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Gallbladder mucocele (GBM) is a common biliary disorder in dogs. Gallbladder hypokinesia has been proposed to contribute to its formation and progression. The specific cause of gallbladder stasis in dogs with GBM as well as viable treatment options to resolve dysmotility remains unknown. Vitamin D deficiency is one of the many potential causes of gallbladder hypokinesia in humans and repletion results in complete resolution of stasis. Improving our understanding of the relationship between serum vitamin D and GBM could help identify dogs as a model for humans with gallbladder hypokinesia. Furthermore, this relationship could provide insight into the pathogenesis of GBM and support the need for future studies to investigate vitamin D as a novel treatment target. Therefore, goals of this study were i) to determine if serum 25-hydroxyvitamin(OH)D concentrations were decreased in dogs with GBM, ii) if serum 25(OH)D concentrations were different in clinical versus dogs subclinical for GBM, and iii) to determine if serum 25(OH)D concentrations could predict the ultrasonographic type of GBM. Sixty-two dogs (clinical, n = 26; subclinical, n = 36) with GBM and 20 healthy control dogs were included in this prospective observational study. Serum 25(OH)D concentrations were measured with a competitive chemiluminescence immunoassay. Overall, dogs with GBM had lower serum 25(OH)D concentrations than control dogs (P = 0.004). Subsequent subgroup analysis indicated that this difference was only significant in the subclinical group compared to the control dogs (P = 0.008), and serum 25(OH)D concentrations did not significantly differ between dogs clinical for GBM versus subclinical or control dogs, indicating that inflammatory state in clinical dogs was not the major constituent of the observed findings. Decreasing serum 25(OH)D concentrations, but not clinical status, was associated with a more advanced developmental stage of GBM type determined by ultrasonography. Our results indicate that vitamin D has a role in dogs with GBM. Additional studies are needed to assess if reduced vitamin D in dogs with GBM is a cause or effect of their biliary disease and to investigate if vitamin D supplementation could be beneficial for dogs with GBM.

ABSTRACT Background Vitamin D modulates the immune response in many species, including dogs. To date, research investigating the immunological effects of vitamin D in dogs is limited to in vitro studies. Objectives Provide PO calcifediol supplementation to healthy dogs to evaluate its tolerability and assess its effect on leukocyte production of tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and IL‐10. Animals Eleven healthy client‐owned dogs with serum 25‐hydroxyvitamin‐D3 (25(OH)D3) concentrations ≤ 30 ng/mL. Methods Prospective, randomized, double‐blinded, placebo‐controlled crossover study. Dogs were randomized to receive calcifediol at 2.3 μg/kg0.75 (low‐dose), 4.6 μg/kg0.75 (high‐dose), or placebo for 7 days and crossed over to a different treatment arm after 28‐day washout periods. Serum 25(OH)D3 was measured using a modified high‐performance liquid chromatography method. Whole blood cultures were performed by incubating blood with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate‐buffered saline (PBS) for 24 h, and TNF‐α, IL‐6, and IL‐10 were measured in supernatant using a canine‐specific multiplex assay. Results Both low‐dose (median, interquartile range [IQR]; 62 ng/mL, 59–82) and high‐dose (93 ng/mL, 80–113) PO calcifediol supplementation increased serum 25(OH)D3 concentrations from baseline (22.2 ng/mL, 20.3–29.3; both p < 0.0001). Low‐dose and high‐dose calcifediol supplementation decreased LPS‐stimulated IL‐6 by 197 pg/mL (95% confidence interval [CI]: −369.0 to −24.0; p = 0.03) and 182 pg/mL (95% CI: −355.0 to −8.0; p = 0.04), respectively. Then LPS‐stimulated IL‐6 concentrations decreased by 2 pg/mL for every 1 ng/mL increase in serum 25(OH)D3 concentration (95% CI: −3.0 to −0.1; p = 0.03). Conclusion and Clinical Importance Calcifediol supplementation for 7 days was well‐tolerated and decreased LPS‐stimulated IL‐6 concentrations. Oral calcifediol supplementation may have anti‐inflammatory effects in dogs.

