Preoperative computed tomographic evaluation of neonatal foals with rib fractures.

OBJECTIVE: To compare ultrasonographic and computed tomographic findings in neonatal foals prior to surgical repair of rib fractures as well as postoperative outcomes in foals with and without preoperative thoracic computed tomography (CT). Study design Retrospective cohort study. Sample population 43 neonatal foals undergoing surgical treatment of rib fractures between 2013 and 2021. METHODS: Medical records were reviewed for age, sex, delivery method, comorbidities, presurgical anesthetic time, surgical time, number and location of fractured ribs identified with ultrasound and CT, number and location of ribs surgically repaired, survival to discharge, and post-mortem findings. Statistical analyses were performed using chi-square, Fisher's exact, and t-tests. RESULTS: Twenty-two foals underwent surgical repair of rib fractures after preoperative CT from 2019-2021 (median: 4/18/20) and 21 foals were anesthetized (20 underwent repair) for surgical repair of rib fractures without preoperative CT from 2013-2020 (median: 4/9/15). Ultrasound and CT findings differed in number and location of fractured ribs in 13/17 (76%) foals (p = .049). More cranially positioned ribs were identified as fractured with CT than with ultrasonography (p = .035). Survival to discharge was improved when foals underwent CT (20/22, 91%) than when they did not (12/20, 60%, p = .019). CONCLUSION: Ultrasound findings differed from CT findings in most foals. Foals evaluated with CT were more likely to survive to hospital discharge. CLINICAL SIGNIFICANCE: When available, CT is recommended prior to surgical repair of rib fractures in neonatal foals.

Role of 1-Deoxysphingolipids in docetaxel neurotoxicity.

A major dose-limiting side effect of docetaxel chemotherapy is peripheral neuropathy. Patients' symptoms include pain, numbness, tingling and burning sensations, and motor weakness in the extremities. The molecular mechanism is currently not understood, and there are no treatments available. Previously, we have shown an association between neuropathy symptoms of patients treated with paclitaxel and the plasma levels of neurotoxic sphingolipids, the 1-deoxysphingolipids (1-deoxySL) (Kramer et al, FASEB J, 2015). 1-DeoxySL are produced when the first enzyme of the sphingolipid biosynthetic pathway, serine palmitoyltransferase (SPT), uses L-alanine as a substrate instead of its canonical amino acid substrate, L-serine. In the current investigation, we tested whether 1-deoxySL accumulate in the nervous system following systemic docetaxel treatment in mice. In dorsal root ganglia (DRG), we observed that docetaxel (45 mg/kg cumulative dose) significantly elevated the levels of 1-deoxySL and L-serine-derived ceramides, but not sphingosine-1-phosphate (S1P). S1P is a bioactive sphingolipid and a ligand for specific G-protein-coupled receptors. In the sciatic nerve, docetaxel decreased 1-deoxySL and ceramides. Moreover, we show that in primary DRG cultures, 1-deoxysphingosine produced neurite swellings that could be reversed with S1P. Our results demonstrate that docetaxel chemotherapy up-regulates sphingolipid metabolism in sensory neurons, leading to the accumulation of neurotoxic 1-deoxySL. We suggest that the neurotoxic effects of 1-deoxySL on axons can be reversed with S1P.

Circadian rhythm phase shifts caused by timed exercise vary with chronotype.

BACKGROUNDThe circadian system entrains behavioral and physiological rhythms to environmental cycles, and modern lifestyles disrupt this entrainment. We investigated a timed exercise intervention to phase shift the internal circadian rhythm.METHODSIn 52 young, sedentary adults, dim light melatonin onset (DLMO) was measured before and after 5 days of morning (10 hours after DLMO; n = 26) or evening (20 hours after DLMO; n = 26) exercise. Phase shifts were calculated as the difference in DLMO before and after exercise.RESULTSMorning exercise induced phase advance shifts (0.62 ± 0.18 hours) that were significantly greater than phase shifts from evening exercise (-0.02 ± 0.18 hours; P = 0.01). Chronotype also influenced the effect of timed exercise. For later chronotypes, both morning and evening exercise induced phase advances (0.54 ± 0.29 hours and 0.46 ±0.25 hours, respectively). In contrast, earlier chronotypes had phase advances from morning exercise (0.49 ± 0.25 hours) but had phase delays from evening exercise (-0.41 ± 0.29 hours).CONCLUSIONLate chronotypes - those who experience the most severe circadian misalignment - may benefit from phase advances induced by exercise in the morning or evening, but evening exercise may exacerbate circadian misalignment in early chronotypes. Thus, personalized exercise timing prescription, based on chronotype, could alleviate circadian misalignment in young adults.TRIAL REGISTRATIONTrial registration can be found at www.clinicaltrials.gov (NCT04097886).FUNDINGFunding was supplied by NIH grants UL1TR001998 and TL1TR001997, the Barnstable Brown Diabetes and Obesity Center, the Pediatric Exercise Physiology Laboratory Endowment, the Arvle and Ellen Turner Thacker Research Fund, and the University of Kentucky.

Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice.

INTRODUCTION: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD. METHODS: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aß plaques, Aß levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively. RESULTS: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aß levels, plaque density, or neuroinflammation. Effects of DORA-22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits. DISCUSSION: These findings suggest that DORAs may improve sleep in AD patients. Further investigations should optimize the dose and duration of DORA-22 treatment and explore additional AD-relevant animal models and cognitive tests.