Linder, K.L. and Day, M.J. and Maggi, R.G. and Chomel, B.B. and Kempf, V.A.J.}, year={2013}, month={Feb}, pages={115–125} }
 @article{banovic_olivry_linder_tobias_2013, title={Lichenoid psoriasifrom dermatitis}, volume={245}, number={11}, journal={Journal of the American Veterinary Medical Association}, author={Banovic, F and Olivry, T and Linder, KE and Tobias, JR}, year={2013}, pages={1237–1239} }
 @article{asakawa_cullen_linder_2013, title={Necrolytic migratory erythema associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat}, volume={24}, ISSN={["0959-4493"]}, DOI={10.1111/vde.12041}, abstractNote={In humans, necrolytic migratory erythema (NME) is a syndrome with a characteristic skin rash that is associated most often with a pancreatic glucagonoma and is recognized as part of the glucagonoma syndrome. In veterinary medicine, NME (also called as superficial necrolytic dermatitis, hepatocutaneous syndrome or metabolic epidermal necrosis) has been described in dogs in association with chronic liver diseases or, less frequently, glucagonoma, but NME associated with glucagonoma has not previously been reported in cats. A 6-year-old male neutered domestic short hair cat was diagnosed with NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma (hepatic carcinoid). The cat presented with a 2 week history of vomiting and anorexia, and a 5-cm-diameter liver mass was detected by abdominal ultrasound. The cat exhibited general weakness, crusted skin lesions and pain in all four limbs. It was euthanized 11 months after the initial presentation. Histopathological review of the paw pads revealed the classic ‘red, white and blue’ lesion composed of parakeratotic hyperkeratosis, epidermal hydropic change and hyperbasophilia of the deep epidermis. The liver mass was diagnosed as a neuroendocrine carcinoma (hepatic carcinoid). Neoplastic cells were strongly immunoreactive for glucagon. This is the first case report of NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat. Chez l'homme, l'érythème nécrolytique migrant (ENM) est un syndrome avec un rash cutané caractéristique associé le plus souvent à un glucagonome pancréatique et est reconnu comme une composante du syndrome du glucagonome. En médecine vétérinaire, l'ENM (aussi appelé dermatite nécrolytique superficielle, syndrome hépato-cutané ou nécrose épidermique métabolique) a été décrit chez le chien en association à des maladies hépatiques chroniques ou moins souvent, à un glucagonome. L'ENM associé à un glucagonome n'a pas été précédemment rapporté chez le chat. Un chat européen mâle castré de 6 ans a été diagnostiqué avec un ENM associé à un carcinome neuro-endocrine hépatique primaire produisant du glucagon (carcinoïde hépatique). Le chat présentait des vomissements et de la diarrhée depuis 2 semaines et une masse hépatique de 5 cm de diamètre a été détectée par échographie abdominale. Le chat présentait une faiblesse générale, des lésions cutanées croûteuses et de la douleur des quatre membres. Il a été euthanasié 11 mois après l'apparition des premières lésions. L'examen histopathologique des coussinets a mis en évidence les lésions classiques « bleu-blanc-rouge » composées d'hyperkératose parakératosique, de dégénérescence hydropique épidermique et d'hyperbasophilie de l'épiderme profond. La masse hépatique a été diagnostiquée comme un carcinome neuroendocrine (carcinoïde hépatique). Les cellules néoplasiques étaient fortement immunoréactives pour le glucagon. Ceci est le premier cas clinique chez un chat d'ENM associé à un carcinome neuro-endocrine hépatique primaire sécrétant du glucagon. en seres humanos, el eritema migratorio necrolítico (NME) es un síndrome con característica erupción cutánea, que se asocia comúnmente con la presencia de un glucagonoma pancreático y se reconoce como parte del síndrome glucagonoma. En medicina veterinaria, NME (también llamado dermatitis necrolítica superficial, síndrome hepatocutáneo o necrosis epidermal metabólica) ha sido descrito en perros en asociación con enfermedades crónicas del hígado, y con menor frecuencia, glucagonoma, pero NME asociado a glucagonoma no ha sido descrito en gatos. un gato de raza domestica de pelo corto, macho de seis años de edad fue diagnosticado con NME asociada con un carcinoma primario neuroendocrino hepático productor de glucagón (carcinoide hepático). El gato se presentó con historia de dos semanas con vómito y anorexia, y una masa de cinco centímetros de diámetro se observó en el hígado mediante ultrasonido del abdomen. El gato presentaba debilidad generalizada, lesiones costrosas en la piel y dolor en las cuatro extremidades. Fue sacrificado 11 meses tras la presentación inicial. El examen histopatológico de las almohadillas plantares reveló las lesiones en patrón clásico ‘rojo, blanco y azul’ compuestas de hiperqueratosis paraqueratótica, degeneración hidrópica de la epidermis e hiperbasofilia de la dermis profunda. El tumor del hígado fue diagnosticado como un carcinoma neuroendocrino (carcinoide hepático). Las células neoplásicas fueron altamente positivas para glucagón. este es el primer caso clínico publicado de NME asociado con un carcinoma neuroendocrino primario del hígado productor de glucagón. En un gato. Beim Menschen ist das Erythema necrolyticum migrans (NME) ein Syndrom mit einem charakteristischen Hautausschlag, der am häufigsten mit einem pankreatischen Glukagonom im Zusammenhang steht und einen Teil des Glukagonom Syndroms darstellt. In der Veterinärmedizin ist NME (auch superfizielle nekrolytische Dermatitis, hepatokutanes Syndrom oder metabolische epidermale Nekrose) bei Hunden in Zusammenhang mit chronischen Lebererkrankungen oder, weniger häufig, Glukagonomen beschrieben worden, aber ein NME, vergesellschaftet mit einem Glukagonom ist bisher bei der Katze nicht beschrieben worden. Ein 6 Jahre alter kastrierter Europäisch Kurzhaar Kater wurde mit NME und einem Glukagon-produzierenden primären neuroendokrinen Leberzellkarzinom (Leberkarzinoid) diagnostiziert. Die Katze wurde mit einer 2 wöchigen Anamnese von Vomitus und Anorexie und einer Lebermasse von 5-cm im Durchmesser, welche mittels Abdominalultraschall festgestellt wurde, vorgestellt. Die Katze zeigte eine allgemeine Schwäche, krustige Hautveränderungen und Schmerzen an allen vier Extremitäten. Das Tier wurde 11 Monate nach der Erstvorstellung eingeschläfert. Eine histopathologische Review der Fussballen zeigte eine klassische „rot-weiß-blaue” Veränderung, die aus parakeratotischer Hyperkeratose, epidermalen hydropischen Veränderungen und Hyperbasophilie der tiefen Epidermis bestand. Die Umfangsvermehrung in der Leber wurde als neuroendokrines Karzinom (hepatisches Karzinoid) beurteilt. Die neoplastischen Zellen zeigten eine heftige Immunreaktion auf Glukagon. Es handelt sich hierbei um den ersten Fallbericht einer NME im Zusammenhang mit einem Glukagon-produzierenden primären neuroendokrinen Leberkarzinom bei der Katze. 1}, number={4}, journal={VETERINARY DERMATOLOGY}, author={Asakawa, Midori G. and Cullen, John M. and Linder, Keith E.}, year={2013}, month={Aug}, pages={466–E110} }
 @article{jennings_wise_nickeleit_maes_cianciolo_piero_law_kim_mccalla_breuhaus_et al._2013, title={Polyomavirus-Associated Nephritis in 2 Horses}, volume={50}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985813476063}, DOI={10.1177/0300985813476063}, abstractNote={Polyomaviruses produce latent and asymptomatic infections in many species, but productive and lytic infections are rare. In immunocompromised humans, polyomaviruses can cause tubulointerstitial nephritis, demyelination, or meningoencephalitis in the central nervous system and interstitial pneumonia. This report describes 2 Standardbred horses with tubular necrosis and tubulointerstitial nephritis associated with productive equine polyomavirus infection that resembles BK polyomavirus nephropathy in immunocompromised humans.}, number={5}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Jennings, S. H. and Wise, A. G. and Nickeleit, V. and Maes, R. K. and Cianciolo, R. E. and Piero, F. Del and Law, J. M. and Kim, Y. and McCalla, A. C. and Breuhaus, B. A. and et al.}, year={2013}, month={Feb}, pages={769–774} }
 @article{boswell_fogle_linder_copple_2013, title={What Is Your Diagnosis?}, volume={242}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.242.3.311}, DOI={10.2460/javma.242.3.311}, number={3}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Boswell, Stacie G. and Fogle, Callie A. and Linder, Keith and Copple, Christina N.}, year={2013}, month={Feb}, pages={311–313} }
 @article{stowe_anderson_guy_linder_grindem_2012, title={A Case of Enzootic Nasal Adenocarcinoma in a Ewe}, volume={2012}, ISSN={2090-7001 2090-701X}, url={http://dx.doi.org/10.1155/2012/347193}, DOI={10.1155/2012/347193}, abstractNote={An approximately 2-year-old open Suffolk ewe presented to the North Carolina State University College of Veterinary Medicine Veterinary Health Complex for evaluation of a left nasal mass. An ultrasound-guided aspirate and core biopsies were performed. An epithelial neoplasia with mild mixed inflammation (neutrophils and plasma cells) was diagnosed on cytology and confirmed on histopathology. Immunohistochemistry (IHC), reverse transcriptase polymerase chain reaction (RT-PCR), and transmission electron microscopy were also performed. IHC and RT-PCR identified the presence of enzootic nasal tumor virus and confirmed the final diagnosis of enzootic nasal adenocarcinoma.}, journal={Case Reports in Veterinary Medicine}, publisher={Hindawi Limited}, author={Stowe, Devorah Marks and Anderson, Kevin L. and Guy, James S. and Linder, Keith E. and Grindem, Carol B.}, year={2012}, pages={1–4} }
 @article{beerlage_varanat_linder_maggi_cooley_kempf_breitschwerdt_2012, title={Bartonella vinsonii subsp. berkhoffii and Bartonella henselae as potential causes of proliferative vascular diseases in animals}, volume={201}, ISSN={0300-8584 1432-1831}, url={http://dx.doi.org/10.1007/s00430-012-0234-5}, DOI={10.1007/s00430-012-0234-5}, number={3}, journal={Medical Microbiology and Immunology}, publisher={Springer Science and Business Media LLC}, author={Beerlage, Christiane and Varanat, Mrudula and Linder, Keith and Maggi, Ricardo G. and Cooley, Jim and Kempf, Volkhard A. J. and Breitschwerdt, Edward B.}, year={2012}, month={Mar}, pages={319–326} }
 @article{olivry_linder_2012, title={Bilaterally Symmetrical Alopecia With Reticulated Hyperpigmentation}, volume={50}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985812463406}, DOI={10.1177/0300985812463406}, abstractNote={An adult castrated male Doberman Pinscher was presented with a 6-month history of well-demarcated alopecic patches with reticulated hyperpigmentation and fine peripheral scaling on the axillae, thorax, abdomen, inguinal region, and thighs. The dog later developed hyperthermia, lethargy, apparent joint pain, peripheral lymphadenomegaly, vomiting, and diarrhea. Relevant laboratory tests results included anemia, thrombocytopenia, proteinuria, and an elevated antinuclear antibodies serum titer. Histologically, skin biopsy specimens had a lymphocyte-rich interface dermatitis and interface mural folliculitis ending in follicular destruction. Altogether, these signs were consistent with a unique alopecic variant of chronic cutaneous lupus erythematosus, eventually associated with the development of systemic lupus erythematosus. This rare form of chronic cutaneous lupus needs to be added to the expanding list of lymphocyte-mediated autoimmune alopecias in dogs.}, number={4}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Olivry, T. and Linder, K. E.}, year={2012}, month={Oct}, pages={682–685} }
 @article{schramme_josson_linder_2012, title={Characterization of the origin and body of the normal equine rear suspensory ligament using ultrasonography, magnetic resonance imaging, and histology}, volume={53}, ISSN={1058-8183}, url={http://dx.doi.org/10.1111/j.1740-8261.2011.01922.x}, DOI={10.1111/j.1740-8261.2011.01922.x}, abstractNote={The suspensory ligament is difficult to image accurately, partly because it contains ligamentous fibers, as well as noncollagenous adipose and muscle tissue in the normal horse. Our hypothesis was that magnetic resonance (MR) imaging would be more accurate than ultrasonography in identifying the size of the suspensory ligament and the presence and size of noncollagenous tissues within the ligament. Eleven horses were used for ultrasonographic and MR imaging and histologic evaluation of the rear suspensory ligament. The origin and body of the normal suspensory ligament had a heterogenous appearance on MR images with two separate islands of mixed signal intensity evident throughout its otherwise hypointense cross-sectional area. Histologically, there were isolated islands of muscle, adipose, loose connective tissue and dense collagenous partitions, organized in two separate bundles that extended through the full length of the suspensory ligament origin and body to the level of its bifurcation. Comparison of MR images with corresponding histologic sections confirmed that islands of heterogenous signal intensity in normal suspensory ligaments correlated well with these bundles. Using ultrasonography, it was impossible to distinguish these islands from surrounding dense collagenous tissue consistently. MR imaging determined the cross-sectional area of the suspensory ligament more accurately than ultrasonography. Based upon these results, MR imaging is superior to ultrasonography for assessment of the suspensory ligament. The appearance associated with normal ligament anatomy needs to be understood before MR signal variation can be considered as indicative of disease in the suspensory ligament.}, number={3}, journal={Veterinary Radiology & Ultrasound}, publisher={Wiley}, author={Schramme, Michael and Josson, Anne and Linder, Keith}, year={2012}, month={Feb}, pages={318–328} }
 @article{olivry_linder_wang_bizikova_bernstein_dunston_paps_casal_2012, title={Deficient Plakophilin-1 Expression Due to a Mutation in PKP1 Causes Ectodermal Dysplasia-Skin Fragility Syndrome in Chesapeake Bay Retriever Dogs}, volume={7}, ISSN={1932-6203}, url={http://dx.doi.org/10.1371/journal.pone.0032072}, DOI={10.1371/journal.pone.0032072}, abstractNote={In humans, congenital and hereditary skin diseases associated with epidermal cell-cell separation (acantholysis) are very rare, and spontaneous animal models of these diseases are exceptional. Our objectives are to report a novel congenital acantholytic dermatosis that developed in Chesapeake Bay retriever dogs. Nine affected puppies in four different litters were born to eight closely related clinically normal dogs. The disease transmission was consistent with an autosomal recessive mode of inheritance. Clinical signs occurred immediately after birth with superficial epidermal layers sloughing upon pressure. At three month of age, dogs exhibited recurrent superficial skin sloughing and erosions at areas of friction and mucocutaneous junctions; their coat was also finer than normal and there were patches of partial hair loss. At birth, histopathology revealed severe suprabasal acantholysis, which became less severe with ageing. Electron microscopy demonstrated a reduced number of partially formed desmosomes with detached and aggregated keratin intermediate filaments. Immunostaining for desmosomal adhesion molecules revealed a complete lack of staining for plakophilin-1 and anomalies in the distribution of desmoplakin and keratins 10 and 14. Sequencing revealed a homozygous splice donor site mutation within the first intron of PKP1 resulting in a premature stop codon, thereby explaining the inability to detect plakophilin-1 in the skin. Altogether, the clinical and pathological findings, along with the PKP1 mutation, were consistent with the diagnosis of ectodermal dysplasia-skin fragility syndrome with plakophilin-1 deficiency. This is the first occurrence of ectodermal dysplasia-skin fragility syndrome in an animal species. Controlled mating of carrier dogs would yield puppies that could, in theory, be tested for gene therapy of this rare but severe skin disease of children.}, number={2}, journal={PLoS ONE}, publisher={Public Library of Science (PLoS)}, author={Olivry, Thierry and Linder, Keith E. and Wang, Ping and Bizikova, Petra and Bernstein, Joseph A. and Dunston, Stanley M. and Paps, Judy S. and Casal, Margret L.}, editor={Brandner, Johanna M.Editor}, year={2012}, month={Feb}, pages={e32072} }
 @article{varanat_maggi_linder_breitschwerdt_2012, title={Infection of human brain vascular pericytes (HBVPs) by Bartonella henselae}, volume={202}, ISSN={0300-8584 1432-1831}, url={http://dx.doi.org/10.1007/s00430-012-0279-5}, DOI={10.1007/s00430-012-0279-5}, number={2}, journal={Medical Microbiology and Immunology}, publisher={Springer Science and Business Media LLC}, author={Varanat, Mrudula and Maggi, Ricardo G. and Linder, Keith E. and Breitschwerdt, Edward B.}, year={2012}, month={Nov}, pages={143–151} }
 @article{monteiro-riviere_linder_inman_saathoff_xia_riviere_2012, title={LACK OF HYDROXYLATED FULLERENE TOXICITY AFTER INTRAVENOUS ADMINISTRATION TO FEMALE SPRAGUE-DAWLEY RATS}, volume={75}, ISSN={["1087-2620"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000303594100001&KeyUID=WOS:000303594100001}, DOI={10.1080/15287394.2012.670894}, abstractNote={Hydroxylated fullerenes (C60OHx) or fullerols are water-soluble carbon nanoparticles that have been explored for potential therapeutic applications. This study assesses acute in vivo tolerance in 8-wk-old female Sprague-Dawley rats to intravenous (iv) administration of 10 mg/kg of well-characterized C60(OH)30. Complete histopathology and clinical chemistries are assessed at 8, 24, and 48 h after dosing. Minor histopathology changes are seen, primarily in one animal. No clinically significant chemistry changes were observed after treatment. These experiments suggest that this fullerol was well tolerated after iv administration to rats.}, number={7}, journal={JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES}, author={Monteiro-Riviere, Nancy A. and Linder, Keith E. and Inman, Alfred O. and Saathoff, John G. and Xia, Xin-Rui and Riviere, Jim E.}, year={2012}, pages={367–373} }
 @article{urkasemsin_linder_bell_lahunta_olby_2012, title={Mapping of Purkinje Neuron Loss and Polyglucosan Body Accumulation in Hereditary Cerebellar Degeneration in Scottish Terriers}, volume={49}, ISSN={["1544-2217"]}, DOI={10.1177/0300985811412622}, abstractNote={A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid-Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P = .0104). The degeneration was significantly more pronounced dorsally than ventrally (P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half (P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs (P = .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non-membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.}, number={5}, journal={VETERINARY PATHOLOGY}, author={Urkasemsin, G. and Linder, K. E. and Bell, J. S. and Lahunta, A. and Olby, N. J.}, year={2012}, month={Sep}, pages={852–859} }
 @article{stevens_linder_2012, title={Pathology in Practice}, volume={241}, ISSN={["1943-569X"]}, DOI={10.2460/javma.241.5.567}, number={5}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Stevens, Brenda J. and Linder, Keith E.}, year={2012}, month={Sep}, pages={567–569} }
 @article{stevens_linder_2012, title={Proliferative and necrotizing otitis externa}, volume={241}, number={5}, journal={Journal of the American Veterinary Medical Association}, author={Stevens, BJ and Linder, KE}, year={2012}, month={Sep}, pages={567–569} }
 @article{oberkirchner_linder_olivry_2012, title={Successful treatment of a novel generalized variant of canine discoid lupus erythematosus with oral hydroxychloroquine}, volume={23}, ISSN={["0959-4493"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84855339558&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2011.00994.x}, abstractNote={Discoid lupus erythematosus (DLE) is a common canine autoimmune disease that usually manifests as a localized ulcerative and scarring nasal dermatitis. We report herein a generalized variant of canine DLE successfully treated with the antimalarial immunomodulator hydroxychloroquine (HCQ). A 9-year-old hairless Chinese crested dog was presented with annular and polycyclic hyperpigmented and scaly skin lesions with central erosions, hypopigmentation and/or scarring on the trunk, neck and lateral extremities. Associated systemic signs were not seen. The clinical diagnosis of generalized DLE was supported by the demonstration of lymphocyte-rich interface dermatitis with epidermal atrophy and dermo-epidermal deposition of immunoglobulins and activated complement. As for human DLE, treatment was initiated with HCQ at 5 mg/kg once daily along with 2 weeks of 0.1% tacrolimus ointment and restriction of sun exposure. Over the following year, complete remission was maintained with HCQ at 5 mg/kg orally once daily with the exception of three relapses; two occurred during treatment induction and the third arose when the frequency of HCQ administration was reduced to every other day. Disease flares were controlled with 0.1% tacrolimus ointment alternating with 0.1% prednicarbate cream once daily for 5-10 days. Altogether, adverse drug events were not seen with this regimen. In summary, clinically, histologically and immunologically, this dog's disease mirrored the generalized discoid variant of chronic cutaneous lupus erythematosus of humans. The apparent benefit of HCQ, its safety and low cost warrant future investigations of its use for treatment of canine cutaneous lupus variants.}, number={1}, journal={VETERINARY DERMATOLOGY}, author={Oberkirchner, Ursula and Linder, Keith E. and Olivry, Thierry}, year={2012}, month={Feb}, pages={65–E16} }
