Publications by authors named "Umar F Bhatti"

37 Publications

Delay in Hip Fracture Repair in the Elderly: A Missed Opportunity Towards Achieving Better Outcomes.

J Surg Res 2021 May 11;266:142-147. Epub 2021 May 11.

Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan. Electronic address:

Background: Hip fractures are a major cause of morbidity and mortality in the elderly. The American Academy of Orthopedic Surgeons (AAOS) recommends surgical repair within 48 hours of admission, as this is associated with lower postoperative mortality and complications. This study demonstrates the association between patient demographics, level of care, and hospital region to delay in hip fracture repair in the elderly.

Methods: The National Trauma Data Bank (NTDB) was queried for elderly patients (age >65 years) who underwent proximal femoral fracture repair. Identified patients were subcategorized into two groups: hip fracture repair in <48 hours, and hip fracture repair > 48 hours after admission. Patient and hospital characteristics were collected. Outcome variables were timed from the day of admission to surgery and inpatient mortality.

Results: Out of 69,532 patients, 28,031 were included after inclusion criteria were applied. 23,470 (83.7%) patients underwent surgical repair within 48 hours. The overall median time to procedure was 21 (interquartile range [IQR] 7-38) hours. Females were less likely to undergo a delay in hip fracture repair (odds ratio [OR; 95% confidence interval {CI}]: 0.82 [0.76-0.88], P< 0.05), and patients with higher Injury Severity Score (ISS ≥25) had higher odds of delay in surgical repair (OR; 95% CI: 1.56 [1.07-2.29], P< 0.05). Patients treated at hospitals in the Western regions of the United States had lower odds of delay, and those treated in the Northeast and the South had higher odds of delay compared to the hospitals in the Midwest (taken as standard). There was no association between trauma level designation and odds of undergoing delay in hip fracture repair.

Conclusion: Variables related to patient demographic and hospital characteristics are associated with delay in hip fracture repair in the elderly. This study delineates key determinants of delay in hip fracture repair in the elderly patients.
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http://dx.doi.org/10.1016/j.jss.2021.03.027DOI Listing
May 2021

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

J Surg Res 2021 May 11;266:125-141. Epub 2021 May 11.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan; Department of Surgery, Feinberg School of Medicine/Northwestern University, Chicago, Illinois. Electronic address:

Objective: Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants.

Methods: Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively.

Results: For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02).

Conclusions: VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.
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http://dx.doi.org/10.1016/j.jss.2021.03.025DOI Listing
May 2021

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia.

Trauma Surg Acute Care Open 2021 1;6(1):e000636. Epub 2021 Feb 1.

Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Background: Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.

Methods: Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.

Results: All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.

Conclusion: We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.

Level Of Evidence: Not applicable. Animal study.
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http://dx.doi.org/10.1136/tsaco-2020-000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852924PMC
February 2021

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

J Trauma Acute Care Surg 2021 02;90(2):346-352

From the Department of Surgery (G.K.W., B.E.B., M.T.K., R.L.O., A.M.W., K.C., A.Z.S., U.F.B., C.A.V., H.B.A.), Department of Clinical Pharmacy (M.P.P.), and Section of Neuroradiology, Department of Radiology (A.S.), Michigan Medicine, University of Michigan, Ann Arbor, Michigan.

Background: Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock.

Methods: Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3.

Results: Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001).

Conclusion: In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.
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http://dx.doi.org/10.1097/TA.0000000000003036DOI Listing
February 2021

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

J Trauma Acute Care Surg 2021 03;90(3):507-514

From the Department of Surgery (U.F.B., I.S.D., A.M.W., V.C.N., B.E.B., A.S., R.L.O., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (U.F.B.), Washington University, St. Louis, Missouri; Department of Surgery (H.B.A.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Computational Medicine and Bioinformatics (A.K.), and Michigan Regional Comprehensive Metabolomics Resource Core (M.K.), University of Michigan Health System, Ann Arbor, Michigan.

Objective: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

Methods: We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).

Results: In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).

Conclusion: Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
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http://dx.doi.org/10.1097/TA.0000000000003026DOI Listing
March 2021

Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock.

Surg Infect (Larchmt) 2021 May 20;22(4):421-426. Epub 2020 Aug 20.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.
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http://dx.doi.org/10.1089/sur.2020.189DOI Listing
May 2021

Early treatment with exosomes following traumatic brain injury and hemorrhagic shock in a swine model promotes transcriptional changes associated with neuroprotection.

