The effects of an alpha-2-adrenoceptor agonist, antagonist, and their combination on the blood insulin, glucose, and glucagon concentrations in insulin sensitive and dysregulated horses

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0,1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Spatiotemporal correlations of handset-based service usages

We study spatiotemporal correlations and temporal diversities of handset-based service usages by analyzing a dataset that includes detailed information about locations and service usages of 124 users over 16 months. By constructing the spatiotemporal trajectories of the users we detect several meaningful places or contexts for each one of them and show how the context affects the service usage patterns. We find that temporal patterns of service usages are bound to the typical weekly cycles of humans, yet they show maximal activities at different times. We first discuss their temporal correlations and then investigate the time-ordering behavior of communication services like calls being followed by the non-communication services like applications. We also find that the behavioral overlap network based on the clustering of temporal patterns is comparable to the communication network of users. Our approach provides a useful framework for handset-based data analysis and helps us to understand the complexities of information and communications technology enabled human behavior.Comment: 11 pages, 15 figure

Variation in insulin response to oral sugar test in a cohort of horses throughout the year and evaluation of risk factors for insulin dysregulation

Background The oral sugar test (OST) is commonly used to diagnose insulin dysregulation (ID) and equine metabolic syndrome; however, possible seasonal changes in OST results have not been evaluated. Objective To determine the possible variation in insulin response to OST throughout the year and risk factors associated with maximum insulin concentration (InsMax) and ID. Study design Prospective, longitudinal cohort study. Methods The OST was performed on 29 Finnhorses every other month six times. Serum total adiponectin concentration and phenotypic variables related to obesity were also measured. Changes in InsMax, adiponectin, scale weight, body condition score, cresty neck score (CNS), and fasting glucose concentration were assessed. Risk factor analyses were performed on InsMax and ID status, and ID groups were compared with each other. Results Fourteen horses were categorised with non-ID each time and 15 as having ID at least once during the follow-up period. The ID status of 12 horses varied throughout the year, but neither the insulin variables measured during the OST nor adiponectin expressed significant seasonal variation. Increasing age and CNS, and decreasing adiponectin were observed as risk factors for a high InsMax after OST. The risk of ID was higher in horses with no exercise compared to horses with exercise (OR 7.6, 95% CI 1.2-49.3, P = .03). Horses with ID had lower serum adiponectin concentrations, longer neck circumference and larger height than horses in the non-ID group. Main limitations The environmental conditions (feeding, exercise) were not constant for all horses throughout the study and only one breed was used. Conclusions Neither OST results nor adiponectin varies with season; however, there were a substantial number of horses with variable ID status throughout the year, in which repeated OSTs may be beneficial. Lack of exercise was a risk factor for ID.Peer reviewe

Insulin dysregulation in a population of Finnhorses and associated phenotypic markers of obesity

Background Obesity and insulin dysregulation (ID) predispose horses to laminitis. Determination of management practices or phenotypic markers associated with ID may benefit animal welfare. Objectives Determine ID status of a population of Finnhorses using an oral sugar test (OST) and compare phenotypes and management factors between ID and non-ID Finnhorses. Animals One hundred twenty-eight purebred Finnhorses >= 3 years of age. Methods Owners were recruited using an online questionnaire regarding signalment, history, feeding, and exercise of their horses. Selected contributing stables within a predefined area were visited. Phenotypic markers of obesity and the weight of each horse were recorded. After fasting overnight, horses received 0.45 mL/kg corn syrup PO. Serum samples before and at 60 and 90 minutes after syrup administration were analyzed for insulin by chemiluminescent assay. Horses met ID criteria if insulin concentrations were >= 33 mu IU/mL at T0, >= 66 mu IU/mL at T60 or T90 or some combination thereof. Associations between phenotypic markers, feeding and exercise variables, and ID were examined using mixed effects logistic regression modeling. Results Several phenotypic markers of obesity were significant on univariable analysis but in the final multivariable model, only obesity (body condition score >= 8) was associated with ID (P= .04). Over half of the horses (60% [95% confidence interval (CI), 51%-68%]) were considered overweight or obese whereas 16% (95% CI, 10%-23%) were classified as having ID. Conclusions and Clinical Importance Because obesity is associated with ID in cold-blooded type horses, objective monitoring of phenotypic markers by owners may be beneficial for health outcomes.Peer reviewe

Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1)

Congenital nephrotic syndrome of the Finnish type (NPHS1) is a rare genetic disease caused by mutations in the NPHS1 gene encoding a major podocyte slit-diaphragm protein, nephrin. Patients with NPHS1 have severe nephrotic syndrome from birth and develop renal fibrosis in early childhood. In this work, we studied the development of glomerular sclerosis in kidneys removed from 4- to 44-month-old NPHS1 patients. The pathological lesions and expression of glomerular cell markers were studied in nephrectomized NPHS1 and control kidneys using light and electron microscopy and immunohistochemistry. An analysis of 1528 glomeruli from 20 patients revealed progressive mesangial sclerosis and capillary obliteration. Although few inflammatory cells were detected in the mesangial area, paraglomerular inflammation and fibrosis was common. The podocytes showed severe ultrastructural changes and hypertrophy with the upregulation of cyclins A and D1. Podocyte proliferation, however, was rare. Apoptosis was hardly detected and the expression of antiapoptotic B-cell lymphoma-2 and proapoptotic p53 were comparable to controls. Moderate amounts of podocytes were secreted into the urine of NPHS1 patients. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. The results indicate that, in NPHS1 kidneys, the damaged podocytes induce progressive mesangial expansion and capillary obliteration. Podocyte depletion, glomerular tuft adhesion, and misdirected filtration, however, seem to play a minor role in the nephron destruction

