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PurposeSpontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high-grade glioma and human glioblastomas share many molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford to target the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic glioma model. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma.MethodsWe performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine.ResultsWe established a flow cytometry gating strategy for identifying and isolating FOXP3+ Tregs in dogs. The canine CD4 + CD25high T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines, and expression increased when exposed to Tregs but not CD4 + helper T-cells.ConclusionOur study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.

Abstract Global health is affected by viral, bacterial, and fungal infections that cause chronic and often fatal diseases. Identifying novel antimicrobials through innovative methods that are active against human pathogens will create a new, necessary pipeline for chemical discovery and therapeutic development. Our goal was to determine whether algal production systems represent fertile ground for discovery of antibiotics and antifungals. To this end, we collected high-biomass algal-bacterial samples from outdoor mass cultivation systems, 18-L outdoor algal open cultures mesocosms, and non-axenic laboratory samples. We also cultivated 33 marine bacterial isolates for chemical extraction. Ultimately, we filtered, concentrated, extracted, and screened 77 chemically-complex mixtures using a conventional agar-based microbial growth inhibition assay against three microbes: Escherichia coli, Bacillus subtilis, and Candida albicans. We discovered that 23 of our chemical extracts (almost one-third of the chemical samples tested) exhibited some degree of growth inhibition toward B. subtilis and/or C. albicans. Our work here demonstrates the feasibility and potential of isolating bioactive natural products from high-biomass algal-bacterial samples from algal mass cultivation systems.

BACKGROUND: Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disease that primarily affects young, genetically predisposed horses that are deficient in vitamin E. Equine NAD/EDM has not previously been documented in Gypsy Vanner horses (GVs). OBJECTIVES: To evaluate: (1) the clinical phenotype, blood vitamin E concentrations before and after supplementation and pedigree in a cohort of GV horses with a high prevalence of neurologic disease suspicious for eNAD/EDM and (2) to confirm eNAD/EDM in GVs through postmortem evaluation. ANIMALS: Twenty-six GVs from 1 farm in California and 2 cases from the Midwestern U.S. METHODS: Prospective observational study on Californian horses; all 26 GVs underwent neurologic examination. Pre-supplementation blood vitamin E concentration was assessed in 17- GVs. Twenty-three were supplemented orally with 10 IU/kg of liquid RRR-alpha-tocopherol once daily for 28 days. Vitamin E concentration was measured in 23 GVs after supplementation, of which 15 (65%) had pre-supplementation measurements. Two clinically affected GVs from California and the 2 Midwestern cases had necropsy confirmation of eNAD/EDM. RESULTS: Pre-supplementation blood vitamin E concentration was ≤2.0 μg/mL in 16/17 (94%) of GVs from California. Post-supplementation concentration varied, with a median of 3.39 μg/mL (range, 1.23-13.87 μg/mL), but only 12/23 (52%) were normal (≥3.0 μg/mL). Normalization of vitamin E was significantly associated with increasing age (P = .02). Euthanized horses (n = 4) had eNAD/EDM confirmed at necropsy. CONCLUSIONS AND CLINICAL IMPORTANCE: GVs could have a genetic predisposition to eNAD/EDM. Vitamin E supplementation should be considered and monitored in young GVs.

BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs

BackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with vitamin E deficiency. In humans, polymorphisms in genes involved in vitamin E uptake and distribution determines individual vitamin E requirements.Hypothesis/objectivesGenetic polymorphisms in genes involved in vitamin E metabolism would be associated with an increased risk of eNAD/EDM in Quarter Horses (QHs).AnimalsWhole-genome sequencing: eNAD/EDM affected (n = 9, postmortem [PM]-confirmed) and control (n = 32) QHs.ValidationeNAD/EDM affected (n = 39, 23-PM confirmed) and control (n = 68, 7-PM confirmed) QHs. Allele frequency (AF): Publicly available data from 504 horses across 47 breeds.MethodsRetrospective, case control study. Whole-genome sequencing was performed and genetic variants identified within 28 vitamin E candidate genes. These variants were subsequently genotyped in the validation cohort.ResultsThirty-nine confirmed variants in 15 vitamin E candidate genes were significantly associated with eNAD/EDM (P

