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Background: Cats presenting with upper urinary tract uroliths (UUTUs) and ureteral obstruction ("obstructive UUTU") are typically younger than cats with idiopathic CKD that often have incidental nephroliths. Hypothesis: Cats with upper urinary tract urolith have 2 clinical phenotypes; a more aggressive phenotype at risk of obstructive UUTU at a young age and a more benign phenotype in older cats, with reduced risk of obstructive UUTU. Objectives: Identify risk factors for UUTU and for obstructive UUTU. Animals: Eleven thousand four hundred thirty‐one cats were referred for care over 10 years; 521 (4.6%) with UUTU. Methods: Retrospective VetCompass observational cross‐sectional study. Multivariable logistic regression models were performed to identify risk factors for a diagnosis of UUTU vs no UUTU and additionally, obstructive UUTU vs nonobstructive UUTU. Results: Risk factors for UUTU included female sex (odds ratio [OR] 1.6, confidence interval [CI] 1.3‐1.9; P <.001), British shorthair, Burmese, Persian, Ragdoll or Tonkinese (vs non‐purebred ORs 1.92‐3.31; P <.001) breed and being ≥4 years (ORs 2.1‐3.9; P <.001). Risk factors for obstructive UUTU were female sex (OR 1.8, CI 1.2‐2.6; P =.002), having bilateral uroliths (OR 2.0, CI 1.4‐2.9; P =.002) and age, with the odds of obstructive UUTU increasing as age at diagnosis of UUTU decreased (≥12 years, reference category; 8‐11.9 years, OR 2.7, CI 1.6‐4.5; 4‐7.9 years, OR 4.1, CI 2.5‐7.0; 0‐3.9 years, OR 4.3, CI 2.2‐8.6; P < 0.001). Conclusions and Clinical Importance: Cats diagnosed with UUTU at a younger age have a more aggressive phenotype with higher risk of obstructive UUTU compared to cats over 12 years of age diagnosed with UUTU. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to validate a commercially available luteinising hormone (LH) cat ELISA, to determine whether the increases in plasma LH concentration that occur after neutering are maintained throughout cats' lives and if other factors such as calendar seasons in both intact and neutered cats, and neutering age in neutered cats, influence plasma LH concentrations. Methods: Stored plasma samples from client-owned cats were used for the measurement of LH concentrations. Clinical data, including age, sex, age at neutering and medical history, were reviewed. Two populations were included in this study: (1) a senior and geriatric cat population (⩾9 years old), including 18 intact and 18 neutered cats matched for age, sex and month of sample collection; and (2) an adult cat population (2–8 years old), including 45 neutered cats. LH concentrations were measured using a commercially available feline ELISA. Results: Senior and geriatric neutered cats had higher plasma LH concentrations than age-matched intact cats (P <0.001). Calendar season did not influence plasma LH concentrations in the adult (P = 0.727) or senior/geriatric (P = 0.745) cats included in this study. No influence of age at neutering was observed on plasma LH concentrations (P = 0.296). Conclusions and relevance: Neutering causes a significant long-term increase in LH concentrations in cats and further studies are required to determine the consequences on feline health. [ABSTRACT FROM AUTHOR]

Summary: Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta; a.k.a. ticked), mackerel (Tm; a.k.a. striped) and blotched (tb; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby – Abyssinian (Ta; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine‐rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B. [ABSTRACT FROM AUTHOR]

Abstract Background The detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable. Methods We have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories. Results Our ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories. Conclusions These novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials.

GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. Ex vivo studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H)-dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84−/− cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases. [ABSTRACT FROM AUTHOR]

Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also similar to human type 1 diabetes, the canonical canine disorder appears to be increasing in prevalence. Whereas islet architecture in rodents is distinctly different from humans, canine pancreatic endocrine cell distribution is more similar. Differences in breed susceptibility alongside associations with MHC and other canine immune response genes parallel that of different ethnic groups within the human population, a potential benefit over NOD mice. The impact of environment on disease development also favors canine over rodent models. Herein, we consider the potential for canine diabetes to provide valuable insights for human type 1 diabetes in terms of pancreatic histopathology, impairment of β-cell function and mass, islet inflammation (i.e., insulitis), and autoantibodies specific for β-cell antigens. [ABSTRACT FROM AUTHOR]

People working in market research and consumer insights advise clients on their brands a great deal - it is often our bread and butter. But in this paper the authors propose that researchers often do not apply that learning to themselves. It suggests that in order to thrive and survive in the future, agencies and the industry as a whole should think and behave like true brands, with a strong philosophy and view of how the world works. The paper looks at how another B2B industry has approached this issue and reinvented itself successfully. The authors suggest that good branding could change existing perceptions of researchers as dull, grey and boring; it could attract new talent to the industry; engage audiences; demonstrate that we are a dynamic and exciting business; enable us to compete with a broader range of competitors; charge more money and behave with confidence in the future. [ABSTRACT FROM AUTHOR]

The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3+ T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms. [ABSTRACT FROM AUTHOR]

A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease. [ABSTRACT FROM AUTHOR]

The presence of anti-insulin antibodies was determined by ELISA in serum samples from 30 diabetic dogs receiving bovine insulin therapy and 30 normoglycaemic dogs. Twenty of the diabetic dogs had significant reactivity to both bovine (heterologous) and porcine (homologous) insulin compared to control dogs. In contrast there was no significant difference between the two populations in reactivity to canine distemper virus (CDV) or canine thyroglobulin. The high degree of correlation between anti-bovine insulin and anti-porcine insulin antibodies suggested cross-reactivity which was confirmed by performing a competition ELISA, with antibody binding to bovine insulin inhibited by pre-incubating serum with porcine insulin. The insulin B-chain, rather than the A-chain was the most reactive component of the insulin molecule although in some cases, diabetics with antibody reactivity to whole insulin protein showed minimal reactivity to the individual subunits. The data suggest that treatment of diabetic dogs with bovine insulin can lead to anti-insulin antibody production. These antibodies cross-react with homologous insulin and recognise conformational as well as linear epitopes. [Copyright &y& Elsevier]

Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC) varied with age. Concentrations of white blood cells (WBCs), neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH), MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition. [ABSTRACT FROM AUTHOR]