 @article{chanoit_mathews_keene_small_linder_2012, title={Surgical treatment of a pulmonary artery vascular hamartoma in a dog}, volume={240}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.240.7.858}, DOI={10.2460/javma.240.7.858}, abstractNote={Abstract Case Description —A 6-year-old Siberian Husky–mix dog was examined for episodes of collapse. Clinical Findings —Physical examination, echocardiography, abdominal ultrasonography, ECG, and thoracic computed tomography with contrast were performed and revealed a 2.5 × 2.3 × 2.0-cm mass over the pulmonic valve leaflets, resulting in moderate pulmonic stenosis. Other abnormal findings included systemic hypertension, right bundle branch block, proteinuria, and a urinary bladder mass. Treatment and Outcome —Pulmonary arteriotomy was performed under inflow occlusion, and the mass was resected with transesophageal echocardiographic guidance and direct visualization. Results of histologic examination of the mass revealed a vascular hamartoma. Sequential follow-up examinations and telephone contacts (at 0.5, 5, and 15 months after surgery) revealed that the patient had been free from episodes of collapse since surgery. No regrowth of the mass was noted on follow-up echocardiograms, and the pulmonic stenosis had resolved, although mild to moderate pulmonary insufficiency later developed. The bladder mass was excised 15 months after the first surgery when hematuria developed, and results of histologic examination of this mass revealed a vascular hamartoma. The dog was eventually euthanized 31 months after the initial surgery for reasons that could not be directly linked to any recurrence of the pulmonary artery mass. Clinical Relevance —Hamartomas are benign tumors that can be located in various tissues, including large arteries. Computed tomography was helpful in predicting the resectability of the intracardiac mass in this dog. Treatment with arteriotomy under inflow occlusion and mild hypothermia resulted in a favorable outcome.}, number={7}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={Chanoit, Guillaume and Mathews, Kyle G. and Keene, Bruce W. and Small, Merrilee T. and Linder, Keith}, year={2012}, month={Apr}, pages={858–862} }
 @article{thrall_maccarini_stauffer_macfall_hauck_snyder_case_linder_lan_mccall_et al._2012, title={Thermal dose fractionation affects tumour physiological response}, volume={28}, ISSN={["0265-6736"]}, DOI={10.3109/02656736.2012.689087}, abstractNote={Purpose: It is unknown whether a thermal dose should be administered using a few large fractions with higher temperatures or a larger number of fractions with lower temperatures. To evaluate this we assessed the effect of administering the same total thermal dose, approximately 30 CEM43T90, in one versus three to four fractions per week, over 5 weeks.Materials and methods: Canine sarcomas were randomised to receive one of the hyperthermia fractionation schemes along with fractionated radiotherapy. Tumour response was based on changes in tumour volume, oxygenation, water diffusion quantified using MRI, and a panel of histological and immunohistochemical end points.Results: There was a greater reduction in tumour volume and water diffusion at the end of therapy in tumours receiving one hyperthermia fraction per week. There was a weak but significant association between improved tumour oxygenation 24 h after the first hyperthermia treatment and extent of volume reduction at the end of therapy. Finally, the direction of change of HIF-1α and CA-IX immunoreactivity after the first hyperthermia fraction was similar and there was an inverse relationship between temperature and the direction of change of CA-IX. There were no significant changes in interstitial fluid pressure, VEGF, vWF, apoptosis or necrosis as a function of treatment group or temperature.Conclusions: We did not identify an advantage to a three to four per week hyperthermia prescription, and response data pointed to a one per week prescription being superior.}, number={5}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={Thrall, Donald E. and Maccarini, Paolo and Stauffer, Paul and Macfall, James and Hauck, Marlene and Snyder, Stacey and Case, Beth and Linder, Keith and Lan, Lan and Mccall, Linda and et al.}, year={2012}, pages={431–440} }
 @article{wood_breitschwerdt_nordone_linder_gookin_2012, title={Uropathogenic E. coli Promote a Paracellular Urothelial Barrier Defect Characterized by Altered Tight Junction Integrity, Epithelial Cell Sloughing and Cytokine Release}, volume={147}, ISSN={0021-9975}, url={http://dx.doi.org/10.1016/j.jcpa.2011.09.005}, DOI={10.1016/j.jcpa.2011.09.005}, abstractNote={The urinary bladder is a common site of bacterial infection with a majority of cases attributed to uropathogenic Escherichia coli. Sequelae of urinary tract infections (UTIs) include the loss of urothelial barrier function and subsequent clinical morbidity secondary to the permeation of urine potassium, urea and ammonia into the subepithelium. To date there has been limited research describing the mechanism by which this urothelial permeability defect develops. The present study models acute uropathogenic E. coli infection in vitro using intact canine bladder mucosa mounted in Ussing chambers to determine whether infection induces primarily a transcellular or paracellular permeability defect. The Ussing chamber sustains tissue viability while physically separating submucosal and lumen influences, so this model is ideal for quantitative measurement of transepithelial electrical resistance (TER) to assess alterations of urothelial barrier function. Using this model, changes in both tissue ultrastructure and TER indicated that uropathogenic E. coli infection promotes a paracellular permeability defect associated with the failure of umbrella cell tight junction formation and umbrella cell sloughing. In addition, bacterial interaction with the urothelium promoted secretion of cytokines from the urinary bladder with bioactivity capable of modulating epithelial barrier function including tumour necrosis factor-α, interleukin (IL)-6 and IL-15. IL-15 secretion by the infected bladder mucosa is a novel finding and, because IL-15 plays key roles in reconstitution of tight junction function in damaged intestine, this study points to a potential role for IL-15 in UTI-induced urothelial injury.}, number={1}, journal={Journal of Comparative Pathology}, publisher={Elsevier BV}, author={Wood, M.W. and Breitschwerdt, E.B. and Nordone, S.K. and Linder, K.E. and Gookin, J.L.}, year={2012}, month={Jul}, pages={11–19} }
 @article{stringer_de voe_linder_troan_mccalla-martin_loomis_2012, title={VESICULOBULLOUS SKIN REACTION TEMPORALLY RELATED TO FIROCOXIB TREATMENT IN A WHITE RHINOCEROS (CERATOTHERIUM SIMUM)}, volume={43}, ISSN={["1042-7260"]}, DOI={10.1638/2011-0128.1}, abstractNote={A 40 yr-old female white rhinoceros (Ceratotherium simum) suffered from chronic nail-bed abscesses. Due to worsening of clinical signs, the animal's nonsteroidal anti-inflammatory treatment was switched to firocoxib. Approximately 7 days after this change, the animal developed multifocal vesicles and bullae along the lateral aspects of the thorax and abdomen, the dorsum, and the proximal limbs. Cytology and culture did not identify an infectious etiology. Histologically, the lesions consisted of a severe, subacute vesiculobullous dermatitis with intraepidermal to subepidermal clefting with areas of individual keratinocyte necrosis and minor neutrophilic epidermal infiltrates. These findings are similar to those seen in some drug reactions in people; therefore an adverse drug reaction to the firocoxib was suspected.}, number={1}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Stringer, Elizabeth M. and De Voe, Ryan S. and Linder, Keith and Troan, Brigid and McCalla-Martin, Amy and Loomis, Michael R.}, year={2012}, month={Mar}, pages={186–189} }
 @article{olivry_linder_paps_bizikova_dunston_donne_mondoulet_2012, title={Validation of a novel epicutaneous delivery system for patch testing of house dust mite-hypersensitive dogs}, volume={23}, number={6}, journal={Veterinary Dermatology}, author={Olivry, T. and Linder, K. E. and Paps, J. S. and Bizikova, P. and Dunston, S. and Donne, N. and Mondoulet, L.}, year={2012} }
 @article{foster_chinnadurai_nutt_pandiri_linder_alley_smith_2011, title={Congenital peritoneopericardial diaphragmatic hernia in an alpaca}, volume={89}, ISSN={0005-0423}, url={http://dx.doi.org/10.1111/j.1751-0813.2010.00661.x}, DOI={10.1111/j.1751-0813.2010.00661.x}, abstractNote={An adult alpaca was presented because of abdominal pain and was diagnosed with an intestinal obstruction. The putative diagnosis at surgery was an intestinal obstruction caused by peritonitis and intra-abdominal adhesions. The cause of the inflammation was not determined at that time. The alpaca died soon after surgery from post-surgical complications and a peritoneopericardial diaphragmatic hernia that was not diagnosed until necropsy.}, number={1-2}, journal={Australian Veterinary Journal}, publisher={Wiley}, author={Foster, DM and Chinnadurai, SK and Nutt, JN and Pandiri, A and Linder, KE and Alley, ML and Smith, GW}, year={2011}, month={Jan}, pages={51–54} }
 @article{snyder_linder_hedan_hauck_2011, title={Establishment and Characterization of a Canine Soft Tissue Sarcoma Cell Line}, volume={48}, ISSN={["1544-2217"]}, DOI={10.1177/0300985810383871}, abstractNote={Stringently controlled in vitro experiments are a necessary part of translational research. Cell lines are useful for exploring the underlying biology of cancer. Very few canine soft tissue sarcoma cell lines exist. This report describes the establishment of a new canine soft tissue sarcoma cell line (MBSa1) derived from a high-grade, metastatic neurofibrosarcoma. The primary tumor tissue was obtained from a 12-year-old neutered male German Shepherd Dog and was maintained in tissue culture for a minimum of 20 passages over 7 months. MBSa1 was injected into athymic mice to determine tumorigenicity. Five million cells were injected into the subcutis of the right flank of athymic nude mice. Nine of the 10 mice grew tumors 1 cm or larger within 8 weeks of cell injection. The large number of in vitro passages coupled with solid tumor formation in athymic nude mice demonstrates that MBSa1 has been immortalized and is tumorigenic.}, number={2}, journal={VETERINARY PATHOLOGY}, author={Snyder, S. A. and Linder, K. and Hedan, B. and Hauck, M. L.}, year={2011}, month={Mar}, pages={482–485} }
 @article{varanat_broadhurst_linder_maggi_breitschwerdt_2011, title={Identification of Bartonella henselae in 2 Cats With Pyogranulomatous Myocarditis and Diaphragmatic Myositis}, volume={49}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985811404709}, DOI={10.1177/0300985811404709}, abstractNote={Most cats infected with Bartonella henselae remain outwardly healthy carriers for years; however, self-limiting fever, transient anemia, neurologic dysfunction, lymphadenopathy, reproductive disorders, aortic valvular endocarditis, and neutrophilic myocarditis have been described in experimentally or naturally infected cats. Two cats in a North Carolina shelter died with pyogranulomatous myocarditis and diaphragmatic myositis. Bacteria were visualized in the lesions by Warthin-Starry silver impregnation and by B. henselae immunohistochemistry. B. henselae DNA was amplified and sequenced from the heart of 1 cat and from multiple tissue samples, including heart and diaphragm, from the second cat. This study supports a potential association between B. henselae and what has been historically described as “transmissible myocarditis and diaphragmitis” of undetermined cause in cats.}, number={4}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Varanat, M. and Broadhurst, J. and Linder, K. E. and Maggi, R. G. and Breitschwerdt, E. B.}, year={2011}, month={Apr}, pages={608–611} }
 @article{bizikova_linder_olivry_2011, title={Immunomapping of desmosomal and nondesmosomal adhesion molecules in healthy canine footpad, haired skin and buccal mucosal epithelia: comparison with canine pemphigus foliaceus serum immunoglobulin G staining patterns}, volume={22}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79952335927&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2010.00924.x}, abstractNote={Pemphigus foliaceus (PF) is the most common canine autoimmune skin disease. In contrast to human PF (hPF), desmoglein-1 is a minor autoantigen in the canine disease. The major autoantigen(s) of canine PF (cPF) remain(s) unknown, which limits the ability to perform mechanistic studies of lesion formation and the development of novel diagnostic and therapeutic strategies for this disease. The immunofluorescence patterns of selected desmosomal (desmoglein-1, desmoglein-3, desmocollin-1, desmocollin-3, desmoplakin-1/2, plakoglobin and plakophilin-1) and nondesmosomal adhesion proteins (E-cadherin, claudin-1, zona occludens-1 and occludin) in healthy canine footpad, haired skin and buccal mucosal epithelia were determined using hPF and pemphigus vulgaris sera and specific antibodies. The immunostaining patterns were then compared with that of indirect immunofluorescence staining with 66 cPF sera. Most cPF sera (58 of 66; 88%) exhibited positive staining along keratinocyte margins in the stratum spinosum and stratum granulosum of canine footpad. One serum contained autoantibodies binding solely to stratum granulosum keratinocytes. Concurrent intercellular fluorescence in the stratum basale was limited to seven of 66 cPF sera (11%). Only 12 of 66 cPF sera (18%) also exhibited positive IF staining of the buccal mucosa. This study confirms the immunological heterogeneity of cPF immunoglobulin G autoantibodies. Moreover, the major indirect immunofluorescence staining pattern and the inability of most cPF sera to label the buccal mucosa closely matched that of desmocollin-1. These observations warrant further investigation of desmocollin-1 as a potential major cPF autoantigen.}, number={2}, journal={VETERINARY DERMATOLOGY}, author={Bizikova, Petra and Linder, Keith E. and Olivry, Thierry}, year={2011}, month={Apr}, pages={132–142} }
 @article{oberkirchner_linder_dunston_bizikova_olivry_2011, title={Metaflumizone-amitraz (Promeris)-associated pustular acantholytic dermatitis in 22 dogs: evidence suggests contact drug-triggered pemphigus foliaceus}, volume={22}, ISSN={["0959-4493"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-80052525616&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2011.00974.x}, abstractNote={Promeris Duo (PD) is a novel topical flea and tick preventative for dogs, which is also licensed for treatment of canine demodicosis. In this article, we present 22 dogs that all developed pemphigus foliaceus (PF)-like cutaneous drug reactions at the site of PD application. In eight dogs, the lesions were restricted to the application site (localized group). Signs of systemic illness were reported in three dogs, and four required immunosuppressive treatment. Direct immunofluorescence for IgG was positive in four dogs, although circulating antikeratinocyte IgG could not be detected in any tested sera. Complete remission was achieved in all dogs, with one patient still remaining on treatment. Fourteen dogs developed skin lesions at the application site as well as other noncontiguous areas (distant group). Systemic signs were reported in 11 dogs, and immunosuppression was required in 10 cases. Direct and indirect immunofluorescence tests were positive for antikeratinocyte autoantibodies in 10 of 13 and six of 10 patients with distant disease, respectively. Complete remission was achieved in 10 of 13 dogs with distant disease; one-third are still on treatment. Histological changes were similar to canine PF. Desmosomal architectural changes, assessed by desmoglein-1 immunostaining, were also similar to those of dogs with spontaneous autoimmune PF. Apoptosis did not appear to contribute to lesion formation, in either autoimmune or PD-associated PF. In conclusion, PD has the potential of triggering a variant of PF that resembles spontaneously occurring autoimmune PF at clinical, morphological, immunological and treatment outcome levels. Le Promeris Duo (PD) est un nouveau topique préventif des puces et tiques pour chiens ayant également une indication pour le traitement de la démodécie canine. Dans cet article, nous présentons 22 chiens qui ont tous développé des réactions cutanées médicamenteuses PF-like (pemphigus foliaceus) au site d’application du PD. Chez huit chiens, les lésions étaient circonscrites au site d’application (groupe localisé). Des signes d’atteinte systémique ont été rapportés chez trois chiens et un traitement immunosuppressif a été nécessaire pour quatre chiens. Une immunofluorescence directe pour IgG était positive chez quatre chiens bien qu’aucun IgG anti-kératinocyte circulant n’ai été détecté quelque soit la zone testée. Il y a eu rémission complète pour tous les chiens, un d’entre eux restant encore sous traitement. Quatorze chiens ont développé des lésions cutanées sur le site d’application ainsi que sur d’autres zones non-contigües (groupe distant). Des signes systémiques ont été rapportés chez 11 chiens et une immunosuppression a été nécessaire dans 10 cas. Les tests d’immunofluorescence directe et indirecte étaient respectivement positifs pour les auto-anticorps anti-kératinocytes pour 10 sur 13 et 6 sur 10 des patients avec une atteinte à distance; un tiers sont encore sous traitement. Les modifications histologiques étaient identiques au PF canin. Les modifications architecturales desmosomales, mises en évidence par immunomarquage de la desmogléine-1, étaient également identiques à celles des chiens atteints de PF autoimmun spontané. L’apoptose ne semblait pas contribuer à la formation des lésions, ni pour les PF autoimmuns ni pour les PF associé au PD. En conclusion, le PD a le potentiel d’entrainer une variante de PF qui ressemble à un PF autoimmun spontané tant sur le plan clinique, morphologique, immunologique que sur les doses thérapeutiques nécessaires à sa résolution. Promeris Duo (PD) es un nuevo tratamiento tópico para pulgas y garrapatas para perros, también con licencia para el tratamiento de demodicosis. En este artículo se presentan 22 perros que desarrollaron lesiones similares a pénfigo foliáceo (PF) inducido por fármacos en las zonas de aplicación de PD. En ocho perros las lesiones se restringieron a la zona de aplicación (grupo localizado). Se observaron signos sistémicos en tres perros, y cuatro necesitaron tratamiento inmunosupresivo. Inmunofluorescencia directa para IgG fue positiva en cuatro perros, aunque no se detectó IgG circulante frente a queratinocitos en ninguno de los sueros probados. Se observo remisión completa en todos los perros, con un paciente aun bajo tratamiento. Catorce perros desarrollaron lesiones de la piel en el lugar de aplicación y en áreas no contiguas (grupo a distancia). Se observaron signos sistémicos en 11 perros, y se necesitó inmunosupresión en diez casos. Pruebas de inmunofluorescencia directa e indirecta resultaron positivas para autoanticuerpos frente a queratinocitos en diez de 13 y 6 de 10 pacientes con enfermedad a distancia, respectivamente. Se observó remisión completa en 10 de 13 perros con enfermedad a distancia; un tercio están aun en tratamiento. Los cambios histológicos fueron similares a PF canino. Cambios en la arquitectura de los desmosomas, demostrados mediante inmunotinción frente a desmogleina-1, fueron similares a aquellos con perros con PF espontáneo. Apoptosis no parecía contribuir a la formación de lesiones, ni en PF autoinmune ni en PF asociado a tratamiento con PD. En conclusión, PD tiene potencial de iniciar una variante de PF que se asemeja casos espontáneos de PF autoinmune a nivel clínico, morfológico, inmunológico y de respuesta al tratamiento. Promeris Duo (PD) ist ein neues topisches Produkt zur Floh- und Zeckenprophylaxe bei Hunden, welches auch für die Behandlung der caninen Demodikose lizenziert ist. In diesem Artikel präsentieren wir 22 Hunde, die alle Pemphigus foliaceus (PF)-ähnliche Hautreaktionen an der Stelle der PD Applikation entwickelten. Bei acht Hunden waren die Veränderungen auf die Applikationsstelle beschränkt (Gruppe: lokalisiert). Anzeichen von systemischer Erkrankung wurden bei drei Hunden beschrieben, bei vier Hunden war eine immunsuppressive Therapie nötig. Die direkte Immunfluoreszenz für IgG war bei vier Hunden positiv, obwohl zirkulierendes Antikeratinozyten IgG in keinem der untersuchten Seren gefunden werden konnte. Eine komplette Remission wurde bei allen Hunden erreicht, wobei ein Patient weiterhin behandelt wird. Vierzehn Hunde entwickelten Hautveränderungen an der Applikationsstelle, sowie an anderen nicht angrenzenden Stellen (Gruppe: entfernte Läsionen). Es wurden bei 11 Hunden systemische Symptome beschrieben und eine Immunsuppression war in zehn Fällen notwendig. Die direkten und indirekten Immunfluoreszenztests waren für Antikeratinozyten Autoantikörper bei zehn von 13 bzw. bei sechs der zehn Patienten mit Hautveränderungen an nicht angrenzenden Stellen positiv. Eine völlige Remission wurde bei 10 von 13 Hunden mit Hautveränderungen an nicht angrenzenden Stellen erreicht; ein Drittel dieser Hunde werden noch immer behandelt. Die histologischen Veränderungen waren ähnlich wie beim caninen PF. Architekturveränderungen der Desmosomen, die mittels Desmoglein-1 Immunfärbung erhoben wurden, waren ebenfalls jenen von Hunden mit spontanem autoimmunen PF ähnlich. Apoptose schien weder beim autoimmunen noch bei PD-assoziiertem PF an der Ausbildung der Läsionen beteiligt zu sein. Zusammenfassend kann man sagen, dass PD eine Variante von PF auslösen kann, die dem spontan auftretenden autoimmunen PF in klinischer, morphologischer und im Bezug auf Therapieerfolge ähnlich ist.}, number={5}, journal={VETERINARY DERMATOLOGY}, author={Oberkirchner, Ursula and Linder, Keith E. and Dunston, Stan and Bizikova, Petra and Olivry, Thierry}, year={2011}, month={Oct}, pages={436–448} }
