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Objective: To describe cytologic findings from mandibular and superficial cervical lymph nodes in dogs with thyroid carcinoma and to determine prognostic factors associated with lymph node metastasis. Animals: A total of 71 client-owned dogs with confirmed thyroid carcinoma that had cytologic results from at least 1 mandibular or superficial cervical lymph node between 2010 and 2020. Procedure: Medical records from 2 referral veterinary hospitals were retrospectively reviewed. Cytology of lymph nodes was reviewed for presence of metastasis by diplomates of the American College of Veterinary Pathologists. Thyroid tumor diameter and volume, tumor fixation, bilateral location, vascular invasion, and stage were recorded to determine effects on nodal metastasis. Results: A total of 154 lymph nodes (104 mandibular and 50 superficial cervical lymph nodes) from 71 dogs were cytologically evaluated, and 1/154 (0.6%) and 2/154 (1.3%) lymph nodes were noted to be definitively metastatic or probably metastatic, respectively. Given the infrequent rate of nodal metastasis (1.9% or less), statistical analysis of potential prognostic variables was not completed. Conclusion and clinical relevance: Routine lymph node cytology of mandibular and superficial cervical lymph nodes appeared to be of low yield when assessing for metastasis of canine thyroid carcinomas. The medial retropharyngeal and deep cervical lymph nodes should continue to be evaluated as they appeared to have higher metastatic rates, based on historic reports. Additional studies are needed to determine prognostic factors associated with lymph node metastasis and effects on patient survival.

Résultats cytologiques dans les ganglions lymphatiques cervicaux mandibulaires et superficiels de chiens atteints d'un carcinome thyroïdien. Objectif: Décrire les résultats cytologiques obtenus des ganglions lymphatiques mandibulaires et cervicaux superficiels chez des chiens atteints d'un carcinome thyroïdien et déterminer les facteurs pronostiques associés aux métastases ganglionnaires. Animaux: Un total de 71 chiens appartenant à des clients atteints d'un carcinome thyroïdien confirmé avec des résultats cytologiques d'au moins un ganglion lymphatique cervical mandibulaire ou superficiel entre 2010 et 2020. Procédure: Les dossiers médicaux de 2 hôpitaux vétérinaires de référence ont été examinés rétrospectivement. La cytologie des ganglions lymphatiques a été examinée pour détecter la présence de métastases par des diplomates de l'American College of Veterinary Pathologists. Le diamètre et le volume de la tumeur thyroïdienne, la fixation de la tumeur, la localisation bilatérale, l'invasion vasculaire et le stade ont été notés pour déterminer les effets sur les métastases ganglionnaires. Résultats: Au total, 154 ganglions lymphatiques (104 ganglions lymphatiques mandibulaires et 50 ganglions lymphatiques cervicaux superficiels) provenant de 71 chiens ont été évalués par cytologie, et 1/154 (0,6 %) et 2/154 (1,3 %) ganglions lymphatiques ont été notés comme définitivement métastatiques ou probablement métastatiques, respectivement. Compte tenu du taux peu fréquent de métastases ganglionnaires (1,9 % ou moins), l'analyse statistique des variables pronostiques potentielles n'a pas été complétée. Conclusion et pertinence clinique: La cytologie de routine des ganglions lymphatiques mandibulaires et cervicaux superficiels semblait être de faible rendement lors de l'évaluation des possibilités de métastases des carcinomes thyroïdiens canins. Les ganglions lymphatiques rétropharyngés médiaux et cervicaux profonds doivent continuer à être évalués car ils semblent présenter des taux métastatiques plus élevés, sur la base des rapports historiques. Des études supplémentaires sont nécessaires pour déterminer les facteurs pronostiques associés aux métastases ganglionnaires et les effets sur la survie des patients.(Traduit par Dr Serge Messier).

