Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.

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This study reports the clinical, clinicopathological and ultrasonographic findings from dogs with chronic pancreatitis (CP). Fourteen dogs with clinical signs consistent with CP and histological confirmation of the disease were evaluated. Abdominal ultrasound and clinical pathology results were recorded. Sensitivities of pancreatic enzymes for diagnosis of CP were calculated with two different cut-off values. The mean age of affected dogs was 9.1 years. Spaniels were the most common breed with CP, representing seven of the 14 dogs in this study. CP was histologically severe in nine cases. Most dogs showed chronic low-grade gastrointestinal signs and abdominal pain. Five dogs had exocrine pancreatic insufficiency and five dogs had diabetes mellitus. The sensitivity of elevated trypsin-like immunoreactivity for CP was 17 per cent. The sensitivities of canine pancreatic lipase immunoreactivity, lipase and amylase for CP were 44 to 67 per cent or 14 to 28 per cent depending on the cut-off value used. Cholesterol was elevated in 58 per cent of samples. Liver enzymes were often elevated. The pancreas appeared abnormal on 56 per cent of ultrasound examinations. Ten dogs had died by the end of the study period; only one case was due to CP.

This report describes the clinical and pathological findings of a suspected idiosyncratic adverse drug reaction in a young dog. The patient presented with sudden onset, severe skin lesions together with episodes of collapse. Investigations revealed a neutrophilic dermatitis with vasculitis, immune-mediated haemolytic anaemia and thrombocytopenia. Similar pathology has been described in human cases of Sweet's syndrome. The chronology of events suggested an adverse drug reaction to carprofen, although two antibiotics had been prescribed within the dog's recent history. Lymphocyte transformation tests were performed and tended to exclude both antibiotics as the cause of the reaction. To the authors' knowledge, lymphocyte transformation tests have not previously been described with regard to drug hypersensitivity assessment in the veterinary literature, and this is the first peer-reviewed case report of neutrophilic dermatitis and vasculitis with immune-mediated haemolytic anaemia and thrombocytopenia occurring as a suspected adverse drug reaction to carprofen in the dog.

Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of pro-regenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease.

Objectives: To assess the prevalence of canine chronic hepatitis (CH) and other liver diseases in first opinion practice and identify associations with concurrent chronic pancreatitis (CP). Methods: One large section of left lateral lobe of liver was taken from 200 unselected canine post‐mortem examinations from first opinion practices. Histological changes were categorised based on WSAVA criteria. Prevalence of CH and other liver diseases were calculated. Relative risks (RR) for liver histopathology in association with CP and for CH in different breeds were also calculated. Results: The prevalence of CH was 12%. Some breeds had an increased RR of CH, although sample sizes were small. Dogs with CP had an increased RR of reactive hepatitis but no significant association with the other liver diseases. Clinical Significance: CH is common in the first opinion dog population but less common than CP. CP was significantly associated with reactive hepatitis but not CH. Possible breed associations mirrored another recent UK study. Some dogs with CP may be erroneously diagnosed clinically as having CH on the basis of increased serum liver enzymes because of concurrent reactive hepatitis if the diagnosis is not confirmed histologically.

Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome-wide selectivity screen is a valid approach to identifying and progressing safer compounds.

Protein-losing enteropathies were diagnosed in two dogs that were initially presented with diarrhoea and weight loss. Plasma biochemistry in both cases revealed low concentrations of albumin, calcium and ionised calcium. Both dogs had an elevated plasma parathyroid hormone concentration and low serum 25-hydroxyvitamin D (25[OH]D) concentration. The first dog was diagnosed with lymphangiectasia on postmortem examination, and the second dog was diagnosed with chronic lymphocytic/ plasmacytic enteritis and severe cystic mucoid changes based on endoscopic duodenal biopsies. While a causal effect was not demonstrated, the protein-losing enteropathies may have caused reduced intestinal absorption of vitamin D leading to low plasma concentrations of ionised calcium and secondary hyperparathyroidism. To the authors' knowledge, this is the first report of low ionised calcium concentrations, low 25(OH)D and 1,25-dihydroxyvitamin D concentrations, and high parathyroid hormone concentrations in dogs with protein-losing enteropathies.