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Background: Oral melanoma (OM) and oral squamous cell carcinoma (OSCC) are frequently diagnosed in dogs, presenting a challenge in distinguishing them from benign oral tumors (BN). Salivary metabolomic biomarkers offer a practical solution because of saliva's direct contact with tumors and the noninvasive nature of collection., Objective: Assess the diversity and abundance of the salivary metabolome in dogs with BN, OM, and OSCC using amine/phenol submetabolome analysis and high-performance chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS)., Animals: Study included 11 BN, 24 OM, 10 OSCC, and 20 healthy control dogs., Methods: Case-control cross-sectional study was conducted to assess salivary submetabolic profiles in dogs with BN, OM, and OSCC and healthy dogs. Samples were labeled with 12 C-dansyl chloride and analyzed using CIL LC-MS targeted to amine- and phenol-containing metabolites for amine/phenol submetabolome analysis., Results: Distinct clusters and significant differences in metabolite concentrations were observed among the oral cancer, BN, and control groups. A total of 154 and 66 metabolites showed significantly altered concentrations, particularly in OM and OSCC, respectively, when compared with BN (Padj < .05). Potential metabolic biomarkers were identified for each cancer, including decreased concentrations of seryl-arginine and sarcosine in OSCC. Moreover, high-confidence putative metabolites were identified, including an increase in tryptophyl-threonine and a decrease in 1,2-dihydroxynapthalene-6-sulfonic acid and hydroxyprolyl-hydroxyproline for OM., Conclusions and Clinical Importance: We identified high coverage of the amine/phenol submetabolome, including seryl-arginine, and sarcosine, in OSCC. Our findings emphasize the potential of these biomarkers for distinguishing between oral OSCC and BN in dogs., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Epilepsy in dogs and humans is associated with blood-brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine., Hypothesis: Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future., Animals: Twenty-seven dogs with IE and 10 healthy controls., Methods: Retrospective, prospective cohort study. Blood-brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase-9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe., Results: The DCE-MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P = .02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin-5 in the piriform lobe of IE dogs was significantly lower than in control dogs., Conclusions and Clinical Importance: Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Altered trace element status is associated with epilepsy in humans and dogs with idiopathic epilepsy (IE)., Objectives: Compare hair element concentrations in epileptic and healthy dogs., Animals: Sixty-three dogs with IE (53 treated, 10 untreated) and 42 controls., Methods: Case-control study using ICP-MS to determine hair calcium, magnesium, phosphorus, sodium, potassium, iron, copper, manganese, zinc, selenium, chromium, lead, mercury, cadmium, arsenic, aluminum, and nickel concentration. Groups were compared using nonparametric tests. Results were controlled for diet, sex, age, and hair color using generalized linear mixed models., Results: Compared to healthy controls, dogs with IE had lower hair phosphorus (mean ± SD; IE: 286.19 ± 69.62 μg/g, healthy: 324.52 ± 58.69 μg/g; P = .001), higher hair copper (IE: 10.97 ± 3.51 μg/g, healthy: 8.41 ± 1.27 μg/g; P < .001), zinc (IE: 158.25 ± 19.64 μg/g, healthy: 144.76 ± 32.18 μg/g; P < .001), copper/zinc ratio (IE: 0.07 ± 0.02, healthy: 0.06 ± 0.01; P = .003), selenium (IE: 1.65 ± 0.43 μg/g, healthy: 0.94 ± 0.73 μg/g; P < .001), and arsenic (IE: 0.40 ± 0.78 μg/g, healthy: 0.05 ± 0.08 μg/g; P < .001). When comparing treated and untreated epileptic dogs with healthy dogs, the differences in phosphorus and selenium remained significant for both groups, whereas the differences in copper, zinc, and arsenic were significant only for treated dogs. Potassium bromide treatment was strongly associated with high hair arsenic (P = .000)., Conclusions and Clinical Importance: Altered trace element status could be involved in the pathophysiology of IE in dogs. Antiseizure drugs might affect trace element and arsenic metabolism., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Background: Endogenous production of carbon monoxide during hemoglobin metabolism leads to the formation of carboxyhemoglobin. Carboxyhemoglobin concentration is abnormally high in humans with hemolytic anemia (HA)., Hypothesis: Measurement of carboxyhemoglobin concentration can discriminate HA from other forms of anemia., Animals: Twenty-seven dogs with HA (immune-mediated HA, n = 22; microangiopathic HA, n = 5), 27 dogs with non-HA (kidney disease, n = 14; immune-mediated thrombocytopenia, [n = 6]; miscellaneous, n = 7) and 24 nonanemic control dogs., Methods: Prospective cohort study. Carboxyhemoglobin quantification, a CBC and biochemistry profile were performed upon admission, and survival to hospital discharge and at 30 days were the measured outcomes. Groups were compared by the Mann-Whitney and Kruskal-Wallis tests. Receiver-operator characteristic (ROC) analyses were used to examine the predictive utility of carboxyhemoglobin for the diagnosis of HA in anemic dogs., Results: Carboxyhemoglobin (median [interquartile range]) differed between dogs with HA (7.7% [2.5%]) and non-HA (3.6% [1.05]; P < .001) and dogs with HA and nonanemic dogs (3.5% [0.65%]; P < .001). No difference was detected between nonHA and nonanemic dogs. The area under the ROC curve for carboxyhemoglobin as predictor of HA in anemic dogs was 0.997 (95% CI, 0.99-1.00). Three optimal cut-off points were identified, including 5.05%, 4.55% and 4.85%, with corresponding sensitivity/specificity of 92.6%/100%, 100%/92.6% and 96.3%/96.3%, respectively. Neither carboxyhemoglobin nor any of the CBC or chemistry analytes were associated with survival., Conclusions and Clinical Importance: Carboxyhemoglobin proved an excellent predictor of HA in dogs and might constitute a useful, ancillary tool for diagnosing and monitoring hemolytic anemias., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Compression of epidural adipose tissue (EAT) within the scope of cauda equina syndrome (CES) could lead to an enhanced expression of inflammatory mediators, possibly contributing to pain amplification in dogs., Objectives: To analyze expression of inflammatory adipo(-cyto)kines within the EAT of dogs with CES., Animals: Client-owned dogs: 15 dogs with CES and 9 dogs euthanized for unrelated medical reasons (controls)., Methods: Prospective, experimental study. Epidural adipose tissue and subcutaneous adipose tissue were collected during dorsal laminectomy and used for real-time quantitative polymerase chain reaction. Tissue explants were cultured for measurements of inflammation-induced release of cytokines., Results: Results show a CES-associated upregulation of the cytokines tumor necrosis factor alpha (TNFα: mean ± SD: 18.88 ± 11.87, 95% CI: 10.90-26.86 vs 9.66 ± 5.22, 95% CI: 5.29-14.02, *: P = .04) and interleukin- (IL-) 10 (20.1 ± 9.15, 95% CI: 14.82-25.39 vs 11.52 ± 6.82, 95% CI: 5.82-17.22, *: P = .03), whereas the expression of the adipokine leptin was attenuated in EAT of dogs with CES (3.07 ± 2.29, 95% CI: 1.80-3.34 vs 9.83 ± 8.42, 95% CI: 3.36-16.30, **: P = .007). Inflammatory stimulation of EAT explant cultures resulted in an enhanced release of IL-6 (LPS: 5491.55 ± 4438, 95% CI: 833.7-10 149; HMGB1: 1001.78 ± 522.2, 95% CI: 518.8-1485; PBS: 310.9 ± 98.57, 95% CI: 228.5-393.3, ***: P < .001)., Conclusion and Clinical Importance: Expression profile of inflammatory adipo(-cyto)kines by EAT is influenced from compressive forces acting in dogs with CES and might contribute to amplification of pain., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: An angiotensin-converting enzyme (ACE) gene polymorphism occurs in dogs; however, functional importance is not well studied., Hypothesis: We hypothesized that dogs with the polymorphism would show alternative renin-angiotensin aldosterone system (RAAS) pathway activation and classical RAAS pathway suppression before and after ACE-inhibitor administration, as compared to dogs without the polymorphism that would show this pattern only after ACE-inhibitor administration., Animals: Twenty-one dogs with mitral valve disease that were genotyped for the ACE gene polymorphism., Methods: This retrospective study utilized stored samples from 8 ACE gene polymorphism-negative (PN) dogs and 13 ACE gene polymorphism-positive (PP) dogs before and after enalapril administration. Equilibrium analysis was performed to evaluate serum RAAS metabolites and enzyme activities. Results were compared before and after enalapril, and between groups., Results: The classical RAAS pathway was suppressed and the alternative RAAS pathway was enhanced for both genotypes after administration of enalapril, with no differences before enalapril administration. Aldosterone breakthrough occurred in both PN (38%) and PP (54%) dogs despite angiotensin II suppression. Aldosterone was significantly higher (P = .02) in ACE gene PP dogs (median, 92.17 pM; IQR, 21.85-184.70) compared to ACE gene PN dogs (median, 15.91 pM; IQR, <15.00-33.92) after enalapril., Conclusions and Clinical Importance: The ACE gene polymorphism did not alter baseline RAAS activity. Aldosterone breatkthrough in some dogs suggests nonangiotensin mediated aldosterone production that might be negatively influenced by genotype. These results support the use of aldosterone receptor antagonists with ACE-inhibitors when RAAS inhibition is indicated for dogs, especially those positive for the ACE gene polymorphism., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The strong ion model (SIM) is an alternative paradigm in