 @article{varanat_maggi_linder_breitschwerdt_2011, title={Molecular Prevalence of Bartonella, Babesia, and Hemotropic Mycoplasma sp. in Dogs with Splenic Disease}, volume={25}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/j.1939-1676.2011.00811.x}, DOI={10.1111/j.1939-1676.2011.00811.x}, abstractNote={Among diseases that cause splenomegaly in dogs, lymphoid nodular hyperplasia (LNH), splenic hemangiosarcoma (HSA), and fibrohistiocytic nodules (FHN) are common diagnoses. The spleen plays an important role in the immunologic control or elimination of vector-transmitted, blood-borne pathogens, including Bartonella sp., Babesia sp., and hemotropic Mycoplasma sp.To compare the prevalence of Bartonella sp., Babesia sp., and hemotropic Mycoplasma sp. DNA in spleens from dogs with LNH, HSA, and FHN.Paraffin-embedded, surgically obtained biopsy tissues from LNH (N = 50), HSA (N = 50), and FHN (N = 37) were collected from the anatomic pathology archives. Spleens from specific pathogen-free (SPF) dogs (N = 8) were used as controls. Bartonella sp., Babesia sp., and Mycoplasma sp. DNA was amplified by PCR, followed by DNA sequencing.Bartonella sp. DNA was more prevalent in FHN (29.7%) and HSA (26%) as compared to LNH (10%) (P = .019, .0373, respectively) or control spleens (0.0%). The prevalence of Babesia sp. and hemotropic Mycoplasma sp. DNA was significantly lower than Bartonella sp. DNA in HSA (P = .0005, .006, respectively) and FHN (P = .003, .0004, respectively). There was no statistically significant difference in DNA prevalence among the 3 genera in the LNH group.The higher prevalence of Bartonella sp. in FHN and HSA warrants future investigations to determine if this bacterium plays a role in the development of these splenic diseases.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Varanat, M. and Maggi, R.G. and Linder, K.E. and Breitschwerdt, E.B.}, year={2011}, month={Oct}, pages={1284–1291} }
 @article{oberkirchner_linder_olivry_2011, title={Recognizing and treating ProMeris-triggered pemphigus foliaceus in dogs}, volume={106}, number={6}, journal={Veterinary Medicine}, author={Oberkirchner, U and Linder, K and Olivry, T}, year={2011}, pages={284} }
 @article{house_zhu_ranjan_linder_smart_2010, title={C/EBP alpha and C/EBP beta Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin}, volume={5}, ISSN={["1932-6203"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79952118221&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0009837}, abstractNote={C/EBPα and C/EBPβ are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPα and C/EBPβ in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPα or C/EBPβ alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPα and C/EBPβ in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPα and C/EBPβ in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPα and C/EBPβ are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.}, number={3}, journal={PLOS ONE}, author={House, John S. and Zhu, Songyun and Ranjan, Rakesh and Linder, Keith and Smart, Robert C.}, year={2010}, month={Mar} }
 @article{bizikova_linder_paps_olivry_2010, title={Effect of a novel topical diester glucocorticoid spray on immediate- and late-phase cutaneous allergic reactions in Maltese-beagle atopic dogs: a placebo-controlled study}, volume={21}, ISSN={0959-4493 1365-3164}, url={http://dx.doi.org/10.1111/j.1365-3164.2009.00782.x}, DOI={10.1111/j.1365-3164.2009.00782.x}, abstractNote={The inhibitory effect of 0.0584% hydrocortisone aceponate spray on immediate- and late-phase skin reactions and the duration of inhibition after medication withdrawal were studied in 10 Maltese-beagle atopic dogs. All subjects were sprayed on axillary and inguinal regions and on one randomly chosen side of the thorax once daily for 14 (phase 1) or 7 days (phase 2). Intradermal injections (IDT) of histamine and anticanine IgE antiserum were performed bilaterally on the thorax before, 7 and 14 days after treatment. During phase 2, IDT was performed once weekly for 5 weeks. Each IDT was evaluated by an investigator blinded to the site of active treatment. Skin biopsies of 24-h anti-IgE-associated late-phase reactions were collected from both thoracic sides before and 14 days after treatment to determine the number of inflammatory cells and dermal thickness. Phase 1: Histamine and anti-IgE-induced global wheal scores at treated sites were significantly lower after 7 and 14 days with negative reactions present in >90% of dogs. Late-phase reactions at both sides were also significantly decreased compared with that at baseline, and this was associated with reduced inflammatory cell influx. Moreover, a significant decrease in dermal thickness was recorded at treated sides after 14 days. Phase 2: Histamine reactions became positive at untreated sides in all dogs 2 weeks after treatment. In conclusion, the 0.0584% hydrocortisone aceponate spray significantly decreased immediate- and late-phase IDT reactions, and prolonged application caused skin atrophy at treated sites. A 2-week withdrawal period prior to IDT is proposed. L’effet inhibiteur d’un spray d’acéponate d’hydrocortisone à 0.0584% sur les réactions cutanées immédiates et retardées (LPR) et la durée de l’inhibition après arrêt du traitement ont étéétudiés chez dix bichons maltais atopiques. Tous les chiens ont reçus des applications au niveau des plis axillaires et inguinaux et, au hasard, sur un des deux cotés du thorax, une fois par jour pendant 14 jours (phase 1) ou pendant 7 jours (phase 2). Des injections intradermiques (IDT) d’histamine et d’IgE anti-chien ont été réalisées sur chaque coté du thorax avant, 7 jours et 14 jours après traitement. Au cours de la phase 2, les IDT ont été réalisées une fois par semaine pendant cinq semaines. Chaque intradermoréaction a étéévaluée en aveugle par un investigateur sur la zone traitée. Des biopsies cutanées des réactions retardées aux anti-IgE ont été réalisées à 24 h et prélevées à partir des deux cotés du thorax avant et 14 jours après traitement afin de déterminer le nombre de cellules inflammatoires et l’épaisseur du derme. Phase 1: Les scores des plaques ortiées liées à l’histamine et aux anticorps anti-IgE sur les zones traitées étaient significativement plus faibles après 7 et 14 jours avec des réactions négatives pour plus de 90% des chiens. Les réactions retardées étaient également significativement diminuées des deux cotés en comparaison avec les valeurs de référence. Ceci était également associéà une diminution de la réponse inflammatoire cellulaire. De plus, une diminution significative de l’épaisseur dermique a été enregistrée sur les cotés traités après 14 jours. Phase 2: les réactions liées à l’histamine étaient positives sur les zones non-traitées deux semaines après traitement dans tous les cas. En conclusion, le spray d’acéponate d’hydrocortisone à 0.0584% diminue significativement les intradermoréactions immédiates et retardées et une application prolongée provoque une atrophie cutanée des zones traitées. Un arrêt du traitement deux semaines avant la réalisation de tests intradermiques est proposé. Se estudiaron el efecto inhibitorio de 0,0584% del pulverizado de aceponato de hidrocortisona en las reacciones inmediatas y tardías de la piel así como la duración de la inhibición tras la interrupción de la medicación en diez perros cruzados Maltés-Beagle con atopia. Todos los individuos fueron pulverizados en las regiones axilares e inguinales y en un lado del tórax elegido al azar, una vez al día durante 14 días (fase 1) o siete días (fase 2). Se aplicaron inyecciones intradérmicas bilaterales de histamina y antisuero canino frente IgE en el tórax antes, siete y 14 días tras el tratamiento. Durante la fase 2, la inyección intradérmica se realizó una vez a la semana durante cinco semanas. Cada inyección intradérmica se evaluó por un investigador a ciegas para el lugar de tratamiento activo. Se tomaron biopsias de piel de la reacción tardía al suero anti-IgE a las 24 horas de ambos lados del tórax antes y catorce días tras el tratamiento, para determinar el número de células inflamatorias y el grosor de la dermis. Fase 1: los valores de los habones inducidos por la histamina y la anti-IgE en los sitios tratados fueron significativamente menores tras siete y catorce días con reacciones negativas, estando presentes en >90% de los perros. Las reacciones de fase tardía en ambos lados también estuvieron reducidas comparadas con el nivel basal, y esto se asoció con un flujo celular inflamatorio reducido. Además se observo una reducción significativa en el grosor de la dermis en las zonas tratadas tras 14 días. Fase 2: las reacciones a la histamina fueron positivas en los lados no tratados en todos los perros dos semanas tras el tratamiento. En conclusión, el pulverizado al 0,0584% de aceponato de hidrocortisona redujo significativamente las reacciones inmediata y tardía intradermales, y la aplicación prolongada causó atrofia de la dermis en los lugares de aplicación. Se propone la interrupción del tratamiento durante dos semanas antes de realizar pruebas intradermales. Der inhibitorische Effekt von 0,0584%igem Hydrocortison-Aceponat Spray auf die Sofortreaktion der Haut und auf die Spätphase (LPR) der Hautreaktion und die Dauer der Hemmung nach Absetzen der Medikamente wurden bei zehn atopischen Malteser-Beagle Mischungen untersucht. Alle Hunde wurden in der Achsel- und Leistengegend, sowie an einer zufällig ausgewählten Seite des Thorax einmal täglich für 14 (Phase 1) oder sieben Tage (Phase 2) besprüht. Beidseits am Thorax wurden vor, sieben und 14 Tage nach der Behandlung intradermale Injektionen (IDT) von Histamin und Anti-caninem IgE Antiserum durchgeführt. Während der 2. Phase wurde der IDT einmal wöchentlich fünf Wochen lang durchgeführt. Jeder IDT wurde von einem geblindeten Untersucher durchgeführt, der nicht wusste welche Stelle behandelt wurde. Nach 24 Stunden Anti-IgE-assoziierter LPR wurden vor und 14 Tage nach einer Behandlung Hautbiopsien von beiden Thoraxseiten entnommen, um die Anzahl an Entzündungszellen und die dermale Dicke zu bestimmen. Phase 1: Histamin und Anti-IgE induzierten generell Quaddeln, deren Größe an den behandelten Stellen nach sieben und 14 Tagen signifikant niedriger waren, wobei bei >90% der Hunde negative Reaktionen vorlagen. Reaktionen der Spätphase waren im Vergleich zum Ausgangswert auf beiden Seiten signifikant reduziert, was mit einem reduzierten Einwandern der Entzündungszellen in Zusammenhang gebracht wurde. Darüber hinaus bestand an den behandelten Seiten nach 14 Tagen eine signifikante Abnahme der dermalen Dicke. Phase 2: Auf den unbehandelten Seiten wurden die Histaminreaktionen bei allen Hunden zwei Wochen nach der Behandlung positiv. Zusammenfassend kann man sagen, dass der 0,0584%ige Hydrocortison-Aceponat Spray die Sofortreaktion und die Spätphase der IDT Reaktionen vermindert hat und dass eine längere Gabe auf allen behandelten Stellen eine Atrophie der Haut ergab. Es wird ein Absetzen des Sprays für zwei Wochen vor Durchführung eines IDT empfohlen.}, number={1}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Bizikova, Petra and Linder, Keith E. and Paps, Judy and Olivry, Thierry}, year={2010}, month={Feb}, pages={71–80} }
 @article{urkasemsin_linder_bell_lahunta_olby_2010, title={Hereditary Cerebellar Degeneration in Scottish Terriers}, volume={24}, ISSN={["1939-1676"]}, DOI={10.1111/j.1939-1676.2010.0499.x}, abstractNote={Background: Hereditary cerebellar degeneration is described in several dog breeds. This heterogeneous group of diseases causes cerebellar ataxia associated with cerebellar cortical degeneration. Objective: To report the clinical and histopathological features, and describe the mode of inheritance of hereditary cerebellar degeneration in Scottish Terriers. Animals: Sixty-two affected dogs recruited through the Scottish Terrier Club of America. Materials and Methods: Prospective, observational study: Owners of affected dogs were contacted for a description of clinical signs, age of onset, and disease progression. Medical records, videotapes of gait, and brain imaging were evaluated. When possible, necropsy was performed and the brain examined histopathologically. Prevalence of the disease was estimated and a pedigree analysis was performed to determine mode of inheritance. Results: Gait abnormalities were noted in the 1st year of life in 76% of dogs, and progressed slowly; only 1 of 27 dogs dead at time of writing was euthanized because of cerebellar degeneration. Clinical signs included wide based stance, dysmetria, intention tremor, and difficulty negotiating stairs and running. Cerebellar atrophy was detected on magnetic resonance imaging. On histopathological examination, there was segmental loss of Purkinje neurons, thinning of molecular and granular layers, and polyglucosan bodies in the molecular layer. Prevalence of disease was estimated at 1 in 1,335 American Kennel Club registered Scottish Terriers. Genetic analysis results are consistent with an autosomal recessive mode of inheritance. Conclusion and Clinical Importance: A hereditary cerebellar degenerative disorder with a relatively mild phenotype has emerged in the Scottish Terrier. Genetic studies are needed.}, number={3}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Urkasemsin, G. and Linder, K. E. and Bell, J. S. and Lahunta, A. and Olby, N. J.}, year={2010}, pages={565–570} }
 @article{kim_chiera_linder_trempus_smart_horowitz_2010, title={Overexpression of Transcription Factor Sp2 Inhibits Epidermal Differentiation and Increases Susceptibility to Wound- and Carcinogen-Induced Tumorigenesis}, volume={70}, ISSN={["1538-7445"]}, DOI={10.1158/0008-5472.can-10-1213}, abstractNote={Sp proteins are evolutionarily conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell cycle progression. Deregulated expression of certain Sp proteins is associated with the formation of a variety of human tumors; however, direct evidence that any given Sp protein is oncogenic has been lacking. Here, we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within 2 weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional effect.}, number={21}, journal={CANCER RESEARCH}, author={Kim, Tae-Hyung and Chiera, Shannon L. and Linder, Keith E. and Trempus, Carol S. and Smart, Robert C. and Horowitz, Jonathan M.}, year={2010}, month={Nov}, pages={8507–8516} }
 @article{oberkirchner_linder_zadrozny_olivry_2010, title={Successful treatment of canine necrolytic migratory erythema (superficial necrolytic dermatitis) due to metastatic glucagonoma with octreotide}, volume={21}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-77956458558&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2009.00876.x}, abstractNote={Necrolytic migratory erythema (NME; also known as superficial necrolytic dermatitis) is a syndrome most often associated with certain chronic liver diseases or pancreatic glucagonomas. In humans with glucagonoma-associated NME, skin lesions usually respond to octreotide, a somatostatin analogue that inhibits glucagon release. In this report an 11-year-old golden retriever dog with pancreatic glucagonoma and metastasis to the regional lymph nodes, spleen and liver was diagnosed with NME. The dog exhibited erosions, ulcers and crusts on the paws, pressure points, muzzle, periocular area and prepuce. The dog was also anorexic and had difficulty walking. Because metastasis precluded surgery, treatment was initiated with subcutaneous octreotide (2 μg/kg twice daily). Skin lesions and systemic clinical signs improved markedly within 5 days. The dosage was increased to nearly 3 μg/kg twice daily and signs almost completely resolved within 10 days. Anorexia was the major adverse effect observed. During the following month, both dosage (1-3.7 μg/kg) and frequency (two to four times daily) of the octreotide injections were adjusted to permit control of clinical signs while maintaining adequate appetite. Temporary cessation of octreotide administration resulted in the rapid recurrence of skin lesions. Resuming injections led to improvement of clinical signs within 48 h. The dog was later euthanized because of progressive metastatic disease. In conclusion, subcutaneous octreotide injections were beneficial in this dog with glucagonoma-associated NME. This somatostatin analogue could be a valuable option to treat canine patients with non-resectable or relapsing pancreatic glucagonoma-associated NME.}, number={5}, journal={VETERINARY DERMATOLOGY}, author={Oberkirchner, Ursula and Linder, Keith E. and Zadrozny, Leah and Olivry, Thierry}, year={2010}, month={Oct}, pages={510–516} }
 @article{liles_linder_cain_pease_2010, title={ULTRASONOGRAPHY OF HISTOLOGICALLY NORMAL PARATHYROID GLANDS AND THYROID LOBULES IN NORMOCALCEMIC DOGS}, volume={51}, ISSN={["1058-8183"]}, DOI={10.1111/j.1740-8261.2010.01686.x}, abstractNote={The purpose of this study is to characterize the sonographic appearance of canine parathyroid glands using high-resolution ultrasonography. Ten cadaver dogs were studied after euthanasia for reasons not relating to the parathyroid. The cervical region was examined using a 13–5 MHz linear transducer in right and left recumbency. Ultrasonographic features of the parathyroid and thyroid glands were compared with the gross and histopathologic findings. Thirty-five structures were identified sonographically as parathyroid glands but only 26 of 35 glands (74% positive predictive value) were proven to be normal parathyroid glands histopathologically. Of the nine false positives, five (14%) were proven to be lobular thyroid tissue. The remaining four (11%) structures were visible grossly or found histopathologically. There were no statistical differences between ultrasonographic and gross measurements of the parathyroid glands. The average size as seen sonographically was 3.3 × 2.2 × 1.7 mm and the average gross size was 3.7 × 2.6 × 1.6 mm (length, width, height). The average size of the thyroid lobules assessed sonographically was 2.3 × 1.6 × 0.8 mm (length, width, height). Normal parathyroid glands can be identified using high-resolution ultrasonography. But some thyroid lobules will be misinterpreted as parathyroid glands; this will result in false positives when identifying parathyroid glands with ultrasonography.}, number={4}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={Liles, Sofija R. and Linder, Keith E. and Cain, Brandon and Pease, Anthony P.}, year={2010}, pages={447–452} }
