Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis.

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01 µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus's ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug's ability to restore multiple cellular homeostasis mechanisms.

MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.

Metabolism research is increasingly recognizing the contributions of organelle crosstalk to metabolic regulation. Mitochondria-associated membranes (MAMs), which are structures connecting the mitochondria and endoplasmic reticulum (ER), are critical in a myriad of cellular functions linked to cellular metabolism. MAMs control calcium signaling, mitochondrial transport, redox balance, protein folding/degradation, and in some studies, metabolic health. The possibility that MAMs drive changes in cellular function in individuals with Type 2 Diabetes (T2D) is controversial. Although disruptions in MAMs that change the distance between the mitochondria and ER, MAM protein composition, or disrupt downstream signaling, can perpetuate inflammation, one key trait of T2D. However, the full scope of this structure's role in immune cell health and thus T2D-associated inflammation remains unknown. We show that human immune cell MAM proteins and their associated functions are not altered by T2D and thus unlikely to contribute to metaflammation.

Postprandial triglycerides across the aging spectrum: A secondary analysis utilizing an abbreviated fat tolerance test.

BACKGROUND & AIMS: Elevated postprandial triglycerides are an independent cardiovascular disease risk factor and observed in older adults. However, differences in postprandial triglycerides across the spectrum of adulthood remain unclear. METHODS AND RESULTS: We performed a secondary analysis of six studies where adults (aged 18-84 years; N = 155) completed an abbreviated fat tolerance test (9 kcal/kg; 70% fat). Differences in postprandial triglycerides were compared in those ≥50 and <50 years and by decade of life, adjusting for sex and BMI. Compared to those <50 years, participants ≥50 years had higher fasting, 4 h, and Δ triglycerides from baseline (p's < 0.05). When examining triglyceride parameters by decade, no differences were observed for fasting triglycerides, but 50 s, 60 s, and 70s-80 s displayed greater 4 h and Δ triglycerides versus 20 s (p's ≤ 0.001). The frequency of adverse postprandial triglyceride responses (i.e., ≥220 mg/dL) was higher in participants ≥50 versus <50 years (p < 0.01), and in 60 s compared to all other decades (p = 0.01). CONCLUSION: Older age was generally associated with higher postprandial triglycerides, with no divergence across the spectrum of older adulthood. In our sample, postprandial triglyceride differences in older and younger adults were driven by those >50 years relative to young adults in their 20 s. REGISTRATION: N/A (secondary analysis).

Cardiorespiratory fitness and submaximal exercise dynamics in normal-weight obesity and metabolically healthy obesity.

PURPOSE: Cardiorespiratory fitness (CRF) is critical for cardiovascular health. Normal-weight obesity (NWO) and metabolically healthy obesity (MHO) may be at increased risk for cardiovascular disease, but a comparison of CRF and submaximal exercise dynamics against rigorously defined low- and high-risk groups is lacking. METHODS: Four groups (N = 40; 10/group) based on body mass index (BMI), body fat %, and metabolic syndrome (MetS) risk factors were recruited: healthy controls (CON; BMI 18.5-24.9 kg/m2, body fat < 25% [M] or < 35% [F], 0-1 risk factors), NWO (BMI 18.5-24.9 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F]), MHO (BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 0-1 risk factors), or metabolically unhealthy obesity (MUO; BMI > 30 kg/m2, body fat ≥ 25% [M] or ≥ 35% [F], 2 + risk factors). All participants completed a V ˙ O2peak test on a cycle ergometer. RESULTS: V ˙ O2peak was similarly low in NWO (27.0 ± 4.8 mL/kg/min), MHO (25.4 ± 6.7 mL/kg/min) and MUO (24.6 ± 10.0 mL/kg/min) relative to CON (44.2 ± 11.0 mL/kg/min) when normalized to total body mass (p's < 0.01), and adjusting for fat mass or lean mass did not alter these results. This same differential V ˙ O2 pattern was apparent beginning at 25% of the exercise test (PGroup*Time < 0.01). CONCLUSIONS: NWO and MHO had similar peak and submaximal CRF to MUO, despite some favorable health traits. Our work adds clarity to the notion that excess adiposity hinders CRF across BMI categories. CLINICALTRIALS: gov registration: NCT05008952.