the characterization of acid-base disturbances particularly in complex disorders., Hypothesis/objectives: To compare the acid-base changes in dogs with parvoviral enteritis (PE) using the Henderson-Hasselbalch (HH) approach, with 2 strong ion approaches., Animals: Forty-four dogs with PE, and 16 age-matched control dogs., Methods: Prospective controlled observational study. Acid-base status was evaluated using the HH model, Fencl-Stewart (FS) approach and a validated strong ion model (VDM). The acid-base changes according to each model were classified and compared. Statistical correlations between pH, CO 2 , and various SIM variables were performed, as well as between the sum of effects (SOE) of the SIM and the individual variables comprising the SOE., Results: The HH model identified acid-base disorders in 31/44 cases of which 16/31 were mixed with metabolic acidosis and concurrent respiratory alkalosis the most common (10/31). Using the FS approach, metabolic changes were present 36/42 cases, with changes in free water (FW), chloride, and unmeasured anions (UA) being the most prevalent. Both FW and UA correlated well with pH; however, UA were most consistently abnormal in severe acidemia. Similarly to the HH, the VDM detected acid-base disturbances in 28/44 cases. Major contributors to the acid-base changes were hyponatremia, hypochloremia, and A tot acidosis because of elevated globulins and increased UA., Conclusions and Clinical Importance: Acid-base changes are common and complex in dogs with PE, and were easier to understand using a SIM paradigm. Increases in UA have not been documented in PE in dogs., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Serum creatinine and symmetric dimethylarginine (SDMA) are used as surrogate markers of glomerular filtration rate (GFR) in clinical practice. Data pertaining to the correlations between GFR, SDMA, and serum creatinine in client-owned dogs are limited., Objectives: To describe the relationship between GFR, SDMA, and serum creatinine in a population of client-owned dogs, and to compare clinical utility of SDMA to GFR estimation for detecting pre-azotemic chronic kidney disease., Animals: Medical records of 119 dogs that had GFR estimation performed via serum iohexol clearance between 2012 and 2017., Methods: Prospective study using archived samples. GFR, SDMA, and serum creatinine results were reviewed and submitting practices contacted for outcome data. All dogs included in the study population were non-azotemic. Correlations between GFR, SDMA, and serum creatinine were determined by regression analysis. Sensitivity, specificity, and positive and negative likelihood ratios of different cutoffs for SDMA and serum creatinine for detecting decreased GFR were calculated, using a 95% confidence interval., Results: Serum creatinine and SDMA were moderately correlated with GFR (R 2 = 0.52 and 0.27, respectively, P < .0001) and with each other (R 2 = 0.33, P < .0001). SDMA >14 μg/dL was sensitive (90%) but nonspecific (50%) for detecting a ≥40% decrease in GFR. Optimal SDMA concentration cutoff for detecting a ≥40% GFR decrease was >18 μg/dL (sensitivity 90%, specificity 83%)., Conclusions and Clinical Importance: In non-azotemic dogs being screened for decreased renal function, using a cutoff of >18 μg/dL rather than >14 μg/dL increases the specificity of SDMA, without compromising sensitivity., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Refractory congestive heart failure (CHF) and associated diuretic resistance are not well defined., Objectives: To characterize renal function, electrolyte concentrations, indices of diuretic efficacy, and renin-angiotensin-aldosterone system (RAAS) activation in dogs with naturally occurring heart disease (HD) in American College of Veterinary Internal Medicine stages B1, B2, C, and D and to determine their usefulness in defining HD stages., Animals: Group 1:149 dogs with HD stages B1, B2, C, and D. Group 2:22 dogs with HD stages C and D., Methods: Group 1: Renal parameters, serum and urine electrolyte and diuretic concentrations, and urine aldosterone concentrations were measured. Medication dosages and measured variables were compared among stages. Correlation of furosemide dosages to serum concentrations was explored. Group 2: Angiotensin-converting enzyme activity and RAAS components were measured and compared among CHF stages., Results: Serum chloride concentration was the best differentiator of HD stage. Furosemide PO dosages (≤6 mg/kg/day) were weakly correlated with serum furosemide concentrations, whereas higher dosages were not significantly correlated. Angiotensin-converting enzyme inhibitor dosage and RAAS inhibition were greater in stage D, compared to stage C dogs., Conclusions and Clinical Importance: Hypochloremia is a useful marker for stage D HD in dogs. Poor furosemide dosage correlation to serum concentration may indicate variable and poor absorption, especially at higher dosages, advanced disease, or both. A small number of stage D dogs met proposed criteria for diuretic resistance. Greater RAAS inhibition in stage D versus stage C indicates effectiveness of RAAS-suppressive treatments in this group of dogs with refractory CHF., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Osseous-associated cervical spondylomyelopathy (OA-CSM) is a common condition of the cervical vertebral column that affects giant dog breeds. MicroRNAs (miRNAs) are small RNAs that regulate gene expression, and recent data suggest that circulating miRNAs present in biological fluids may serve as potential biomarkers for disease. The miRNA profiles of cerebrospinal fluid (CSF) from healthy dogs and dogs clinically affected by OA-CSM have not been described., Objective: To characterize the expression levels of miRNAs present in the CSF of normal Great Danes and identify differentially expressed miRNAs in the CSF of Great Danes clinically affected with OA-CSM., Animals: Client-owned dogs: 12 control, 12 OA-CSM affected., Methods: Cerebrospinal fluid samples were collected prospectively. MicroRNA expression was evaluated using the NanoString nCounter platform and quantitative real-time PCR., Results: We identified 8 miRNAs with significant differential expression. MiR-299-5p and miR-765 had increased expression levels in the CSF of OA-CSM-affected dogs, whereas miR-494, miR-612, miR-302-d, miR-4531, miR-4455, and miR-6721-5p had decreased expression levels in OA-CSM affected dogs compared to clinically normal dogs. Quantitative real-time PCR was performed to validate the expression levels of 2 miRNAs (miR-494 and miR-612), and we found a 1.5-fold increase in miR-494 expression and a 1.2-fold decrease in miR-612 in the CSF of the OA-CSM affected group (P = .41 and .89, respectively)., Conclusions and Clinical Importance: Data generated from our study represent an initial characterization of the miRNA profile of normal canine CSF and suggest that a distinct CSF miRNA expression profile is associated with OA-CSM., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Sudden acquired retinal degeneration syndrome (SARDS) has clinical similarity to pituitary-dependent hypercortisolism (PDH) in dogs. Some studies have identified a greater frequency of SARDS in seasons with reduced daylight hours. Neurohormone imbalances contribute to retinal lesions in other species, warranting further study in dogs with SARDS., Hypothesis: Dysregulation of circulating melatonin concentration is present in dogs with SARDS but not in dogs with PDH., Animals: Fifteen client-owned dogs with spontaneous SARDS (median time of vision loss 18 days), 14 normal dogs, and 13 dogs with confirmed PDH., Procedures: Prospective case-control study. ELISA on samples (obtained in the morning) for measurement of plasma melatonin and dopamine, serum serotonin, urine 6-sulfatoxymelatonin (MT6s), and creatinine. Statistical analysis was performed using 1-way ANOVA, Spearman correlation and receiver operator characteristic area under the curve analysis., Results: There were no significant differences in circulating melatonin, serotonin or dopamine concentrations between the 3 groups, although the study was underpowered for detection of significant differences in serum serotonin. Urine MT6s:creatinine ratio was significantly higher in dogs with PDH (4.08 ± 2.15 urine [MT6s] ng/mL per mg of urine creatinine) compared with dogs with SARDS (2.37 ± .51, P < .01), but not compared with normal dogs., Conclusions and Clinical Relevance: We have identified neurohormone differences between dogs with SARDS and PDH., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor in dogs. Abnormalities in hepatic copper, iron, zinc, and selenium concentrations increase risk for HCC development in other species, but trace mineral concentrations have not been evaluated in dogs with HCC., Objectives: To investigate hepatic trace mineral concentrations in dogs with HCC., Animals: Archived liver specimens from 85 dogs with HCC and 85 control dogs., Methods: Retrospective case-control study. A histopathology database was searched to identify dogs with HCC (test population) and an age-matched control population. Demographic information was retrieved, and H&E and rhodanine stained slides were reviewed for all cases. Copper, iron, zinc, and selenium concentrations were determined in noncancerous liver tissues (test and control population) and in HCC tissues (test population) using inductively coupled plasma mass spectrometry., Results: Hepatic copper concentrations (non-neoplastic hepatic tissue) were greater in test population dogs (median, IQR; 294.9 μg/g, 233.5-475.9 μg/g) than in control dogs (202.8 μg/g, 135.0-295.3 μg/g; P < .001). Hepatic zinc concentrations in test (132.1 μg/g,108.6-163.2 μg/g) and control dogs (151.5 μg/g, 117.1-184.5 μg/g) also were different (P = .03). Within test population dogs, all trace mineral concentrations were decreased in the HCC tissue as compared to the