BackgroundExperiencing a traumatic event can significantly impact mental and emotional well-being. Social media platforms offer spaces for sharing stories, seeking support, and accessing psychoeducation. TikTok (ByteDance), a rapidly growing social media platform, is increasingly used for advice, validation, and information, although the content of this requires further study. Research is particularly needed to better understand TikTok content relating to trauma and the potential implications for young viewers, considering the distressing nature of the subject and the possibility of users experiencing vicarious trauma through exposure to these videos. ObjectiveThis study aims to explore the content of trauma-related videos on TikTok, focusing on hashtags related to trauma. Specifically, this study analyzes how TikTok videos present information, advice, stories, and support relating to trauma. MethodsA quantitative cross-sectional descriptive content analysis was performed on TikTok in December 2022. A total of 5 hashtags related to trauma were selected: #trauma, #traumatized, #traumatok, #traumatic, and #traumabond, with the top 50 videos from each hashtag analyzed (total N=250 videos). A standardized codebook was developed inductively to analyze the content of the videos, while an existing generic codebook was used to collect the video features (eg, age of people in the video) and metadata (likes, comments, and shares) for each video. ResultsA total of 2 major content themes were identified, which were instructional videos (54/250, 21.6%) and videos disclosing personal stories (168/250, 67.3%). The videos garnered significant engagement, with a total of 296.6 million likes, 2.3 million comments, and 4.6 million shares, indicating that users find this content engaging and useful. Alarmingly, only 3.7% (9/250) of videos included a trigger warning, despite many featuring highly distressing stories that young people and those with trauma may be exposed to. ConclusionsThe study highlights the potential risks of vicarious trauma due to trauma dumping without trigger warnings on TikTok, and the need for further research to assess the accuracy of advice and information in these videos. However, it also underscores the platform’s potential to foster social connections, provide validation, and reduce stigma around mental health issues. Public health professionals should leverage social media to disseminate accurate mental health information, while promoting user education and content moderation to mitigate potential harms. People often use social media, such as TikTok to share advice, stories, and support around mental health, including their experiences with trauma. Out of 250 videos, most were either giving advice (54/250, 21.6%) or sharing personal experiences (168/250, 67.3%). The study found many videos lacked warnings about upsetting content, which could potentially harm young viewers or people suffering from trauma. While TikTok can help people feel connected and reduce the stigma around mental health, it is important to seek support from professionals when needed.

Sibling female and male Chihuahuas were evaluated for a 9-month history of tachypnea that failed to respond to fenbendazole, doxycycline, amoxicillin-clavulanate, and prednisone. Physical examination identified tachypnea, hyperpnea, and harsh bronchovesicular lung sounds. Fundic examination disclosed diffuse chorioretinitis, manifested as multifocal chorioretinal granulomas in the female dog and occasional chorioretinal scars in the male dog. Thoracic radiographs indicated moderate to severe interstitial to broncho-interstitial infiltrates in both dogs. Serum and urine antigen and antibody testing in the female dog failed to identify infectious agents, but cytologic assessment of hepatic lymph node, liver, and splenic aspirates identified Pneumocystis trophozoites. Infection was confirmed in both dogs by 28S rRNA PCR sequencing from multiple tissue samples. The female dog responded well to trimethoprim-sulfamethoxazole, but the male dog was euthanized because of liver failure, presumably related to antimicrobial treatment.

Free-living amoebae are rare causes of morbidity and mortality in humans and animals around the globe. Because the route of exposure and clinical progression of disease caused by different species of amoebae may vary in people and animals, determining the species of amoeba present is important. We describe here a fatal infection by the free-living amoeba Balamuthia mandrillaris in a Siberian tiger (Panthera tigris altaica). The 17-y-old patient had a rapid clinical decline after a peracute onset of severe lethargy, dull mentation, and anorexia. Autopsy did not identify a cause of death. Histology revealed inflammation associated with amoebic trophozoites in the brain, lungs, and iris of one eye. These amoebae were confirmed to be B. mandrillaris based on a PCR assay and sequencing. Although there are subtle morphologic differences between cyst stages of Acanthamoeba spp., B. mandrillaris, and Naegleria fowleri when present and identified on routine staining, other modalities, including PCR, immunofluorescence, electron microscopy, and immunohistochemistry, are typically utilized to confirm the pathogen involved in these cases. We review the reports of balamuthosis in animals.