 @article{mccalla-martin_chen_linder_estrada_piedrahita_2010, title={Varying phenotypes in swine versus murine transgenic models constitutively expressing the same human Sonic hedgehog transcriptional activator, K5-HGLI2ΔN}, volume={19}, ISSN={0962-8819 1573-9368}, url={http://dx.doi.org/10.1007/s11248-010-9362-0}, DOI={10.1007/s11248-010-9362-0}, number={5}, journal={Transgenic Research}, publisher={Springer Science and Business Media LLC}, author={McCalla-Martin, Amy C. and Chen, Xiaoxin and Linder, Keith E. and Estrada, Jose L. and Piedrahita, Jorge A.}, year={2010}, month={Jan}, pages={869–887} }
 @article{tuttle_maclean_linder_cullen_wolfe_loomis_2009, title={ACQUIRED ARTERIOVENOUS FISTULA IN A GRIZZLY BEAR (URSUS ARCTOS HORRIBILIS)}, volume={40}, ISSN={["1042-7260"]}, DOI={10.1638/2007-0030.1}, abstractNote={A captive adult male grizzly bear (Ursus arctos horribilis) was evaluated due to multifocal wounds of the skin and subcutaneous tissues sustained as a result of trauma from another grizzly bear. On presentation, one lesion that was located in the perineal region seemed to be a deep puncture with purple tissue protruding from it. This perineal wound did not heal in the same manner or rate as did the other wounds. Twenty-five days after initial detection, substantial active hemorrhage from the lesion occurred and necessitated anesthesia for examination of the bear. The entire lesion was surgically excised, which later proved curative. An acquired arteriovenous fistula was diagnosed via histopathology. Arteriovenous fistulas can develop after traumatic injury and should be considered as a potential complication in bears with nonhealing wounds.}, number={1}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Tuttle, Allison D. and MacLean, Robert A. and Linder, Keith and Cullen, John M. and Wolfe, Barbara A. and Loomis, Michael}, year={2009}, month={Mar}, pages={193–195} }
 @article{mathews_linder_davidson_goldman_papich_2009, title={Assessment of clotrimazole gels for in vitro stability and in vivo retention in the frontal sinus of dogs}, volume={70}, ISSN={["0002-9645"]}, DOI={10.2460/ajvr.70.5.640}, abstractNote={Abstract Objective —To evaluate the stability and retention of viscous formulations of the antifungal drug clotrimazole in vitro and to evaluate retention times, absorption, and histologic response to these compounds when placed in the frontal sinus of dogs. Animals —6 male Beagles. Procedures —1% clotrimazole gels were formulated with hydroxypropyl cellulose, poloxamer, and carboxymethylcellulose sodium bases. Commercially available 1% clotrimazole creams were also evaluated. Each compound was incubated at 37°C in a funnel. Volume retained and clotrimazole stability were evaluated for 4 weeks. Six compounds were then chosen for in vivo evaluation. The frontal sinuses of 6 dogs were filled with 1 of the 6 compounds. Computed tomographic evaluation was performed weekly for up to 4 weeks to evaluate gel retention. Blood samples were collected to evaluate clotrimazole absorption. Following euthanasia, sinuses were examined histologically. Results —Commercially available clotrimazole creams were not retained in funnels in vitro. In vivo, hydroxypropyl cellulose– and carboxymethylcellulose-based gels resulted in the most severe inflammatory response and were retained the longest. Poloxamer-based gels had a shorter retention time and were associated with less inflammation. Clotrimazole was minimally absorbed. Despite a marked inflammatory response to several of the clotrimazole-containing gels, no notable adverse clinical responses were observed. Conclusions and Clinical Relevance —Poloxamer gels had the most promise for improving drug contact within the frontal sinus of dogs, while limiting the inflammatory response. Poloxamer gels have the additional benefit of improved handling as a result of reverse gelation (ie, they gel when warmed to 37°C).}, number={5}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Mathews, Kyle G. and Linder, Keith E. and Davidson, Gigi S. and Goldman, Rebecca B. and Papich, Mark G.}, year={2009}, month={May}, pages={640–647} }
 @article{bizikova_linder_suter_van wettere_olivry_2009, title={Canine cutaneous epitheliotropic T-cell lymphoma with vesiculobullous lesions resembling human bullous mycosis fungoides}, volume={20}, ISSN={0959-4493 1365-3164}, url={http://dx.doi.org/10.1111/j.1365-3164.2009.00760.x}, DOI={10.1111/j.1365-3164.2009.00760.x}, abstractNote={The broad spectrum of clinical signs in canine cutaneous epitheliotropic T-cell lymphoma mimics many inflammatory skin diseases and is a diagnostic challenge. A 13-year-old-male castrated golden retriever crossbred dog presented with multifocal flaccid bullae evolving into deep erosions. A shearing force applied to the skin at the periphery of the erosions caused the epidermis to further slide off the dermis suggesting intraepidermal or subepidermal separation. Systemic signs consisted of profound weight loss and marked respiratory distress. Histologically, the superficial and deep dermis were infiltrated by large, CD3-positive neoplastic lymphocytes and mild epitheliotropism involved the deep epidermis, hair follicle walls and epitrichial sweat glands. There was partial loss of the stratum basale. Bullous lesions consisted of large dermoepidermal and intraepidermal clefts that contained loose accumulations of neutrophils mixed with fewer neoplastic cells in proteinaceous fluid. The lifted epidermis was often devitalized and bordered by hydropic degeneration and partial epidermal collapse. Similar neoplastic lymphocytes formed small masses in the lungs associated with broncho-invasion. Clonal rearrangement analysis of antigen receptor genes in samples from skin and lung lesions using primers specific for canine T-cell receptor gamma (TCRgamma) produced a single-sized amplicon of identical sequence, indicating that both lesions resulted from the expansion of the same neoplastic T-cell population. Macroscopic vesiculobullous lesions with devitalization of the lesional epidermis should be included in the broad spectrum of clinical signs presented by canine cutaneous epitheliotropic T-cell lymphoma.}, number={4}, journal={Veterinary Dermatology}, publisher={Wiley}, author={Bizikova, Petra and Linder, Keith E. and Suter, Steven E. and Van Wettere, Arnaud J. and Olivry, Thierry}, year={2009}, month={Aug}, pages={281–288} }
 @article{varanat_maggi_linder_horton_breitschwerdt_2009, title={Cross-contamination in the Molecular Detection of Bartonella from Paraffin-embedded Tissues}, volume={46}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1354/vp.08-VP-0259-B-BC}, DOI={10.1354/vp.08-VP-0259-B-BC}, abstractNote={The genus Bartonella comprises a group of gram-negative, fastidious bacteria. Because of diagnostic limitations of culture and serologic testing, polymerase chain reaction (PCR) has become a powerful tool for the detection of Bartonella spp. in blood and tissue samples. However, because many wild and domestic animals harbor Bartonella spp., transfer of Bartonella DNA during sample collection or histologic processing could result in false-positive PCR test results. In this study, we describe evidence of Bartonella DNA dissemination and transfer in the necropsy room and during the subsequent processing of formalin-fixed paraffin-embedded tissues. Bartonella DNA was amplified from different areas of the necropsy room, from the liquid paraffin in the tissue processor, and from different parts of the microtome. Unless stringent procedures are established and followed to avoid cross-contamination, the molecular detection of Bartonella spp. from tissue samples obtained at necropsy or processed in a multispecies histopathology laboratory will not be reliable.}, number={5}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Varanat, M. and Maggi, R. G. and Linder, K. E. and Horton, S. and Breitschwerdt, E. B.}, year={2009}, month={May}, pages={940–944} }
 @article{olivry_linder_2009, title={Dermatoses affecting desmosomes in animals: a mechanistic review of acantholytic blistering skin diseases}, volume={20}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-73149118226&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2009.00821.x}, abstractNote={Failure of desmosomal adhesion with ensuing keratinocyte separation - a phenomenon called acantholysis - can result from genetic, autoimmune or infectious proteolytic causes. Rare hereditary disorders of desmosomal formation have been identified in animals. Familial acantholysis of Angus calves and hereditary suprabasal acantholytic mechanobullous dermatosis of buffaloes appear to be similar to acantholytic epidermolysis bullosa of human beings. A genetic acantholytic dermatosis resembling human Darier disease has been rarely recognized in dogs. In autoimmune blistering dermatoses, circulating autoantibodies bind to the extracellular segments of desmosomal proteins and induce acantholysis. Autoantibodies against desmoglein-3 are found in canine pemphigus vulgaris and paraneoplastic pemphigus. Autoantibodies against desmoglein-1 have been rarely detected in dogs with pemphigus foliaceus. When circulating autoantibodies target desmogleins-1 and -3, mucocutaneous pemphigus vulgaris develops in dogs. Finally, several infectious agents can release proteases that cleave desmosomal bonds. In superficial pustular dermatophytosis of dogs and horses, Trichophyton hyphae colonize the stratum corneum, and acantholysis presumably develops because of proteases secreted by the dermatophytes. In exudative epidermitis of piglets, Staphylococcus bacteria - usually Staphylococcus hyicus- release exfoliatin toxins that bind to and specifically cleave desmoglein-1. Any of the above mechanisms can result in impairment of desmosomal function with subsequent acantholysis. The end point of adhesion failure is identical among these diseases: there is cleft formation where desmosomes are affected. The similarity of mechanisms explains why clinical and microscopic skin lesions overlap between entities, thus leaving clinicians and dermatopathologists with the conundrum of determining whether the acantholysis is of genetic, autoimmune or infectious origin.}, number={5-6}, journal={VETERINARY DERMATOLOGY}, author={Olivry, Thierry and Linder, Keith E.}, year={2009}, pages={313–326} }
 @article{mitsui_mathews_linder_kruse_roe_2009, title={Effects of fascial abrasion, fasciotomy, and fascial excision on cutaneous wound healing in cats}, volume={70}, ISSN={0002-9645}, url={http://dx.doi.org/10.2460/ajvr.70.4.532}, DOI={10.2460/ajvr.70.4.532}, abstractNote={OBJECTIVE-To evaluate the effects of fascial abrasion, fasciotomy, and fascial excision on cutaneous wound healing in cats. ANIMALS-Eight 1- to 3-year-old domestic shorthair cats. PROCEDURES-8 evenly spaced 4-cm(2) skin wounds were created on each cat's dorsum, and the underlying subcutaneous tissue was removed to expose the epaxial muscle fascia. Wounds were randomized to receive 1 of 4 treatments (2 wounds/treatment/cat): fascial abrasion, fasciotomy, fascial excision, or control treatment (muscle fascia not disturbed). Bandages were changed and digital photographs and acetate tracings of the wounds were obtained for planimetry daily for 1 week, every other day for 2 weeks, and then every third day for 3 weeks (ie, 40-day observation period). Digitized images were evaluated for granulation tissue formation, wound contraction (surface area measurements), and area of epithelialization. RESULTS-The epithelialized area and open and total wound areas did not differ among treatments at any time point. Time to the first appearance of granulation tissue was significantly shorter for all treatment groups, compared with that of the control group. Time to achieve granulation tissue coverage of wound base was significantly shorter following fasciotomy (9.6 days) and fascial excision (9.0 days), compared with that of control treatment (18.5 days) or abrasion (16.7 days). Numbers of wounds that developed exuberant granulation tissue following fascial excision (9/16) and control treatment (3/16) differed significantly. CONCLUSIONS AND CLINICAL RELEVANCE-Fasciotomy and fascial excision facilitated early granulation tissue development in cutaneous wounds in cats. In clinical use, these fascial treatments may expedite secondary wound closure or skin grafting.}, number={4}, journal={American Journal of Veterinary Research}, publisher={American Veterinary Medical Association (AVMA)}, author={Mitsui, Akiko and Mathews, Kyle G. and Linder, Keith E. and Kruse, Meghan A. and Roe, Simon C.}, year={2009}, month={Apr}, pages={532–538} }
 @article{breitschwerdt_maggi_varanat_linder_weinberg_2009, title={Isolation of Bartonella vinsonii subsp. berkhoffii Genotype II from a Boy with Epithelioid Hemangioendothelioma and a Dog with Hemangiopericytoma}, volume={47}, ISSN={0095-1137}, url={http://dx.doi.org/10.1128/JCM.00069-09}, DOI={10.1128/JCM.00069-09}, abstractNote={ABSTRACT In this report, we describe isolation of Bartonella vinsonii subsp. berkhoffii genotype II from a boy with epithelioid hemangioendothelioma and a dog with hemangiopericytoma. These results suggest that B . vinsonii subsp. berkhoffii may cause vasoproliferative lesions in both humans and dogs.}, number={6}, journal={Journal of Clinical Microbiology}, publisher={American Society for Microbiology}, author={Breitschwerdt, E. B. and Maggi, R. G. and Varanat, M. and Linder, K. E. and Weinberg, G.}, year={2009}, month={Apr}, pages={1957–1960} }
 @article{santoro_pease_linder_olivry_2009, title={Post-traumatic peripheral arteriovenous fistula manifesting as digital haemorrhages in a cat: diagnosis with contrast-enhanced 3D CT imaging}, volume={20}, ISSN={["1365-3164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-65649086814&partnerID=MN8TOARS}, DOI={10.1111/j.1365-3164.2009.00754.x}, abstractNote={Arteriovenous fistulae (AVF) are defined as congenital or acquired abnormal direct communications between an artery and a vein leading to abnormal blood circulation. This report describes an unusual manifestation of acquired peripheral AVF in a cat for which the diagnosis was confirmed by computed tomographic (CT) imaging and three-dimensional (3D) reconstruction. A 10-year-old female spayed domestic shorthaired cat was presented with a 2-month history of nonhealing, crusting, erosive and ulcerative skin lesions on the dorsal right forepaw. Severe chewing and biting, but not lameness, had been reported. Systemic abnormalities were not noted. Histopathology revealed increased numbers of thin-walled and slightly grouped vascular profiles in the superficial and mid-dermis, which were often markedly dilated and partially obscured by prominent hyaline deposits. There were a few pyknotic nuclear fragments and haemorrhages in vascular walls as well as multifocal luminal thrombosis with or without recanalization. Differential diagnoses included progressive angiomatosis with trauma or AVF with secondary regional venous hypertension. Computed tomographic images were acquired using a 16-slice Siemens Somotom Sensation CT scanner, and 3D images were created using the Voxar 3D software. Image reconstruction revealed tortuous aberrant vasculature on the medial aspect of the radius and around the carpus compared to normal vascularization on the contralateral limb. These changes were suggestive of the diagnosis of acquired peripheral AVF. The differential diagnosis for localized, nonhealing, haemorrhagic, crusted, erosive or ulcerative distal extremity skin lesions in cats should include acquired AVF, and diagnosis may be confirmed with contrast-enhanced CT imaging.}, number={3}, journal={VETERINARY DERMATOLOGY}, author={Santoro, Domenico and Pease, Anthony and Linder, Keith E. and Olivry, Thierry}, year={2009}, month={Jun}, pages={206–213} }
 @article{varanat_travis_lee_maggi_bissett_linder_breitschwerdt_2009, title={Recurrent Osteomyelitis in a Cat due to Infection with Bartonella vinsonii subsp. berkhoffii Genotype II}, volume={23}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2009.0372.x}, DOI={10.1111/j.1939-1676.2009.0372.x}, abstractNote={A 4-year-old spayed-female Domestic Shorthair cat, obtained from a shelter as a kitten, was examined in May 2007 because of an intermittent lameness. Rectal temperature was 102°F. The cat weighed 3.3 kg. There was a focal, nonpainful, 2.5-cm-diameter firm swelling at the medial aspect of the left metatarsal region. Radiographs of the left rear leg identified lysis of the distal aspect of the 1st metatarsal bone and adjacent soft tissue swelling. Thoracic radiographs were unremarkable. Neoplasia was suspected and digital amputation was elected. Preanesthetic blood tests identified thrombocytopenia (25,000/μL; reference range, 200,000–500,000) with an adequate estimated platelet count because of clumping, mild lymphopenia (1,071 lymphocytes/μL; reference range, 1,200–8,000), mild hyperglobulinemia (5.4 g/dL; reference range, 2.3–5.3), and negative FIV and FeLV ELISA test results. The neutrophil count was 4,725/μL (reference range, 2,500–8,500) with no bands or neutrophil toxicity. Urinalysis was unremarkable. At surgery, the left medial metatarsophalangeal joint was disarticulated and the digit was removed. Histopathologic evaluation identified a mixed inflammatory response, characterized by a large number of well-differentiated plasma cells, macrophages with erythrophagocytosis and focal aggregates of neutrophils. Pyogranulomatous osteomyelitis was diagnosed. Plasma cell numbers were sufficiently high that plasma cell neoplasia was considered a plausible differential diagnosis. Fungal, acid-fast, and silver stains did not identify infectious agents. Culture of the amputated tissue was not performed. Two weeks postoperatively, an ulcer formed at the surgical site and was accompanied by moderate muscle atrophy. The distal limb became necrotic from the surgical site to the mid-tibia, which was accompanied by severe atrophy of the left rear leg to the level of the stifle and a loss of distal deep pain, which required mid femoral amputation. At no time had the cat traumatized the original incision. Despite necrosis, there was minimal to no purulent discharge and the cat never appeared overtly uncomfortable, despite rapid deterioration in the limb. In November 2007, the cat was examined because of lethargy. The cat was thrombocytopenic (97,000/μL; reference range, 175,000–600,000) and neutropenic (1,064/μL; reference range, 2,500–8,500). Urinalysis identified proteinuria and neutrophils suggestive of a urinary tract infection and the cat was treated with amoxicillin-clavulanate 62.5 mg PO q12h for 7 days. Urine culture was not performed. In February 2008, diffuse distal swelling and lameness developed in the left front leg. Radiographs identified mild soft tissue swelling and mild degenerative joint disease. The cat was treated with meloxicam 0.45 mg PO q24h for 3 days, then q72h to alleviate pain and swelling. Despite this treatment, the cat remained intermittently lame. Swelling and lameness of the left front leg again were documented by physical examination in May 2008, at which time the swelling had become firmer and more localized over the left carpus. There also was thickening of the right carpal region, which was firmer and less pliable than the left carpal region. Radiographs identified osteolysis of the left radial carpal bone with concurrent periosteal reaction. There was also cortical expansion of the right 5th metacarpal bone. Although serum globulin concentration was within reference range, serum protein electrophoresis documented polyclonal gammopathy associated with increased gamma globulins (2.54 g/dL; reference range, 0.5–1.90). By June 2008, the cat had persistent decreased weight bearing on the left thoracic limb. The left carpus was swollen and painful, and the distal limb had developed a valgus deformity. The right thoracic leg was also painful during carpal palpation and range of motion manipulations, but the owner reported no lameness or pain at home. The lateral phalanges of the right thoracic limb were swollen and firm. The cat was sedated with 0.15 mg dexmeditomidine IM. Radiographs of the left and right thoracic limbs, chest, and right pelvic limb were obtained. Cytology samples were also obtained from the lesions in the left and right thoracic limbs by fine needle aspiration. Radiographs documented an ovoid expansile lesion of the right 5th metacarpal bone, characterized by extensive and irregular osteoproliferation, marked cortical bone destruction, and moderate thickening of the soft tissues lateral to the metacarpal lesion (Fig 1). Severe osteolysis of left radial carpal bone was also present, as well as irregular periosteal proliferation involving all left carpal bones and the proximal aspects of all left metacarpal bones. Moderate left carpal joint effusion was also noted. The radiographic findings of polyostotic osteolysis and irregular osteoproliferation in a patient