non-neoplastic hepatic tissue (all P < .001)., Conclusions and Clinical Importance: Hepatic copper accumulation and other abnormalities in hepatic trace mineral concentrations could be involved in the pathogenesis of HCC in some dogs., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Brachycephalic dogs have abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome. Obstructive sleep apnea syndrome is associated with dyslipidemia, hyperglycemia, and insulin resistance. Despite the fact that anatomic and functional alterations are well described in brachycephalic dogs, little is known about the consequences of upper airway obstruction on systemic inflammatory response and metabolic profile., Objectives: To describe history, clinical presentation, and anatomic abnormalities; to evaluate systemic inflammatory response and metabolic profile; and to identify possible associations among clinical signs, anatomic abnormalities, inflammatory response, and metabolic profile in brachycephalic dogs with airway obstruction., Animals: Thirty purebred brachycephalic dogs with brachycephalic airway obstructive syndrome (BAOS)., Methods: Prospective study. The following information was recorded and studied: respiratory and digestive signs, airway and digestive endoscopic anomalies, presence or absence of tracheal hypoplasia, histologic evaluation of gastrointestinal tract biopsy specimens, serum concentrations of C-reactive protein (CRP), fructosamine, insulin, glucose, triglyceride, cholesterol, and plasma concentrations of lipoprotein classes., Results: A high proportion of dogs (76.7%) had gastrointestinal signs. Esophageal deviation, atony of the cardia of the stomach, and distal esophagitis were the most common endoscopic anomalies detected. Twenty-six (86.6%) dogs had different degrees of laryngeal collapse. Gastrointestinal histologic evaluation identified mostly chronic inflammation. Glucose, fructosamine, triglycerides, cholesterol, CRP, pre-beta, beta lipoproteins, and chylomicrons were increased to a variable extent. Significant associations among clinical signs, anatomic abnormalities, CRP, and metabolic profile were not found., Conclusion and Clinical Importance: Despite the presence of inflammation and some mild metabolic derangements, the clinicopathological variables evaluated did not offer valuable information in dogs with BAOS., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Hepatic copper accumulation causes chronic hepatitis in dogs. Mutations in the copper transporters ATP7A and ATP7B were, respectively, associated with attenuation and enhancement of hepatic copper concentrations in Labrador Retrievers. There is a predisposition of Dobermanns to hepatitis with increased hepatic copper concentrations., Objectives: To investigate whether the ATP7A:c.980C>T and ATP7B:c.4358G>A mutations identified in Labrador Retrievers were associated with hepatic copper concentrations in Dobermanns., Animals: Dobermanns from the Netherlands (n = 122) and the United States (n = 78)., Methods: In this retrospective study, mutations in ATP7A and ATP7B were investigated as risk factors for hepatic copper accumulation in Dobermanns. Liver biopsies of 200 Dobermanns were evaluated by histochemical copper staining, quantitative copper measurement, or both modalities. ATP7A and ATP7B genotypes were obtained by Kompetitive Allele Specific PCR. A linear regression model was used to investigate an association between genotype and hepatic copper concentrations., Results: The ATP7A:c.980C>T was identified in both Dutch (2 heterozygous individuals) and American Dobermanns. In the American cohort, the minor allele frequency of the mutation was low (.081) and a possible effect on hepatic copper concentrations could not be established from this data set. A significant association of the ATP7B:c.4358G>A variant with increased hepatic copper concentrations in Dobermanns was observed., Conclusions and Clinical Importance: The ATP7B:c.4358G>A variant could be a contributor to hepatic copper accumulation underlying the risk of development of copper-associated hepatitis in breeds other than the Labrador Retriever., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: A recent genome-wide association study in German Shepherd dogs (GSDs) with chronic enteropathy (CE) has identified polymorphisms in the Th2 cytokine genes., Hypothesis/objective: To determine if the expression of the Th2 cytokines, interleukin-13 (IL-13) and interleukin-33 (IL-33), is altered in the duodenal mucosa of GSDs with CE compared to non-GSDs with CE and healthy dogs., Animals: Twenty client-owned dogs diagnosed with CE (10 GSDs and 10 non-GSDs) at the Bristol Veterinary School and 8 healthy Beagle dogs from the Iowa State University Service Colony., Methods: Retrospective study using archived paraffin-embedded duodenal biopsy samples. A novel RNA in situ hybridization technology (RNAscope) was used to hybridize IL-13 and IL-33 mRNA probes onto at least 10 sections from duodenal biopsy samples for each dog. RNAscope signals were visualized using a microscope and semi-quantitative assessment was performed by a single operator., Results: Based on duodenal villus, subvillus, epithelial, and lamina propria average expression scores, GSDs with CE had significantly lower IL-13 and IL-33 mRNA expression compared to non-GSDs with CE (IL-13, P < .04; IL-33, P < .02) and healthy Beagle dogs (IL-13, P < .02; IL-33, P < .004)., Conclusions and Clinical Importance: Similar to human patients with ulcerative colitis, a subtype of human inflammatory bowel disease, these data indicate that Th2 cytokines may be involved in the pathogenesis of CE in GSDs., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Babesia canis infection induces a marked acute phase response (APR) that might be associated with alteration in lipid and lipoprotein metabolism and disease prognosis., Hypothesis: Dogs with B. canis-induced APR develop dyslipidemia with altered lipoprotein concentration and morphology., Animals: Twenty-nine client-owned dogs with acute B. canis infection and 10 clinically healthy control dogs., Methods: Observational cross-sectional study. Serum amyloid A (SAA) was measured using ELISA. Cholesterol, phospholipids, and triglycerides were determined biochemically. Lipoproteins were separated using agarose gel electrophoresis. Lipoprotein diameter was assessed by polyacrylamide gradient gel electrophoresis; correlation with ApoA-1 (radioimmunoassay) and SAA was determined., Results: Dogs with B. canis infection had a marked APR (median SAA, 168.3 μg/mL; range, 98.1-716.2 μg/mL) compared with controls (3.2 μg/mL, 2.0-4.2 μg/mL) (P < .001). Dogs with B. canis infection had significantly lower median cholesterol (4.79 mmol/L, 1.89-7.64 mmol/L versus 6.15 mmol/L, 4.2-7.4 mmol/L) (P = .02), phospholipid (4.64 mmol/L, 2.6-6.6 mmol/L versus 5.72 mmol/L, 4.68-7.0 mmol/L) (P = .02), and α-lipoproteins (77.5%, 27.7%-93.5% versus 89.2%, 75.1%-93.5%) (P = .04), and higher ApoA-1 (1.36 U, 0.8-2.56 U versus 0.95 U, 0.73-1.54 U) concentrations (P = .02). Serum amyloid A correlated with high-density lipoproteins (HDLs) diameter (rho = .43; P = .03) and ApoA-1 (rho = .63, P < .001)., Conclusions and Clinical Importance: Major changes associated with B. canis-induced APR in dogs are related to concentration, composition, and morphology of HDL particles pointing to an altered reverse cholesterol transport. Parallel ApoA-1 and SAA concentration increase is a unique still unexplained pathophysiological finding., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Mounting evidence from human studies suggests that bile acid dysmetabolism might play a role in various human chronic gastrointestinal diseases. It is unknown whether fecal bile acid dysmetabolism occurs in dogs with chronic inflammatory enteropathy (CE)., Objective: To assess microbial dysbiosis, fecal unconjugated bile acids (fUBA), and disease activity in dogs with steroid-responsive CE., Animals: Twenty-four healthy control dogs and 23 dogs with steroid-responsive CE., Methods: In this retrospective study, fUBA were measured and analyzed. Fecal microbiota were assessed using a dysbiosis index. The canine inflammatory bowel disease activity index was used to evaluate remission of clinical signs. This was a multi-institutional study where dogs with steroid-responsive CE were evaluated over time., Results: The dysbiosis index was increased in dogs with CE (median, 2.5; range, -6.2 to 6.5) at baseline compared with healthy dogs (median, -4.5; range, -6.5 to -2.6; P = .002) but did not change in dogs with CE over time. Secondary fUBA were decreased in dogs with CE (median, 29%; range, 1%-99%) compared with healthy dogs (median, 88%; 4%-96%; P = .049). The percent of secondary fUBA in dogs with CE increased from baseline values (median, 28%; range, 1%-99%) after 2-3 months of treatment (median, 94%; range, 1%-99%; P = 0.0183)., Conclusions and Clinical Importance: These findings suggest that corticosteroids regulate fecal bile acids in dogs with CE. Additionally, resolution of clinical activity index in dogs with therapeutically managed CE and bile acid dysmetabolism are likely correlated. However, subclinical disease (i.e., microbial dysbiosis) can persist in dogs with steroid-responsive CE., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Efficacy of PO cobalamin (Cbl) supplementation in dogs with hereditary Cbl malabsorption (Imerslund-Gräsbeck syndrome, IGS) is unknown., Objectives: To evaluate PO Cbl supplementation in Beagles with IGS previously treated parenterally. We hypothesized that 1 mg cyano-Cbl daily PO would maintain clinical and metabolic remission., Animals: Three client-owned Beagles with IGS and 48 healthy control dogs., Methods: Prospective study. Daily PO cyanocobalamin (cyano-Cbl; 1 mg) supplementation was monitored for 13 (2 dogs) and 8 months (1 dog). Health status was assessed by owner observations. Methylmalonic acid (MMA)-to-creatinine concentrations were measured using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-TMS) method on urine samples collected monthly. Concurrent measurements of serum MMA concentration (n = 7; UPLC-TMS) were available for 1 dog., Results: All dogs remained in excellent health during PO supplementation. Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2-9; healthy dogs [n = 30], median, 2.9 mmol/mol creatinine; range, 1.3-76.5). Urine MMA ranged from 38.9-84.9 mmol/mol creatinine during the first 6 months in 1 dog already known to excrete comparable amounts when supplemented parenterally. Brief antibiotic treatment for an unrelated condition after 6 months resulted in low urine MMA (median, 2.8 mmol/mol creatinine; range, 1.9-4.8) for the next 7 months. All concurrent serum MMA concentrations (median, 651 nmol/L; range, 399-919) before and after month 6 were within the established reference interval (393-1476 nmol/L; n = 48)., Conclusions and Clinical Importance: One milligram of cyano-Cbl daily PO appears efficacious for maintaining normal clinical status and normal cellular markers of Cbl metabolism in Beagles with IGS., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Current recommendation for performing the ACTH stimulation test (ACTHST) for diagnosis of hyperadrenocorticism (HAC) advocates the collection of baseline serum cortisol concentration (BC), but no references for interpretation of its results exist., Objective: Evaluate the contribution of BC of the ACTHST to the diagnosis of HAC., Animals: Fifty-four dogs were evaluated for suspected HAC at a referral hospital., Methods: Records of dogs that had been evaluated by ACTHST for suspected HAC were reviewed. Receiver operator characteristics (ROC) analyses were used to assess the performance of BC, post-stimulation serum cortisol concentrations (PC), post-to-baseline cortisol concentration difference (DeltaC) and quotient (RatioC) for the diagnosis of HAC by comparing the area under the ROC curve (AUC) of PC to each of the other tests., Results: The AUC of PC (95% confidence interval [CI]: 0.92; 95% CI, 0.81-0.98) was significantly higher than AUCs of BC (0.70; 95% CI, 0.56-0.82; P = .01) and RatioC (0.55; 95% CI, 0.41-0.69; P < .001), and was not significantly different from AUC of DeltaC (0.86; 95% CI, 0.74-0.94; P = .09). An optimal cutoff value of 683 nmol/L (24.8 μg/dL) for PC yielded a sensitivity of 86% and a specificity of 94%, respectively, and a cutoff value of 718 nmol/L (26.0 μg/dL) yielded a specificity of 100% with of 81% sensitivity for the diagnosis of pituitary-dependent HAC., Conclusion and Clinical Importance: The PC had good discriminatory ability for the diagnosis of HAC. It was comparable to DeltaC, whereas BC and RatioC were ineffective. Current recommendations to collect samples for BC appear redundant., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Intestinal absorption of bile acids is mediated by the apical sodium-dependent bile acid transporter (ASBT). Fecal bile acid dysmetabolism has been reported in dogs with chronic inflammatory enteropathy (CIE)., Objective: Characterization of ASBT distribution along the intestinal tract of control dogs and comparison to dogs with CIE., Animals: Twenty-four dogs with CIE and 11 control dogs., Methods: The ASBT mRNA and protein expression were assessed using RNA in situ hybridization and immunohistochemistry, respectively. The concentrations of fecal bile acids were measured by gas chromatography-mass spectrometry. The fecal microbiota dysbiosis index was assessed with a quantitative polymerase chain reaction panel., Results: In control dogs, ASBT mRNA expression was observed in enterocytes in all analyzed intestinal segments, with highest expression in the ileum. The ASBT protein expression was restricted to enterocytes in the ileum, cecum, and colon. Dogs with CIE had significantly decreased expression of ASBT protein in the ileum (P = .001), which was negatively correlated with histopathological score (ρ = -0.40; P corr = .049). Additionally, dogs with CIE had a significantly increased percentage of primary bile acids in feces compared to controls (P = .04). The fecal dysbiosis index was significantly higher in dogs with CIE than in control dogs (P = .01)., Conclusions and Clinical Importance: These findings indicate that ileal protein expression of ASBT is downregulated in dogs with CIE. This change may be linked to the inflammatory process, intestinal dysbiosis, and fecal bile acid dysmetabolism observed in these patients., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Chronic hepatitis (CH) occurs commonly in dogs but is associated with a variable and largely unpredictable prognosis. p21, a cell-cycle inhibitor and marker of cellular senescence, is upregulated in human liver disease and is a better prognostic marker than histological or clinical scoring systems., Objective: To quantify hepatocyte p21 immunopositivity in histopathology samples from dogs with CH and determine its association with outcome., Animals: Twenty-six client-owned dogs with histologically confirmed CH, and 15 dogs with normal liver histology., Methods: Medical records and liver histopathology samples were retrospectively reviewed to identify cases of CH. Immunohistochemistry for p21 was performed on all samples and hepatocyte immunopositivity was visually quantified. Relationships between p21 and dog age and dog survival time were statistically evaluated., Results: Hepatocyte p21 immunopositivity in dogs with CH was high (median percentage of positive hepatocytes: 90%, range: 20%-98%) and exceeded 70% in 23/26 cases with no association with age. In control dogs, p21 immunopositivity was low (≤15% positive hepatocytes in 12/15 cases) and was positively correlated with age (r s  = 0.63; P = .011). Dogs with p21 immunopositivity exceeding 91.8% (upper tercile) had significantly shorter survival compared to dogs with less than 88.9% immunopositivity (lowest tercile; 218 versus 874 days, P = .006). Increasing hepatocyte p21 immunopositivity was significantly negatively associated with survival time (HR 4.12; 95% CI 1.34-12.63; P = .013)., Conclusions and Clinical Importance: Marked p21 immunopositivity in dogs with CH might be indicative of widespread hepatocellular senescence. A significant association with survival time also suggests a potential value for p21 quantification in determining prognosis., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Mucosal imbalance of interleukin (IL)-1β and IL-1 receptor antagonist (Ra) has been reported in the duodenal mucosa of dogs with inflammatory bowel disease (IBD). However, the imbalance in the colonic mucosa and its role in duodenitis and colitis in IBD of dogs remain unclear., Objectives: To measure the expression of IL-1β and IL-1Ra proteins in the colonic mucosa of dogs with IBD, and to determine the effect of IL-1β on expression of occludin (ocln) mRNA, a tight junction component, in the duodenal and colonic mucosa of dogs with IBD., Animals: Twelve dogs with IBD and 6 healthy dogs., Methods: IL-1β and IL-1 Ra proteins in the colonic mucosa were quantified by ELISA in 7 of the 12 dogs with IBD. Expression of ocln mRNA in the duodenal and colonic mucosa was examined in the 12 dogs by real-time PCR., Results: The ratio of IL-1β to IL-1Ra in the colonic mucosa was significantly higher in dogs with IBD than in healthy dogs. The ex vivo experiment determined that IL-1β suppressed expression of ocln mRNA in the colonic mucosa, but not in the duodenal mucosa, of healthy dogs. Expression of ocln mRNA in the colonic mucosa, but not in the duodenal mucosa, was significantly lower in dogs with IBD than in healthy dogs., Conclusions and Clinical Importance: A relative increase in IL-1β may attenuate ocln expression, leading to intestinal barrier dysfunction and promotion of intestinal inflammation in the colonic mucosa, but not in the duodenal mucosa, of dogs with IBD., (Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: There is growing evidence linking low blood vitamin D concentration to numerous diseases in people and in dogs. Vitamin D influences cellular function by signaling through the vitamin D receptor (VDR). Little is known about which non-skeletal tissues express the VDR or how inflammation influences its expression in the dog., Objectives: To define which non-skeletal canine tissues express the VDR and to investigate expression in inflamed small intestine., Animals: Thirteen non-skeletal tissues were collected prospectively from 6 control dogs. Thirty-five dogs diagnosed with a chronic enteropathy (CE) and 24 control dogs were prospectively enrolled and duodenal biopsies were evaluated for VDR expression., Methods: Prospective; blinded assessment of canine intestinal VDR. Dogs with CE were included once other identifiable causes of intestinal disease were excluded. Age matched controls were included with no intestinal clinical signs. VDR expression was assessed immunohistochemically in all samples, using a Rat IgG VDR monoclonal antibody. Quantitative real-time polymerase chain reaction (qPCR) was also used for duodenal biopsies., Results: VDR expression as assessed by immunohistochemistry (IHC) was highest in the kidney, duodenum, skin, ileum and spleen, and weak in the colon, heart, lymph node, liver, lung, and ovary. Gastric and testicular tissue did not express the VDR. There was no statistical difference in duodenal VDR expression between the 24 healthy dogs and 34 dogs with CE when quantified by either qPCR (P = 0.87) or IHC (P = 0.099)., Conclusions and Clinical Importance: The lack of down regulation of VDR expression in inflamed intestine contrasts with previous studies in humans. Our findings support future studies to investigate whether vitamin D and its analogues can be used to modulate intestinal inflammation in the dog., (Copyright © 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathways play important roles in the pathogenesis of diffuse large B cell lymphoma (DLBCL) in humans, and up-regulated STAT3 expression and activity are associated with worse clinical outcome in humans. No studies have evaluated the JAK-STAT signaling pathway in DLBCL of dogs., Hypothesis: STAT3 pathway is deregulated in DLBCL in dogs. We aim to assess the expression, activation, and cellular localization of STAT3 and mitogen-activated protein kinase ERK1/2 in DLBCL of dogs., Animals: Forty-three client-owned dogs diagnosed with DLBCL by histopathology METHODS: Retrospective analysis of DLBCL in dogs, including patient characteristics and treatment, immunohistochemistry, and protein expressions by Western blot., Results: A higher percentage of STAT3 and p-STAT3 immunolabelled cells were observed in DLBCL of dogs when compared to normal canine lymph nodes. In STAT3 immunolabelled cells, STAT3 has higher nuclear expression in lymphoma samples than in normal or reactive lymph nodes. In addition to up-regulated STAT3 expression and activation, mitogen-activated kinase ERK1/2 activation is up-regulated in DLBCL of dogs., Conclusion and Clinical Importance: Compared with the normal canine lymph node, DLBCL of dogs has up-regulated STAT3 pathway. Our results support future investigation of JAK inhibitors in the treatment of DLBCL in dogs., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: There are conflicting reports of plasma lipoprotein lipid content in dogs with diabetes mellitus (DM)., Objectives: To determine lipoprotein lipid content of plasma of dogs with DM by spectrophotometry and ultracentrifugation; to compare lipoprotein lipid content in diabetic and healthy dogs; and to quantify apolipoprotein B-100 (ApoB) in dogs with DM., Animals: 22 dogs with DM and 9 healthy dogs., Methods: Cross-sectional study. Triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) concentrations were measured by spectrophotometry. Very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations were calculated after ultracentrifugation. Non-HDL-C cholesterol was calculated by subtracting HDL-C from TC. ApoB was quantified by ELISA. The Mann-Whitney test was used for comparison of median lipoprotein concentrations, and Spearman's correlation was used to assess associations between ApoB and lipoprotein fractions., Results: All values are reported in mg/dL. Median TG (122), TC (343.5), HDL-C, (200), VLDL-C, (27) LDL-C (68), non-HDL-C (114), and ApoB (320) were significantly higher in dogs with DM, compared to healthy dogs (57, 197, 168, 12, 16, 31, and 258, respectively, P-values 0.0079, <0.001, 0.029, 0.011, <0.001, <0.001, 0.025, respectively). A significant association was found between ApoB and LDL-C (Spearman's rho = 0.41, P = 0.022) and between ApoB and non-HDL-C (Spearman's rho = 0.40, P = 0.027)., Conclusions and Clinical Importance: Dyslipidemia of dogs with DM is characterized by pronounced increases in LDL-C and non-HDL-C concentrations, although all lipoprotein fractions are significantly increased. Knowledge of specific lipoprotein fraction alterations in dogs with DM can enhance treatment options for diabetic dyslipidemia in dogs., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Primary hypertriglyceridemia is a common condition in older Miniature Schnauzers that recently has been associated with proteinuria and underlying glomerular pathology, particularly glomerular lipid thromboemboli. Consequences of glomerular disease can include hypertension, thromboembolic disease, and cardiac disease. The incidence of these sequelae in Miniature Schnauzers with hypertriglyceridemia-associated proteinuria (HTGP) is unknown., Objective: To investigate prevalence of hypertension, decreased antithrombin III activity, and cardiac disease in Miniature Schnauzers with and without HTGP., Animals: Thirty-two Miniature Schnauzers ≥7 years old., Methods: Prospective case-control study. Data collected from dogs included a CBC, biochemistry panel, urinalysis, urine protein-to-creatinine ratio, urine cortisol-to-creatinine ratio, serum total thyroxine concentration, fasting serum triglyceride concentration, indirect blood pressure, antithrombin III activity, and serum cardiac troponin I concentration. Results from dogs with HTGP (serum triglyceride concentration ≥ 100 mg/dL and urine protein-to-creatinine ratio >0.5) were statistically compared to normotriglyceridemic, nonproteinuric dogs., Results: Eighteen of the 32 dogs (56%) had primary hypertriglyceridemia. Of those dogs, 8 of 18 had proteinuria. None of the HTGP dogs were azotemic or hypoalbuminemic. Serum albumin concentration, alkaline phosphatase activity, and cholesterol concentration were significantly increased in dogs with HGTP compared to those without HGTP. No increased risk of hypertension, decreased antithrombin III activity, or cardiac disease was noted. Limited data from 8 dogs with HTGP showed no development of hypoalbuminemia or azotemia over a median follow-up period of 18 months., Conclusions and Clinical Importance: Geriatric Miniature Schnauzers with HGTP may have a good prognosis overall, and are not typically azotemic or hypoalbuminemic., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are considered to be key mediators of tumor invasion and metastasis. MMP-2 and MMP-9 are expressed in meningiomas of dogs, but TIMP expression, and variations of specific MMP/TIMP ratios still are unknown in this tumor., Hypothesis/objectives: Expression of MMP/TIMP might increase progressively from grade I to grade III meningioma. Therefore, genetic expression of MMP-2 and MMP-9, and specific TIMP-2 and TIMP-1, respectively, has been investigated in meningiomas of different grades., Animals: Selected formalin-fixed paraffin-embedded tissue from 43 meningiomas of dogs was evaluated., Methods: Genetic material was obtained from pathologic samples and used for quantitative reverse transcriptase real-time polymerase chain reaction (RT-qPCR)., Results: MMP-9 was not expressed in all of the tumors, but MMP-2 was significantly more expressed in papillary meningioma. Likewise, the MMP-2/TIMP-2 ratio was numerically higher in papillary meningiomas compared to all grades (>3.5 times) showing a strong bias in favor of metalloproteinase. In the papillary meningioma, TIMP-1 gene expression was significantly higher than in grades I and III., Conclusions and Clinical Importance: MMP-2/TIMP-2 imbalance might contribute to the aggressive biologic behavior of papillary meningiomas in dogs. TIMP-1 expression may play a role independent of MMP-9 expression in neoplastic progression. These results further support that therapeutic and prognostic evaluations of dogs with meningioma need to be addressed according to different histologic patterns as is performed in humans., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Oxidative stress plays a role in the pathophysiology of several diseases and has been documented as a contributor to disease in both the human and veterinary literature. One at-risk cell is the erythrocyte, however, the role of oxidative stress in anemia in dogs has not been widely investigated., Hypothesis/objective: Anemic dogs will have an alteration in the activity of glutathione peroxidase (GPx), a decrease in of total antioxidant capacity (TAC), and an increased concentration of urinary 15-F 2 -isoprostanes (F 2 -IsoP) when compared to healthy dogs., Animals: 40 client-owned dogs with anemia (PCV <30%) age-matched to 40 client-owned healthy control dogs., Methods: Prospective, cross-sectional study. Whole blood GPx activity, plasma TAC, and urinary F 2 -isoprostane concentrations were evaluated in each dog and compared between groups., Results: Anemic dogs had significantly lower GPx activity (43.1 × 10 3 +/- 1.6 × 10 3 U/L) than did dogs in the control group (75.8 × 10 3 +/- 2.0 × 10 3 U/L; P < 0.0001). The GPx activity in dogs with hemolysis (10 3 +/- 0.8 × 10 3 U/L) was not significantly different (P = 0.57) than in dogs with nonhemolytic anemia (43.5 × 10 3 +/- 1.1 × 10 3 U/L). The TAC concentrations (P = 0.15) and urinary F 2 -isoprostanes (P = 0.73) did not significantly differ between groups., Conclusions and Clinical Importance: Glutathione peroxidase activity was significantly decreased in anemic dogs indicating oxidative stress. Additional studies are warranted to determine if antioxidant supplementation would improve survival and overall outcome as part of a therapeutic regimen for anemic dogs., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The etiology of obesity-related cardiac dysfunction (ORCD) is linked to metabolic syndrome in people. Studies have indicated that obese dogs have components of metabolic syndrome, warranting evaluation for ORCD in obese dogs., Objectives: To evaluate cardiac structure and function and metabolic variables in obese dogs compared to ideal weight dogs., Animals: Forty-six healthy, small-breed (<25 pounds), obese dogs (n = 29) compared to ideal weight dogs (n = 17)., Methods: A cross-sectional study of cardiac structure and function by standard and strain echocardiographic measurements and quantification of serum metabolic variables (insulin:glucose ratios, lipid analysis, adiponectin, inflammatory markers)., Results: Compared to the ideal weight controls, obese dogs had cardiac changes characterized by an increased interventricular septal width in diastole to left ventricular internal dimension in diastole ratio, decreased ratios of peak early to peak late left ventricular inflow velocities, and ratios of peak early to peak late mitral annular tissue velocities, and increased fractional shortening and ejection fraction percentages. The left ventricular posterior wall width in diastole to left ventricular internal dimension in diastole ratios were not significantly different between groups. Systolic blood pressure was not significantly different between groups. Obese dogs had metabolic derangements characterized by increased