Abstract Background In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). Hypothesis/Objectives To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Animals Twelve neurologically affected QH foals and the dams. Methods Genomic DNA was isolated and pedigrees were manually constructed. Results All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma‐glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0–18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. Conclusions and Clinical Importance EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs

Abstract Background Equine neuroaxonal dystrophy/degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disease that primarily affects young, genetically predisposed horses that are deficient in vitamin E. Equine NAD/EDM has not previously been documented in Gypsy Vanner horses (GVs). Objectives To evaluate: (1) the clinical phenotype, blood vitamin E concentrations before and after supplementation and pedigree in a cohort of GV horses with a high prevalence of neurologic disease suspicious for eNAD/EDM and (2) to confirm eNAD/EDM in GVs through postmortem evaluation. Animals Twenty‐six GVs from 1 farm in California and 2 cases from the Midwestern U.S. Methods Prospective observational study on Californian horses; all 26 GVs underwent neurologic examination. Pre‐supplementation blood vitamin E concentration was assessed in 17‐ GVs. Twenty‐three were supplemented orally with 10 IU/kg of liquid RRR‐alpha‐tocopherol once daily for 28 days. Vitamin E concentration was measured in 23 GVs after supplementation, of which 15 (65%) had pre‐supplementation measurements. Two clinically affected GVs from California and the 2 Midwestern cases had necropsy confirmation of eNAD/EDM. Results Pre‐supplementation blood vitamin E concentration was ≤2.0 μg/mL in 16/17 (94%) of GVs from California. Post‐supplementation concentration varied, with a median of 3.39 μg/mL (range, 1.23‐13.87 μg/mL), but only 12/23 (52%) were normal (≥3.0 μg/mL). Normalization of vitamin E was significantly associated with increasing age (P = .02). Euthanized horses (n = 4) had eNAD/EDM confirmed at necropsy. Conclusions and Clinical Importance GVs could have a genetic predisposition to eNAD/EDM. Vitamin E supplementation should be considered and monitored in young GVs.

Background: There is a growing body of research focused on autistic individuals who present with aggressive behaviour. Aggressive behaviour has been found to occur more frequently in autism compared with other developmental disabilities or the general population. The most common types of aggressive behaviours are self-injurious behaviours, aggression towards others and the destruction of property. Aggressive behaviour can threaten access to support services and education. Many types of stigma are experienced by parents as a result of their child's diagnosis or observed aggressive behaviour (e.g. ignorance, prejudice and discrimination). The aim of this systematic review was to synthesise the current research into the experience of stigma by parents of autistic children who display aggressive behaviour. The specific question addressed by this review was 'Do parents of autistic children with aggressive behaviours experience stigma?'. This review found that stigma is experienced in many forms and contributes to higher levels of stress and poorer quality of life for these families than for the general population and other disabilities. Methods: The published English-language literature was examined using multiple online databases, grey literature and hand searches. The review was conducted and reported using PRISMA guidelines. Studies investigating family members of children with a diagnosis of autism who exhibited aggressive behaviour were included. An additional criterion was that the participants had experienced some form of stigma because of their child's autism and/or aggressive behaviour. All studies that met the criteria were critically appraised. No limits were applied for date of publication up until February 6, 2019. Results: Total search results yielded 5707 records. Of these, nine studies were identified and reviewed. Two were identified as mixed method designs and the remaining seven were qualitative designs. Despite diverse research methods, research questions, interview guides, a large variation in age range and year of publication, the stigma associated with caring for an autistic child with aggressive behaviour was consistently identified. Conclusions: Taken together, the available research literature suggests that autistic people and their families experience high levels of stigma. For parents of autistic children who behave aggressively, stigma is even more prominent and invasive. This systematic review can conclude that this triad of autism, aggression and stigma is not well understood and is under-investigated.