of this age were consistent with multifocal osteomyelitis of either bacterial or fungal etiology. Given the presence of left carpal joint effusion and involvement of the left carpal bones, septic arthritis of the left carpal joint was considered likely. Soft tissue swelling adjacent to the right 5th metacarpal bone was thought to represent cellulitis. Other aggressive bone lesions (ie, primary or metastatic osseous neoplasia) were considered less likely. Right pelvic limb and thoracic radiographs were within normal limits. (A) Dorsopalmar radiograph of the right pes. Note the aggressive expansile lesion of the right 5th metacarpal bone and adjacent soft tissue swelling (white arrow). (B) Dorsopalmar radiograph of the left pes. Note the severe osteolysis of the radial carpal bone (large white arrow), osteoproliferation of the carpal and metacarpal bones (small white arrow), and carpal joint effusion (white arrowhead). Cytology from the left carpal lesion identified erythrophagocytosis, nontoxic neutrophils, epithelioid, and multinucleated cells thought to be osteoclasts, scattered plasmacytoid osteoblasts, and numerous benign plasma cells. Organisms were not seen, including lack of viral, anaplasma, or ehrlichial inclusions. The cytology results and clinical information supported chronic neutrophilic and plasmacytic osteomyelitis. Based on cellular appearance and the duration of the disease process, plasma cells were reported to be reactive rather than neoplastic, but myeloma could not be excluded from the differential diagnosis. The cat was treated with tramadol hydrochloride 12.5 mg PO q12h while the owner decided whether to pursue additional diagnostic testing. In August 2008 the cat was sedated with a combination of 80 mg ketamine, 0.16 mg dexmedetomidine, and 0.27 mg buprenorphine IM. Radiographs showed moderate progression of the osseous lesions identified in June. Blood was obtained for a CBC and serum biochemical profile. With the exception of mild thrombocytopenia (193,000/μL; reference range, 200,000–500,000) potentially associated with platelet clumping, CBC findings were within reference ranges and the neutrophil count was 5,355/μL (reference range, 2,500–8,500). Serum biochemical abnormalities included hypercalcemia (11.6 mg/dL; reference range, 8.2–10.8) and hyperglobulinemia (6.0 g/dL; reference range, 2.3–5.3). Fungal serology for aspergillosis, blastomycosis, coccidiomycosis, and histoplasmosis was negative and repeat FIV and FeLV test results were negative. A bone marrow aspiration sample, obtained to further assess the possibility of a plasma cell myeloma, was unremarkable. Aerobic culture of the bone marrow aspirate yielded mild growth of Salmonella enterica subsp. enterica, which was considered a potential sample collection contaminant. Mycoplasma and fungal cultures of the bone marrow aspirate were negative. Aerobic, anaerobic, fungal, and Mycoplasma cultures of joint fluid, aspirated from the left carpal-metacarpal joint were negative for growth. An aseptically obtained jugular blood sample, submitted to the Vector Borne Diseases Diagnostic Laboratory, NCSU-CVM, was cultured in BAPGM (Bartonella alpha proteobacteria growth medium).1 Although awaiting test results, the cat was treated with 20 mg PO q12h and azithromycin 20 mg PO q48h for presumptive intracellular bacterial infection. Bartonella spp. PCR following direct extraction from the blood sample was negative. After a 7-day incubation period, Bartonella vinsonii subsp. berkhoffii genotype II DNA was PCR amplified and sequenced from the BAPGM enrichment blood culture.1Bartonella henselae DNA and DNA from a healthy dog served as positive and negative controls, respectively. Subculture onto an agar plate did not result in bacterial growth. By IFA testing, B. vinsonii subsp. berkhoffii and B. henselae antibody titers were 1 : 128 and 1 : 64, respectively. The cat was treated for bartonellosis for 3 months with azithromycin 36 mg (10 mg/kg) PO q48h and concurrently with amoxicillin-clavulanate 62.5 mg PO q12h for 2 months for possible infection with S. enterica. During this time period, the owner reported a progressive increase in weight bearing on the left forelimb and decreased pain when walking, and meloxicam and tramadol were discontinued. In February 2009, repeated BAPGM blood culture failed to detect B. vinsonii subsp. berkhoffii DNA or growth of bacteria. B. vinsonii subsp. berkhoffii and B. henselae antibody titers were negative. The cat continued to be less painful, but both the left and right carpi were grossly larger than in November 2008. Radiographs showed continued progression of the previously described thoracic limb lesions. Radiographs of the right pelvic limb and thorax remained within normal limits. Azithromycin was discontinued once blood culture results became available. Reculture was recommended, but not performed 1 month after cessation of antibiotics. As of June 2009, the cat was healthy, was walking without pain, and had not received additional antibiotics or pain medications. After successful blood culture detection of B. vinsonii subsp. berkhoffii in August 2008, the original formalin-fixed, paraffin-embedded left medial metatarsal osteomyelitis lesion, was sent to the Intracellular Pathogens Research Laboratory to determine if the cat was infected with B. vinsonii subsp. berkhoffii at the time of digital amputation. B. vinsonii subsp. berkhoffii genotype II DNA again was amplified and sequenced from the original lesion. B. vinsonii subsp. berkhoffii genotype I was isolated for the 1st time in 1993 from a dog with shifting leg lameness, epistaxis, recent-onset seizures, and endocarditis.2 Subsequently, 3 additional genotypes (designated II–IV), all of which have been implicated as a cause of endocarditis in dogs, were described based upon sequence differences in the Bartonella 16S-23S intergenic spacer region and the pap31 gene.3,4 In pet dogs, both seroprevalence studies and blood culture isolation results indicate infrequent exposure to or active infection with any of the 4 B. vinsonii subsp. berkhoffii genotypes, whereas exposure is more frequent in rural and working dogs, and in coyotes and feral dog populations.1,3,5,6 On a comparative medical basis, dogs and humans infected with Bartonella spp. can develop similar disease manifestations, including endocarditis, granulomatous lymphadenitis, granulomatous hepatitis, bacillary angiomatosis, peliosis hepatis, seizures, and arthritis.5,6 Although seemingly well-adapted on an evolutionary basis to induce persistent infection in canine reservoir hosts (eg, coyotes), B. vinsonii subsp. berkhoffii has only rarely been isolated from pet dogs, foxes, or humans.2,3 To our knowledge, this case report describes the 1st isolation of B. vinsonii subsp. berkhoffii from a cat and the 1st association of a Bartonella spp. with osteomyelitis in any animal other than a human being. B. henselae and Bartonella clarridgeiae are transmitted among cats by Ctenocephalides felis.5,7 Healthy cats are considered reservoir hosts for these 2 Bartonella spp. and are generally nonclinical carriers of these intravascular bacteria.5,7 In various study populations throughout the world, B. henselae bacteremia has been reported in 8–56% of healthy cats whereas prevalence of B. clarridgeiae bacteremia generally is much lower.7 Although disease associated with B. henselae and B. clarridgeiae is not commonly recognized in cats, other non–reservoir-adapted Bartonella spp., such as B. vinsonii subsp. berkhoffii, for which dogs are the only known reservoir hosts,3–5 may be pathogenic when transmitted to cats. In humans, musculoskeletal manifestations, including osteomyelitis, have been reported as a complication of cat scratch disease (CSD), caused by B. henselae. In a study by Maman et al,8 about 10% of CSD patients developed chronic musculoskeletal complications including myalgia, arthritis, osteomyelitis, and neuralgia. There are also case reports of B. henselae-associated osteomyelitis, most often in children, at times, not accompanied by fever or lymphadenopathy.9,10 Non–host-adapted Bartonella spp. are more likely to be associated with development of pathology, for example B. henselae osteomyelitis in people and B. vinsonii subsp. berkhoffii osteomyelitis in this cat. Because B. vinsonii subsp. berkhoffii genotype II was PCR amplified and sequenced from an enrichment blood culture obtained 15 months after digital amputation and then was retrospectively amplified and sequenced from the paraffin block produced at the time of initial surgery, it is likely that this organism caused persistent bacteremia, recurrent osteomyelitis, and arthritis in this cat. Recently, we described Bartonella spp. DNA carryover when processing necropsy and biopsy tissue samples, which represents a potentially unique problem for the molecular diagnosis of bartonellosis in veterinary medicine.11 In this cat, recurrent disease accompanied by repeated sequencing of an infrequently detected subspecies and defined genotype makes DNA carryover less likely. In addition, special precautions were taken in our laboratory when sampling paraffin blocks to minimize this possibility. Whether infection with B. vinsonii subsp. berkhoffii after digital amputation contributed to postoperative necrosis and what appeared to be ischemic atrophy of the left rear leg could not be determined because tissues from the amputated leg were not submitted for histopathology. Current recommendations for the treatment of Bartonella musculoskeletal infections are based predominantly on empirical data. Although reinfection cannot be ruled out, it seems likely that B. vinsonii subsp. berkhoffii was not immunologically or therapeutically eliminated after digital and rear leg amputations in this cat. BAPGM enrichment cultures of blood and joint fluid recently were used to document failure of azithromycin or marbofloxacin to eliminate B. henselae and B. vinsonii subsp. berkhoffii from a dog that progressed from nonerosive to erosive polyarthritis.12 Resistance to macrolide antibiotics has been reported for B. henselae,13 but additional studies are required to determine if B. vinsonii subsp. berkhoffii can also develop macrolide resistance. In addition to osteomyelitis, clinical and radiographic findings in this cat suggested chronic, progressive polyarthritis, which also was reported in 3 dogs that were seroreactive to B. vinsonii subsp. berkhoffii antigens.14 As reported in this cat, clinical improvement occurred in these dogs in conjunction with antimicrobial therapy and was accompanied by a rapid decrease in B. vinsonii subsp. berkhoffii antibodies.14 In humans with B. henselae osteomyelitis, prognosis is good with patients being treated for a median duration of 32 days with mono, dual, or triple antibiotic therapy.9 Bartonella sp. are highly fastidious organisms that can be difficult or impossible to isolate by conventional blood culture or to detect by PCR amplification after direct extraction of DNA from patient samples.1,15 These diagnostic limitations are especially applicable when attempting to document infection with a Bartonella spp. in a nonreservoir host.16,17 In conjunction with efforts to enhance the sensitivity of PCR for detection of Bartonella-specific DNA sequences, we have recently incorporated pre-enrichment culture of aseptically obtained diagnostic samples (blood, cerebrospinal, aqueous, and joint fluids and effusions) using a liquid insect cell culture-based medium (BAPGM) before PCR testing.8 Combining pre-enrichment culture with PCR amplification has substantially improved diagnostic sensitivity when testing samples from dogs and humans infected with novel Bartonella species.18 Historically, because B. henselae and B. clarridgeiae could be readily isolated from cat blood after an incubation period of a few weeks in a high CO2 incubator, our laboratory did not initially recommend the use of BAPGM when culturing cat blood samples. As illustrated by this cat, direct PCR from blood was negative, suggesting that an enrichment culture approach may be necessary to diagnose infection with non–reservoir-adapted Bartonella spp. in cats, as has been shown for dogs and human patients.1,4,16,17 In addition, PCR amplification of B. vinsonii subsp. berkhoffii DNA only after enrichment culture supports the presence of viable bacteria in the blood sample, because the initial PCR-negative blood sample was diluted 1 part blood to 10 parts BAPGM before incubation for 7 days. Various Bartonella spp. are transmitted among reservoir hosts by fleas, lice, sand flies, keds, and possibly biting flies and ticks.19 Transmission to non–reservoir-adapted hosts can occur via an arthropod bite or a scratch or bite by a carrier animal. The mode of B. vinsonii subsp. berkhoffii transmission to this cat is unknown. B. vinsonii subsp. berkhoffii DNA has been amplified and sequenced from saliva obtained from healthy dogs, and dogs have been implicated in the direct transmission of B. henselae to humans.20 Therefore, dog bite transmission could have been a source of infection for this cat. Although there is clinical and epidemiological evidence to support B. vinsonii subsp. berkhoffii transmission by Rhipicephalus sanguineus, tick transmission has not been proven.19 In recent years, Bartonella spp. have been associated with a wide spectrum of inflammatory lesions in dogs and human patients, including endocarditis, encephalitis, meningitis, granulomatous hepatitis, splenitis, and necrotizing granulomatous lymphadenitis.6,21,22 Classically these facultative, intracellular bacteria induce a B-cell–associated granulomatous reaction, characterized by numerous histiocytes, plasmacytoid monocytes, small lymphocytes, multinucleated giant cells, and plasma cells intermingled with monocytoid B-cells.23 Granulomatous inflammation, accompanied by an unusually large number of plasma cells and hyperglobulinemia, was most likely related to B. vinsonii subsp. berkhoffii infection in this cat. Importantly, 2 pathologists thought plasma cell tumor was a diagnostic consideration. Fever and leukocytosis were not associated with polyarthritis and osteomyelitis in this cat. Thrombocytopenia and neutropenia have been reported in dogs and humans infected with Bartonella spp.24 Although osteomyelitis may have caused hypercalcemia, endogenous production of active vitamin D may have contributed, as reported in twins with CSD.25 Additional studies are needed to determine the frequency of B. vinsonii subsp. berkhoffii infection in cats. Based on this case report, Bartonella spp. infection should be considered in the differential diagnosis of osteomyelitis, hypercalcemia, hyperglobulinemia, and thrombocytopenia in cats. This study was supported by the State of North Carolina and in part through graduate student stipend or salary support provided by Bayer Animal Health and IDEXX Laboratories.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Varanat, M. and Travis, A. and Lee, W. and Maggi, R.G. and Bissett, S.A. and Linder, K.E. and Breitschwerdt, E.B.}, year={2009}, month={Nov}, pages={1273–1277} }
 @article{van wettere_linder_suter_olby_2009, title={Solitary Intracerebral Plasmacytoma in a Dog: Microscopic, Immunohistochemical, and Molecular Features}, volume={46}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1354/vp.08-VP-0012-V-BC}, DOI={10.1354/vp.08-VP-0012-V-BC}, abstractNote={A primary intracerebral plasmacytoma was identified in a 7-year-old spayed female Boston Terrier. Grossly, a well-demarcated, 2 cm in diameter, roughly spherical tumor was in the rostral aspect of the left cerebral hemisphere. Histologically, the neoplasm was composed of sheets of round cells with distinct plasmacytoid features and marked anisocytosis and anisokaryosis. Cells were positive for vimentin, CD18, CD79a, and lambda light-chain, and negative for kappa light chain, cytokeratin, lysozyme, glial fibrillary acidic protein, and S100 protein. Clonally rearranged B-cell antigen receptor genes were detected by PARR (polymerase chain reaction for antigen receptor rearrangements), confirming clonal proliferation of B lymphocytes. Although primary solitary intracerebral plasmacytoma is rare in dogs and other species, it should be included in the differential diagnosis for central nervous system round-cell neoplasms. Clonality testing can be utilized to support the histological diagnosis of this neoplasm type.}, number={5}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Van Wettere, A. J. and Linder, K. E. and Suter, S. E. and Olby, N. J.}, year={2009}, month={May}, pages={949–951} }
 @article{thomas_duke_wang_breen_higgins_linder_ellis_langford_dickinson_olby_et al._2009, title={‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors}, volume={94}, ISSN={0167-594X 1573-7373}, url={http://dx.doi.org/10.1007/s11060-009-9877-5}, DOI={10.1007/s11060-009-9877-5}, abstractNote={Numerous attributes render the domestic dog a highly pertinent model for cancer-associated gene discovery. We performed microarray-based comparative genomic hybridization analysis of 60 spontaneous canine intracranial tumors to examine the degree to which dog and human patients exhibit aberrations of ancestrally related chromosome regions, consistent with a shared pathogenesis. Canine gliomas and meningiomas both demonstrated chromosome copy number aberrations (CNAs) that share evolutionarily conserved synteny with those previously reported in their human counterpart. Interestingly, however, genomic imbalances orthologous to some of the hallmark aberrations of human intracranial tumors, including chromosome 22/NF2 deletions in meningiomas and chromosome 1p/19q deletions in oligodendrogliomas, were not major events in the dog. Furthermore, and perhaps most significantly, we identified highly recurrent CNAs in canine intracranial tumors for which the human orthologue has been reported previously at low frequency but which have not, thus far, been associated intimately with the pathogenesis of the tumor. The presence of orthologous CNAs in canine and human intracranial cancers is strongly suggestive of their biological significance in tumor development and/or progression. Moreover, the limited genetic heterogenity within purebred dog populations, coupled with the contrasting organization of the dog and human karyotypes, offers tremendous opportunities for refining evolutionarily conserved regions of tumor-associated genomic imbalance that may harbor novel candidate genes involved in their pathogenesis. A comparative approach to the study of canine and human intracranial tumors may therefore provide new insights into their genetic etiology, towards development of more sophisticated molecular subclassification and tailored therapies in both species.}, number={3}, journal={Journal of Neuro-Oncology}, publisher={Springer Science and Business Media LLC}, author={Thomas, Rachael and Duke, Shannon E. and Wang, Huixia J. and Breen, Tessa E. and Higgins, Robert J. and Linder, Keith E. and Ellis, Peter and Langford, Cordelia F. and Dickinson, Peter J. and Olby, Natasha J. and et al.}, year={2009}, month={Mar}, pages={333–349} }
 @article{hardie_linder_pease_2008, title={Aural Cholesteatoma in Twenty Dogs}, volume={37}, ISSN={["1532-950X"]}, DOI={10.1111/j.1532-950X.2008.00455.x}, abstractNote={To determine the clinical course in dogs with aural cholesteatoma.Case series.Dogs (n=20) with aural cholesteatoma.Case review (1998-2007).Twenty dogs were identified. Clinical signs other than those of chronic otitis externa included head tilt (6 dogs), unilateral facial palsy (4), pain on opening or inability to open the mouth (4), and ataxia (3). Computed tomography (CT) was performed in 19 dogs, abnormalities included osteoproliferation (13 dogs), lysis of the bulla (12), expansion of the bulla (11), bone lysis in the squamous or petrosal portion of the temporal bone (4) and enlargement of associated lymph nodes (7). Nineteen dogs had total ear canal ablation-lateral bulla osteotomy or ventral bulla osteotomy with the intent to cure; 9 dogs had no further signs of middle ear disease whereas 10 had persistent or recurrent clinical signs. Risk factors for recurrence after surgery were inability to open the mouth or neurologic signs on admission and lysis of any portion of the temporal bone on CT imaging. Dogs admitted with neurologic signs or inability to open the mouth had a median survival of 16 months.Early surgical treatment of aural cholesteatoma may be curative. Recurrence after surgery is associated with advanced disease, typically indicated by inability to open the jaw, neurologic disease, or bone lysis on CT imaging.Presence of aural cholesteatoma may affect the prognosis for successful surgical treatment of middle ear disease.}, number={8}, journal={VETERINARY SURGERY}, author={Hardie, Elizabeth M. and Linder, Keith E. and Pease, Anthony P.}, year={2008}, month={Dec}, pages={763–770} }
