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Background Idiopathic pulmonary fibrosis (IPF) affects West Highland white terriers (WHWTs). Osteopontin (SPP1) and fibronectin (FN1) are associated with human IPF and are overexpressed by bronchoalveolar lavage fluid (BALF) macrophages in dogs with IPF. Objective To investigate the value of these proteins as biomarkers of IPF. Animals West Highland white terriers (WHWTs) with IPF, control WHWTs, and terriers. Methods Cross‐sectional observational study. Immunohistochemistry was used to localize SPP1 and FN1 in lung tissue. Serum and BALF SPP1 and FN1 concentrations were measured using canine ELISA kits and compared between groups. Results Osteopontin stained ciliated epithelial cells, smooth muscular cells, and macrophages of all included dogs, and type‐II pneumocytes and extracellular matrix of all 12 diseased WHWTs, 4/6 control WHWTs, and none of the 3 terriers. Osteopontin serum concentration was higher in diseased WHWTs (n = 22; 2.15 ng/mL [0.74‐5.30]) compared with control WHWTs (n = 13; 0.63 ng/mL [0.41‐1.63]; P = .005) and terriers (n = 15; 0.31 ng/mL [0.19‐0.51]; P < .0001), and in control WHWTs compared with terriers (P = .005). Osteopontin BALF concentrations were higher in diseased (0.27 ng/mL [0.14‐0.43]) and control WHWTs (0.25 ng/mL [0.14‐0.40]), compared with terriers (0.02 ng/mL [0.01‐0.08]; P < .0001 and P = .003, respectively). Fibronectin (FN1) serum concentrations were lower in diseased dogs (1.03 ng/mL [0.35‐1.48]) and control WHWTs (0.61 ng/mL [0.24‐0.65]) compared with terriers (2.72 ng/mL [0.15‐5.21]; P < .0001 and P = .0001, respectively). There was no difference in FN1 immunostaining and FN1 BALF concentrations between groups. Conclusions Results suggest that SPP1 is involved in pathogenesis of IPF and could predispose that breed to the disease. Osteopontin serum concentration could serve as a diagnostic biomarker of IPF.

The skin barrier is important in the pathogenesis of atopic dermatitis and stratum corneum lipids have a critical role. Skin surface lipids have been largely overlooked but also contribute to barrier function. An untargeted approach was used to compare the skin surface lipids from atopic and non-atopic West Highland White terrier dogs (WHWT). The primary hypothesis was that a difference in the lipidome would exist. The secondary hypothesis was that affected and unaffected skin lipids would differ. This prospective, cross-sectional, case-controlled study included thirty-nine privately owned WHWTs. Dogs were assigned to one of four disease status groups based on strict criteria. Samples for lipid analysis were collected from the skin surface of unaffected and affected sites. Lipid analysis was by untargeted liquid chromatography/mass spectrometry and utilised lipid identification software packages. Principle component analysis (PCA) and partial least-squares discriminant analysis (sPLS-DA) statistical methods analysed the association between the relative lipid abundance and disease status and affected and unaffected skin. Samples for lipid analysis found 421 lipid soluble features of which ten lipids were positively identified. Statistical analysis could not distinguish between non-atopic and atopic dogs but did reveal a statistically significant difference in the lipid profiles from affected and non-affected skin irrespective of disease status. A large array of unidentified lipids from the skin surface were found with a difference between affected and unaffected skin unrelated to disease status. Investigation into the lipidome of the skin surface is an emerging area of research with clinical and therapeutic applications.

Background Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial fibrosing lung disease, manifesting as cough, exercise intolerance and ultimately, dyspnea and respiratory failure. It mainly affects West Highland white terriers (WHWTs), lacks curable treatment and has a poor prognosis. Aspiration of gastroesophageal refluxate may play a role in the development of CIPF. In the first part of this study, we completed label-free quantitative proteomic analysis of bronchoalveolar lavage fluid (BALF) from CIPF and healthy WHWTs. In the second part, we evaluated potential protein markers of reflux aspiration from canine gastric juice and vomitus and whether these were present in BALF from the two groups. Results Across all BALF samples, 417 proteins were identified, and of these, 265 proteins were identified by two or more unique tryptic peptides. Using the 265 high confidence assignments, the quantitative proteome profiles were very similar in the two cohorts, but they could be readily resolved by principal component analysis on the basis of differential protein expression. Of the proteins that were differentially abundant in the two groups, several (including inflammatory and fibrotic markers) were elevated in CIPF, and a smaller, more diverse group of proteins were diminished in CIPF. No protein markers indicative of reflux aspiration were identified. Conclusions Label-free proteomics allowed discrimination between CIPF and healthy WHWTs, consistent with fibrotic process but did not provide clear evidence for gastrointestinal aspiration. The measurement of proteins may provide a proteomics signature of CIPF that could be used to evaluate treatment options.

Background Copper associated hepatitis (CAH) has been increasingly recognized in dogs, and speculation exists that hereditary defects in copper metabolism have been exacerbated by increased environmental copper exposure. However, no broad epidemiological investigations have been performed to investigate quantitative hepatic copper concentrations ([Cu]H) over time in both dogs that are (predisposed breed [PB]), and are not (non‐predisposed breed [NPB]), considered at‐risk for CAH. Objectives To investigate [Cu]H in dogs and explore temporal, demographic, and histologic associations spanning 34 years. Animals 546 archived liver specimens. Methods Retrospective study. Searches of the Michigan State University Veterinary Diagnostic Laboratory database identified dogs that had undergone hepatic histopathologic assessment. Cases with archived tissue were reviewed and classified by breed, time period, and presence or absence of hepatitis. Inductively coupled plasma mass spectrometry was used to determine [Cu]H. Results In time period 2009–2015, median [Cu]H were 101 μg/g and 313 μg/g greater than median [Cu]H in time period 1982–1988 for NPB and PB dogs, respectively (P < .001 for both comparisons). The proportion of dogs with [CU]H > 300 μg/g increased in NPB (28% to 49%) and PB dogs (48% to 71%) during these periods (P = .002 for both comparisons). Median [Cu]H in dogs with hepatitis increased 3‐fold over time in both NPB (P = .004) and PB populations (P < .001). Conclusions and Clinical Importance The frequent recognition of CAH in recent years is likely due to the observed increases in [Cu]H over time. Importantly, effects are not limited to PB dogs.

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive fibrotic interstitial lung disease of unknown etiology, afflicting aging West Highland white terriers (WHWTs) and leading to progressive respiratory failure. Fibroblast activation protein (FAP), a protease overexpressed in many cancers, is upregulated in idiopathic pulmonary fibrosis in humans. The aim of this study was to investigate FAP as a marker of active fibrosis in lung biopsies from WHWTs affected with CIPF, as well as the potential of plasmatic FAP as a biomarker. After establishing a scoring system to evaluate the severity and activity of fibrosis on histopathological lung sections, anti-FAP immunohistochemistry was performed on healthy and CIPF samples. FAP expression was characterized using both visual and digital quantitative pathology software analyses and then correlated to fibrosis severity and activity. Levels of plasmatic FAP in WHWTs affected with CIPF were measured by enzyme-linked immunosorbent assay and compared with healthy dogs. Lung samples from 22 WHWTs affected with CIPF were collected. According to the fibrosis scoring system, they were classified as cases of mild (5), moderate (9) and severe (8) fibrosis and were attributed scores of fibrosis activity. Fifteen healthy lung samples were classified as non-fibrotic. Healthy lung samples were FAP-negative, whereas fibroblasts were FAP-positive in 20 CIPF samples. FAP immunohistochemical expression correlated mildly with fibrosis severity ( p  < 0.05; R 2  = 0.22) but highly with fibrosis activity scores ( p  < 0.001; R 2  = 0.68). Digital image analysis detected a higher percentage of FAP-positive cells in areas of active fibrosis ( p  < 0.001) and FAP-positive cells were distributed outside mature fibrosis lesions, clustered in active fibrosis areas or scattered within alveolar septa. On the other hand, plasmatic FAP was significantly lower in dogs affected with CIPF compared with healthy dogs ( p  < 0.01). In conclusion, this study provides a valuable histological scoring system to assess the severity and activity of fibrosis in CIPF. It demonstrates that FAP is a good cellular marker of fibrotic activity in CIPF, and thus constitutes a promising target to be exploited for diagnostic and therapeutic applications. Additionally, it suggests that plasmatic FAP, although non-specific, could be altered in CIPF.

Overexpression of osteopontin (SPP1) and fibronectin (FN1), two molecules associated with pulmonary fibrosis in humans and mice, was recently identified in pro-fibrotic bronchoalveolar lavage fluid (BALF) macrophage populations in West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF) compared to healthy WHWTs. The aims of the present study were to confirm the overexpression of SPP1 and FN1 genes at the protein level and to assess the potential utility of those proteins as serum and BALF biomarkers of CIPF severity. Serum and BALF concentrations of SPP1 and FN1 were measured using commercially available canine ELISA kits in CIPF WHWTs at diagnosis (n=24), healthy aged-matched WHWTs (n=13) and healthy terriers from other breeds (n=15). Values obtained were compared between groups using Kruskal-Wallis test. Correlations between SPP1 and FN1 concentrations and markers of disease severity (arterial partial pressure in oxygen (PaO2) and 6-minute walked distance (6MWD)) were performed using Spearman test. SPP1 serum concentrations were higher in CIPF WHWTs (median [interquartile range]: 2.15 ng/mL [0.87-5.13]) compared with healthy WHWTs (0.63 ng/mL [0.41-1.63]; P=0.013) and healthy terriers (0.31 ng/mL [0.19-0.51]; P<0.0001), and higher in healthy WHWTs compared with healthy terriers (P=0.002). Higher SPP1 BALF concentrations were found in CIPF (0.34 ng/mL [0.15-0.52]) and healthy WHWTs (0.25 ng/mL [0.14-0.40]) compared with heathy terriers (0.02 ng/mL [0.01-0.08]; P<0.0001 and P=0.002, respectively), while no difference was shown between CIPF and healthy WHWTs (P=0.962). SPP1 serum concentrations negatively correlated with PaO2 (r=-0.502; P=0.007), but not with 6MWD. FN1 serum concentrations were lower in WHWTs either affected with CIPF or healthy (0.81 ng/mL [0.36-1.47] and 0.61 ng/mL [0.24-0.65]) compared with healthy terriers (2.72 ng/mL [2.15-5.21]; P<0.0001 and P=0.001, respectively). No difference was found between groups in BALF FN1 concentrations (P=0.077). No correlation was identified between serum and BALF FN1 concentrations and parameters of CIPF severity. Results of the present study did not confirm the FN1 overexpression found in BALF pro-fibrotic macrophages neither in serum nor in BALF. Serum and BALF FN1 concentrations were not associated with CIPF severity parameters. SPP1 gene overexpression was confirmed at the protein level in serum but not in BALF in CIPF compared with healthy WHWTs. Moreover, SPP1 serum concentration could serve as a biomarker of disease severity as it correlates with PaO2. Finally, the higher serum and BALF SPP1 concentrations found in the WHWT breed compared to other terriers could be linked to their predisposition to CIPF.

West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF) are at risk of developing precapillary pulmonary hypertension (PH). In humans, thoracic computed tomography angiography (CTA) is commonly used to diagnose and monitor patients with lower airway diseases. In such patients, CTA helps to identify comorbidities, such as PH, that could negatively impact prognosis. Diameter of the pulmonary trunk (PT), pulmonary trunk-to-aorta ratio (PT/Ao), and right ventricle-to-left ventricle ratio (RV/LV) are CTA parameters commonly used to assess the presence of PH. Pulmonary vein-to-right pulmonary artery ratio (PV/PA) is a new echocardiographic parameter that can be used in dogs to diagnose PH. The primary aim of this study was to evaluate the use of various CTA parameters to diagnose PH. An additional aim was to evaluate the correlation of RV/LV measurements between different CTA planes. CTA and echocardiography were prospectively performed on a total of 47 WHWTs; 22 affected with CIPF and 25 presumed healthy control dogs. Dogs were considered to have PH if pulmonary vein-to-right pulmonary artery ratio (PV/PA) measured on 2D-mode echocardiography was less than to 0.7. WHWTs affected with CIPF had higher PT/Ao compared with control patients. In WHWTs affected with CIPF, PT size was larger in dogs with PH (15.4 mm) compared with dogs without PH (13 mm, p = 0.003). A cutoff value of 13.8 mm predicted PH in WHWTs affected with CIPF with a sensitivity of 90% and a specificity of 87% (AUC = 0.93). High correlations were observed between the different CTA planes of RV/LV. Results suggest that diameter of the PT measured by CTA can be used to diagnose PH in WHWTs with CIPF.

Background Canine idiopathic pulmonary fibrosis (CIPF) is a progressive interstitial lung disease mainly affecting old West Highland white terriers (WHWTs). The aetiology of CIPF is currently unknown and pathogenesis poorly understood. A genetic basis is strongly suspected based on the breed predisposition. CIPF shares clinical and pathological features with human IPF. In human IPF, coagulation disorders favouring a local and systemic pro-thrombotic state have been demonstrated in association with disease severity and outcome. The aim of this study was to compare the systemic haemostatic, fibrinolytic and inflammatory profiles of WHWTs affected with CIPF with breed-matched controls (CTRLs). Additionally, data collected in both groups were interpreted with regard to the reference intervals (when available) to assess possible pro-thrombotic features of the WHWT breed that may be related to CIPF predisposition. A total of 14 WHWTs affected with CIPF and 20 CTRLs were included. Results WHWTs affected with CIPF had prolonged activated partial thromboplastine time in comparison with CTRLs (12.2 ± 0.9 s vs. 11.5 ± 0.7 s, P  = 0.028), whereas results obtained in both groups were all within reference ranges. There was no significant difference between groups for the other factors assessed including plasmatic concentrations of fibrinogen, D-dimers concentration, antithrombin III activity, protein S and protein C activities, anti-factor Xa activity, activated protein C ratio, serum C-reactive protein concentration, and rotational thromboelastometry indices. Platelet count and plasmatic fibrinogen concentration were found to be above the upper limit of the reference range in almost half of the WHWTs included, independently of the disease status. Conclusions Results of this study provide no clear evidence of an altered systemic haemostatic, fibrinolytic or inflammatory state in WHWTs affected with CIPF compared with CTRLs. The higher platelet counts and fibrinogen concentrations found in the WHWT breed may serve as predisposing factors for CIPF or simply reflect biological variation in this breed.