insulin:glucose ratios, dyslipidemias with increased cholesterol, triglyceride, and high-density lipoprotein concentrations, decreased adiponectin concentrations, and increased concentrations of interleukin 8 and keratinocyte-derived chemokine-like inflammatory cytokines., Conclusions and Clinical Importance: Compared to ideal weight controls, obese dogs have alterations in cardiac structure and function as well as insulin resistance, dyslipidemia, hypoadiponectinemia, and increased concentrations of inflammatory markers. These findings warrant additional studies to investigate inflammation, dyslipidemia, and possibly systemic hypertension as potential contributing factors for altered cardiac function., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Endothelin (ET)-1 is a 21-amino-acid peptide with potent vasoactive properties, which increases intrahepatic resistance in patients with chronic hepatitis (CH) or cirrhosis. ET-1 concentrations have not been investigated in dogs with CH., Hypothesis/objectives: This study compared hepatic and plasma ET-1 levels in healthy dogs and in dogs with CH, and examined the relationship between the plasma ET-1 level and portal vein pressure in dogs with CH., Animals: Fourteen healthy dogs and twenty dogs with CH were used in this study., Methods: Prospective case-control study. Hepatic ET-1 mRNA expression was determined by real-time reverse transcription polymerase chain reaction, and hepatic and plasma ET-1 levels were assessed using ELISA. Splenic pulp pressure (SPP), as an indicator of portal vein pressure, was measured laparoscopically., Results: Hepatic ET-1 mRNA levels were 3.7 times higher in dogs with CH than in healthy dogs (P = .008). The median hepatic and plasma ET-1 protein levels were significantly higher in dogs with CH than in healthy dogs (13.20 pg/mg wet liver vs. 3.42 pg/mg wet liver, P = .004, and 0.99 pg/mL vs. 0.71 pg/mL, P = .013, respectively). Moreover, there was a weak but significant correlation between plasma ET-1 level and SPP in dogs with CH (P = .036; r s = 0.53)., Conclusions and Clinical Importance: The results indicate that ET-1 might play an important role in the pathogenesis of portal hypertension caused by CH., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Leptin and its receptor play a role in several disease processes such as pancreatitis and heart disease. However, their association with gallbladder mucocele (GBM) in dogs has not been reported., Hypothesis/objectives: To evaluate differences in the expression of leptin and leptin receptor between dogs with and without GBM., Animals: Twenty-five healthy dogs, including 9 laboratory beagle dogs, and 22 client-owned dogs with GBM., Methods: Serum leptin concentration was determined in blood samples of all dogs by ELISA. Canine gallbladder samples were collected from 9 dogs with GBM that underwent surgery for therapeutic purposes and from 9 healthy laboratory beagle dogs as a normal control group. Samples were analyzed for leptin and leptin receptor mRNA by real-time polymerase chain reaction., Results: Serum leptin concentration was significantly higher in dogs with GBM than in healthy dogs (medians of 7.03 and 2.18 ng/mL, respectively; P < .001). Patients with GBM that had undergone surgery had significantly higher serum leptin concentrations than those that had not (medians of 12.2 and 4.09 ng/mL, respectively; P = .001). However, no difference in serum leptin concentration was found between dogs with GBM with or without endocrinopathies. The mRNA expression levels of leptin and its receptor were significantly increased in the gallbladder tissues of dogs with GBM., Conclusions and Clinical Importance: Dysregulation of leptin might be involved in the pathophysiology of GBM, and leptin concentrations might be associated with GBM severity., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Ascitic fluids of horses and humans have fibrinolytic activity, independent of the underlying mechanism of fluid formation., Objective: To determine whether coagulation and fibrinogenolytic/fibrinolytic activity (ie, low fibrinogen and increased fibrin-fibrinogen degradation products [FDPs], D-dimer, or both) occur in all types of ascitic fluid in dogs., Animals: A total of 70 client-owned dogs with ascites., Methods: In this cross-sectional study, dogs were categorized based on the pathophysiology of fluid formation into 4 groups: transudates due to decreased osmotic pressure, transudates due to increased hydrostatic pressure, exudates, and hemorrhagic ascites. Fibrinogen, FDPs, and D-dimer concentrations were measured and then compared in both ascitic fluid and plasma., Results: Ten dogs had transudates due to decreased colloid osmotic pressure, 18 had transudates due to increased hydrostatic pressure, 13 had exudates, and 29 had hemorrhagic ascites. Ascitic fibrinogen concentrations (n = 70) were significantly lower (median = 59 mg/dL; range: 59-122 mg/dL) than those in the plasma (median = 168 mg/dL, range: 59-879 mg/dL; P < .0001). Ascitic FDPs concentrations (n = 70) were significantly higher (<5 μg/mL: 3/70 dogs, ≥5 to <20 μg/mL: 11/70 dogs, ≥20 μg/mL: 56/70 dogs) than those in the plasma (<5 μg/mL: 17/70 dogs, ≥5 to <20 μg/mL: 28/70 dogs, ≥20 μg/mL: 25/70 dogs; P < .0001). Ascitic D-dimer concentrations (n = 70) were significantly higher (median = 3.98 μg/mL, range: 0.02-9.19) than those in the plasma (median = 0.11 μg/mL, range: 0.01-4.08; P < .0001). Analysis of the data for each of the 4 different types of ascites showed similar results to those of all the data analyzed together., Conclusions and Clinical Importance: Ascitic fluid of dogs has evidence of coagulation activation and fibrinogenolytic/fibrinolytic activity and that this phenomenon occurs independent of the underlying mechanism that leads to the formation of ascites., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Deletion of exon 2 of copper metabolism domain containing 1 (COMMD1) results in copper toxicosis in Bedlington terriers (CT-BT)., Objectives: This study was conducted to identify the prevalence and clinical relevance of the COMMD1 mutation in Bedlington terriers in Korea., Animals: A total of 105 purebred Bedlington terriers (50 males, 55 females) from the kennels and pet dog clubs in Korea were examined during the period 2008-2013., Methods: A multiplex PCR was carried out to detect exon 2 deletion of COMMD1. Clinical analysis was performed on each genetic group, and clinical status of the dogs was followed up to estimate survival probability., Results: Of the 105 samples, 52 (49%) were wild-type homozygote, 47 (45%) were heterozygote, and 6 (6%) were mutant-type homozygote. Plasma alanine aminotransferase (ALT) activity was increased in the mutant-type homozygous group >2 years of age (P < .0001). The survival probability of 6 mutant-type homozygotes surviving 2.5 years was 0.67, and 4 years was 0.5., Conclusions and Clinical Importance: Results show the prevalence and clinical relevance of exon 2 deletion of COMMD1 and could help establish a structured selective breeding program to prevent CT-BT in Korea., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Obese dogs risk poor life quality, creating a need for increased knowledge of metabolism in overweight dogs., Objectives: Investigate postprandial metabolic and hormonal responses to a high-fat mixed-meal in dogs and responses of lean versus overweight dogs., Animals: Twenty-eight healthy intact male Labrador Retrievers were included., Methods: Prospective observational study. Twelve dogs were grouped as lean (body condition score (BCS 4-5), 10 as slightly overweight (BCS 6), and 6 as overweight (BCS 6.5-8) on a 9-point scale. After an overnight fast, urine and blood samples were collected. Dogs were then fed a high-fat mixed-meal, and blood was collected hourly for 4 hours and urine after 3 hours., Results: Postprandial concentrations of insulin and glucagon were increased at 1 hour (both P < 0.0001), triglycerides at 2 hours (P < 0.0001), and glucose at 3 hours (P = 0.004); and all remained increased throughout the feed-challenge in all dogs. Postprandial urine cortisol/creatinine ratio was higher than fasting values (P = 0.001). Comparing between groups, there was an overall higher triglyceride response in overweight compared to lean (P = 0.001) and slightly overweight (P = 0.015) dogs. Overweight dogs also had higher fasting cortisol/creatinine ratio compared to lean dogs (P = 0.024)., Conclusions and Clinical Importance: Postprandial responses of dogs to a high-fat mixed-meal were similar to those previously reported in people. The higher postprandial triglyceride response and fasting cortisol/creatinine ratio in the overweight dogs could be early signs of metabolic imbalance. Thus, although overweight dogs often appear healthy, metabolic alterations might be present., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Diagnosis of pancreatitis in dogs is complicated by extrapancreatic disorders that can alter the results of laboratory tests. Extrapancreatic disorders can also affect the diagnosis of exocrine pancreatic insufficiency (EPI). The effects of acute kidney injury (AKI) on pancreas-specific lipase activity (Spec cPL(®) Test), serum lipase activity and trypsin-like immunoreactivity (TLI) in dogs have not been evaluated., Hypothesis/objectives: Serum Spec cPL, lipase activity, and TLI concentrations will increase secondary to decreased kidney function., Animals: Five purpose-bred dogs., Methods: Experimental prospective study. Gentamicin was used to induce AKI in 5 purpose-bred dogs. Serum samples were collected for measurement of creatinine, Spec cPL, lipase activity and TLI over 60 days, during both induction of, and recovery from, AKI., Results: All dogs developed and recovered from AKI. Six of 52 (12%) serum Spec cPL concentrations were increased (2 in the equivocal zone and 4 consistent with pancreatitis) in 2 of 5 (40%) dogs. Two