Enhanced Antibody Production in Clever-1/Stabilin-1-Deficient Mice

Clever-1, encoded by the Stab1 gene, is a scavenger and leukocyte trafficking receptor expressed by subsets of vascular and lymphatic endothelial cells and immunosuppressive macrophages. Monocyte Clever-1 also modulates T cell activation. However, nothing is known about the possible links between B cell function and Clever-1. Here, we found that Stab1 knockout mice (Stab1(-/-)) lacking the Clever-1 protein from all cells present with abnormally high antibody levels under resting conditions and show enhanced humoral immune responses after immunization with protein and carbohydrate antigens. Removal of the spleen does not abolish the augmented basal and post-immunization antibody levels in Clever-1-deficient mice. The increased IgG production is also present in mice in which Clever-1 is selectively ablated from macrophages. When compared to wildtype macrophages, Clever-1-deficient macrophages show increased TNF-alpha synthesis. In co-culture experiments, monocytes/macrophages deficient of Clever-1 support higher IgM production by B cells, which is blocked by TNF-alpha depletion. Collectively, our data show that the excessive inflammatory activity of monocytes/macrophages in the absence of Clever-1 results in augmented humoral immune responses in vivo

Gene-expression profiling of different arms of lymphatic vasculature identifies candidates for manipulation of cell traffic

Afferent lymphatic vessels bring antigens and diverse populations of leukocytes to draining lymph nodes, whereas efferent lymphatics allow only lymphocytes and antigens to leave the nodes. Despite the fundamental importance of afferent vs. efferent lymphatics in immune response and cancer spread, the molecular characteristics of these different arms of the lymphatic vasculature are largely unknown. The objective of this work was to explore molecular differences behind the distinct functions of afferent and efferent lymphatic vessels, and find possible molecules mediating lymphocyte traffic. We used laser-capture microdissection and cell sorting to isolate lymphatic endothelial cells (LECs) from the subcapsular sinus (SS, afferent) and lymphatic sinus (LS, efferent) for transcriptional analyses. The results reveal marked differences between afferent and efferent LECs and identify molecules on lymphatic vessels. Further characterizations of Siglec-1 (CD169) and macrophage scavenger receptor 1 (MSR1/CD204), show that they are discriminatively expressed on lymphatic endothelium of the SS but not on lymphatic vasculature of the LS. In contrast, endomucin (EMCN) is present on the LS endothelium and not on lymphatic endothelium of the SS. Moreover, both murine and human MSR1 on lymphatic endothelium of the SS bind lymphocytes and in in vivo studies MSR1 regulates entrance of lymphocytes from the SS to the lymph node parenchyma. In conclusion, this paper reports surprisingly distinct molecular profiles for afferent and efferent lymphatics and a function for MSR1. These results may open avenues to explore some of the now-identified molecules as targets to manipulate the function of lymphatic vessels

Prevalence, survival analysis and multimorbidity of chronic diseases in the general veterinarian-attended horse population of the UK

he average age of the global human population is increasing, leading to increased interest in the effects of chronic disease and multimorbidity on health resources and patient welfare. It has been posited that the average age of the general veterinarian-attended horse population of the UK is also increasing, and therefore it could be assumed that chronic diseases and multimorbidity would pose an increasing risk here also. However, evidence for this trend in ageing is very limited, and the current prevalence of many chronic diseases, and of multimorbidity, is unknown. Using text mining of first-opinion electronic medical records from seven veterinary practices around the UK, Kaplan-Meier and Cox proportional hazard modelling, we were able to estimate the apparent prevalence among veterinarian-attended horses of nine chronic diseases, and to assess their relative effects on median life expectancy following diagnosis. With these methods we found evidence of increasing population age. Multimorbidity affected 1.2% of the study population, and had a significant effect upon survival times, with co-occurrence of two diseases, and three or more diseases, leading to 6.6 and 21.3 times the hazard ratio compared to no chronic disease, respectively. Laminitis was involved in 74% of cases of multimorbidity. The population of horses attended by UK veterinarians appears to be aging, and chronic diseases and their co-occurrence are common features, and as such warrant further investigation

Identification of modifiable factors associated with owner-reported equine laminitis in Britain using a web-based cohort study approach

Equine laminitis is a complex disease that manifests as pain and lameness in the feet, often with debilitating consequences. There is a paucity of data that accounts for the multifactorial nature of laminitis and considers time-varying covariates that may be associated with disease development; particularly those that are modifiable and present potential interventions. A previous case-control study identified a number of novel, modifiable factors associated with laminitis which warranted further investigation and corroboration. The aim of this study was to identify factors associated with equine laminitis in horses/ponies in Great Britain (GB) using a prospective, web-based cohort study design, with particular interest in evaluating modifiable factors previously identified in the case-control study

Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL. Trim37(-/-) mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37(-/-) mice as compared with wildtype. Both male and female Trim37(-/-) mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37(-/-) mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37(-/-) mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37(-/-) mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37(-/-) mice. The most consistently seen phenotypes in Trim37(-/-) mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37(-/-) mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis