Ultrasonographic detected adrenomegaly in Clinically Ill Cats: a retrospective study

This retrospective study aimed to assess the prevalence of ultrasonographic detected adrenomegaly in clinically ill cats, evaluating the final established diagnosis, describe adrenal ultrasound findings and if the adrenomegaly was suspected or incidental. Abdominal ultrasonography reports of cats presenting to a veterinary teaching hospital between October 2018 and February 2021 were retrospectively reviewed. Cats showing adrenomegaly (one or both glands having a dorsoventral axis >4.8 mm) were selected and medical records respectively evaluated. Nine-hundred and eighty-three ultrasonographical reports were selected, of which, 68 (7%) disclosed adrenomegaly. European/Domestic Short-Hair (62/68; 91%) male (44/68; 65%) castrated (35/44; 80%) cats were overrepresented. Adrenomegaly was an incidental finding in 62/68 (91%) cats while in 6/68 (9%) it was identified in the context of investigating a potential adrenal disease. Concerning established diagnosis, chronic kidney disease was overrepresented (25/68; 37%), followed by endocrinopathies (20/68; 29%). Adrenomegaly was bilateral in 53% (36/68) of cases. In unilateral cases (32/68; 47%), it was more prevalent on the left side (23/32; 72%), with a normal-sized contralateral adrenal gland. Left adrenal demonstrated a larger size and a tendency to oval shape. This study assesses the prevalence of adrenomegaly in clinically ill cats, reinforcing it can be an incidental ultrasound finding.info:eu-repo/semantics/publishedVersio

Effect of Dietary Phosphate Deprivation on Red Blood Cell Parameters of Periparturient Dairy Cows

Postparturient hemoglobinuria is a sporadic disease characterized by intravascular hemolysis and hemoglobinuria in early lactating dairy cows. The condition has empirically been associated with phosphorus (P) deficiency or hypophosphatemia; however, the exact etiology remains obscure. This paper summarizes two controlled studies investigating the effect of P deprivation during the transition period. In Study I, 36 late pregnant dairy cows were randomly assigned to either a diet with low, or adequate, P content from four weeks before calving to four weeks after calving. In Study II, 30 late pregnant dairy cows were again assigned to either a diet with low, or adequate, P for the last four weeks before calving only. Pronounced hypophosphatemia developed during periods of restricted P supply. In early lactation, a subtle decline of the red blood cell count occurred independently of the dietary P supply. In Study I, anemia developed in 11 cows on deficient P supply, which was associated with hemoglobinuria in five cases. Neither erythrocyte total P content nor osmotic resistance of erythrocytes were altered by dietary P deprivation. Restricted dietary P supply, particularly in early lactation, may lead to postparturient hemoglobinuria, but more frequently causes clinically inapparent hemolysis and anemia in cows

PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled

PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.Analytical BioScience

Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish

In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson's disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons

Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis

Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule

Absence of COVID-19-associated changes in plasma coagulation proteins and pulmonary thrombosis in the ferret model

BACKGROUND: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection. OBJECTIVES: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis. MATERIAL AND METHODS: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed. RESULTS: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation. CONCLUSIONS: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited

Comparison of the Clinical Characteristics of Histiocytic Sarcoma in Bernese Mountain Dogs and Flat-Coated Retrievers

Histiocytic sarcoma (HS) is an aggressive malignant tumor of histiocytes, which can affect almost any organ in the body and is characterized by a broad array of tumor locations and clinical presentations. So far, no complete overview exists of the array of clinical aspects of HS in specific dog breeds in large groups. Therefore, we investigated the clinical characteristics of HS in a population of Bernese Mountain Dogs (BMD; n = 365) and Flat-Coated Retrievers (FCR; n = 289), which are two of the most affected dog breeds. Cases were selected from databases from different pathology services, and clinical information was retrospectively collected for each case. Localized HS was reported significantly more frequently in the FCR (60.6%) than in the BMD (39.2%), and disseminated HS was recorded significantly more frequently in the BMD (60.8%) than in the FCR (39.4%). Lameness was seen more often in FCR than in BMD, and the vast majority (78.1%) of LHS leading to lameness was located in the front legs in the FCR, while in the BMD, there was a more even distribution. BMD had significantly more often leukocytosis and thrombocytopenia, even corrected for the type of HS, than FCR. No significant difference in the frequency of anemia was recorded between BMD and FCR. In those dogs in which blood examination was performed, hypercalcemia was diagnosed in 15 BMD, while none of the FCR had hypercalcemia. The new information provided in this study can aid the diagnostic process and allow for prompt treatment recommendations

Laparoscopic Cisterna Chyli Ablation Combined with Thoracoscopic Thoracic Duct Ligation and Pericardectomy in 5 Dogs and 2 Cats with Idiopathic Chylothorax

Objective: To assess feasibility of a left-sided laparoscopic flank approach for cisterna chyli ablation (CCA) and evaluate effectiveness of a combination of en-block thoracic duct ligation (TDL), sub-phrenic pericardectomy (PC), and CCA in a minimally invasive approach for treatment of idiopathic chylothorax in dogs and cats. Methods: Dogs and cats diagnosed with idiopathic chylothorax were admitted for a minimally invasive surgical treatment combining TDL, PC, and CCA. Results: Five dogs and 2 cats received the minimally invasive combination treatment (TDL + PC + CCA). Two patients were treated for recurrent chylothorax after previous TDL + PC. TDL was performed in sternal recumbence with bilateral approach in 6 cases and unilateral in 1. CCA was successfully performed through a 2-portal left-sided flank approach in sternal recumbence. PC was performed in dorsal recumbence in 6 cases and sternal in 1 cat. Obvious lymph spillage from the cisterna chyli into the abdomen was noted during CCA in all patients. No intraoperative complications occurred. Post-operative complications included development of pyothorax in 1 patient after prolonged maintaining of a thoracic drain, which resolved with antibiotic treatment. Pleural effusion resolved in 4/7 patients (4/5 dogs); 3/7 were eventually euthanized because of continued chylothorax, including both cats. Conclusion: Laparoscopic CCA is feasible through a 2 portal left-sided flank approach in sternal recumbence and seemingly without complications. Further investigation is needed to assess specific value of a combination of all 3 therapies

Pegylated asparaginase in feline high-grade lymphoma: clinical results of single injection and continued incorporation into a modified COP regimen

Objectives: The aim of this retrospective study was to determine the response to a single injection of pegylated asparaginase (‘pegaspargase’) and to assess the tolerability and outcome of prolonged incorporation of pegaspargase into a modified COP (cyclophosphamide, vincristine, prednisolone) regimen in pegaspargase sensitive cats. Methods: Fifty-six client-owned cats with confirmed macroscopic high-grade lymphoma at any anatomical site were included. Treatment was commenced with a single pegaspargase injection. Cats showing an objective response were eligible to continue therapy with pegaspargase incorporated into a modified COP protocol and had their survival analysed using the Kaplan–Meier method and log-rank test. Results: Objective response to pegaspargase was reported in 46 cats (82%), including 21 (38%) complete and 25 (44%) partial responses. Thirty-four responders continued therapy with pegaspargase-COP as the first-line treatment. Of these, 31 cats (92%) achieved complete remission with a median duration of the first remission (disease-free survival [DFS]) of 816 days. The median overall survival time (OST) for all 34 cats treated with pegaspargase-COP was 181 days. Response to the initial pegaspargase injection before COP initiation was significantly associated with DFS (P = 0.04) and OST (P = 0.001). Median DFS/OST for cats with complete response to initial pegaspargase injection was significantly longer compared with those with partial remission (>1273 days/>2066 days vs 77 days/108 days, respectively). Cats with gastric lymphoma showed a significantly longer survival (OST 854 days, 1- and 2-year survival rate 57.1%) compared with cats with intestinal lymphoma (OST 102 days, 1-year survival rate 0%). The pegaspargase-COP protocol was generally well tolerated, but two deaths were likely attributable to treatment-related toxicity during the maintenance phase. Importantly, none of the cats experienced hypersensitivity, despite multiple repeated treatments with pegaspargase. Conclusion and relevance: Pegaspargase is an effective agent for feline lymphoma. Its incorporation into a COP chemotherapy protocol may confer a survival benefit, especially in cats with complete response to pegaspargase. Treatment is generally well tolerated, but careful monitoring is recommended. Further studies are required to assess the benefits of pegaspargase as monotherapy or as part of different multi-agent chemotherapy regimens