Whole-body bone mineral density and markers of bone homeostasis in adults with normal-weight obesity.

Background: Normal-weight obesity (NWO) describes individuals with a normal body mass index (BMI), but high body fat percent. NWO are at-risk for cardiometabolic diseases, but little is known about their bone health. Methods: Adults (N = 24) were classified as NWO (n = 12; 5M/7F) or low body fat percent controls (Con; n = 12; 6M/6F). Body composition and whole-body bone mineral density (BMD) were assessed using DXA. A serum bioplex assay was performed to examine markers related to bone formation and resorption. Results: In addition to higher body fat percent and visceral fat, NWO had lower whole-body BMD relative to Con (p's < 0.05). Circulating leptin was higher in NWO than Con (p < 0.05). Two biomarkers generally associated with lower bone mass - sclerostin and parathyroid hormone - were higher in NWO compared to Con (p's < 0.05). Conclusion: In this preliminary study, adults with NWO displayed lower whole-body BMD alongside evidence of bone resorption. Impaired bone health may be another subclinical risk factor present in NWO.

Alzheimer's disease pathogenetic progression is associated with changes in regulated retained introns and editing of circular RNAs.

Introduction: The molecular changes leading to Alzheimer's disease (AD) progression are poorly understood. A decisive factor in the disease occurs when neurofibrillary tangles (NFT) composed of microtubule associated protein tau (MAPT) form in the entorhinal cortex and then spread throughout the brain. Methods: We therefore determined mRNA and circular RNA changes during AD progression, comparing Braak NFT stages I-VI. Total RNA was isolated from human brain (entorhinal and frontotemporal cortex). Poly(A)+ RNA was subjected to Nanopore sequencing, and total RNA was analyzed by standard Illumina sequencing. Circular RNAs were sequenced from RNase R treated and rRNA depleted total RNA. The sequences were analyzed using different bioinformatic tools, and expression constructs for circRNAs were analyzed in transfection experiments. Results: We detected 11,873 circRNAs of which 276 correlated with Braak NFT stages. Adenosine to inosine RNA editing increased about threefold in circRNAs during AD progression. Importantly, this correlation cannot be detected with mRNAs. CircMAN2A1 expression correlated with AD progression and transfection experiments indicated that RNA editing promoted its translation using start codons out of frame with linear mRNAs, which generates novel proteins. Discussion: Thus, we identified novel regulated retained introns that correlate with NFT Braak stages and provide evidence for a role of translated circRNAs in AD development.

Postprandial triglycerides, endothelial function, and inflammatory cytokines as potential candidates for early risk detection in normal-weight obesity.

PROBLEM: Normal-weight obesity (NWO) is associated with increased cardiovascular disease (CVD) risk. However, NWO's clinical presentation is often unremarkable based on common risk factors. We examined whether CVD risk factors not routinely measured clinically including postprandial triglycerides, flow-mediated dilation (FMD), and inflammatory cytokines would be abnormal in NWO, consistent with their future risk. METHODS: Individuals were recruited into 3 groups (n = 10/ group): controls (Con), NWO, and metabolic syndrome (MetS). Con was defined as a normal body mass index (BMI), < 25% (M) or < 35% (F) body fat, and < 1 International Diabetes Federation (IDF) criteria. NWO were above this body fat cutoff while maintaining a normal BMI and MetS was defined per the IDF. Participants underwent an abbreviated fat tolerance test (i.e., difference in fasting and 4 h triglycerides following a high-fat meal [9 kcal/kg; 73% fat)] and fasting and postprandial lipid and glucose metrics, as well as FMD were measured. A T cell cytokine bioplex was also performed using fasting serum. RESULTS: NWO and MetS had similar body fat% and both were higher than Con (p < 0.0001). Despite having similar fasting triglycerides to Con, NWO had 4-hour triglycerides 66% greater than Con, but 46% lower than MetS (p < 0.01). FMD decreased in all groups after the high-fat meal (p < 0.0001). MetS displayed lower fasting FMD than Con, and NWO was similar to both groups (p < 0.05). No group differences were observed with postprandial FMD and the majority of fasting cytokines assessed. However, MetS exhibited higher fasting TNF-α than Con (p < 0.05), and NWO was similar to both groups. CONCLUSIONS: Overall, NWO was associated with higher postprandial triglycerides than Con, but displayed little evidence of impaired vascular health or inflammation.

