Caudoventral hip luxation in 160 dogs (2003-2023): A multicenter retrospective case series.

OBJECTIVE: To describe patient characteristics, etiology, treatment outcomes and complications of caudoventral hip luxation (CvHL) in a large cohort of dogs and investigate factors associated with nonsurgical treatment outcomes. STUDY DESIGN: Multicenter retrospective case series. ANIMAL POPULATION: A total of 160 client-owned dogs (170 limbs). METHODS: Medical records from 2003 to 2023 were reviewed for signalment, history, treatment outcomes and complications. Logistic regression was performed to investigate factors associated with nonsurgical treatment outcome. RESULTS: Low-trauma accidents accounted for 82.9% of cases. Over-represented breeds included poodles (38.1%) and poodle crosses (11.3%). On a per-treatment basis, success rates of closed reduction alone, closed reduction/Ehmer sling, closed reduction/hobbles were 9.1%, 15.2% and 48.8%, respectively. When accounting for repeated attempts using closed reduction alone, Ehmer sling, or hobbles, eventual success rate increased to 10.3%, 18.5% and 61.8%, respectively. Success rate for toggle rod stabilization was 88.2%. Complication rate of hobbles was 31.9% versus 60.6% for Ehmer slings. Use of hobbles (OR:7.62, p = .001, CI:2.23-26.05), treatment by specialist surgeons (OR:2.68, p = .047, CI: 1.01-7.08) and increasing age (OR:1.15, p < .005, CI: 1.08-1.23) were associated with successful nonsurgical treatments. CONCLUSION: Low-trauma etiology, and poodles and their crosses were over-represented in cases of CvHL. Success rate of nonsurgical treatments was lower than previously reported. Hobbles were 7.6 times more likely to be successful when compared to dogs treated without hobbles and remains a viable noninvasive first-line treatment. CLINICAL SIGNIFICANCE/IMPACT: Hobbles are recommended as a low-morbidity first-line treatment for CvHL. An Ehmer sling is not recommended. Toggle rod stabilization is an effective surgical treatment for CvHL.

Altered metabolism and DAM-signatures in female brains and microglia with aging.

Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age- and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17ß-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging.

Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age-and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17ß-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

Fatty acid sensing in the brain: The role of glial-neuronal metabolic crosstalk and horizontal lipid flux.

The central control of energy homeostasis is a regulatory axis that involves the sensing of nutrients, signaling molecules, adipokines, and neuropeptides by neurons in the metabolic centers of the hypothalamus. However, non-neuronal glial cells are also abundant in the hypothalamus and recent findings have underscored the importance of the metabolic crosstalk and horizontal lipid flux between glia and neurons to the downstream regulation of systemic metabolism. New transgenic models and high-resolution analyses of glial phenotype and function have revealed that glia sit at the nexus between lipid metabolism and neural function, and may markedly impact the brain's response to dietary lipids or the supply of brain-derived lipids. Glia comprise the main cellular compartment involved in lipid synthesis, lipoprotein production, and lipid processing in the brain. In brief, tanycytes provide an interface between peripheral lipids and neurons, astrocytes produce lipoproteins that transport lipids to neurons and other glia, oligodendrocytes use brain-derived and dietary lipids to myelinate axons and influence neuronal function, while microglia can remove unwanted lipids in the brain and contribute to lipid re-utilization through cholesterol efflux. Here, we review recent findings regarding glial-lipid transport and highlight the specific molecular factors necessary for lipid processing in the brain, and how dysregulation of glial-neuronal metabolic crosstalk contributes to imbalanced energy homeostasis. Furthering our understanding of glial lipid metabolism will guide the design of future studies that target horizontal lipid processing in the brain to ameliorate the risk of developing obesity and metabolic disease.

Altered substrate metabolism in neurodegenerative disease: new insights from metabolic imaging.

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS), are relatively common and devastating neurological disorders. For example, there are 6 million individuals living with AD in the United States, a number that is projected to grow to 14 million by the year 2030. Importantly, AD, PD and MS are all characterized by the lack of a true disease-modifying therapy that is able to reverse or halt disease progression. In addition, the existing standard of care for most NDs only addresses the symptoms of the disease. Therefore, alternative strategies that target mechanisms underlying the neuropathogenesis of disease are much needed. Recent studies have indicated that metabolic alterations in neurons and glia are commonly observed in AD, PD and MS and lead to changes in cell function that can either precede or protect against disease onset and progression. Specifically, single-cell RNAseq studies have shown that AD progression is tightly linked to the metabolic phenotype of microglia, the key immune effector cells of the brain. However, these analyses involve removing cells from their native environment and performing measurements in vitro, influencing metabolic status. Therefore, technical approaches that can accurately assess cell-specific metabolism in situ have the potential to be transformative to our understanding of the mechanisms driving AD. Here, we review our current understanding of metabolism in both neurons and glia during homeostasis and disease. We also evaluate recent advances in metabolic imaging, and discuss how emerging modalities, such as fluorescence lifetime imaging microscopy (FLIM) have the potential to determine how metabolic perturbations may drive the progression of NDs. Finally, we propose that the temporal, regional, and cell-specific characterization of brain metabolism afforded by FLIM will be a critical first step in the rational design of metabolism-focused interventions that delay or even prevent NDs.

Outcome after surgical management of canine insulinoma in 49 cases.

Canine insulinoma has historically been associated with a poor prognosis; however, prolonged survival times have recently been reported. Prognostic indicators that are available preoperatively are of limited predictive accuracy, and consensus on post-operative treatment recommendations is lacking. The objectives of this study were to describe outcomes in dogs with insulinoma treated surgically, and to assess whether selected potential risk factors are strongly associated with outcomes after surgery. Medical records of two institutions were searched for dogs with insulinoma that were treated surgically. Forty-nine dogs were included. Thirty-nine dogs (80%) had immediate resolution of hypoglycaemia and 10 (20%) remained persistently hypoglycaemic postoperatively. The median survival time (MST) for all dogs was 561 days. The MST for dogs that had resolution of hypoglycaemia was 746 days. The median of the overall euglycaemic time (times from surgery to first detection of hypoglycaemia at any time point after surgery) for all dogs was 424 days. Forty-four percent of those that had resolution of hypoglycaemia experienced recurrence of hypoglycaemia by 2 years postoperatively. Pathological stage was a predictor of persistent post-operative hypoglycaemia which, in turn, was a predictor of survival time. These results show that dogs with insulinoma can have prolonged survival, and that pathological stage is a predictor of outcome.