[This corrects the article DOI: 10.1371/journal.pone.0244102.].[This corrects the article DOI: 10.1371/journal.pone.0244102.].

Hypovitaminosis D has been extensively documented in critically ill humans. However, whether or not critically ill dogs have alterations in vitamin D concentrations remains unconfirmed. The primary aims of our study were to compare serum 25-hydroxycholecalciferol [25(OH)D] concentrations in critically ill dogs with healthy control dogs, determine the prognostic utility of serum 25(OH)D concentration as a biomarker in critically ill dogs, and to assess if serum 25(OH)D concentrations in critically ill dogs are associated with length of stay in the intensive care unit or illness severity. Serum concentrations of 25(OH)D together with a range of other clinical, biochemical, and hematological parameters, were measured in 99 dogs within 24 hours of admission to the Intensive Care Unit (ICU). Critically ill dogs (P = 0.001) and dogs with sepsis (P = 0.002) had significantly lower serum 25(OH)D concentrations compared to healthy control dogs. In addition, serum 25(OH)D concentration was an independent predictor of in-hospital and 30 day survival. Using a cut-off of 33 ng/mL, serum 25(OH)D concentrations had excellent sensitivity (0.94; 95% CI, 0.71-1.00), but poor specificity (0.41; 95% CI, 0.31-0.53) for detection of survival. Serum 25(OH)D concentrations were inversely associated with acute patient physiologic and laboratory evaluation (APPLE) fast score but were not associated with ICU length of stay. Hospitalized dogs with critical illness have decreased serum 25(OH)D concentrations compared to healthy dogs and can be used to predict survival in this cohort.

Background Clinicopathologic variables predictive of disseminated coccidioidomycosis are known in humans but have not been explored in dogs. Serum 25‐hydroxyvitamin (OH)D correlates with severity of disease of various etiologies in dogs but its role in coccidioidomycosis is unknown. Objective Determine whether serum 25(OH)D concentrations are different in dogs with coccidioidomycosis compared with healthy controls and if clinicopathologic variables are associated with extent of disease. Animals Thirty‐five dogs with coccidioidomycosis (pulmonary, n = 13; disseminated, n = 15; uncharacterized, n = 7), and 25 healthy control dogs. Methods Prospective cohort study. Serum 25(OH)D and C‐reactive protein (CRP) concentrations were measured with modified‐HPLC and a commercial ELISA kit, respectively. Results There was no difference in 25(OH)D concentrations between dogs with coccidioidomycosis (median, interquartile range [IQR]; 31.9 ng/mL, 23.3‐49.2) and controls (29.5 ng/mL, 25.6‐40.8, P = .73). Serum 25(OH)D concentration was lower in dogs with coccidioidomycosis and IgG titers ≥1:32 than dogs with titers below this cut‐off (P = .02). Dogs with IgG titers ≥1:32 were more likely to have disseminated disease (OR, 7.5; 95% CI: 1.1‐68; P = .03). Serum CRP concentrations were higher in dogs with IgG titers ≥1:16 (median, IQR; 4474.8 ng/mL, 2885.8‐8236.1) than in those below this cut‐off (151.2 ng/mL, 30.4‐2907.3; P = .02). There was a significant inverse association between serum 25(OH)D and CRP at 25(OH)D concentrations ≤33 ng/mL. Conclusion and Clinical Importance Serum 25(OH)D concentration was lower for dogs with IgG titers ≥1:32, indicating a potential association between semi‐quantitative titers and 25(OH)D concentrations in dogs with coccidioidomycosis. IgG titers ≥1:32 yielded higher odds of disseminated disease, but was inadequate as a standalone test to determine form of disease.