 @article{chinnadurai_brown_van wettere_tuttle_fatzinger_linder_harms_2008, title={MORTALITIES ASSOCIATED WITH SEPSIS, PARASITISM, AND DISSEMINATED ROUND CELL NEOPLASIA IN YELLOW-LIPPED SEA KRAITS (LATICAUDA COLUBRINA)}, volume={39}, ISSN={["1937-2825"]}, DOI={10.1638/2008-0018.1}, abstractNote={This case series describes multiple mortalities associated with sepsis, neoplasia, and endoparasitism in yellow-lipped sea kraits (Laticauda colubrina) at an exhibit aquarium. Over a 2-yr period, the facility kept 42 L. colubrina, of which 38 died and 19 were suitable for necropsy and histopathology. The common clinical syndrome seen in these animals consisted of partial to compete anorexia, increased time spent “hauled-out” on land, intermittent regurgitation, chronic lethargy, and weight loss. Few animals died without premonitory signs. Nutritional support and treatment for presumptive parasitism and sepsis were unsuccessful. The mortality seen in this collection of sea kraits could be placed into three groups; one group of animals (n = 9) died of sepsis secondary to necrotizing enteritis or pneumonia; one group (n = 6) remained apparently healthy for over 1 yr and then died with multifocal granulomas and sepsis; and the last group (n = 3) died as a result of multicentric lymphoid neoplasia with secondary sepsis. The unifying factor in the majority of these cases is the presence of septicemia as the proximate cause of death. Based on the clinical picture, it is presumed that an immunosuppressive event, such as transport, captivity stress, or possible concurrent viral infection, resulted in a septic event and death.}, number={4}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Chinnadurai, Sathya K. and Brown, Danielle L. and Van Wettere, Arnaud and Tuttle, Allison D. and Fatzinger, Michael H. and Linder, Keith E. and Harms, Craig A.}, year={2008}, month={Dec}, pages={626–630} }
 @article{ranck_linder_haber_meuten_2008, title={Primary intimal aortic angiosarcoma in a dog}, volume={45}, ISSN={["0300-9858"]}, DOI={10.1354/vp.45-3-361}, abstractNote={A primary intimal aortic angiosarcoma was diagnosed in a 4-year-old, spayed female German Shepherd that presented for complications of thromboembolic disease because of infarcts in multiple organs. On gross examination, aneurysmal dilatation of the aorta was associated with a friable, necrotic mass attached to the endothelial surface, which partially occluded the aortic lumen. On histologic examination, plump neoplastic spindle cells formed a plaque-like mass arising from the intima that merged with a large accumulation of fibrin and necrotic debris, and projected into the lumen. Neoplastic cells invaded periaortic vessels and were seen in some infarct-associated thromboemboli. Tumor cells expressed vimentin and CD31, with infrequent, patchy staining with factor VIII-related antigen; tumor cells were negative for cytokeratin and smooth-muscle actin. Aortic angiosarcoma is a rare malignancy in humans. This is the first description of a primary intimal aortic angiosarcoma in a dog, with immunohistochemical evidence of endothelial origin.}, number={3}, journal={VETERINARY PATHOLOGY}, author={Ranck, R. S. and Linder, K. E. and Haber, M. D. and Meuten, D. J.}, year={2008}, month={May}, pages={361–364} }
 @article{chinnadurai_van wettere_linder_harms_devoe_2008, title={Secondary amyloidosis and renal failure in a captive California sea lion (Zalophus californianus)}, volume={39}, ISSN={["1937-2825"]}, DOI={10.1638/2007-0096R.1}, abstractNote={A 16-yr-old, captive-born, female California sea lion (Zalophus californianus) was evaluated for intermittent lethargy, partial anorexia, and polydipsia of 2 wk duration. The animal was immobilized for physical examination. It was in thin body condition, with multifocal mucosal ulcerations over the caudal and ventral tongue. Blood was collected for hematology, serum chemistry, and leptospirosis serology. Serum chemistry revealed severe azotemia, mild hyperglycemia, and severe hyperphosphatemia. The animal went into cardiac arrest during recovery from anesthesia and died. On histopathology, abundant amorphous, finely fibrillar, eosinophilic material was deposited in the kidneys, and smaller amounts of the same material were found in the splenic and pancreatic vessels; these findings are consistent with systemic secondary amyloidosis. The animal also had chronic nephritis, which, coupled with renal amyloidosis, resulted in renal failure and death. Systemic amyloidosis should be considered as an additional differential diagnosis for renal failure in California sea lions.}, number={2}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, author={Chinnadurai, Sathya K. and Van Wettere, Arnaud and Linder, Keith E. and Harms, Craig A. and DeVoe, Ryan S.}, year={2008}, month={Jun}, pages={274–278} }
 @article{mackillop_thrall_ranck_linder_munana_2007, title={Imaging diagnosis-synchronous primary brain tumors in a dog}, volume={48}, ISSN={["1058-8183"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-35448932842&partnerID=MN8TOARS}, DOI={10.1111/j.1740-8261.2007.00294.x}, abstractNote={Veterinary Radiology & UltrasoundVolume 48, Issue 6 p. 550-553 IMAGING DIAGNOSIS—SYNCHRONOUS PRIMARY BRAIN TUMORS IN A DOG EDWARD MacKILLOP, EDWARD MacKILLOP Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428,Search for more papers by this authorDONALD E. THRALL, DONALD E. THRALL Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428Search for more papers by this authorROSE S. RANCK, ROSE S. RANCK Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428, andSearch for more papers by this authorKEITH E. LINDER, KEITH E. LINDER Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428, andSearch for more papers by this authorKAREN R. MUNANA, KAREN R. MUNANA Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428,Search for more papers by this author EDWARD MacKILLOP, EDWARD MacKILLOP Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428,Search for more papers by this authorDONALD E. THRALL, DONALD E. THRALL Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428Search for more papers by this authorROSE S. RANCK, ROSE S. RANCK Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428, andSearch for more papers by this authorKEITH E. LINDER, KEITH E. LINDER Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428, andSearch for more papers by this authorKAREN R. MUNANA, KAREN R. MUNANA Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, NC 277606 1428,Search for more papers by this author First published: 22 October 2007 https://doi.org/10.1111/j.1740-8261.2007.00294.xCitations: 10 Address correspondence and reprint requests to Dr. Karen Munana at the above address. E-mail: karen_munana@ncsu.edu Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume48, Issue6November–December 2007Pages 550-553 RelatedInformation}, number={6}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={MacKillop, Edward and Thrall, Donald E. and Ranck, Rose S. and Linder, Keith E. and Munana, Karen R.}, year={2007}, pages={550–553} }
 @article{mackillop_olby_linder_brown_2007, title={Intramedullary cavernous malformation of the spinal cord in two dogs}, volume={44}, ISSN={["1544-2217"]}, DOI={10.1354/vp.44-4-528}, abstractNote={Intramedullary cavernous malformations (CVMs) of the spinal cord were diagnosed in 2 adult dogs that presented for paraparesis. An intramedullary spinal cord lesion was identified on a myelogram in the first dog, and expansion of the vertebral canal was evident on radiographs in the second. Extensive intraparenchymal hemorrhage was found on gross postmortem examination in both dogs, and a distinct lobulated intramedullary mass was evident in the second dog. Microscopically, both lesions were composed of dilated, thin-walled vascular channels with little-to-no intervening neural parenchyma. Both dogs had evidence of channel thrombosis along with perilesional hemorrhage and hemosiderin accumulation. The second dog had additional degenerative changes, including thickened fibrous channel walls with hyalinization, foci of mineralization, and occasional tongues of entrapped gliotic neuropil. CVMs appear to be an uncommon cause of both acute and chronic spinal cord disease in the dog.}, number={4}, journal={VETERINARY PATHOLOGY}, author={Mackillop, E. and Olby, N. J. and Linder, K. E. and Brown, T. T.}, year={2007}, month={Jul}, pages={528–532} }
 @article{snyder_linder_neel_2007, title={Malignant peripheral nerve sheath tumor in a hamster}, volume={46}, number={6}, journal={Journal of the American Association for Laboratory Animal Science}, author={Snyder, L. A. and Linder, K. E. and Neel, J. A.}, year={2007}, pages={55–57} }
 @article{tuttle_frederico_linder_gunkel_remick_redding_2007, title={Pathological fracture of the ulna due to osteosarcoma in an Arabian camel (Camelus dromedarius)}, volume={161}, ISSN={["0042-4900"]}, DOI={10.1136/vr.161.1.30}, abstractNote={Veterinary RecordVolume 161, Issue 1 p. 30-33 Short Communication Pathological fracture of the ulna due to osteosarcoma in an Arabian camel (Camelus dromedarius) A. D. Tuttle DVM, A. D. Tuttle DVM Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorL. Frederico DVM, L. Frederico DVM Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorK. Linder DVM, DACVP, K. Linder DVM, DACVP Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorC. Gunkel DrMedVet, DACVA, Corresponding Author C. Gunkel DrMedVet, DACVA n/[email protected] Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USA Dr Gunkel's present address is Oregon State University, College of Veterinary Medicine, 219 Magruder Street, Corvallis, OR 97331, USA Dr Remick's present address is Biotechnics, LLC 310 Millstone Drive, Hillsborough, NC 27278, USA Dr Frederico's present address is 2753 Michelle Park, Lexington, KY 40511, USASearch for more papers by this authorA. Remick DVM, A. Remick DVM Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorR. Redding DVM, DACVS, R. Redding DVM, DACVS Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this author A. D. Tuttle DVM, A. D. Tuttle DVM Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorL. Frederico DVM, L. Frederico DVM Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorK. Linder DVM, DACVP, K. Linder DVM, DACVP Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorC. Gunkel DrMedVet, DACVA, Corresponding Author C. Gunkel DrMedVet, DACVA n/[email protected] Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USA Dr Gunkel's present address is Oregon State University, College of Veterinary Medicine, 219 Magruder Street, Corvallis, OR 97331, USA Dr Remick's present address is Biotechnics, LLC 310 Millstone Drive, Hillsborough, NC 27278, USA Dr Frederico's present address is 2753 Michelle Park, Lexington, KY 40511, USASearch for more papers by this authorA. Remick DVM, A. Remick DVM Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this authorR. Redding DVM, DACVS, R. Redding DVM, DACVS Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606 USASearch for more papers by this author First published: 07 July 2007 https://doi.org/10.1136/vr.161.1.30Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume161, Issue1July 2007Pages 30-33 RelatedInformation}, number={1}, journal={VETERINARY RECORD}, author={Tuttle, A. D. and Frederico, L. and Linder, K. and Gunkel, C. and Remick, A. and Redding, R.}, year={2007}, month={Jul}, pages={30–33} }
 @article{cannon_linder_brizuela_harvey_2006, title={Marked swelling with coalescing ecchymoses of the lower mandible in a Xenopus laevis frog}, volume={35}, ISSN={["1548-4475"]}, DOI={10.1038/laban0506-19}, number={5}, journal={LAB ANIMAL}, author={Cannon, Coralie Zegre and Linder, Keith and Brizuela, Brenda J. and Harvey, Stephen B.}, year={2006}, month={May}, pages={19–22} }
 @article{tarigo_linder_neel_harvey_remick_grindem_2006, title={What is your diagnosis? Reluctant to dive: coelomic effusion in a frog}, volume={35}, ISSN={["0275-6382"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-33750693063&partnerID=MN8TOARS}, DOI={10.1111/j.1939-165X.2006.tb00145.x}, abstractNote={Abstract An adult female, albino South African Clawed frog (Xenopus laevis) from a research colony at the Biological Resources Facility of the College of Agriculture and Life Sciences at North Carolina State University (NCSU) was presented with depression, lethargy, loss of diving reflex, and a distended abdomen. Cytologic examination of coelomic effusion fluid at the NCSU veterinary teaching hospital revealed a mixed population of inflammatory cells, including heterophils and a predominance of large mononuclear cells (macrophages) that often contained intracytoplasmic, negatively-stained, rod-shaped to filamentous organisms consistent with Mycobacterium sp. Ziehl-Neelsen stain revealed bright pink to red, acid-fast organisms with a beaded appearance. Histopathologic findings in tissues obtained at necropsy included marked, multifocal to coalescing, heterophilic, granulomatous and fibrinous coelomitis as well as severe multifocal heterophilic and granulomatous hepatitis, interstitial pneumonia and sinusitis/rhinitis. Slender gram-positive, acid-fast bacterial rods were identified in sections of coelomic pleura, kidneys, nasal cavities, spleen, liver, and pulmonary interstitium, indicative of systemic mycobacteriosis. Based on mycobacterial culture, the organism was identified as M marinum complex. Mycobacteria are variably gram-positive, often acid-fast, small rods that are ubiquitous in aquatic environments. The clinical and pathologic spectrum of disease in amphibians depends on host and pathogen status. Xenopus sp and several other frogs are good models for studying the pathogenesis of M tuberculosis infection. In addition to culture, polymerase chain reaction assays may be used for definitive identification of the organisms; accurate speciation may require further genetic investigation.}, number={3}, journal={VETERINARY CLINICAL PATHOLOGY}, author={Tarigo, Jaime and Linder, Keith and Neel, Jennifer and Harvey, Stephen and Remick, Amera and Grindem, Carol}, year={2006}, month={Sep}, pages={341–344} }
 @article{govett_harms_linder_marsh_wyneken_2004, title={Effect of four different suture materials on the surgical wound healing of loggerhead sea turtles, Caretta caretta}, volume={14}, ISBN={1529-9651}, DOI={10.5818/1529-9651.14.4.6}, abstractNote={ABSTRACT The tissue reaction to four suture materials placed in the skin of juvenile loggerhead sea turtles, Caretta caretta, was evaluated both grossly and histologically. Chromic gut, polyglyconate, polyglactin 910, and poliglecaprone 25 were used in 258 turtles to close a wound produced at the time of laparoscopic sex determination. Gross tissue reactions were graded in 68 turtles at one week, and in the remaining 190 turtles at two weeks following surgery. Gross observations (eversion formation, holding of sutures, epibiont [organisms growing on suture site] present and crusts) were graded from one to three with one being mild and three being most severe. Gross observation scores did not differ among suture types. Crust scores were significantly greater for chromic gut and for polyglactin than for poliglecaprone 25 and polyglyconate. At the suture site, 32% of the turtles had an eversion in the incision ranging in size from 0.25 to 10 mm2 [mean 2.02 (+/− 1.95) mm2]. Eversion size did not vary signific...}, number={4}, journal={Journal of Herpetological Medicine and Surgery}, author={Govett, P. D. and Harms, Craig and Linder, K. E. and Marsh, J. C. and Wyneken, J.}, year={2004}, pages={6} }
 @article{mozzachio_linder_dixon_2004, title={Uterine smooth muscle tumors in potbellied pigs (Sus scrofa) resemble human fibroids: A potential animal model}, volume={32}, ISSN={["1533-1601"]}, DOI={10.1080/01926230490440880}, abstractNote={Uterine leiomyomas, commonly termed fibroids. clinically affect approximately 25% of women of reproductive age in the United States, with a subclinical incidence as high as 77%. The pathogenesis of fibroid formation remains poorly understood, due in large part to the lack of a suitable animal model. This retrospective study characterizes the clinical, gross, and histopathologic features of similar, spontaneously occurring uterine tumors in potbellied pigs. Medical records available through a local Potbellied Pig Spay/Neuter Program, pig sanctuaries, and the Duchess Fund database were reviewed for evidence of reproductive disease or surgery. One-hundred and six female potbellied pigs were evaluated and uterine neoplasia was identified in 17 animals: tissues were available for 13 of these. Uterine leiomyoma was diagnosed in 11 of 13 cases, leiomyosarcoma in 1 of 13 cases, and undifferentiated sarcoma in 1 case. Pigs presented with clinical signs including abdominal distension or vaginal bleeding or were subclinical and identified during ovariohysterectomy. Tumors ranged from microscopic to 45 kg, were often multiple, and primarily involved the uterine horns. Hematoxylin and eosin and trichrome-stained sections were evaluated for morphological features of human and animal leiomyomas: immunohistochemistry to detect smooth muscle actin was also performed. The cellular pattern/morphology and variable degree of fibroplasia of the leiomyomas were similar to that reported for human fibroids. These results support further investigation of uterine leiomyomas in potbellied pigs as a potentially valuable animal model for studying human fibroids.}, number={4}, journal={TOXICOLOGIC PATHOLOGY}, author={Mozzachio, K and Linder, K and Dixon, D}, year={2004}, pages={402–407} }
 @inbook{linder_2003, place={Boston, MA}, title={The skin xenograft mouse model in veterinary dermatology research modeling canine demodicosis}, volume={4}, booktitle={Advances in Veterinary Dermatology}, publisher={Blackwell Science}, author={Linder, K.}, editor={Thoday, K and Foil, C and Bond, R and Linder, K and Parker, W and Kunkle, G and Yager, JEditors}, year={2003} }