T-cell Metabolism as Interpreted in Obesity-associated Inflammation.

The appreciation of metabolic regulation of T-cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T-cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain underrepresented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work. We investigated primary papers cited by reviews found in these searches and highlighted recent work with >100 citations to illustrate the state of the art in understanding mechanisms that control metabolism and thus function of various T-cell subsets in obesity. However, "popularity" of a paper over the first 5 years after publication cannot assess long-term impact; thus, some likely important work with fewer citations is also highlighted. We feature studies of human cells, supplementing with studies from animal models that suggest future directions for human cell research. This approach identified gaps in the literature that will need to be filled before we can estimate efficacy of mitochondria-targeted drugs in clinical trials to alleviate pathogenesis of obesity-associated inflammation.

Rat Spinal Cord Injury Associated with Spasticity Leads to Widespread Changes in the Regulation of Retained Introns.

To determine molecular changes that correlate with long-term physiological changes after spinal cord injury associated with spasticity, we used a complete transection model with an injury at sacral spinal level S2, wherein tail spasms develop in rats weeks to months post-injury. Using Illumina and nanopore sequencing, we found that from 12,266 expressed genes roughly 11% (1,342) change expression levels in the rats with spasticity. The transcription factor PU.1 (Spi-1 proto-oncogene) and several of its known regulated genes were upregulated during injury, possibly reflecting changes in cellular composition. In contrast to widespread changes in gene expression, only a few changes in alternative exon usage could be detected because of injury. There were more than 1,000 changes in retained intron usage, however. Unexpectedly, most of these retained introns have not been described yet but could be validated using direct RNA nanopore sequencing. In addition to changes from injury, our model allowed regional analysis of gene expression. Comparing the segments rostral and caudal to the injury site in naïve animals showed 525 differentially regulated genes and differential regional use of retained introns. We did not detect changes in the serotonin receptor 2C editing that were implicated previously in this spinal cord injury model. Our data suggest that regulation of intron retention of polyadenylated pre-mRNA is an important regulatory mechanism in the spinal cord under both physiological and pathophysiological conditions.

Comparison of a Standardized High-Fat Meal versus a High-Fat Meal Scaled to Body Mass for Measuring Postprandial Triglycerides: A Randomized Crossover Study.

Post-meal triglycerides are an independent cardiovascular disease (CVD) risk factor, but the ideal high-fat meal formulation has yet to be standardized and is one challenge prohibiting widespread clinical adoption of postprandial triglyceride assessment. Two general approaches often used are giving individuals a high-fat meal scaled to body weight or a standardized high-fat meal containing a set fat bolus. A recent expert panel statement has endorsed the latter, specifying 75 g of fat as an appropriate fat dosage. Despite this recommendation, no study to date has tested whether there is a difference in postprandial triglycerides or if risk classification is affected based on these different approaches. We recruited 16 generally healthy individuals with roughly equal distribution among body mass index (BMI)class (n = 5-6/per BMI category) and sex (n = 2-3 M/F) within each BMI class. Each participant underwent two abbreviated fat tolerance tests separated by ~1 week: one with a scaled to body weight high-fat meal (9 kcal/kg; 70% fat) and a standardized meal containing 75 g of fat (70% fat). Fasting, 4 h, and absolute change in triglycerides across the entire sample and within each BMI category were similar regardless of high-fat meal. Only one participant with obesity had discordant postprandial responses between the fat tolerance tests (i.e., different CVD risk classification). These findings suggest that, within a certain range of fat intake, generally healthy individuals will have a similar postprandial triglyceride response. Considering the greater convenience of utilizing standardized high-fat meals, our data suggest that a standardized high-fat meal may be acceptable for large-scale studies and clinical implementation.