Background Human patients with Ehlers‐Danlos syndrome (EDS) are categorized into subtypes based on causative genetic variants and phenotypes. The classical form of EDS, primarily caused by variants in COL5A1 or COL5A2, is a very common subtype in people but is poorly characterized in dogs. Objective Describe likely causal COL5A1 variants in dogs with classical EDS, summarize clinical histories, discuss potential disease mechanisms, and draw conclusions about disease prognosis. Animals Seven client‐owned dogs that exhibited clinical signs of classical EDS. Methods Clinical information was recorded from medical records and communication with attending veterinarians and dog owners. To identify potential causal gene sequence variants whole‐genome sequence analyses (n = 6) or Sanger sequencing (n = 1) were performed on DNA isolated from the probands. Pathological abnormalities in skin biopsy samples were assessed using histology and electron microscopy in 3 dogs. Results Six distinct heterozygous COL5A1 sequence variants were identified. The most common clinical signs included fragile skin (n = 7), hyperextensible skin (n = 7), joint hypermobility (n = 6), and atrophic scars (n = 5). The median age at last follow‐up or death was 12 years (range, 6.5‐14 years). Ultrastructural abnormalities in dermal collagen differed among dogs with different COL5A1 variants. Conclusion and Clinical Importance We describe the genotypic and phenotypic spectrum of the classical subtype of EDS by identifying 6 novel COL5A1 variants in conjunction with detailed clinical histories that included long‐term follow‐up information in 7 dogs.

Background Albuterol by inhalation (IH) is a common treatment for hyperkalemia in humans but its effect on blood potassium concentrations in dogs is unknown. Objective Determine whether albuterol (IH) decreases blood potassium concentrations in healthy normokalemic dogs and if effects are dose‐dependent. Animals Ten healthy dogs. Methods Prospective, crossover experimental study. Albuterol sulfate was administered at a low‐dose (90 μg) in phase I and, 7 days later, high‐dose (450 μg) in phase II. Blood potassium and glucose concentrations (measured via blood gas analyzer) and heart rates were obtained at baseline and then 3, 5, 10, 15, 30, 60, 90, 120, 180, and 360 minutes after inhaler actuation. Results Blood potassium concentrations decreased rapidly after albuterol delivery with a significant reduction compared to baseline within 30 minutes in both phases (P = .05). The potassium nadir concentration of phase I occurred at 60 minutes (mean, SD; 4.07 mmol/L, 0.4) and was significantly decreased from baseline, (4.30 mmol/L, 0.3; t(9) = 2.40, P = .04). The potassium nadir concentration of phase II occurred at 30 minutes (mean, SD; 3.96 mmol/L, 0.39) and was also significantly decreased from baseline, (4.33 mmol/L, 0.4; t(9) = 2.22, P = .05). The potassium nadir concentration decreased by 0.1 mmol/L for each 10 μg/kg increase in dose of albuterol (P = .01). Five dogs had ≥1 hyperglycemic measurement (ie, >112 mg/dL). No median heart rate was tachycardic nor was any mean blood glucose concentration hyperglycemic at any time point. Conclusion and Clinical Importance Albuterol IH decreases blood potassium concentrations in a dose‐dependent manner without clinically meaningful alterations to heart rate or blood glucose concentrations in healthy dogs. The mean decrease in potassium concentration at the high‐dose of albuterol was modest (0.38 mmol/L).

Background Hypovitaminosis D is a risk factor for the development of respiratory infections in humans and repletion can be protective. Objectives Determine if serum 25‐hydroxyvitamin (OH)D concentrations are lower in shelter dogs and if 25(OH)D concentrations are associated with clinical signs of canine infectious respiratory disease complex (CIRDC) or with time in the shelter. Animals One hundred forty‐six shelter dogs (clinically ill n = 36, apparently healthy n = 110) and 23 nonshelter control dogs. Methods Prospective cohort study. Shelter dogs were grouped as clinically ill or apparently healthy based on the presence or absence, respectively, of clinical signs associated with CIRDC. Serum 25(OH)D concentrations were measured with a competitive chemiluminesence immunoassay. Nucleic acids of agents associated with the CIRDC were amplified by polymerase chain reaction assays. Results The concentration of 25(OH)D was 7.3 ng/mL (4.5‐9.9, 95% confidence interval [CI]) lower in dogs with signs of CIRDC than apparently healthy shelter dogs (t(142) = 2.0, P = .04). Dogs positive for DNA of canine herpesvirus (CHV)‐1 had serum 25(OH)D concentrations 14.9 ng/mL (−3.7 to 29.6, 95% CI) lower than dogs that were negative (t(137) = 2.0, P = .04). Serum 25(OH)D concentrations in shelter dogs were not different from control dogs (t(45) = −1.4, P = .17). Serum 25(OH)D concentration was not associated with duration of time in the shelter (F(1, 140) = 1.7, P = .2, R2 = 0.01). Conclusion and Clinical Importance Vitamin D could have a role in acute respiratory tract infections in shelter dogs.