Mothers with asthma or atopy have a higher likelihood of having autistic children, with maternal immune activation in pregnancy implicated as a mechanism. This study aimed to determine, in a prospective cohort of mothers with asthma and their infants, whether inflammatory gene expression in pregnancy is associated with likelihood of future autism.Mothers with asthma were recruited to the Breathing for Life Trial. RNA was extracted from blood samples collected at mid-pregnancy. 300 ng total RNA was hybridized with the nCounter Human Inflammation gene expression panel (Nanostring Technologies, 249 inflammation-related genes). Parents completed the First Year Inventory (FYI) at 12-month follow-up, which assessed an infant's likelihood for autism across 2 behavioural domains: social communication and sensory regulation. A total score ≥19.2 indicated increased likelihood for future autism.Inflammatory gene expression was profiled from 24 mothers: four infants scored in the high autism likelihood range; 20 scored in the low autism likelihood range. Six inflammatory genes were differentially expressed and significantly up-regulated in the high autism likelihood group: CYSLTR2, NOX1, C1QA, CXCL10, C8A, IL23R. mRNA count significantly correlated with social communication FYI score for CYSLTR2 (Pearson r = 0.46, p = 0.024) and CXCL10 (r = 0.43, p = 0.036) and with sensory regulation score for ALOX5 (r = −0.43, p = 0.038) and MAFK (r = −0.46, p = 0.022).In this proof-of-concept study, inflammatory gene expression during pregnancy in mothers with asthma was associated with an infant's likelihood of future autism as well as scores relating to social communication and sensory regulation.

Abstract The current study serves to demonstrate the potential utilization of devulcanized rubber produced using Tulbaghia violacea Harv. in a supercritical media. The devulcanized rubber, ranging from 5 to 35 wt% is incorporated into virgin natural rubber (NR)/styrene‐butadiene rubber (SBR) blends. The effect of devulcanized rubber addition is assessed by evaluating variations in the curing characteristics, physical attributes, morphologies, mechanical properties, and dynamic mechanical analysis of several vulcanized blends. The findings indicate a reduction in the blends' curing characteristics with an increase in devulcanized rubber proportion, except for minimum torque. Furthermore, the ultimate tensile strength, elongation at break, tear strength, and rebound resilience decrease, while the tensile moduli and stiffness exhibit an increase with an increase in devulcanized rubber proportion. The observed decline in mechanical property is associated with failure points identified through surface fracture imaging. Additionally, an increase in crosslink density and hardness aligned with the alterations in dynamic mechanical properties as the proportion of devulcanized rubber is increased. The study suggests that the rubber devulcanized with T. violacea Harv.—when blended with virgin NR/SBR blends—could be tailored for specific applications.

The goal of this study was to define the glioma-associated microglia/macrophage (GAM) response and associated molecular landscape in canine oligodendrogliomas. Here, we quantified the intratumoral GAM density of low- and high-grade oligodendrogliomas compared to that of a normal brain, as well as the intratumoral concentration of several known GAM-derived pro-tumorigenic molecules in high-grade oligodendrogliomas compared to that in a normal brain. Our analysis demonstrated marked intra- and intertumoral heterogeneity of GAM infiltration. Correspondingly, we observed significant variability in the intratumoral concentrations of several GAM-associated molecules, unlike what we previously observed in high-grade astrocytomas. However, high-grade oligodendroglioma tumor homogenates (n = 6) exhibited an increase in the pro-tumorigenic molecules hepatocyte growth factor receptor (HGFR) and vascular endothelial growth factor (VEGF), as we observed in high-grade astrocytomas. Moreover, neoplastic oligodendrocytes displayed robust expression of GAL-3, a chimeric galectin implicated in driving immunosuppression in human glioblastoma. While this work identifies shared putative therapeutic targets across canine glioma subtypes (HGFR, GAL-3), it highlights several key differences in the immune landscape. Therefore, a continued effort to develop a comprehensive understanding of the immune microenvironment within each subtype is necessary to inform therapeutic strategies going forward.

Abstract The concept of agonist-independent signalling that can be attenuated by inverse agonists is a fundamental element of the cubic ternary complex model of G protein-coupled receptor (GPCR) activation. This model shows how a GPCR can exist in two conformational states in the absence of ligands; an inactive R state and an active R* state that differ in their affinities for agonists, inverse agonists, and G-protein alpha subunits. The proportion of R* receptors that exist in the absence of agonists determines the level of constitutive receptor activity. In this study we demonstrate that mechanical stimulation can induce β2-adrenoceptor agonist-independent Gs-mediated cAMP signalling that is sensitive to inhibition by inverse agonists such as ICI-118551 and propranolol. The size of the mechano-sensitive response is dependent on the cell surface receptor expression level in HEK293G cells, is still observed in a ligand-binding deficient D113A mutant β2-adrenoceptor and can be attenuated by site-directed mutagenesis of the extracellular N-glycosylation sites on the N-terminus and second extracellular loop of the β2-adrenoceptor. Similar mechano-sensitive agonist-independent responses are observed in HEK293G cells overexpressing the A2A-adenosine receptor. These data provide new insights into how agonist-independent constitutive receptor activity can be enhanced by mechanical stimulation and regulated by inverse agonists.