Identifying Interventions and Their Efficacy as Used by a Community Agency Managing and Responding to Elder Abuse.

Limited research has been conducted to identify how elder abuse (EA) can be managed and prevented. Interventions employed by a community agency multidisciplinary team across 164 EA cases were examined. Results identified the largest number (N = 369) and widest variety of EA interventions to date. Using content analysis, interventions with similar proximal goals were grouped into 30 intervention strategies to evaluate efficacy and 12 higher-order intervention categories to guide practice. Intervention outcomes were rated as positive, negative, neutral, could not implement, or unknown. Positive outcomes were the most common (35%), and also included novel and/or effective interventions aimed at perpetrators such as physical treatment, social support, and communication. Few (1%) interventions had negative outcomes. Many interventions could not be implemented (21%), often due to a lack of funding or victim refusal. Results suggest changes to policy, practice, and research methodology, which could increase positive outcomes through facilitation of intervention implementation and improved data access.

Successful management of persistent tachycardia using esmolol in 2 dogs with septic shock.

OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short-acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4-year-old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7-year-old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long-term follow-up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.

Suspected Compartment Syndrome, Consumptive Thrombocytopenia, and Anemia Secondary to a Ruptured Arterial Aneurysm or Pseudoaneurysm Following Multiple Stifle Surgeries.

A 12 yr old male neutered beagle was presented on transfer to the intensive care unit with severe anemia, thrombocytopenia, and bruising detected 1 day after undergoing tibial plateau leveling osteotomy surgery. The patient had undergone extra-capsular stifle stabilization surgery 14 wk prior to treat ligament disease in the same knee. Laboratory testing and treatment for anemia, presumptive immune-mediated thrombocytopenia, and possible hemostatic disorder was initiated. A persistent anemia, progressive thrombocytopenia, and the development of a firm swelling and neurologic impairment in the limb raised concerns for compartment syndrome (CS). A musculoskeletal ultrasound revealed a large aneurysm in the caudal thigh surrounded by abnormal muscle tissue. The patient underwent amputation of the limb and recovered without further complication. Pathology findings were consistent with the development of femoral CS secondary to a ruptured peripheral arterial aneurysm or a pseudoaneurysm. A consumptive thrombocytopenia and regenerative anemia were attributed to periodic or progressive thrombosis of the vessel and regional hemorrhage. Postoperative CS can develop in combination with peripheral arterial aneurysm or pseudoaneurysm, and screening for vascular abnormalities as well as CS should be considered in complicated recovery from orthopedic surgery with compatible clinical signs including progressive soft tissue swelling, persistent anemia, and thrombocytopenia.

Emulsion droplet crystallinity attenuates early in vitro digestive lipolysis and beta-carotene bioaccessibility.

The impacts of lipid crystallinity on in vitro digestive lipolysis and bioaccessibility of encapsulated (0.1 wt%) beta-carotene (BC) were investigated for a 15 wt% cocoa butter emulsion prepared as crystalline (i.e. solid emulsions, SE & SE-BC) or undercooled (liquid emulsions, LE & LE-BC) droplets at 25 °C. Particle size distributions (D4,3 ∼0.7 µm), morphology (spherical), polymorphism (beta-V), thermal behavior (peak melting ∼30 °C), zeta potential (∼-44 mV) and BC degradation under accelerated lighting conditions were similarly extensive. Following exposure to simulated gastric conditions, duodenal hydrolysis and BC bioaccessibility were lower for SE-BC up to 2 h (P < 0.05). Ultimately, samples with both solid and liquid droplets were hydrolyzed extensively and BC bioaccessibility did not differ (P > 0.05). Therefore, for compositionally equivalent emulsions, lipid droplet solid state delayed digestive lipolysis and bioactive solubilization. These results help to clarify the role of lipid physical state on dietary lipid digestion and bioactive release.