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Skin grafting is a simple technique that can be performed by equine practitioners to improve cosmetic outcomes in wounds with large skin defects that would not heal functionally or cosmetically with standard wound therapy interventions. Successful skin grafting is not difficult but relies upon appropriate preparation of the wound bed and effective immobilisation of the grafted area after skin graft placement. Prior to grafting, the wound bed should be treated with a moist wound healing dressing to prepare the granulation tissue bed to receive the graft. For best results, skin grafts should be placed in wounds free of infection with healthy granulation tissue, and motion should be reduced in the graft region in the early postoperative period. When successful, skin grafts cover granulation tissue and encourage wound contraction and epithelialisation while decreasing exuberant granulation tissue resulting in a more cosmetic result. This review will advance practitioners' understanding of skin grafting in horses, including graft classification and techniques, donor site selection, recipient site preparation, postoperative management strategies to optimise graft retention and ongoing research in this field.

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Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

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BACKGROUND: Pulsatile tinnitus (PT) is a debilitating condition with substantial morbidity related to quality of life. Cerebral venous sinus stenosis has recently emerged as a noninfrequent cause of PT, either in the setting of concurrent idiopathic intracranial hypertension (IIH) or due to primary venous stenosis. Venous sinus stenting (VSS) is an endovascular technique that can be used to treat venous stenosis. However, it is unclear if outcomes are different between patients with primary venogenic PT and IIH associated PT. METHODS: A systematic literature review and pooled analysis was completed to evaluate the clinical outcomes of PT in patients undergoing cerebral VSS. Outcome measures included: Improved PT, complete resolution of PT, and PT recurrence at follow-up. Subgroup analysis between patients with IIH and primary PT was completed. RESULTS: In total, 28 studies were identified with 616 patients. The proportion of improved PT symptoms after VSS had an overall pooled rate of 91.7% (confidence interval [CI]:88.1%-95.2%; I2 = 65%) and no difference between subgroups (P = 0.12). Complete resolution after VSS had an overall pooled rate of 88.6% (CI: 84.0%-93.3%; I2 = 68%) and no significant difference between subgroups (P = 0.35). Recurrent PT after stenting occurred in 6.5% of cases (CI: 1.7%-11.3%; I2 = 62%). Furthermore, subgroup analysis demonstrated that IIH patients had a significantly higher recurrence rate (10.6%; CI: 5.2%-16.1%; I2 = 26%) compared to patients treated with venous stenting for PT as the primary indication (2.0%; CI: 0.8%-4.7%; I2 = 0%) (P < 0.0001). CONCLUSIONS: Venous stenting in patients with PT results in a substantial decrease and often complete resolution of symptoms. PT is more likely to recur in patients with IIH-associated PT.

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Bladder diverticula are herniations of the bladder mucosa through the muscular layer and can be congenital or acquired. Acquired bladder diverticula are almost always associated with bladder outlet obstruction. Bladder diverticula are uncommon and often asymptomatic, however, can present with non-specific lower urinary tract symptoms, haematuria, or urinary tract infection. We report a rare case of a large bladder diverticulum causing extrinsic left ureteric compression in a 37-year-old male with a high bladder neck presenting as left flank pain and hydronephrosis. A bladder neck incision successfully resolved voiding symptoms and decompressed the diverticulum leading to resolution of ureteric obstruction.

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Pituitary adenomas are very common representing 18.1% of all brain tumors and are the second most common brain pathology. Transsphenoidal surgery is the mainstay of treatment for all pituitary adenomas except for prolactinomas which are primarily treated medically with dopamine agonists. A thorough endocrine evaluation of pituitary adenoma preoperatively is crucial to identify hormonal compromise caused by the large sellar mass, identifying prolactin-producing tumors and comorbidities associated with Cushing and acromegaly to improve patient care and outcome. Transsphenoidal surgery is relatively safe in the hands of experienced surgeons, but still carries a substantial risk of causing hypopituitarism that required close follow-up in the immediate postoperative period to decrease mortality. A multidisciplinary team approach with endocrinologists, ophthalmologists, and neurosurgeons is the cornerstone in the perioperative management of pituitary adenomas.

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BACKGROUND: Idiopathic intracranial hypertension (IIH) is a complex neurological condition characterized by symptoms of increased intracranial pressure of unclear etiology. While transverse sinus stenosis (TSS) is often present in patients with IIH, how and why it occurs remains unclear. METHODS: IIH patients and a set of age-matched normal controls were identified from our single-center tertiary care institution from 2016 to 2024. Brain MRIs before treatment were computationally segmented and parcellated using FreeSurfer software. Extent of TSS on MR venograms was graded using the Farb scoring system. Relationship between normalized brain volume, normalized brain-to-CSF volume, and TSS was investigated. Multiple linear regression was conducted to investigate the association between continuous variables, accounting for the covariates body mass index, sex, and age. RESULTS: In total, 84 IIH patients (mean age, 29.8 years; 87% female) and 15 normal controls (mean age, 28.1 years) were included. Overall, increasing/worsening TSS was found to be significantly associated with normalized total brain volume (p=0.018, R=0.179) and brain-to-CSF ratio volume (p=0.026, R=0.184). Additionally, there was a significant difference between controls and IIH patients with mild and severe stenosis regarding normalized total brain volume (ANCOVA, p=0.023) and brain-to-CSF ratio volume (ANCOVA, p=0.034). Likewise, IIH patients with severe TSS had a significantly higher brain-to-CSF volume compared with controls (p=0.038) and compared with IIH patients with mild TSS (p=0.038). CONCLUSIONS: These findings suggest that total brain volume is associated with extent of TSS, which may reflect extramural venous compression due to enlarged brain and/or venous hypertension with associated cerebral congestion/swelling.

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When localised prostate cancer recurs after treatment, it occurs predictably in sites such as the prostatic bed, pelvic lymph nodes, spine, lung, and liver. Urethral metastasis of prostate cancer is exceedingly rare. We report a case of urethral recurrence of prostate cancer presenting as new lower urinary tract symptoms in an 82-year-old male 10 years after robotic radical prostatectomy with a very low PSA level of 0.05µg/L. This rare case highlights the need to maintain a degree of suspicion for prostate cancer recurrence in patients with a late onset of or changing lower urinary tract symptoms after radical prostatectomy.

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Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed "senotherapeutics" selectively clear senescent cells and represent a promising strategy to prevent or treat multiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine.

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Non-invasive neuromodulation of non-compressible internal organs has significant potential for internal organ bleeding and blood-shift in aero/space medicine. The present study aims to investigate the potential influences of the non-invasive transcutaneous electrical nerve stimulation (TENS) on multiple non-compressible internal organs' blood flow. Porcine animal model (n = 8) was randomized for a total of 48 neuromodulation sessions with two different TENS stimulation frequencies (80 Hz, 10 Hz) and a placebo stimulation. A combination of two different electrode configurations (Abdominal-only or Abdominal and hind limb) were also performed. Intraarterial blood flow measurements were taken during pre and post-stimulation periods at the left renal artery, common hepatic artery, and left coronary artery. Intracranial, and extracranial arterial blood flows were also assessed with digital subtraction angiography. TENS with abdominal-only electrode configurations at 10 Hz demonstrated significant reductions in average peak blood flow velocity (APV) of the common hepatic artery (p = 0.0233) and renal arteries (p = 0.0493). Arterial pressures (p = 0.0221) were also significantly lower when renal APV was reduced. The outcome of the present study emphasises the potential use of TENS in decreasing the blood flow of non-compressible internal organs when the correct combination of electrodes configuration and frequency is used.