IntroductionMutations in isocitrate dehydrogenase 1/2 (IDHmut) identify a subset of gliomas that exhibit epigenetic dysregulation via aberrant DNA methylation. These tumors are ultimately fatal and lack effective therapeutic strategies. Considering the epigenetic dysregulation of IDHmut gliomas, we hypothesized that epigenetic-targeting drugs may yield therapeutic benefits in gliomas bearing IDHmut. One set of targets includes the bromodomain and extraterminal (BET) family of transcriptional coactivators.MethodsWe used TCGA data from glioma patients to determine whether BET proteins affect patient survival differently based on IDH status. Follow-up experiments using a set of IDH wildtype/mutant glioma cultures, as well as an IDH wildtype glioblastoma cell line expressing exogenous R132H IDH1, focused on cell health assays to investigate whether IDHmut was associated with increased sensitivity to the BET inhibitor JQ1. Immunoblots were used to evaluate the molecular response to JQ1 in these cultures.ResultsWe identified that high BRD4 expression associated with decreased survival only in IDHmut glioma patients. Cell viability analysis showed that IDHmut sensitized glioma cells to delayed cytotoxicity (10 days) in response to JQ1. Early effects of JQ1 (3 days) were primarily antiproliferative, with IDHmut glioma exhibiting a modest increase in sensitivity. Finally, exogenous R132H IDH1 expression in a resistant IDH wildtype cell line recapitulated the JQ1-mediated delayed cytotoxicity seen in our endogenous IDHmut glioma cells.ConclusionOverall, these data suggest that BRD4 enhances malignancy primarily in gliomas bearing IDHmut and is associated with greater sensitivity to BET inhibition. The finding that BET inhibition primarily exhibits delayed cytotoxicity may be overlooked in conventional short endpoint dose-response assays. Follow-up mechanistic and animal studies will help address the translational potential of these findings.

PurposeAlthough recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure.Experimental designWe performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary.ResultsFrom October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS.ConclusionsIn this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15.

Abstract Background Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with vitamin E deficiency. In humans, polymorphisms in genes involved in vitamin E uptake and distribution determines individual vitamin E requirements. Hypothesis/Objectives Genetic polymorphisms in genes involved in vitamin E metabolism would be associated with an increased risk of eNAD/EDM in Quarter Horses (QHs). Animals Whole‐genome sequencing: eNAD/EDM affected (n = 9, postmortem [PM]‐confirmed) and control (n = 32) QHs. Validation: eNAD/EDM affected (n = 39, 23‐PM confirmed) and control (n = 68, 7‐PM confirmed) QHs. Allele frequency (AF): Publicly available data from 504 horses across 47 breeds. Methods Retrospective, case control study. Whole‐genome sequencing was performed and genetic variants identified within 28 vitamin E candidate genes. These variants were subsequently genotyped in the validation cohort. Results Thirty‐nine confirmed variants in 15 vitamin E candidate genes were significantly associated with eNAD/EDM (P

Bromethalin toxicosis is an increasingly common clinical presentation in dogs that may be fatal depending on the extent of intoxication. Antemortem diagnosis of bromethalin toxicosis was achieved in three dogs by demonstration of the active metabolite desmethylbromethalin in fat or serum. Magnetic resonance imaging (MRI) findings were consistent with a diffuse leukoencephalopathy with restricted diffusion and prominent involvement of the corticospinal motor tracts on T2-weighted and diffusion-weighted sequences. Imaging findings were confirmed in one non-surviving dog at necropsy. Resolution of MRI abnormalities was demonstrated in one surviving dog that was consistent with the associated resolution of clinical signs. Initial findings in these dogs support further investigation of specific MRI patterns in cases of leukoencephalopathy to aid differential diagnosis. While antemortem detection of bromethalin and its metabolites confirms exposure, quantitation may be informative as a prognostic biomarker.