Suspected drug-induced infiltrative lung disease culminating in acute respiratory failure in a dog treated with cytarabine and prednisone.

OBJECTIVE: To describe a case of suspected drug-induced infiltrative lung disease (ILD) and acute respiratory failure associated with the administration of cytarabine and prednisone in a dog requiring mechanical ventilation. CASE SUMMARY: A 4.5-year-old, female spayed Yorkshire Terrier presented to the ICU with acute onset of respiratory distress following a 24-hour cytarabine infusion. The patient was previously diagnosed with meningoencephalitis of unknown etiology (MUO), caudal occipital malformation, and syringohydromyelia, and was being treated with oral prednisone and levetiracetam, and cytarabine infusions. The patient developed tachypnea and dyspnea, and had diffuse crackles on auscultation of all lung fields, and hypoxemia 6 hours following completion of the fourth cytarabine infusion (300 mg/m2 ). Thoracic radiographs revealed diffuse, bilateral infiltrates consistent with noncardiogenic pulmonary edema or acute respiratory distress syndrome. Respiratory distress and hypoxemia persisted despite oxygen supplementation and furosemide therapy and led to initiation of mechanical ventilation. Approximately 12 hours later, the dog became progressively hypoxemic with worsening pulmonary edema. The owners elected euthanasia. Postmortem examination revealed pulmonary edema and diffuse interstitial pneumonia. Histopathologic evaluation revealed pulmonary edema, severe acute neutrophilic and histiocytic pneumonia, and multifocal interstitial fibrosis. Bacterial culture yielded no growth. NEW OR UNIQUE INFORMATION PROVIDED: Drug-induced ILD is rarely reported in the veterinary literature, and has not previously been reported in dogs receiving cytarabine. As with administration of any medication, adverse events may occur. While ILD is unlikely to be commonly recognized, it may be considered in veterinary patients receiving chemotherapy that acutely become dyspneic.

The activity and inhibition of poly(ADP-ribose) polymerase-1 in equine peripheral blood mononuclear cells in vitro.

OBJECTIVES: To evaluate the poly (ADP-ribose) polymerase-1 (PARP1) enzyme and its inhibition in horses and explore its potential as a novel therapeutic target for equine intestinal ischemia-reperfusion injury by (1) identifying poly (ADP-ribose) (PAR) as an indication of PARP1 activation in equine cells using available immunoblot analytical techniques, (2) inducing PARP1 activation in an in vitro oxidative DNA damage model, (3) and demonstrating the inhibition of PARP1 in equine cells using commercially available PARP1 inhibitors. DESIGN: Experimental study. ANIMALS: Blood samples were collected from systemically healthy ponies (n = 3) and horses (n = 3). INTERVENTIONS: (1) Equine peripheral blood mononuclear cells were exposed to 3 different concentrations of hydrogen peroxide (H2 O2 ) and were lysed at specific time points. PARP1 activity was then assessed by using immunoblot analyses to determine PAR levels. (2) Equine peripheral blood mononuclear cells were preincubated with defined concentrations of PARP1 inhibitors prior to H2 O2 -mediated PARP1 stimulation. PAR levels reflecting PARP1 activity were determined using immunoblot analyses. MEASUREMENTS AND MAIN RESULTS: Commercially available anti-PAR antibodies were used successfully to identify equine PAR. There was a significant increase in PAR accumulation following treatment with H2 O2 . All of the tested PARP inhibitors significantly reduced PAR accumulation to or below basal levels following treatment with H2 O2 . CONCLUSIONS: This proof of principle study demonstrated that PAR, an indicator of PARP1 activity, can be identified in the equine species using immunoblot techniques, that equine PARP1 can be activated by H2 O2 -induced DNA damage, and that this activation can be inhibited by PARP1 enzyme inhibitors. The data suggest that the PARP1 pathway plays a role in the equine cellular response to oxidative DNA damage and supports its potential as a novel therapeutic target. Further research documenting an increase in PAR levels in vivo and the efficacy of PARP1 inhibitors in an equine intestinal ischemia-reperfusion model is needed.