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Companion animals in veterinary medicine develop multiple naturally occurring diseases analogous to human conditions. We previously reported a comprehensive review on the feasibility, safety, and biologic activity of using novel stem cell therapies to treat a variety of inflammatory conditions in dogs and cats (2008-2015) [Hoffman AM, Dow SW. Concise review: stem cell trials using companion animal disease models. Stem Cells. 2016;34(7):1709-1729. https://doi.org/10.1002/stem.2377]. The purpose of this review is to provide an updated summary of current studies in companion animal disease models that have evaluated stem cell therapeutics that are relevant to human disease. Here we have reviewed the literature from 2015 to 2023 for publications on stem cell therapies that have been evaluated in companion animals, including dogs, cats, and horses. The review excluded case reports or studies performed in experimentally induced models of disease, studies involving cancer, or studies in purpose-bred laboratory species such as rodents. We identified 45 manuscripts meeting these criteria, an increase from 19 that were described in the previous review [Hoffman AM, Dow SW. Concise review: stem cell trials using companion animal disease models. Stem Cells. 2016;34(7):1709-1729. https://doi.org/10.1002/stem.2377]. The majority of studies were performed in dogs (n = 28), with additional studies in horses (n = 9) and cats (n = 8). Disease models included those related to musculoskeletal disease (osteoarthritis and tendon/ligament injury), neurologic disease (canine cognitive dysfunction, intervertebral disc disease, spinal cord injury) gingival/dental disease (gingivostomatitis), dermatologic disease (atopic dermatitis), chronic multi-drug resistant infections, ophthalmic disease (keratoconjunctivitis sicca, eosinophilic keratitis, immune-mediated keratitis), cardiopulmonary disease (asthma, degenerative valve disease, dilated cardiomyopathy), gastrointestinal disease (inflammatory bowel disease, chronic enteropathy), and renal disease (chronic kidney disease). The majority of studies reported beneficial responses to stem cell treatment, with the exception of those related to more chronic processes such as spinal cord injury and chronic kidney disease. However, it should also be noted that 22 studies were open-label, baseline-controlled trials and only 12 studies were randomized and controlled, making overall study interpretation difficult. As noted in the previous review, improved regulatory oversight and consistency in manufacturing of stem cell therapies are needed. Enhanced understanding of the temporal course of disease processes using advanced-omics approaches may further inform mechanisms of action and help define appropriate timing of interventions. Future directions of stem-cell-based therapies could include use of stem-cell-derived extracellular vesicles, or cell conditioning approaches to direct cells to specific pathways that are tailored to individual disease processes and stages of illness.

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Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

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Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.

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Physical exercise has been positioned as a promising strategy to prevent and/or alleviate anxiety and depression, but the biological processes associated with its effects on mental health have yet to be entirely determined. Although the prevalence of depression and anxiety in women is about twice that of men, very few studies have examined whether physical exercise could affect mental health differently according to sex. This study examined, in singly-housed mice, the sex-specific effects of voluntary exercise on depressive- and anxiety-like behaviors as well as on different markers along the gut microbiota-immune-brain axis. Male and female C57BL/6N mice had voluntary access to running wheels in their home-cages for 24 days or were left undisturbed in identical home-cages without running wheels. Behaviors were then examined in the open field, splash, elevated plus maze, and tail suspension tests. Gene expression of pro-inflammatory cytokines, microglia activation-related genes, and tight junction proteins was determined in the jejunum and the hippocampus, while microbiota composition and predicted function were verified in cecum contents. Voluntary exercise reduced anxiety-like behaviors and altered grooming patterns in males exclusively. Although the exercise intervention resulted in changes to brain inflammatory activity and to cecal microbiota composition and inferred function in both sexes, reductions in the jejunal expression of pro-inflammatory markers were observed in females only. These findings support the view that voluntary exercise, even when performed during a short period, is beneficial for mental and intestinal health and that its sex-specific effects on behavior could be, at least in part, related to some components of the gut microbiota-immune-brain axis.