J Trauma Acute Care Surg 2020 09;89(3):536-543

From the Department of Surgery (A.M.W., U.F.B., B.E.B., S.E.D., R.G.K., Y.T., Z.W., M.T.K., G.K.W., B.L., Y.L., H.B.A.), Department of Computational Medicine and Bioinformatics (G.A.H.), University of Michigan, Ann Arbor; and Department of Neurology (B.B.), Henry Ford Hospital, Detroit, Michigan.

Background: We have shown that administration of mesenchymal stem cell-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy.

Methods: Yorkshire swine (40-45 kg) were subjected to a severe TBI (12-mm cortical impact) and hemorrhagic shock (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or exosomes suspended in LR (LR + EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Periinjured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA sequencing data analysis, and results compared between control and experimental groups.

Results: Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation, and nonneuronal cell proliferation contributing to reactive gliosis. Exosome treatment also significantly increased (p < 0.005) the genes that are associated with stability of blood-brain barrier.

Conclusions: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment for TBI is promising and requires further investigation for human translation.
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http://dx.doi.org/10.1097/TA.0000000000002815DOI Listing
September 2020

Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

J Trauma Acute Care Surg 2020 10;89(4):752-760

From the Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics. Dried plasma (DP) is a practical alternative to conventional blood products in austere settings, and valproic acid (VPA) improves survival in preclinical models of trauma and hemorrhage. We performed the current experiment to study the synergistic effects of VPA and DP and hypothesized that VPA treatment would decrease the fluid resuscitation requirements in p-DCR.

Methods: Female swine were subjected to 50% hemorrhage (associated with 20% survival using non-plasma-based p-DCR) and left unresuscitated for 1 hour to simulate medic response time. They were then randomized to receive VPA (150 mg/kg + DP 250 mL; DP-VPA group; n = 5) or DP alone (DP group; n = 6). All animals were resuscitated to a systolic blood pressure of 80 mm Hg with lactated Ringer according to the Tactical Combat Casualty Care Guidelines for 72 hours, after which packed red blood cells were transfused to simulate evacuation to higher levels of care.

Results: The DP-VPA group needed significantly (p = 0.002) less volume of lactated Ringer to reach and maintain the target systolic blood pressure. This would translate to a 4.3 L volume sparing effect for a 70-kg person.

Conclusion: Addition of a single dose of VPA significantly decreases the volume of resuscitation required in a p-DCR model.
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http://dx.doi.org/10.1097/TA.0000000000002876DOI Listing
October 2020

Higher Long-Term Quality of Life Metrics After VATS Lobectomy Compared to Robotic-Assisted Lobectomy.

Ann Thorac Surg 2020 Jun 26. Epub 2020 Jun 26.

University of Michigan Medical School, Ann Arbor, MI, USA; Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Robotic-assisted thoracic surgery (RATS) lung lobectomy has emerged as an alternative approach to video-assisted thoracoscopic surgery (VATS). Patient-reported outcomes (PROs) comparing these approaches have been limited.

Methods: At a single, high-volume academic center, patients undergoing VATS and RATS lobectomies for Stage I and II non-small cell lung cancer from 2014 to 2018 were evaluated. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), EORTC Quality of Life Questionnaire in Lung Cancer (QLQ-LC13), and Fear of Recurrence (FoR) survey were administered preoperatively, and at 1, 6 and 12 months post-operation. Raw scores underwent linear transformation (0-100 scale). Linear mixed-effects models were used for QoL and FoR score comparisons.

Results: 219 patients (139 VATS and 80 RATS) were included. RATS patients had longer (p < 0.05) operative times and a higher incidence (p < 0.05) of postoperative myocardial infarction compared to VATS patients. VATS patients reported higher (p < 0.05) QLQ-C30 summary scores postoperatively and at 12 months, including higher (p < 0.05) Social Functioning and Cognitive scores, and less (p < 0.05) appetite loss. VATS patients also reported decreased (p < 0.05) QLQ-LC13 symptom summary scores at 6 months postoperatively, including decreased (p < 0.05) dyspnea, neuropathy, and pain compared to RATS patients. VATS patients also reported lower (p < 0.05) FoR summary scores at 6 months post-operation.

Conclusions: VATS patients report improvement in select QoL and FoR measures following lobectomy. Further study comparing these two approaches is required.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.033DOI Listing
June 2020

Life on the battlefield: Valproic acid for combat applications.

J Trauma Acute Care Surg 2020 08;89(2S Suppl 2):S69-S76

From the Department of Surgery (R.R., M.K., U.F.B., G.W., B.B., H.B.A.), University of Michigan Health System, Ann Arbor, Michigan; United States Air Force, Medical Corps (R.R.), David Grant Medical Center, Travis AFB, California; and Department of Pharmacology (M.P.), University of Michigan, Ann Arbor, Michigan.