ObjectivesTo describe the diagnostic techniques, surgical treatments, and outcomes of two cats with recurrent pleural transudate caused by urinary ultrafiltrate.AnimalsTwo cats without evidence of trauma, urinary tract obstruction, or concurrent perinephric pseudocysts that were evaluated and treated for recurrent pleural transudate caused by urinary ultrafiltrate.Study designShort case series.MethodsMultiphase contrast CT scan revealed leakage of contrast media from the kidneys bilaterally into the retroperitoneal spaces in both cats. Renal scintigraphy performed in one cat revealed progressive accumulation of 99mTc diethylenetriamine penta-acetic acid (Tc-DTPA) in the pleural space. Exploratory laparotomy localized the leakage of fluid to renal capsular defects bilaterally in both cats. The retroperitoneum was incised bilaterally to promote fluid drainage into the peritoneum, and nephropexies were performed.ResultsOne cat had long-term survival with recurrent, though decreasing volumes of, pleural effusion. The second cat was euthanized 16 days postoperatively for progressive renal disease.ConclusionThe diagnosis of spontaneous urinary ultrafiltrate accumulation in the pleural space of cats without evidence of trauma, urinary tract obstruction, or concurrent perinephric pseudocysts has not previously been reported. The surgical correction described reduced but did not completely eliminate the rate of pleural effusion accumulation.

An outbreak of acute encephalopathy occurred in pregnant ewes and their newborn lambs associated with consumption of Talisia esculenta fruits and bark. Clinical signs in 5 adult pregnant ewes included drooling, bloat, tachypnea, depression, ataxia, body shaking, difficulty in rising, and recumbency. Three neonatal lambs born to some of those ewes had similar clinical signs. No significant gross abnormalities were observed on autopsy. Histologically, neuronal necrosis, axonal and dendritic swelling, and loss of Purkinje neurons were observed in the cerebellum. The observation of similar neurologic clinical signs and lesions in pregnant ewes and their neonatal lambs suggests that the toxic principle of T. esculenta crosses the placenta and reaches the fetus.

IntroductionA large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2mut) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2mut gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors.MethodsSix cultured patient-derived glioma cell lines, IDH1wt (n = 3) and IDH1mut (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA.ResultsIDH1mut gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1mut were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1wt glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1mut glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1mut glioma cells.ConclusionThese data suggest that IDH1mut gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1mut glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1mut gliomas.

BackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM.Hypothesis/objectivesBased on the association of α-tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α-tocopherol, but not γ-tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM-affected horses.AnimalsVitamin E metabolism: Proof of concept (POC) study; eNAD/EDM-affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM-affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM-affected (n = 12) and age- and sex-matched control (n = 11-12) horses.MethodsThe rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog.ResultsMetabolic rate of α-tocopherol was increased in eNAD/EDM horses (POC,P

Infants diagnosed with autism spectrum disorder (autism) have difficulty engaging in social communication and interactions with others and often experience language impairment. The use of infant-directed speech (IDS), which is the speech register used when interacting with infants, is associated with infant language and socio-communicative development. The aim of this study was twofold; the first aim was to scope the literature to determine if evidence exists for differences between the IDS caregivers use to infants at high-risk or those later diagnosed with autism, and the IDS typically spoken to neurotypical infants. The second aim was to investigate if any IDS characteristics used by caregivers of high-risk or diagnosed infant populations predicted language development. Twenty-six studies were included and provided evidence that high-risk and later diagnosed infants are exposed to similar amounts of IDS as their neurotypical peers. There is evidence, however, that the IDS used with high-risk and later diagnosed infants may comprise shorter utterances, more action-directing content, fewer questions, more attention bids, and more follow-in commenting. There is also evidence that more attention bids and follow-in commenting used to infants at high risk or those later diagnosed with autism were associated with better language abilities longitudinally.

Social scientists have developed numerous asset-based wealth indices to assess and target socioeconomic inequalities globally. However, there are no systematic studies of the relative performance of these different measures as proxies for socioeconomic position. In this study, we compare how five asset-based wealth indices--the International Wealth Index (IWI), the Standard of Living portion of the Multi-Dimensional Poverty Index (MPI-SL), the Poverty Probability Index (PPI), the Absolute Wealth Estimate (AWE), and the DHS Wealth Index (DHS)--predict benchmarks of socioeconomic position across 11 communities in rural Bangladesh. All indices were highly correlated. The IWI best explained variation in individual and community ranking of economic well-being, while the PPI best explained variation both between and within communities for total household wealth and a general measure of subjective social status.