Background Serum 25‐hydroxyvitamin (OH)D, C‐reactive protein (CRP), and haptoglobin are useful biomarkers in various infectious diseases and inflammatory disorders in dogs, but their utility in histoplasmosis is unknown. Objective Determine if serum 25(OH)D, CRP, and haptoglobin concentrations are different in dogs with histoplasmosis compared to healthy controls and whether serum globulin, albumin, CRP, or haptoglobin are associated with 25(OH)D concentration. Animals Twenty‐two client‐owned dogs (histoplasmosis, n = 12; controls, n = 10). Methods Prospective case‐control study. Dogs with histoplasmosis were categorized as pulmonary, disseminated, or gastrointestinal (GI) tract. Serum 25(OH)D was measured using modified high‐performance liquid chromatography (HPLC). Serum CRP and haptoglobin were measured with ELISA assays. Results Dogs with histoplasmosis were grouped as disseminated (n = 8) and GI tract (n = 4). No dogs had pulmonary tract involvement alone. Dogs with histoplasmosis (median, interquartile range [IQR]; 11.6 ng/mL, 16.8) had lower serum 25(OH)D concentrations than controls (35.7 ng/mL, 17.6; P < .001). Serum CRP and haptoglobin concentrations were higher in dogs with histoplasmosis (CRP: median, IQR; 63.5 mg/L, 37.1 and haptoglobin: 459.7 mg/dL, 419.6) than controls (CRP: 1.9 mg/L, 2; P < .001 and haptoglobin: 85.5 mg/dL, 106.7; P = .003). Serum 25(OH)D concentration was positively associated with fold change in serum albumin concentration (ρ = 0.77; P < .001), and negatively associated with fold change in serum globulin (ρ = −0.61; P = .003) and CRP concentrations (ρ = −0.56; P = .01). Conclusion and Clinical Importance Assay of serum 25(OH)D, CRP, and haptoglobin could have clinical value in dogs with histoplasmosis.

Background A panel of IgA‐based serologic assays might aid in the diagnosis of chronic enteropathy (CE) in dogs, a syndrome encompassing conditions such as food‐responsive enteropathy, immunosuppressant‐responsive enteropathy, and inflammatory bowel disease (also referred to as chronic inflammatory enteropathy). However, it is unclear whether these biomarkers discriminate between CE and other types of primary intestinal disorders. Objectives To evaluate a diagnostic panel that measures serum concentrations of IgA directed against OmpC (ACA), canine calprotectin (ACNA), and gliadin‐derived peptides (AGA) in dogs with well‐characterized intestinal diseases. Animals Fifty‐five dogs with primary intestinal disease. Methods Serum ACA, ACNA, and AGA concentrations were measured in 30 dogs with CE and 25 dogs with other intestinal diseases (non‐CE population), including histoplasmosis, parasitism, E. coli‐associated granulomatous colitis, and lymphoma. Serum IgA concentrations were compared among populations, and sensitivities and specificities were calculated using laboratory‐provided cut‐points. Results Twenty‐six of 30 (87%) CE dogs and 21 of 25 (84%) non‐CE dogs had abnormal concentrations (intermediate or high) of at least 2 markers; these proportions were not significantly different (P = .99). A serum ACA concentration ≥15 EU/mL was 86.7% (95% confidence interval [CI], 69.3%‐96.2%) sensitive and 24.0% (95% CI, 9.4%‐45.1%) specific for CE diagnosis. High AGA concentrations were observed in 16 of 25 (64%) non‐CE dogs. Conclusions and Clinical Importance The evaluated serologic markers were poorly specific for CE diagnosis, which raises concerns that their use in clinical practice might lead to misdiagnoses and delayed or even detrimental treatments in dogs with non‐CE intestinal diseases.