 @article{spirito_charlesworth_ortonne_meneguzzi_linder_baird_2002, title={Animal Models for Skin Blistering Conditions: Absence of Laminin 5 Causes Hereditary Junctional Mechanobullous Disease in the Belgian Horse}, volume={119}, ISSN={0022-202X}, url={http://dx.doi.org/10.1046/j.1523-1747.2002.01852.x}, DOI={10.1046/j.1523-1747.2002.01852.x}, abstractNote={Recent achievements in the genetic correction of keratinocytes isolated from patients with junctional epidermolysis bullosa have paved the way to a gene therapy approach for the disease. Because gene therapy protocols require preclinical validation in animals, we have characterized spontaneous animal models of junctional epidermolysis bullosa. In this study we have elucidated the genetic basis of the hereditary junctional mechanobullous disease in the Belgian horse, a condition characterized by blistering of the skin and mouth epithelia, and exungulation (loss of the hoof). Immunofluorescence analysis associated the condition to the absent expression of the γ2 chain of laminin 5 and designated Lamc2 as the candidate gene. Comparative analysis of the nucleotide sequence of the full-length γ2 cDNA isolated by reverse transcription polymerase chain reaction amplification of total RNA purified from the epithelium of a junctional epidermolysis bullosa foal and a healthy control disclosed a homozygous basepair insertion (1368insC) in the affected animal. Mutation 1368insC results in a downstream premature termination codon and is predicted to cause absent expression of the laminin γ2 polypeptide. Our results also show that: (i) the horse junctional epidermolysis bullosa genetically corresponds to the severe Herlitz form of junctional epidermolysis bullosa in man; (ii) the amino acid sequence and structure of the horse laminin γ2 chain are virtually identical to the human counterpart; (iii) the moderate eruption of skin blisters in the affected animals with respect to the human Herlitz junctional epidermolysis bullosa patients correlates with the protection provided by hair. Our observations suggest that the affected foals are a convenient source of epithelial cells from tissues that cannot be obtained from human junctional epidermolysis bullosa patients, and imply that hairless strains of animals with recessive skin disorders would be the best models for in vivo gene therapy approaches to skin blistering diseases. Recent achievements in the genetic correction of keratinocytes isolated from patients with junctional epidermolysis bullosa have paved the way to a gene therapy approach for the disease. Because gene therapy protocols require preclinical validation in animals, we have characterized spontaneous animal models of junctional epidermolysis bullosa. In this study we have elucidated the genetic basis of the hereditary junctional mechanobullous disease in the Belgian horse, a condition characterized by blistering of the skin and mouth epithelia, and exungulation (loss of the hoof). Immunofluorescence analysis associated the condition to the absent expression of the γ2 chain of laminin 5 and designated Lamc2 as the candidate gene. Comparative analysis of the nucleotide sequence of the full-length γ2 cDNA isolated by reverse transcription polymerase chain reaction amplification of total RNA purified from the epithelium of a junctional epidermolysis bullosa foal and a healthy control disclosed a homozygous basepair insertion (1368insC) in the affected animal. Mutation 1368insC results in a downstream premature termination codon and is predicted to cause absent expression of the laminin γ2 polypeptide. Our results also show that: (i) the horse junctional epidermolysis bullosa genetically corresponds to the severe Herlitz form of junctional epidermolysis bullosa in man; (ii) the amino acid sequence and structure of the horse laminin γ2 chain are virtually identical to the human counterpart; (iii) the moderate eruption of skin blisters in the affected animals with respect to the human Herlitz junctional epidermolysis bullosa patients correlates with the protection provided by hair. Our observations suggest that the affected foals are a convenient source of epithelial cells from tissues that cannot be obtained from human junctional epidermolysis bullosa patients, and imply that hairless strains of animals with recessive skin disorders would be the best models for in vivo gene therapy approaches to skin blistering diseases. IIn recent years, novel approaches have been explored to treat inherited skin disorders in which a failing function of the keratinocytes cannot be compensated by conventional pharmacologic treatments (Meneguzzi et al., 2000Meneguzzi G. Vailly J. Gene therapy of inherited skin diseases.in: Hengge U.R. Volc-Platzer B. The Skin and Gene Therapy. Springer-Verlag, Berlin2000: 97-116Google Scholar). Autologous transplantation of epithelial sheets derived from ex vivo genetically modified keratinocytes is the most direct approach that may allow replacement of the defective tissue and restoration of a deficient function (Spirito et al., 2001Spirito F. Meneguzzi G. Danos O. Mezzina M. Cutaneous gene transfer and therapy: the present and the future.J Gene Med. 2001; 3: 21-31Crossref PubMed Scopus (52) Google Scholar). Transduction by retroviral vectors expressing a therapeutic gene has been shown to correct the genetic defects in keratinocytes isolated from patients affected by X-linked ichthyosis, lamellar ichthyosis, and junctional epidermolysis bullosa (JEB), both in vitro and in vivo (Choate et al., 1996Choate K.A. Kinsella T.M. Williams M.L. Nolan G.P. Khavari P.A. Transglutaminase 1 delivery to lamellar ichthyosis keratinocytes.Hum Gene Ther. 1996; 7: 2247-2253Crossref PubMed Scopus (66) Google Scholar;Freiberg et al., 1997Freiberg R.A. Choate K.A. Deng H. Alperin E.S. Shapiro L.J. Khavari P.A. A model of corrective gene transfer in X-linked ichthyosis.Hum Mol Genet. 1997; 6: 927-933Crossref PubMed Scopus (62) Google Scholar;Dellambra et al., 1998Dellambra E. Vailly J. Pellegrini G. et al.Corrective transduction of human epidermal stem cells in laminin-5-dependent junctional epidermolysis bullosa.Hum Gene Ther. 1998; 9: 1359-1370Crossref PubMed Scopus (109) Google Scholar;Vailly et al., 1998Vailly J. Gagnoux-Palacios L. Dell'Ambra E. et al.Corrective gene transfer of keratinocytes from patients with junctional epidermolysis bullosa restores assembly of hemidesmosomes in reconstructed epithelia.Gene Ther. 1998; 5: 1322-1332Crossref PubMed Scopus (83) Google Scholar;Seitz et al., 1999Seitz C. Giudice G. Balding S. Marinkovich M. Khavari P. BP180 gene delivery in junctional epidermolysis bullosa.Gene Ther. 1999; 6: 42-47Crossref PubMed Scopus (71) Google Scholar). The expression of the curative transgenes is permanent in epithelia reconstructed using keratinocytes genetically modified ex vivo and transplanted onto immune-deficient mice. These achievements demonstrate that successful targeting of epithelial stem-like cells by retroviral vectors allows generation of an engineered self-renovating integument. The fate of the transgene product expressed by the engineered epithelia grafted onto immunocompetent hosts, however, remains an open question (Ghazizadeh et al., 1999Ghazizadeh S. Harrington R. Taichman L. In vivo transduction of mouse epidermis with recombinant retroviral vectors: implication for cutaneous gene therapy.Gene Ther. 1999; 6: 1267-1275Crossref PubMed Scopus (79) Google Scholar). JEB is a recessive inherited disease that causes blister formation after minor trauma (Fine et al., 2000Fine J.D. Eady R.A.J. Bauer E.A. et al.Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.J Am Acad Dermatol. 2000; 42: 1051-1066Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar). The plane of the blisters localizes within the lamina lucida of the dermal-epidermal junction. The heterogeneity of the clinical phenotypes correlates with a variety of genetic mutations in the genes encoding three components of the hemidesmosome-anchoring filament complex (Uitto and Pulkkinen, 2001Uitto J. Pulkkinen L. Molecular genetics of heritable blistering disorders.Arch Dermatol. 2001; 137: 1458-1461Crossref PubMed Scopus (57) Google Scholar). The mild JEB variants that do not affect the patients' life span are associated with mutations in integrin α6β4, laminin 5, and collagen XVII, whereas the severe and life threatening variants of the conditions are associated with absent expression of integrin α6β4 and laminin 5 (Uitto and Pulkkinen, 2001Uitto J. Pulkkinen L. Molecular genetics of heritable blistering disorders.Arch Dermatol. 2001; 137: 1458-1461Crossref PubMed Scopus (57) Google Scholar). Genetic correction of primary JEB keratinocytes enriched in stem cells has been reported to fully restore cell adhesion and stably maintain the high proliferative and clonogenic potential of the engineered cells that upon grafting onto immune-deficient mice regenerate firmly adhering epithelia (Dellambra et al., 1998Dellambra E. Vailly J. Pellegrini G. et al.Corrective transduction of human epidermal stem cells in laminin-5-dependent junctional epidermolysis bullosa.Hum Gene Ther. 1998; 9: 1359-1370Crossref PubMed Scopus (109) Google Scholar;Robbins et al., 2001Robbins P.B. Lin Q. Goodnough J.B. Tian H. Chen X. Khavari P.A. In vivo restoration of laminin 5 beta 3 expression and function in junctional epidermolysis bullosa.Proc Natl Acad Sci USA. 2001; 98: 5193-5198Crossref PubMed Scopus (115) Google Scholar). Evaluation of therapeutic efficacy of the gene therapy approach in preclinical trials, however, is so far hampered by the unavailability of suitable immunocompetent JEB animal models. Indeed, in mice strains with null mutations in the genes for laminin 5, the homozygous JEB pups die shortly after birth (Kuster et al., 1997Kuster J.E. Guarnieri M.H. Ault J.G. Flaherty L. Swiatek P.J. IAP insertion in the murine LamB3 gene results in junctional epidermolysis bullosa.Mamm Genome. 1997; 8: 673-681Crossref PubMed Scopus (79) Google Scholar;Ryan et al., 1999Ryan M.C. Lee K. Miyashita Y. Carter W.G. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells.J Cell Biol. 1999; 145: 1309-1323Crossref PubMed Scopus (247) Google Scholar). 2Uitto J, Meng X, Klement J, Pulkkinen L: Targeted ablation of the murine LAMC2 gene recapitulates human Herlitz junctional epidermolysis bullosa phenotype. J Invest Dermatol 117:1680, 2001 (Abstr.)2Uitto J, Meng X, Klement J, Pulkkinen L: Targeted ablation of the murine LAMC2 gene recapitulates human Herlitz junctional epidermolysis bullosa phenotype. J Invest Dermatol 117:1680, 2001 (Abstr.) The development of conditional mouse models that harbor mutations found in JEB patients is expected to provide the means to assess gene therapy approaches. Comparative genotype-phenotype correlations, however, may be biased by morphologic dissimilarities between human and adult mouse skin, such as, for instance, the reduced number of cell layers in the mouse epidermis and the presence of dense hair that protects the integument of animals from trauma. To establish a genotype-phenotype correlation in a spontaneous animal model of JEB, we have assessed the molecular basis of a mechanobullous disease with a suspected inherited etiology (online Mendelian inheritance in animals, OMIA #000342) that has been described in Belgian foals in the U.S.A. (Kohn et al., 1989Kohn C.W. Johnson G.C. Garry F. Johnson C.W. Martin S. Scott D.W. Mechanobullous disease in two Belgian foals.Equine Vet J. 1989; 21: 297-301Crossref PubMed Scopus (25) Google Scholar) and Canada (Shapiro and Mcewen, 1995Shapiro J. Mcewen B. Mechanobullous disease in a Belgian foal in eastern Ontario.Can Vet J. 1995; 36: 572PubMed Google Scholar). This condition is also designated “epitheliogenesis imperfecta neonatorum” (OMIA #000348) (Berthelsen and Eriksson, 1935Berthelsen H. Eriksson K. Epitheliogenesis imperfecta neonatorum in a foal, possibly of a hereditary nature.J Comp Pathol. 1935; 48: 285-297Crossref Google Scholar). Clinically, the affected foals exhibit generalized skin blistering at the pressure points, severe oral cavity involvement, and exungulation (Frame et al., 1988Frame S.R. Harrington D.D. Fessler J. Frame P.F. Hereditary junctional mechanobullous disease in a foal.J Am Vet Med Assoc. 1988; 193: 1420-1424PubMed Google Scholar;Kohn et al., 1989Kohn C.W. Johnson G.C. Garry F. Johnson C.W. Martin S. Scott D.W. Mechanobullous disease in two Belgian foals.Equine Vet J. 1989; 21: 297-301Crossref PubMed Scopus (25) Google Scholar;Shapiro and Mcewen, 1995Shapiro J. Mcewen B. Mechanobullous disease in a Belgian foal in eastern Ontario.Can Vet J. 1995; 36: 572PubMed Google Scholar). Electron microscopy examination revealed junctional blistering and abnormal hemidesmosomes (Johnson et al., 1988Johnson G.C. Kohn C.W. Johnson C.W. Garry F. Scott D. Martin S. Ultrastructure of junctional epidermolysis bullosa in Belgian foals.J Comp Pathol. 1988; 98: 329-336Crossref Scopus (30) Google Scholar); therefore, by analogy to the ultrastructural features of human JEB, the condition was also designated “hereditary junctional mechanobullous disease” (Gourreau et al., 1990Gourreau J.-M. Feillou C. Dupere A.-M. Courreau J.-F. Alliot A. Menguy R. Epidermolyse bulleuse jonctionnelle letale chez le cheval de trait.Le Point Veterinaire. 1990; 22: 65-67Google Scholar). In this study we report the immunochemical characterization of this disorder, and provide the genetic evidence that, despite the reduced tendency of the skin to form blisters, the condition corresponds to the severe (Herlitz) form of JEB in man. The animals were Belgian foals, born on different farms in Ontario, Canada, and suffering from extensive skin blistering associated with severe oral cavity involvement. Foal no. 1 was the fourth foal of a mare that had previously had an affected offspring. One day after birth, multiple ulcerations of the skin were present over the pressure points on the legs and head. Erosions were also observed on the tongue and the mucous membrane of rostral maxillae. Foal no. 2 presented multiple mucosal and epithelial erosions at birth. Multifocal, irregular areas of erosions were noted over the pressure points of the legs, along the coronary band of all four hooves, and on the oral and conjunctival mucous membranes. An abnormally roughened enamel was present over the teeth and there was evidence of bleeding from oral erosions. In foal no. 3, multiple skin defects were noticed shortly after birth. Eight days after birth, large, extensive, and confluent ulcerated areas were present over the pressure points of the body (Figure 1a). The right front hoof had detached and the underlying lamina was exposed (Figure 1b). The buccal mucous membranes were hyperemic. Due to the grave prognosis the foal was euthanized and submitted for necropsy. Foal no. 4 presented ulcerated skin lesions over the limbs and at the base of the hooves 1 d after birth. Extensive ulcerations were noted over the gingival mucosa and the soft palate. Teeth were visible and dysplastic, with white serrated edges (Figure 1c,d). Biopsies were obtained from involved and noninvolved areas of the skin and from tongue epithelia of the affected foals. Tissue samples were also obtained from a wild-type unrelated horse. The biopsies were snap frozen in liquid nitrogen and preserved at -70°C until processing. Total RNA was purified from the frozen skin biopsies using the RNable extraction kit (Eurobio, Les Ullis, France). Genomic DNA was purified from peripheral blood following standard methods (Sambrook et al., 1989Sambrook J. Fritsch E.F. Maniatis T. Molecular Cloning.A Laboratory Manual. Cold Spring Harbor Press, New York1989Google Scholar). Indirect immunofluorescence analysis was performed on 5 µm sections of the frozen tongue samples using antibodies raised against the human basement membrane components and crossreacting with the horse counterparts. Polyclonal antibody (pAb) SE85 is specific to the laminin α3 chain (Vidal et al., 1995Vidal F. Aberdam D. Miquel C. et al.Integrin β4 mutations associated with junctional epidermolysis bullosa with pyloric atresia.Nat Genet. 1995; 10: 229-234Crossref PubMed Scopus (308) Google Scholar); pAb SE144 (Vailly et al., 1994Vailly J. Verrando P. Champliaud M.F. et al.The 100-kDa chain of nicein/kalinin is a laminin B2 chain variant.Eur J Biochem. 1994; 219: 209-218Crossref PubMed Scopus (102) Google Scholar) and pAb SE1097 (Gagnoux-Palacios et al., 2001Gagnoux-Palacios L. Allegra M. Spirito F. Pommeret O. Romero C. Ortonne J.P. Meneguzzi G. The short arm of the laminin γ2 chain plays a pivotal role in the incorporation of laminin 5 into the extracellular matrix and in cell adhesion.J Cell Biol. 2001; 153: 835-849Crossref PubMed Scopus (97) Google Scholar) are directed against the laminin γ2 chain, and monoclonal antibody (mAb) K140 against the laminin β3 chain (Marinkovich et al., 1992Marinkovich M.P. Lunstrum G.P. Burgeson R.E. The anchoring filament protein kalinin is synthesized and secreted as a high molecular weight precursor.J Biol Chem. 1992; 267: 17900-17906Abstract Full Text PDF PubMed Google Scholar). pAb GOH3 is specific to integrin α6 (Sonnenberg et al., 1987Sonnenberg A. Janssen H. Hogervorst F. Calafat J. Hilgers J. A complex of platelet glycoproteins Ic and IIa identified by a rat monoclonal antibody.J Biol Chem. 1987; 262: 10376-10383Abstract Full Text PDF PubMed Google Scholar); mAb 233 is directed against BP180 (Nishizawa et al., 1993Nishizawa Y. Uematsu J. Owaribe K. HD4, a 180 kDa bullous pemphigoid antigen, is a major transmembrane glycoprotein of the hemidesmosome.J Biochem (Tokyo). 1993; 113: 493-501Crossref PubMed Scopus (131) Google Scholar), and mAb LH7:2 is specific to the collagen VII C-terminal domain (Sigma Immunochemical). pAb antilaminin 1 (L9393, Sigma) was also used. Secondary antibodies were fluorescein-isothiocyanate-conjugated goat antimouse and antirabbit Ig (Dako, Trappes, France), and goat antirat IgG (Cappel, ICN Biomedicals, Orsay, France). The samples were processed as previously reported (Gache et al., 1996Gache Y. Chavanas S. Lacour J.P. Wiche G. Owaribe K. Meneguzzi G. Ortonne J.P. Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy.J Clin Invest. 1996; 97: 2289-2298Crossref PubMed Scopus (201) Google Scholar). The tissue sections were examined using a Zeiss Axiophot microscope. Total RNA was purified from frozen tongue biopsies obtained from a wild-type nonrelated horse. Five micrograms of RNA were reverse transcribed in a volume of 25 µl in the presence of 100 U of M-MLV reverse transcriptase (Gibco-BRL, Life Technologies,). One microliter of the reaction mixture was then used in polymerase chain reaction (PCR) amplifications to obtain overlapping cDNA fragments spanning the open reading frame of the horse laminin γ2 chain. Specifically, eight primer pairs were devised on the basis of the most conserved nucleotide sequence between the human (GenBank accession no. Z15008) (Kallunki et al., 1992Kallunki P. Sainio K. Eddy R. et al.A truncated laminin chain homologous to the B2 chain: structure, spatial expression, and chromosomal assignment.J Cell Biol. 1992; 119: 679-693Crossref PubMed Scopus (204) Google Scholar) and mouse (GenBank no. NM_008485) (Sugiyama et al., 1995Sugiyama S. Utani A. Yamada S. Kozak C.A. Yamada Y. Cloning and expression of the mouse laminin gamma 2 (B2t) chain, a subunit of epithelial cell laminin.Eur J Biochem. 1995; 228: 120-128Crossref PubMed Scopus (62) Google Scholar) laminin γ2 cDNAs (not shown). Direct sequencing of the different PCR amplification products resulted in the disclosure of 82% of the horse laminin γ2 cDNA sequence. Primers specific to the horse γ2 cDNA sequence were then designed to complete and verify the sequence of the full-length γ2 cDNA (Table I). The PCR conditions were as follows: 95°C for 5 min, followed by 35 cycles at 95°C for 40 s, annealing temperature (Table I) for 40 s, 72°C for 40 s, and a final elongation for 7 min at 72°C. The amplification products were purified using a QIAquick kit (Qiagen, Madison, WI), and were subjected to automated nucleotide sequencing using an ABI Prism Model 310 Genetic Analyzer (Perkin-Elmer, Foster City, CA).Table IOligonucleotide primers used to amplify the horse laminin γ2 cDNAPrimersaL, sense primer; R, antisense primer.PositionbThe position number designates the 5 ′end of each primer in accordance with the horse laminin γ2 cDNA sequence (GenBank accession no. AY082802).Nucleotide sequenceannealing Temp. (C°)Product size (bp)1L1ATGCCTGCGCTCTGGCTCAG635911R592TGTGGCAGCTGGCGGAATGC2L406GACTCCAAGTGTGACTGTGA603882R794TAGCTCACCTGTTGATTCCC3L742CCTGTCTATTTTGTAGCTCC576703R1412CAGCTGAACCCATTGCGACA4L1003GAGTATCGGAGGTTACTGCG597564R1759GACACTCCACAGGCTCCGAG5L1477CGCTGTGAGCTCTGTGCTGA654225R1899CTCCAGGATCTGGAGCTGCT6L1705GACAAGTGTCGAGCTTGCAA603956R2100TCATCATGAGGTCATCCAGG7L1992GAGAGAAGCCCAGATTTCAC595247R2516GCTTCCATGTCGGTTTGCGT8L2312CAGCCAGTAACATGGAGCAA604358R2747GTCTGTCTCCCATTCTTTCC9L2658GGATGAGTTCAAGCACGTGC575149R3172ACAGCTCTCCTTCCACTTCT10L2955CAAGACGAAGCAAGCAGAAG6044510R3400GGCTGTTGATCTGAGTCTTGPCR-5′L–197GTGAGTCACACCCTGAAACA57460PCR-5′R263GAGTTACAATTGCAGGGTAAACRT-PCR 3′–GGCCATGCGTAGACTCTTAA(T)16PCR-3′L3226GCAGAGGCCCAAAGAGTTG57474Pcr-3′R–GGCCATGCGTAGACTCTTAAPCR-3A′L3325CCTGGCAGTGTGGATGAAGA57375a L, sense primer; R, antisense primer.b The position number designates the 5 ′end of each primer in accordance with the horse laminin γ2 cDNA sequence (GenBank accession no. AY082802). Open table in a new tab To obtain the 5′ end of the γ2 cDNA, the sense oligonucleotide PCR-5′L corresponding to a 5′ noncoding sequence of the human laminin γ2 cDNA (Salo et al., 1999Salo S. Haakana H. Kontusaari S. Hujanen E. Kallunki T. Tryggvason K. Laminin-5 promotes adhesion and migration of epithelial cells: identification of a migration-related element in the gamma2 chain gene (LAMC2) with activity in transgenic mice.Matrix Biol. 1999; 18: 197-210Crossref PubMed Scopus (61) Google Scholar) and the antisense primer PCR-5′R specific to the horse γ2 cDNA sequence were used to amplify a 460 bp cDNA fragment (Table I). To obtain the 3′ end of the γ2 cDNA, the antisense primer RT-PCR-3′ that contains a poly T tag sequence was used for reverse transcription PCR (RT-PCR) amplification of total RNA. A PCR was then performed using primers PCR-3′L (position 3226 on the horse γ2 cDNA) and PCR-3′R (Table I) to obtain the 474 bp 3′-terminal γ2 cDNA fragment. The 474 bp cDNA fragment was then used as a template for PCR amplification using the nested primers PCR-3A′L and PCR-3′R. The PCR cycling conditions, purification, and sequence analysis for the isolation of the 5′ and 3′ ends were as previously mentioned. Analysis, alignment, and translation of the nucleotide sequence into the amino acid sequence were performed using the software Lalign and Clustal W (Thompson et al., 1994Thompson J.D. Higgins D.G. Gibson T.J. Clustal W. Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.Nucl Acids Res. 1994; 22: 4673-4680Crossref PubMed Scopus (53349) Google Scholar). Total mRNA extracted from skin biopsies of foal no. 1 was reverse transcribed using a universal oligo-dT and PCR amplified using the nested primer 9R (Table I). Overlapping cDNA fragments spanning the full-length sequence of the γ2 cDNA were then obtained by PCR amplification using the primer pairs listed in Table I. The PCR amplification products were purified and subjected to automated nucleotide sequencing. The γ2 cDNA sequence of the affected foal was compared with the wild-type nucleotide sequence using the software program Sequencher (Gene Codes, Ann Arbor, MI). Identification of mutation 1368insC at the genomic level was performed by PCR amplification of a 170 bp DNA fragment (nucleotides 1291–1461 of γ2 cDNA sequence) using genomic DNA as a template and the following primers: (sense) 5′-TGTTACTCAGGGGATGAGAA-3′ and (antisense) 5′-CTGGGGGCAGTTATTGCAC-3′. PCR cycling conditions were as follows: 5 min at 95°C, followed by 30 s at 95°C, 30 s at 56°C, 30 s at 72°C (35 cycles), and extension for 7 min at 72°C. After purification the amplification product was submitted to automated nucleotide sequencing. We have studied four Belgian foals born on three different farms in Ontario, Canada, and affected by a skin blistering disease. Immediately after birth, the foals developed generalized cutaneous blisters and erosions at sites of the body exposed to friction (Figure 1a). Involvement of the ungueal lamina resulted in hoof loss (Figure 1b). The oral mucosa exhibited erosions (Figure 1c); the teeth were apparent and abnormally shaped, with pitted enamel and serrated edges (Figure 1e). The clinical observations were consistent with the hallmarks of epidermolysis bullosa. Histological examination of frozen samples of the blistered skin and mucosa localized the plane of the cleavage within the basement membrane zone of the dermal-epidermal junction (not shown). Immuno fluorescence examination of noninvolved epithelia was performed using antibodies directed against the components of the basement membrane of the dermal-epidermal junction. Reactivity to pAb SE144 specific to the human laminin γ2 chain was absent in the affected foals (Figure 2a), whereas pAb SE85 and mAb K140 directed against the human laminin α3 and β3 chains, respectively, were faintly reactive (Figure 2c,e). Reactivity to collagen type VII (Figure 2g,h), integrin α6, collagen type XVII, and laminin 1 was comparable to that observed in wild-type foals (not shown). These observations suggested that expression of laminin 5 was hampered in the affected animals and indicated that Lamc2, the gene encoding the laminin γ2 chain, was involved in the etiology of the condition. We therefore isolated and analyzed the full-length laminin γ2 cDNA to identify possible genetic mutation in the gene Lamc2. Total RNA extracted from the tongue epithelia of an unrelated wild-type horse was used for RT-PCR amplification. The coding sequence of the γ2 mRNA was reverse transcribed and PCR-amplified using sets of oligonucleotide primers designed on the basis of the sequence homology between the human (GenBank accession no. Z15008) (Kallunki et al., 1992Kallunki P. Sainio K. Eddy R. et al.A truncated laminin chain homologous to the B2 chain: structure, spatial expression, and chromosomal assignment.J Cell Biol. 1992; 119: 679-693Crossref PubMed Scopus (204) Google Scholar) and mouse (GenBank accession no. NM_008485) (Sugiyama et al., 1995Sugiyama S. Utani A. Yamada S. Kozak C.A. Yamada Y. Cloning and expression of the mouse laminin gamma 2 (B2t) chain, a subunit of epithelial cell laminin.Eur J Biochem. 1995; 228: 120-128Crossref PubMed Scopus (62) Google Scholar) γ2 cDNA, and was expected to yield overlapping cDNA fragments spanning the entire open reading frame of the horse γ2 mRNA. Direct sequencing of the PCR amplification products led to the partial identification (82%) of the horse γ2 cDNA sequence. On the basis of the disclosed cDNA sequence, new sets of oligonucleotide primers specific to the horse γ2 cDNA were designed and used to obtain the full-length nucleotide sequence of the γ2 cDNA (Table I). The horse γ2 cDNA (GenBank accession no. AY082802) comprises a 3570 bp full-length open reading frame, and a 199 bp 5′ and a 222 bp 3′ untranslated region. The polypeptide contains an N-terminal short arm, rich in EGF-like repeats, and extends into a long rod-like C-terminal arm. The N-terminal short arm domain V (residues 28-195) consists of three and a half cysteine-rich EGF-like repeats; domain IV (residues 196–382) has a globular structure and contains two cysteines; domain III (residues 383–607) comprises four and a half EGF-like repeats and contains the proteolytic cleavage site YSGD (Gagnoux-Palacios et al., 2001Gagnoux-Palacios L. Allegra M. Spirito F. Pommeret O. Romero C. Ortonne J.P. Meneguzzi G. The short arm of the laminin γ2 chain plays a pivotal role in the incorporation of laminin 5 into the extracellular matrix and in cell adhesion.J Cell Biol. 2001; 153: 835-849Crossref PubMed Scopus (97) Google Scholar). Domain I/II (residues 608–1190) constitutes the rod-like long arm of the polypeptide and is formed by heptad repeats typical of the α-helical coiled-coil domains of the laminin chains. Computer-assisted analysis of the nucleotide sequence revealed that identity of the coding sequence in man and horse (88.6%) is higher than that between horse and mouse (83.7%) and that between man and mouse (84.4%). The 5′ untranslated region contains a GATAA box, which is located -113 to -117 bp from the initiation ATG, and two AP-1 binding sites at positions -130 to -136 and -172 to -178, respectively. Comparison of the 5′ untranslated region of the horse and the human γ2 mRNA revealed 90.7% identity with two base additions and seven base deletions. The horse γ2 cDNA encodes a polypeptide of 1190 residues, which is three amino acids shorter than in man (1193 aa) and two amino acids shorter than in the mouse (1192 aa) counterpart. As in man and mouse, the initiation ATG codon is followed by a signal peptide of 20 amino acids. The position of the predicted signal peptide cleavage site (Ala 21) of the human γ2 chain is conserved. The horse γ2 polypeptide shows a domain organization identical to that of the human and mouse γ2 chains with 67 cysteine residues and six putative N-glycosylation sites (Asn-X-Ser/Thr) that are all conserved in the three species (Figure 3). The deduced primary sequence of the horse γ2 chain revealed > 90% identity at the amino acid level of domains V, IV, III in horse and man, and > 80% identity in horse and mouse. Identity of domains I/II is 81.3% in horse and man, and 76.6% in horse and mouse (Table II).Table IISequence identity (percentage) between the domains of the horse l}, number={3}, journal={Journal of Investigative Dermatology}, publisher={Elsevier BV}, author={Spirito, Flavia and Charlesworth, Alexandra and Ortonne, Jean-Paul and Meneguzzi, Guerrino and Linder, Keith and Baird, John}, year={2002}, month={Sep}, pages={684–691} }
 @article{croy_linder_yager_2001, title={Primer for non-immunologists on immune-deficient mice and their applications in research}, volume={45}, number={4}, journal={Comparative Medicine}, author={Croy, B. and Linder, K. and Yager, J.}, year={2001}, pages={300–313} }
 @article{linder_2001, title={Skin biopsy site selection in small animal dermatology with an introduction to histologic pattern-analysis of inflammatory skin lesions}, volume={16}, ISSN={["1096-2867"]}, DOI={10.1053/svms.2001.27595}, abstractNote={The skin biopsy is an invaluable diagnostic tool in veterinary dermatology. Biopsy site selection and interpretation of the biopsy report significantly influence the value of this procedure for diagnosing inflammatory skin diseases and are discussed in this article. Skin diseases often present with several different recognizable lesions that change significantly during their evolution. Individual lesions are typically heterogenous--some areas are diagnostic and some are not. Understanding which skin lesions to biopsy, and when and where to sample them, can significantly improve the value of information collected. To increase the information returned to clinicians for a biopsy, veterinary dermatopathologists have adopted the pattern-analysis method of classifying inflammatory skin lesions. This approach is based on recognizing morphologically distinct inflammatory patterns in skin biopsies and their association with particular sets of diseases. A basic knowledge of the pattern-analysis method is essential for maximizing the interpretation of skin biopsy reports.}, number={4}, journal={CLINICAL TECHNIQUES IN SMALL ANIMAL PRACTICE}, author={Linder, KE}, year={2001}, month={Nov}, pages={207–213} }
 @article{bröjer_parsons_linder_peregrine_dobson_2000, title={Halicephalobus gingivalis encephalomyelitis in a horse}, volume={41}, number={7}, journal={Canadian Veterinary Journal}, author={Bröjer, J and Parsons, D and Linder, K and Peregrine, A and Dobson, H}, year={2000}, month={Jul}, pages={559–561} }
 @article{white_linder_schultheiss_scott_garnett_taylor_best_walder_rosenkrantz_yaeger_2000, title={Sebaceous adenitis in four domestic rabbits (Oryctatagus cuniculus)}, volume={11}, ISSN={0959-4493 1365-3164}, url={http://dx.doi.org/10.1046/j.1365-3164.2000.00144.x}, DOI={10.1046/j.1365-3164.2000.00144.x}, abstractNote={Four domestic rabbits were presented with a history of nonpruritic scale. Multiple skin biopsies revealed findings compatible with sebaceous adenitis as reported in other species: inflammation directed at the sebaceous gland, and/or an absence of sebaceous glands, a perifollicular lymphocytic infiltrate at the level of the absent sebaceous glands, hyperkeratosis, follicular keratosis, follicular dystrophy, perifollicular fibrosis, and a mural infiltrative lymphocytic folliculitis. Histological changes not consistent with sebaceous adenitis in other species were interface dermatitis and interface folliculitis with single cell necrosis and basal cell hydropic degeneration.}, number={1}, journal={Veterinary Dermatology}, publisher={Wiley}, author={White, Stephen D. and Linder, Keith E. and Schultheiss, Patricia and Scott, Kathryn V. and Garnett, Page and Taylor and Best and Walder, Emily J. and Rosenkrantz, Wayne and Yaeger, Julie A.}, year={2000}, month={Mar}, pages={53–60} }
 @article{bowker_van wulfen_springer_linder_1998, title={Functional anatomy of the cartilage of the distal phalanx and digital cushion in the equine foot and a hemodynamic flow hypothesis of energy dissipation}, volume={59}, number={8}, journal={American Journal of Veterinary Research}, author={Bowker, R. and Van Wulfen, K. and Springer, S. and Linder, K.}, year={1998}, month={Aug}, pages={961–968} }
 @article{anderson_linder_peregrine_1998, title={Halicephalobus gingivalis (Stefanski, 1954) from a fatal infection in a horse in Ontario, Canada with comments on the validity of H. deletrix and a review of the genus}, volume={5}, ISSN={1252-607X 1776-1042}, url={http://dx.doi.org/10.1051/parasite/1998053255}, DOI={10.1051/parasite/1998053255}, abstractNote={Although the original description given by Stefanski (1954) was satisfactory, Anderson & Bemrick (1965), in describing H. deletrix (= Micronema deletrix), claimed Stefanski's description was "inadequate" and the species a "species inquirenda". Thus, infections in horses and humans have been assigned to H. deletrix. We believe the species reported in horses and humans is H. gingivalis and that H. deletrix is its synonym. H. gingivalis is separated herein from forms found free-living. The genital tract in the advanced fourth stage of H. gingivalis is didelphic and amphidelphic and terminal ends of the horns are reflected, the anterior one ventrally, the posterior one dorsally. In the adult parthenogen the latter forms a short ovary, whereas most of the anterior horn forms a combined uterus-oviduct as a receptacle for a single large egg which is laid in the 2-cell or multi-cell stage. Eggs in the 2-cell stage embryonated to larvae in 17 hours at 28 degrees C but did not hatch until an additional 24 hours. First-stage larvae were unusually large and variable in length (136-199 microns x = 168). Inactive third-stage larvae were 180-240 microns (x = 203) in length. The possible route of infection in horses and humans is briefly discussed.}, number={3}, journal={Parasite}, publisher={EDP Sciences}, author={Anderson, R. and Linder, K. and Peregrine, A.}, year={1998}, month={Sep}, pages={255–261} }
 @article{bowker_linder_wulfen_sonea_1997, title={Anatomy of the distal interphalangeal joint of the mature horse: relationships with navicular suspensory ligaments, sensory nerves and neurovascular bundle}, volume={29}, ISSN={0425-1644 2042-3306}, url={http://dx.doi.org/10.1111/j.2042-3306.1997.tb01654.x}, DOI={10.1111/j.2042-3306.1997.tb01654.x}, abstractNote={The anatomy of the distal interphalangeal (DIP) joint in the adult horse is described in relationship to the suspensory ligaments of the navicular bone, the neurovascular bundle and the sensory nerves to these periarticular regions. Using polymer plastic injections, the synovial cavity of the DIP joint was observed to have a complex relationship to the proximal suspensory or collateral sesamoidean ligament (CSL) of the navicular bone with the cavity forming cranial and caudal compartments around the CSL abaxially. Sensory nerves, as identified by peptide immunocytochemistry and silver/gold chloride axonal impregnation, were present superficially throughout the dorsal and palmar parts of the CSL, the distal sesamoidean impar ligament and in the periarticular connective tissues. These anatomical observations provide support for the idea that a DIP joint injection of local anaesthetic cannot be considered to be selective for only the joint surfaces, but must be considered also to desensitise much of the navicular suspensory apparatus, navicular bone and proximal intramedullary portions of the distal phalanx. However, while a DIP joint injection is not selective for only the joint surfaces, we believe that it is useful in terms of the diagnosis of painful sensations arising from parts of the navicular bone, the suspensory apparatus and proximal positions of the distal phalanx. These anatomical findings are discussed in terms of the potential effects of local anaesthesia injected into the DIP joint with known clinical and necropsy observations of Dyson and Kidd (1993).}, number={2}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Bowker, R. M. and Linder, K. and Wulfen, Kimberly K. and Sonea, Ioana M.}, year={1997}, month={Mar}, pages={126–135} }
 @article{bowker_linder_van wulfen_perry_ocello_1996, title={Verteilung eines in das Hufgelenk und in die Bursa podotrochlearis injizierten Lokalanästhetikums: eine experimentelle Studie = Distributions of local anesthetics injected into the distal interphalangeal joint and podotrochlear bursa: an experimental study}, volume={12}, DOI={10.21836/PEM19960454}, number={4}, journal={Pferdeheilkunde}, author={Bowker, R. and Linder, K. and van Wulfen, K. and Perry, R. and Ocello, P.}, year={1996}, pages={609–612} }
 @article{dunstan_linder_1995, title={Mammals, other than man, do not have follicular bulges: implications for the bulge-activation hypothesis}, volume={1}, ISSN={1078-4454}, journal={Dermatopathology, practical & conceptual : dermatology, pathology}, author={Dunstan, R and Linder, K}, year={1995}, pages={155–162} }
 @article{bowker_under_sonea_holland_1995, title={Sensory innervation of the navicular bone and bursa in the foal}, volume={27}, ISSN={0425-1644 2042-3306}, url={http://dx.doi.org/10.1111/j.2042-3306.1995.tb03034.x}, DOI={10.1111/j.2042-3306.1995.tb03034.x}, abstractNote={The sensory innervation of the navicular bone (os sesamoideum distale) and its suspensory ligaments [ligamenta sesamoidea collateralia (CSL) and ligamentum sesamoideum distale impar or distal sesamoidean impar (DS-impar) ligament] and the navicular bursa (podotrochlearis) was examined in the neonatal foal using immunocytochemistry. With antisera raised to substance P (SP) and human calcitonin gene-related peptide (CGRP), immunoreactive nerves were demonstrated to innervate the CSL and navicular bursa. Within CSL, and SP- and CGRP-like nerves were present in the synovial lining of the navicular bursa, appearing to reach the surface lining. These nerves appeared to enter the CSL and navicular bursa via the abaxial regions of the foot. Both peptides were present in the deep digital flexor tendon (DDf) along the palmar border of the navicular bursa, as well as in the DS-impar ligament. More nerve fibres were present in the dorsal part of CSL bordering the distal interphalangeal joint than was observed palmarly in CSL along the navicular bursa. Both peptides were observed to innervate the cartilage canals within the navicular bone. In terms of relative densities of immunoreactive SP- and CGRP-like peptides, the CSL dorsally and the DS-impar ligament had the highest relative densities of nerve fibres followed by the navicular bone, the palmar aspect of CSL and the DDf tendon bordering the navicular bursa. These results are discussed in relationship to local anaesthetic injections into the navicular bursa.}, number={1}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Bowker, R. M. and Under, K. and Sonea, I. M. and Holland, R. E.}, year={1995}, month={Jan}, pages={60–65} }
 @article{bowker_rockershouser_linder_vex_sonea_caron_1994, title={A silver-impregnation and immunocytochemical study of innervation of the distal sesamoid bone and its suspensory ligaments in the horse}, volume={26}, ISSN={0425-1644 2042-3306}, url={http://dx.doi.org/10.1111/j.2042-3306.1994.tb04372.x}, DOI={10.1111/j.2042-3306.1994.tb04372.x}, abstractNote={The innervation of the navicular bone (os sesamoideum distale) and its suspensory ligaments (ligamenta sesamoidea collateralia) (CSL) or proximal suspensory ligament and the ligamentum sesamoideum distale impar or the distal sesamoidean impar ligament (DS-impar ligament) was examined using combined anatomical techniques of silver impregnation and immunocytochemistry. Silver impregnation studies revealed an abundance of nerve fibres present in both the CSL and DS-impar ligament with the latter having relatively more nerve fibres. These silver-impregnated nerves coursed parallel to and were associated with the vasculature rather than appearing to innervate the vessels. Immunocytochemistry identified several sensory-related neuropeptides (calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A (NKA)) in the nerves of the navicular bone and suspensory ligaments. More peptidergic nerves were evident within the synovial membrane and loose connective tissue in the dorsal part than in the palmar aspect of the CSL. In the CSL along the synovial membrane bordering the distal interphalangeal joint, the CGRP, SP and NKA were present in the nerves of vessels as well as the intimal layer of the distal interphalangeal joint. In the DS-impar ligament, there were many more nerves innervating vessels and the synovial membrane between the navicular bone and the third phalanx than were present in these structures in the CSL. Nerves with all 3 peptides entered the navicular bone via the proximal border and the distal groove to innervate the perichondrium, trabeculae and osteons. SP-like nerves also innervated the cortical bone underlying the articular cartilage. We suggest that these sensory nerve peptides contribute to the pathology of the navicular syndrome. The distribution of the nerves in the CSL and the DS-impar ligament could explain the clinical effects of local anaesthetics injected into the distal interphalangeal joint.}, number={3}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Bowker, R. M. and Rockershouser, Sara J. and Linder, K. and Vex, Kelly B. and Sonea, Ioana M. and Caron, J. P.}, year={1994}, month={May}, pages={212–219} }
 @article{bowker_brewer_vex_guida_linder_sonea_stinson_1993, title={Sensory receptors in the equine foot}, volume={54}, number={11}, journal={American Journal of Veterinary Research}, author={Bowker, R. and Brewer, A. and Vex, K. and Guida, L. and Linder, K. and Sonea, I. and Stinson, A.}, year={1993}, pages={1840–1844} }
 @inbook{carey_laurikainen_ptok_reinke_linder_nair_marcelo_1992, title={Culture Conditions Affect Expression of the α6β4 Integrin Associated with Aggressive Behavior in Head and Neck Cancer}, ISBN={9781461365365 9781461534686}, ISSN={0065-2598}, url={http://dx.doi.org/10.1007/978-1-4615-3468-6_10}, DOI={10.1007/978-1-4615-3468-6_10}, abstractNote={Prevention of disease has always been more effective than treatment. Sanitation practices and vaccines have eliminated many of the most dreaded and lethal diseases of man and domestic animals. Cancer, a devastating disease caused by unregulated growth of genetically altered cells, is as daunting a challenge today as smallpox was in Edward Jenner’s time two centuries ago. Fortunately, we are on the threshold of a new era in biology. We can now examine growth-regulatory mechanisms at the cellular and molecular levels, and we can begin to apply what we learn in new clinical and experimental systems.}, booktitle={Advances in Experimental Medicine and Biology}, publisher={Springer US}, author={Carey, Thomas E. and Laurikainen, Leena and Ptok, Angelika and Reinke, Timothy and Linder, Keith and Nair, Thankam S. and Marcelo, Cynthia}, year={1992}, pages={69–79} }