The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients not surviving long enough to obtain surgical care. As a result, there is a significant unmet need for a therapy that stimulates a "prosurvival phenotype" that counteracts the cellular pathophysiology of HS and TBI to prolong survival. Valproic acid (VPA), a well-established antiepileptic therapy for more than 50 years, has shown potential as one such prosurvival therapy. This review details how VPA's role as a nonselective histone deacetylase inhibitor induces cellular changes that promote survival and decrease cellular pathways that lead to cell death. The review comprehensively covers more than two decades worth of studies ranging from preclinical (mice, swine) to recent human clinical trials of the use of VPA in HS and TBI. Furthermore, it details the different mechanisms in which VPA alters gene expression, induces cytoprotective changes, attenuates platelet dysfunction, provides neuroprotection, and enhances survival in HS and TBI. Valproic acid shows real promise as a therapy that can induce the prosurvival phenotype in those injured during military conflict.
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http://dx.doi.org/10.1097/TA.0000000000002721DOI Listing
August 2020

Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock.

Inflammation 2020 Aug;43(4):1436-1445

Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.

Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.
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http://dx.doi.org/10.1007/s10753-020-01221-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384922PMC
August 2020

Early single-dose exosome treatment improves neurologic outcomes in a 7-day swine model of traumatic brain injury and hemorrhagic shock.

J Trauma Acute Care Surg 2020 08;89(2):388-396

From the Department of Surgery (A.M.W., Z.W., U.F.B., B.E.B., M.T.K., G.K.W., C.A.V., K.C., A.Z.S., Z.P., S.E.D., Y.T., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Xiangya 2nd Hospital of Central South University (Z.W.), Changsha, Hunan, China; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.

Background: Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7 days), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model.

Methods: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups.

Results: Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals.

Conclusion: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a 7-day period.
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http://dx.doi.org/10.1097/TA.0000000000002698DOI Listing
August 2020

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

J Trauma Acute Care Surg 2020 11;89(5):932-939

From the Department of Surgery (B.E.B., G.K.W., M.T.K., A.M.W., A.S., R.L.O., A.Z.S., K.C., U.F.B., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan.

Background: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

Methods: Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test.

Results: This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups.

Conclusion: A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.
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http://dx.doi.org/10.1097/TA.0000000000002677DOI Listing
November 2020

What's New in Shock, January 2020?

Shock 2020 01;53(1):1-4

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

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http://dx.doi.org/10.1097/SHK.0000000000001447DOI Listing
January 2020

Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.

J Trauma Acute Care Surg 2020 Feb;88(2):207-218

From the Department of Surgery (A.M.W., U.F.B., J.F.B., B.E.B., R.G.K., N.J.G., K.C., A.Z.S., S.E.D., zH.B.A.), Department of Neuropathology (A.A.), and Department of Bioinformatics and Computational Medicine (G.A.H.), University of Michigan, Ann Arbor; and Department of Neurology (B.B.), Henry Ford Health System, Detroit, Michigan.

Background: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity.

Methods: Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB.

Results: Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment.

Conclusion: In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.
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http://dx.doi.org/10.1097/TA.0000000000002563DOI Listing
February 2020

Peptidylarginine Deiminase 2 Knockout Improves Survival in hemorrhagic shock.

Shock 2020 10;54(4):458-463

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform-specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS.

Methods: HS: Pad2 and wild-type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over 7 days. Myocardial infarction (MI): Pad2 and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 h cardiac function and infarct size were measured.

Results: HS: Pad2 mice demonstrated 100% survival compared with 0% for WT mice (P = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2 compared with WT after 24 h. MI: WT mice demonstrated larger MI (75%) compared with Pad2 (60%) (P < 0.05). Pad2 had significantly higher ejection fraction and fractional shortening compared with WT (P < 0.05).

Conclusions: Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improves survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia, and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.
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http://dx.doi.org/10.1097/SHK.0000000000001489DOI Listing
October 2020

Comparative analysis of isoform-specific and non-selective histone deacetylase inhibitors in attenuating the intestinal damage after hemorrhagic shock.

Trauma Surg Acute Care Open 2019 17;4(1):e000321. Epub 2019 Sep 17.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Background: Isoform-specific histone deacetylase inhibitors (HDACIs) MC1568 and ACY1083 are comparable to the non-selective HDACI valproic acid (VPA) in improving survival in rodents undergoing lethal hemorrhage. However, the organ-specific properties of isoform-specific HDACIs have not been fully evaluated. Also, whether they can act synergistically is not known. We hypothesized that isoform-specific HDACIs are superior to VPA in attenuating intestinal injury and act synergistically when coadministered.