ObjectiveTo determine period prevalences of postmortem diagnoses for spinal cord or vertebral column lesions as underlying causes of ataxia (spinal ataxia) in horses.Animals2,861 client-owned horses (316 with ataxia [ataxic group] and 2,545 without ataxia [control group]).ProceduresThe medical records database of the University of California-Davis Veterinary Medical Teaching Hospital was searched to identify horses necropsied between January 1, 2005, and December 31, 2017. Results were compared between the ataxic and control groups and between various groups of horses in the ataxic group. Period prevalences were determined for the most common causes of ataxia.Results2,861 horses underwent full necropsy, and the period prevalences for the most common definitive diagnoses for ataxia were 2.7% (77/2,861) for cervical vertebral compressive myelopathy (CVCM), 1.3% (38/2,861) for equine neuroaxonal dystrophy or equine degenerative myeloencephalopathy (eNAD-EDM), and 0.9% (25/2,861) for trauma; the period prevalence of ataxia of unknown origin was 2.0% (56/2,861). Horses in the ataxic group (vs the control group) were more likely to have been warmblood horses (OR, 2.70) and less likely to have been Arabian horses (OR, 0.53). In the ataxic group, horses < 5 (vs ≥ 5) years of age had greater odds of CVCM (OR, 2.82) or eNAD-EDM (OR, 6.17) versus trauma or ataxia of unknown origin. Horses in the ataxic group with CVCM were more likely Thoroughbreds (OR, 2.54), whereas horses with eNAD-EDM were more likely American Quarter Horses (OR, 2.95) and less likely Thoroughbreds (OR, 0.11).Conclusions and clinical relevanceResults indicated that breed distributions differed for horses with CVCM versus eNAD-EDM; therefore, breed should be considered in the clinical evaluation of spinal ataxia in horses.

Abstract Background Advances in medicine have improved the chances of survival following burn injuries, however, psychosocial outcomes have not seen the same improvement, and burn injuries can be distressing for both the child or young person, negatively affecting their wellbeing. Pediatric burn patients are at a higher risk of developing psychopathology compared to the general population. In order to promote resilience and prevent psychopathology post-burn injury for pediatric burn patients, it is crucial to understand the experience of children and young people after a burn. This study aimed to understand the psychosocial impact that a pediatric burn has as perceived by the pediatric burn patient. Methods Seven pediatric burn patients were interviewed from the Perth Metropolitan area on average 3.1 years after their injury. All participants had been admitted to hospital for their acute injury and stayed for a median length of 2 days in hospital. Interviews with pediatric patients took place online, and the patients were asked about their mental health, coping strategies, changes to lifestyle and supports following their burn injury. The interviews were transcribed and then thematically analysed using an inductive approach. Results Three overarching themes were developed from the interviews: burn-specific impact on the child or young person (including appearance concerns, family factors, and lifestyle factors), the psychological impact (including positive and negative impact on mental health), and factors supporting the recovery journey (including coping strategies and support services). The participants in our study highlighted issues they faced during recovery, the positive and negative impacts of the injury and recovery process and provided suggestions for future opportunities to bolster resilience and promote growth for pediatric burn patients who may face similar challenges in the future. Conclusion Factors that improve the mental health and wellbeing of pediatric burn patients should be promoted, such as mental health and social supports, the promotion of adaptive coping mechanisms, and meeting the needs of the family unit as a whole. Ultimately, the implementation of trauma-focused, family centred interventions is crucial for the psychosocial recovery of pediatric burn survivors.

Abstract Sibling female and male Chihuahuas were evaluated for a 9‐month history of tachypnea that failed to respond to fenbendazole, doxycycline, amoxicillin‐clavulanate, and prednisone. Physical examination identified tachypnea, hyperpnea, and harsh bronchovesicular lung sounds. Fundic examination disclosed diffuse chorioretinitis, manifested as multifocal chorioretinal granulomas in the female dog and occasional chorioretinal scars in the male dog. Thoracic radiographs indicated moderate to severe interstitial to broncho‐interstitial infiltrates in both dogs. Serum and urine antigen and antibody testing in the female dog failed to identify infectious agents, but cytologic assessment of hepatic lymph node, liver, and splenic aspirates identified Pneumocystis trophozoites. Infection was confirmed in both dogs by 28S rRNA PCR sequencing from multiple tissue samples. The female dog responded well to trimethoprim‐sulfamethoxazole, but the male dog was euthanized because of liver failure, presumably related to antimicrobial treatment.