of 51 (4%) serum lipase activity values were increased in 2 of 5 dogs. Serum TLI was increased above the reference range in 17 of 50 (34%) samples in 3 of 5 dogs. For all biomarkers, there was no consistent correlation with increases in serum creatinine concentration., Conclusions and Clinical Importance: Decreased renal excretion during experimental AKI did not cause consistent and correlated increases in serum Spec cPL, lipase activity, or TLI in this cohort of dogs., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: p53 plays a key role in the apoptotic event induced by chemotherapeutic agents. Mutation of p53 gene has been observed in various spontaneous tumors in humans and is associated with a poor prognosis. p53 abnormalities have been evaluated in several tumors in dogs; however, the association of p53 gene mutation with clinical outcome in dogs with lymphoma has not been documented., Hypothesis/objectives: The aim of this study was to examine p53 mutation in canine lymphoma cells and its association with the clinical outcome., Animals: Forty-three dogs with previously untreated high-grade lymphoma referred to the University of Tokyo were included in this study., Methods: Prospective cohort study. We examined p53 gene (exon 4-8) mutation in the tumor tissues from 43 dogs with lymphoma using PCR-SSCP (polymerase chain reaction-single-strand conformational polymorphism) analysis, followed by nucleotide sequencing of the abnormal bands., Results: Of the 43 dogs, 7 dogs (16%) had p53 mutation, whereas 36 dogs (84%) were devoid of p53 mutation. Overall response rate after remission induction was significantly lower (33% versus 88%, P = .002) in dogs with lymphomas having p53 mutation than those with lymphomas devoid of p53 mutation. Overall survival time was significantly shorter (67 days versus 264 days, P = .004) in dogs with lymphoma with p53 mutation than those with lymphoma retaining wild-type p53., Conclusion and Clinical Importance: Mutations of p53 gene were detected in a proportion of canine lymphoma cells from untreated dogs and can be associated with a poor prognosis., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Acute kidney injury (AKI) is associated with high mortality rates in dogs, which may be a consequence of late recognition using traditional diagnostic tests. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein-induced during kidney injury that may identify AKI earlier than traditional tests., Objectives/hypothesis: To evaluate urinary NGAL (uNGAL) and uNGAL-to-urinary creatinine ratio (UNCR) as early markers of kidney injury and recovery in an AKI model in dogs. It was hypothesized that these markers would document AKI earlier than serum creatinine concentration., Animals: Five purpose-bred dogs., Methods: Prospective study. Acute kidney injury, defined as a > 50% increase in serum creatinine concentration above baseline, was induced in dogs by gentamicin administration (8-10 mg/kg SC q8h). Blood and urine collected for biochemical analyses and uNGAL and urinary creatinine concentrations, respectively, during AKI induction and recovery., Results: Acute kidney injury was diagnosed significantly earlier based on a 7-fold increase in UNCR compared to a > 50% increase in serum creatinine concentration (day 8; range, 2-10 mg/dl vs day 16; range, 14-19 mg/dl; P = .009). During recovery, the initial decrease in UNCR preceded the decrease in serum creatinine concentration by a median of 2 days. The uNGAL changes paralleled UNCR changes, but the increase in uNGAL was triphasic; the initial peak occurred earlier than UNCR (median, day 11 versus median, day 19)., Conclusions and Clinical Importance: The UNCR was early marker of gentamicin-induced AKI and its decrease documented onset of renal recovery. Additional studies are needed to validate this marker in dogs with naturally occurring renal injury., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is an early indicator of acute kidney injury (AKI) in dogs and its use has not been evaluated in dogs with sepsis., Animals: Fifteen dogs with sepsis requiring laparotomy (study dogs) and 10 dogs undergoing surgery for intervertebral disc disease (control dogs)., Objective: To determine whether NGAL increases in dogs with sepsis undergoing emergency laparotomy and whether it is correlated with development of AKI and survival., Methods: Longitudinal study conducted at a referral teaching hospital. Serum neutrophil gelatinase-associated lipocalin (sNGAL), urinary NGAL normalized to urinary creatinine concentration (UNCR), and serum creatinine concentration were measured at 4 time points (admission, after anesthesia, and 24 and 48 hours postsurgery). Development of AKI (increase in serum creatinine concentration of 0.3 mg/dL) and in-hospital mortality were recorded. Linear mixed-model analysis was employed to assess differences between groups over time. Mann-Whitney U-test was performed for comparison of continuous variables between groups and Chi square or Fisher's exact tests were used to assess correlation between discrete data., Results: Serum NGAL and UNCR were significantly higher in study dogs across all time points (P = .007 and P < .001, respectively) compared with controls. Urinary NGAL normalized to creatinine in the study group was not significantly different between survivors (n = 12) and nonsurvivors (n = 3). Dogs that received hydroxyethyl starch had significantly higher UNCR across all time points (P = .04) than those that did not., Discussion-Conclusion: Serum neutrophil gelatinase-associated lipocalin and UNCR are increased in dogs with sepsis requiring emergency laparotomy. Additional studies are needed to evaluate its role as a marker of AKI in this population., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Canine osteosarcoma (OS) is an aggressive sarcoma characterized by pathologic skeletal resorption and pulmonary metastases. A number of negative prognostic factors, including bone alkaline phosphatase, have been identified in dogs with OS, but the underlying biologic factors responsible for such observations have not been thoroughly investigated. Endothelin-1-mediated signaling is active during bone repair, and is responsible for osteoblast migration, survival, proliferation, and bone alkaline phosphatase expression., Hypothesis: The endothelin-1 signaling axis is active in canine OS cells, and this pathway is utilized by malignant osteoblasts for promoting cellular migration, survival, proliferation, and bone alkaline phosphatase activities., Animals: 45 dogs with appendicular OS., Methods: The expressions of endothelin-1 and endothelin A receptor were studied in OS cell lines and in samples from spontaneously occurring tumors. Activities mediated by endothelin-1 signaling were investigated by characterizing responses in 3 OS cell lines. In 45 dogs with OS, bone alkaline phosphatase concentrations were correlated with primary tumor osteoproductivity., Results: Canine OS cells express endothelin-1 and endothelin A receptor, and this signaling axis mediates OS migration, survival, proliferation, and bone alkaline phosphatase activities. In OS-bearing dogs, circulating bone alkaline phosphatase activities were positively correlated with primary tumor relative bone mineral densities., Conclusions and Clinical Importance: Canine OS cells express endothelin-1 and functional endothelin A receptors, with the potential for a protumorigenic signaling loop. Increases in bone alkaline phosphatase activity are associated with osteoblastic OS lesions, and might be an epiphenomenon of active endothelin-1 signaling or excessive osteoproduction within the localized bone microenvironment., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Levetiracetam (LEV) is a common add-on antiepileptic drug (AED) in dogs with refractory seizures. Concurrent phenobarbital administration alters the disposition of LEV in healthy dogs., Hypothesis/objectives: To evaluate the pharmacokinetics of LEV in dogs with epilepsy when administered concurrently with conventional AEDs., Animals: Eighteen client-owned dogs on maintenance treatment with LEV and phenobarbital (PB group, n = 6), LEV and bromide (BR group, n = 6) or LEV, phenobarbital and bromide (PB-BR group, n = 6)., Methods: Prospective pharmacokinetic study. Blood samples were collected at 0, 1, 2, 4, and 6 hours after LEV administration. Plasma LEV concentrations were determined by high-pressure liquid chromatography. To account for dose differences among dogs, LEV concentrations were normalized to the mean study dose (26.4 mg/kg). Pharmacokinetic analysis was performed on adjusted concentrations, using a noncompartmental method, and area-under-the-curve (AUC) calculated to the last measured time point., Results: Compared to the PB and PB-BR groups, the BR group had significantly higher peak concentration (Cmax ) (73.4 ± 24.0 versus 37.5 ± 13.7 and 26.5 ± 8.96 μg/mL, respectively, P < .001) and AUC (329 ± 114 versus 140 ± 64.7 and 98.7 ± 42.2 h*μg/mL, respectively, P < .001), and significantly lower clearance (CL/F) (71.8 ± 22.1 versus 187 ± 81.9 and 269 ± 127 mL/h/kg, respectively, P = .028)., Conclusions and Clinical Importance: Concurrent administration of PB alone or in combination with bromide increases LEV clearance in epileptic dogs compared to concurrent administration of bromide alone. Dosage increases might be indicated when utilizing LEV as add-on treatment with phenobarbital in dogs., (Copyright © 2015 by the American College of Veterinary Internal Medicine.)

Background: Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities., Hypothesis: Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment., Animals: Ten dogs with appendicular OS., Methods: Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies., Results: Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples., Conclusions and Clinical Importance: Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.)

Background: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD)., Hypothesis/objectives: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity., Animals: Client-owned dogs (n = 291)., Methods: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity., Results: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity., Conclusions and Clinical Importance: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Background: Acute kidney injury (AKI) is common in dogs. Few studies have assessed sequential changes in indices of kidney function in dogs with naturally occurring AKI., Objective: To document sequential changes of conventional indices of renal function, to better define the course of AKI, and to identify a candidate marker for recovery., Animals: Ten dogs with AKI., Methods: Dogs were prospectively enrolled and divided into surviving and nonsurviving dogs. Urine production was measured with a closed system for 7 days. One and 24-hour urinary clearances were performed daily to estimate solute excretion and glomerular filtration rate (GFR). Solute excretion was calculated as an excretion ratio (ER) and fractional clearance (FC) based on both the 1- and 24-hour urine collections., Results: Four dogs survived and 6 died. At presentation, GFR was not significantly different between the outcome groups, but significantly (P = .03) increased over time in the surviving, but not in the nonsurviving dogs. Fractional clearance of Na decreased significantly over time (20.2-9.4%, P < .0001) in the surviving, but not in the nonsurviving dogs. The ER and FC of solutes were highly correlated (r, 0.70-0.95)., Conclusion and Clinical Impact: Excretion ratio might be used in the clinical setting as a surrogate marker to follow trends in solute excretion. Increased GFR, urine production, and decreased FC of Na were markers of renal recovery. The FC of Na is a simple, noninvasive, and cost-effective method that can be used to evaluate recovery of renal function., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.)

Background: Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol-secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin-like growth factor (IGF) signaling represents a promising therapeutic target., Objectives: To investigate the involvement of PI3K signaling in the pathogenesis of ATs in dogs and to identify pathway components that may hold promise as future therapeutic targets or as prognostic markers., Animals: Analyses were performed on 36 canine cortisol-secreting ATs (11 adenomas and 25 carcinomas) and 15 normal adrenal glands of dogs., Methods: mRNA expression analysis was performed for PI3K target genes, PI3K inhibitor phosphatase and tensin homolog (PTEN), IGFs, IGF receptors, IGF binding proteins and epidermal growth factor receptors. Mutation analysis was performed on genes encoding PTEN and PI3K catalytic subunit (PIK3CA)., Results: Target gene expression indicated PI3K activation in carcinomas, but not in adenomas. No amino acid-changing mutations were detected in PTEN or PIK3CA and no significant alterations in IGF-II or IGFR1 expression were detected. In carcinomas, ERBB2 expression tended to be higher than in normal adrenal glands, and higher expression of inhibitor of differentiation 1 and 2 (ID1 and ID2) was detected in carcinomas with recurrence within 2.5 years after adrenalectomy., Conclusions and Clinical Importance: Based on these results, ERBB2 might be a promising therapeutic target in ATs in dogs, whereas ID1 and 2 might be valuable as prognostic markers and therapeutic targets., (Copyright © 2015 by the American College of Veterinary Internal Medicine.)

Background: Myocardial injury can be detected by cardiac troponin I (cTnI) concentration, which appears to be a predictor of short-term death in critically ill patients. It is unknown if the best prognostic indicator of short-term survival is cTnI measurement at admission or at later time points., Hypothesis/objectives: Measuring cTnI with a high-sensitivity (HS) test at different time points after admission may be a better short-term prognostic indicator than a single cTnI measurement at admission in dogs with systemic inflammatory response syndrome (SIRS)., Animals: Prospective, observational clinical study of 60 dogs with SIRS., Methods: Cardiac troponin I concentration was measured in 133 serum samples, collected at days 1, 2, 3, and 5. Additionally, the acute patient physiologic and laboratory evaluation (APPLE) fast score was evaluated at admission. Prognostic capabilities of cTnI measurement and APPLE fast score for 28-day mortality were assessed by receiver operating characteristic curve analysis., Results: Forty-one dogs with SIRS that survived 28 days had significantly lower serum cTnI concentrations at admission (median, 0.09 ng/mL; P = .004) and at the peak time point (median, 0.23 ng/mL; P = .01) compared to 19 nonsurvivors (median at admission, 0.63 ng/mL; median at peak, 1.22 ng/mL). Area under the curve to predict survival, using cTnI was similar at admission (0.732) and at peak (0.708), and was 0.754 for the APPLE fast score., Conclusions and Clinical Importance: Increased cTnI concentration in dogs with SIRS is associated with poor outcome. Daily follow-up measurement of cTnI concentration provides no additional prognostic information for short-term mortality., (Copyright © 2015 by the American College of Veterinary Internal Medicine.)

Background: Serum N-terminal pro-C-natriuretic peptide (NT-proCNP) concentration at hospital admission has sufficient sensitivity and specificity to differentiate naturally occurring sepsis from nonseptic systemic inflammatory response syndrome (SIRS). However, little is known about serum NT-proCNP concentrations in dogs during the course of sepsis., Objective: To determine serum NT-proCNP and cytokine kinetics in dogs with endotoxemia, a model of canine sepsis., Samples: Eighty canine serum samples., Methods: Eight healthy adult Beagles were randomized to receive Escherichia coli lipopolysaccharide (LPS, 5 μg/kg) or placebo (0.9% NaCl) as a single IV dose in a randomized crossover study. Serum collected at 0, 1, 2, 4, and 24 hours was stored at -80°C for batch analysis. Serum NT-proCNP was measured by ELISA and 13 cytokines and chemokines by multiplex magnetic bead-based assay., Results: Serum NT-proCNP concentrations did not differ significantly between LPS- and placebo-treated dogs at any time. When comparing serum cytokine concentrations, LPS-treated dogs had higher interleukin-6 (IL-6), IL-10, TNF-α and KC-like at 1, 2, and 4 hours; higher CCL2 at 1, 2, 4, and 24 hours; and higher IL-8 and CXCL10 at 4 hours compared to placebo-treated dogs. There were no differences in serum GM-CSF, IFN-γ, IL-2, IL-7, IL-15 or IL-18 between LPS- and placebo-treated dogs., Conclusions and Clinical Importance: Serum NT-proCNP concentration does not change significantly in response to LPS administration in healthy dogs. Certain serum cytokine and chemokine concentrations are significantly increased within 1-4 hours after LPS administration and warrant further investigation as tools for the detection and management of sepsis in dogs., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Hypothesis/objectives: Altered serotonin (5-hydroxytryptamine, 5HT) signaling is postulated in development and progression of canine myxomatous mitral valve disease (MMVD). Little is known regarding platelet, plasma, valvular, or myocardial 5HT concentration ([5HT]) in affected dogs. We quantified [5HT] in platelet-rich plasma (PRP), platelet-poor plasma (PPP), mitral valve leaflets (MV), and left ventricular myocardium (LV)., Animals: Forty-five dogs comprised 4 plasma groups of Cavalier King Charles Spaniels (CKCS) or non-CKCS, either healthy (CON) or MMVD affected: CKCS CON (n = 12); non-CKCS CON (n = 8); CKCS MMVD (n = 14); non-CKCS MMVD (n = 11). Twenty-four dogs comprised 3 tissue groups: MMVD (n = 8); other-HD (heart disease) (n = 7); non-HD, extracardiac disease (n = 9)., Methods: High-performance liquid chromatography measured PRP, PPP, MV, and LV [5HT]., Results: Platelet-rich plasma platelet [5HT] was greater in CKCS CON (1.83 femtograms/platelet [fg/plt]; range, 0.20-4.76; P = .002), CKCS MMVD (1.58 fg/plt; range, 0.70-4.03; P = .005), and non-CKCS MMVD (1.72 fg/plt; range, 0.85-4.44; P = .003) versus non-CKCS CON (0.92 fg/plt; range, 0.63-1.30). There was no group difference in PPP [5HT]. MV [5HT] was significantly higher in MMVD (32.4 ng/mg; range, 8.4-106.7) versus non-HD (3.6 ng/mg; range, 0-28.3; P = .01) and LV [5HT] was significantly higher in MMVD (11.9 ng/mg; range, 4.0-104.8) versus other-HD (0.9 ng/mg; range, 0-10.1; P = .011) and non-HD (2.5 ng/mg; range, 0-6.9; P = .001)., Conclusions and Clinical Importance: Platelet [5HT] was highest in healthy CKCS and both MMVD groups, but plasma [5HT] showed no group differences. Tissue [5HT] was highest in MV and LV of MMVD-affected dogs, suggesting altered 5HT signaling as a potential feature of MMVD. Interactions of platelet, valvular, and myocardial 5HT signaling warrant further investigation., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)

Background: Microcytic anemia is common in dogs with a congenital portosystemic shunt (cPSS) and typically resolves after surgical attenuation of the anomalous vessel. However, the pathophysiology of the microcytic anemia remains poorly understood. Hepcidin has been a key role in controlling iron transport in both humans and animals and in mediating anemia of inflammatory disease in humans. The role of hepcidin in the development of microcytic anemia in dogs with a cPSS has not been examined., Hypothesis: To determine whether hepatic hepcidin mRNA expression decreases, while red blood cell count (RBC) and mean corpuscular volume (MCV) increase in dogs after surgical attenuation of a cPSS., Animals: Eighteen client-owned dogs with confirmed cPSS undergoing surgical attenuation., Method: Prospective study. Red blood cell count (RBC) and mean corpuscular volume (MCV), together with hepatic gene expression of hepcidin, were measured in dogs before and after partial attenuation of a cPSS., Results: There was a significant increase in both RBC (median pre 6.17 × 10(12) /L, median post 7.08 × 10(12) /L, P < .001) and MCV (median pre 61.5fl, median post 65.5fl, P = .006) after partial surgical attenuation of the cPSS. Despite the increase in both measured red blood cell parameters, hepatic gene expression of hepcidin remained unchanged., Conclusions and Clinical Importance: This study found no evidence that dysregulated production of hepcidin was associated with anemia in dogs with a cPSS., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)