Impact of colic surgery on return to function in racing Thoroughbreds: 59 cases (1996-2009).

OBJECTIVE: To determine the effect of colic surgery on return to function in Thoroughbred racehorses, identify clinical variables associated with successful return to racing, and compare racing performance between horses undergoing colic surgery and an untreated cohort. DESIGN: Retrospective cohort study. ANIMALS: 59 Thoroughbred racehorses 2 to 5 years of age that underwent colic surgery and survived to hospital discharge and 90 untreated Thoroughbred racehorses equivalent in class. PROCEDURES: Medical records of patients evaluated for colic between January 1996 and July 2009 were reviewed, and horses with a Jockey Club Information Systems record were included. Physical examination and laboratory findings on hospital admission, lesion location and type, duration of surgery, duration of hospitalization, and any postoperative complications were recorded. The untreated cohort comprised 2 untreated horses randomly selected from runners in each treated horse's last race immediately prior to the date of colic surgery. Records were obtained from the Jockey Club Information Systems in April 2011. Only horses that raced at least once before and after surgery were included in the performance analysis. Number of starts, earnings per start, and total earnings were determined from race records for all horses. Quarterly earnings and number of starts for 12 quarters following the date of surgery were compared between treated and untreated horses via a Wilcoxon rank sum test. Longevity of racing was assessed by means of survival analysis. Poisson regression was used to compare rates of return to racing and active quarters aggregated across the first 12 quarters after surgery and for the available follow-up period for treated and untreated horses. RESULTS: 45 of 59 (76%) horses that raced prior to surgery returned to racing. Return to racing was significantly associated with admission heart rate and blood lactate concentration. From quarters 3 to 12, treated and untreated horses had slight differences in the number of starts but no difference in earnings per quarter. Treated and untreated horses had no difference in total number of quarters raced, number of starts, or earnings after surgery. Treated horses had higher earnings per start, compared with untreated horses. CONCLUSIONS AND CLINICAL RELEVANCE: In the present study, racing Thoroughbreds that underwent colic surgery and successfully returned to racing had no differences in performance variables, compared with their untreated cohorts.

Diaphragmatic hernia in horses: 44 cases (1986-2006).

OBJECTIVES: To present a case series of horses diagnosed with diaphragmatic hernia, and to determine the significance of (1) historical information, examination findings, and laboratory data; and (2) exploratory laparotomy or necropsy findings on short- and long-term outcome. SETTING: University Referral Hospital. DESIGN: Retrospective study. ANIMALS: Forty-four horses/foals admitted between 1986 and 2006 with a diagnosis of diaphragmatic hernia made either at exploratory laparotomy or necropsy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Information from the medical records included history, clinical examination findings at presentation, and findings of exploratory laparotomy or necropsy. Logistic regression or the Fisher exact test was used to determine factors associated with survival. Outcome was defined as survival to discharge (short-term survival), and long-term survival was defined as horses alive at least 1-year post surgery. Of the 44 horses, 18 died or were euthanized before surgery. Twenty-six were taken to surgery, 17 were euthanized. Nine horses recovered from anesthesia, 7 of which survived to hospital discharge. Of these, 5 were alive at long-term follow-up. Survival was significantly associated with the age of the horse (≤2 y old) at presentation, presence of normal peritoneal fluid at presentation, amount of compromised viscera at surgery (<50% small intestine), and the size (<10 cm) and location (ventral) of the diaphragmatic tear. CONCLUSION: This study confirms that size and location of the lesion do play a significant role in prognosis. And, although the prognosis for horses with diaphragmatic hernia is poor, if horses have operable lesions there is a fair prognosis for long-term survival.