Eighty-three dogs with clinical signs of otitis externa and with ear cytology revealing microbial organisms were studied. Samples were collected from both ears of each dog by inserting two swabs successively into each ear canal, rotating each once through 360° and then rolling it out in a line on to a glass slide. For each animal, four single parallel smears (SPS) were made on one slide, which was then appropriately labelled to identify the animal as well as the order of the samples. The slides, one representing each animal, were subsequently stained with modified Wright's stain. Six high-power fields of every SPS were counted. Golden retrievers and West Highland white terriers were found to be predisposed to developing otitis externa (P=0.0006 and P=0.0123, respectively). Otitis externa occurred significantly more frequently in dogs with pendulous pinnae than in dogs with erect pinnae (P=0.0009). There was no significant difference between the first and the second samples with respect to the number of microorganisms found (P>0.1 for cocci and P>0.5 for rods and yeasts), and there was a substantial agreement between the results of the two successive swabs for the presence of cocci (κ=0.765) and rods (κ=0.705). For yeasts, the agreement was only moderate (κ=0.581).

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive parenchymal lung disease affecting aging West Highland white terriers (WHWTs). Pulmonary hypertension (PH) is a known co-morbidity in WHWTs affected with CIPF necessitating close monitoring. The aim of this descriptive study was to assess echocardiographic variations of PH parameters and the effect of treatment with sildenafil in WHWTs affected with CIPF. WHWTs with compatible imaging and/or histopathological features of CIPF that had an echocardiography performed at diagnosis and a minimum of one echocardiographic followup were retrospectively selected over an 11-year period (2013-2024) (n=28, median age 11.0 years, range 7.4-15.3). Rechecks were conducted approximately every 6 months until death or loss of follow-up. Echocardiographic data were collected for a maximum of 4 follow-ups for the purpose of this study. Right heart parameters were measured off-line. The probability of PH was defined as low, intermediate, or high according to the 2020 ACVIM consensus guidelines. Linear mixed models were used to investigate the effects of sildenafil treatment, time, and their interaction with echocardiographic parameters. Statistical significance was set at P<0.05. At baseline, 11 (39.3%), 8 (28.6%), and 9 (32.1%) WHWTs affected with CIPF had low, intermediate, or high probability respectively, for PH, with none receiving sildenafil therapy. Median follow-up time was 21.6 months (range 14.7-35.0). At the first recheck, the probability of PH increased in 9 (31.2%), decreased in 3 (10.7%), and remained unchanged in 16 (57.1%) WHWTs, with 13 (46.4%) receiving sildenafil treatment for approximately 6 months. Sildenafil treatment significantly reduced main pulmonary artery to aorta ratio (MPA/Ao) with an estimated decrease of 0.06 units (95%CI:0.01-0.11) in treated dogs (P=0.027). Time was associated with an enlargement in minimum right pulmonary artery diameter (RPADmin) and right ventricular internal dimension in diastole (RVIDd), with an estimated increase of 0.35 mm (95%CI:0.09-0.62, P=0.013) and 0.07 cm (95%CI:0.02-0.11, P=0.004) respectively, every 6 months. Significant interactions between treatment and time were found for MPA/Ao (Est.:0.02, 95%CI:0-0.04, P=0.023), RVID_Ao (Est.:0.04, 95%CI:0.01-0.07, P=0.015) and right ventricle fractional area change (FAC) (Est.:−2.57, 95%CI:−4.81,−0.33, P=0.041), suggesting a moderating effect of sildenafil on the impact of time for these parameters. No other significant effects of treatment or time were noted on echocardiographic measurements. Over the study period, 24 WHWTs died including 17 from cardio-respiratory causes. In conclusion, this study highlights the importance of regular echocardiographic follow-ups over the course of CIPF and suggests that sildenafil may mitigate the progression of specific echocardiographic parameters related to PH.