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Horses have a slow rate of muscle glycogen repletion relative to other species for unknown reasons. Our aim was to determine the expression of glucose transporters (GLUT) and genes impacting GLUT4 expression and translocation in the gluteal muscle. Five fit Thoroughbred horses performed glycogen-depleting exercises on high-starch (HS, 2869 g starch/day) and low-starch, high-fat diets (LS-HF, 358 g starch/d) with gluteal muscle biopsies obtained before and after depletion and during repletion. Muscle glycogen declined by ≈30% on both diets with little increase during repletion on LS-HF. Transcriptomic analysis identified differential expression (DE) of only 2/12 genes impacting GLUT4 translocation (two subunits of AMP protein kinase) and only at depletion on LS-HF. Only 1/13 genes encoding proteins that promote GLUT4 transcription had increased DE (PPARGC1A at depletion LS-HF). GLUT4 comprised ≈30% of total GLUT mRNA expression at rest. Remarkably, by 72 h of repletion expression of GLUT3, GLUT6 and GLUT10 increased to ≈25% of total GLUT mRNA. Expression of GLUT6 and GLUT10 lagged from 24 h of repletion on HS to 72 h on LS-HF. Lacking an increase in GLUT4 gene expression in response to glycogen-depleting exercise, equine muscle increases GLUT3, GLUT6 and GLUT10 expression potentially to enhance glucose transport, resembling responses observed in resistance trained GLUT4-null mice.

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BACKGROUND: Shivers in horses is characterized by abnormal hindlimb movement when walking backward and is proposed to be caused by a Purkinje cell (PC) axonopathy based on histopathology. OBJECTIVES: Define region-specific differences in gene expression within the lateral cerebellar hemisphere and compare cerebellar protein expression between Shivers horses and controls. ANIMALS: Case-control study of 5 Shivers and 4 control geldings ≥16.2 hands in height. METHODS: Using spatial transcriptomics, gene expression was compared between Shivers and control horses in PC soma and lateral cerebellar hemisphere white matter, consisting primarily of axons. Tandem-mass-tag (TMT-11) proteomic analysis was performed on lateral cerebellar hemisphere homogenates. RESULTS: Differences in gene expression between Shivers and control horses were evident in principal component analysis of axon-containing white matter but not PC soma. In white matter, there were 455/1846 differentially expressed genes (DEG; 350 ↓DEG, 105 ↑DEG) between Shivers and controls, with significant gene set enrichment of the Toll-Like Receptor 4 (TLR4) cascade, highlighting neuroinflammation. There were 50/936 differentially expressed proteins (DEP). The 27 ↓DEP highlighted loss of axonal proteins including intermediate filaments (5), myelin (3), cytoskeleton (2), neurite outgrowth (2), and Na/K ATPase (1). The 23 ↑DEP were involved in the extracellular matrix (7), cytoskeleton (7), redox balance (2), neurite outgrowth (1), signal transduction (1), and others. CONCLUSION AND CLINICAL IMPORTANCE: Our findings support axonal degeneration as a characteristic feature of Shivers. Combined with histopathology, these findings are consistent with the known distinctive response of PC to injury where axonal changes occur without a substantial impact on PC soma.

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BACKGROUND: Poststroke homonymous hemianopia is disabling, and complete spontaneous recovery is rare. In this randomized, placebo-controlled, double-blind, pilot clinical trial, we tested whether fluoxetine enhances vision recovery after stroke. METHODS: We randomized 17 consecutive adults 1:1 to 90 days of fluoxetine 20 mg daily vs placebo within 10 days of an ischemic stroke causing isolated homonymous hemianopia. The primary end point was percent improvement in 24-2 automated perimetry at 6 months. Twelve participants completed the study. Clinical trial registration NCT02737930. RESULTS: Intention-to-treat analysis of the primary end point, percent improvement in perimetric mean deviation, showed a nonsignificant benefit of fluoxetine (64.4%, n = 5) compared with placebo (26.0%, n = 7, one-tailed 95% confidence interval (CI) = (-2.13, ∞), P = 0.06). The original blind field completely recovered in 60% receiving fluoxetine and 14% receiving placebo (odds ratio = 7.22, one-tailed 95% CI = (0.50, ∞)). CONCLUSION: These results suggest a trend in favor of fluoxetine for vision recovery after stroke and have the potential to inform the design of a larger multicenter trial.

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