Methods: Sprague Dawley rats were hemorrhaged (40% of total blood volume) and randomized to receive (n=4 per group) (1) MC1568 (5 mg/kg), (2) ACY1083 (30 mg/kg), (3) MC1568+ACY1083 (combination: 5 mg/kg + 30 mg/kg, respectively), (4) VPA (250 mg/kg), or (5) normal saline (NS; vehicle; 250 μL). Animals were observed for 3 hours, after which blood samples were collected and samples of the ileum were harvested. Expression of interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) was assessed in the tissues using enzyme-linked immunosorbent assay. Intestinal cleaved caspase 3 (c-caspase 3) levels were assessed as a marker of apoptosis, and histologic sections of the ileum were examined for signs of bowel injury. Levels of IL-1β and TNF-α were also measured in the serum as global markers of inflammation.

Results: Treatments with MC1568, ACY1083, MC1568+ACY1083, and VPA were associated with decreased IL-1β levels in the intestine and serum compared with NS. IL-1β and TNF-α levels were significantly lower in the ACY1083 group compared with the VPA group. CINC-1 levels were significantly lower in the isoform-specific HDACI groups compared with the NS; however, no significant differences were seen with VPA. All treatment groups had a lower expression of intestinal c-caspase 3 compared with NS. Furthermore, MC1568 and ACY1083 groups had lower apoptosis compared with the VPA group. Bowel injury scores were significantly lower in the isoform-specific HDACI groups compared with the NS group; however, the attenuation in the VPA-treated animals did not reach statistical significance.

Discussion: Isoform-specific HDACIs provide superior intestinal protection compared with VPA in a rodent model of hemorrhagic shock.

Level Of Evidence: Preclinical study.
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http://dx.doi.org/10.1136/tsaco-2019-000321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804098PMC
September 2019

The 'Omics' of Epigenetic Modulation by Valproic Acid Treatment in Traumatic Brain Injury-What We Know and What the Future Holds.

Proteomics Clin Appl 2019 11 6;13(6):e1900068. Epub 2019 Sep 6.

Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Traumatic brain injury (TBI) is a heterogeneous injury that is a major cause of morbidity and mortality worldwide. Epigenetic modulation through the alteration of cellular acetylation by valproic acid (VPA) administration has shown promise as a novel pharmacological treatment for TBI. It improves clinical outcomes through multiple mechanisms, many of which are still poorly understood. In recent years, omics technologies have emerged as a promising strategy to detect molecular changes at the cellular level. This review highlights the use of these high throughput technologies in advancing the understanding of epigenetic modulation by VPA in TBI. It also describes the future role of omics techniques in developing a point of care test to guide patient selection for VPA administration.
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http://dx.doi.org/10.1002/prca.201900068DOI Listing
November 2019

Defining the Burden of Emergency General Surgery in Transplant Patients: A Nationwide Examination.

J Surg Res 2020 01 14;245:315-320. Epub 2019 Aug 14.

Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Transplant patients are at the risk of serious sequelae from medical and surgical intervention. The incidence and burden of emergency general surgery (EGS) in transplant patients are scarcely known. This study aims to identify predictors of outcomes in transplant patients with EGS needs.

Methods: The Nationwide Inpatient Sample (2007-2011) was queried for adult patients (aged ≥16 y) who underwent abdominal visceral transplantation. These were further queried for a secondary diagnosis of an American Association for the Surgery of Trauma-defined EGS condition. Outcome measures included mortality, complications, length of stay, and cost of care. Propensity scores were used to match patients across baseline characteristics. Multivariate analysis was used to further adjust propensity score quintiles and hospital-level characteristics.

Results: A total of 35,573 transplant patients were identified. Of these, 30% (n = 10,676) developed an EGS condition. Most common EGS conditions were resuscitation (7.7%), intestinal obstruction (7.3%), biliary conditions (3.9%), and hernias (3.2%). Patients with public insurance, those in the highest income quartile, and those treated at larger hospitals had a lower likelihood of developing an EGS condition (P < 0.05). Patients with an EGS condition had a ninefold higher likelihood of mortality and a threefold higher likelihood of developing complications (odds ratio [95% confidence interval (CI)]: 9.21 [1.80-10.89] and 3.17 [3.02-3.34], respectively). Transplant patients after EGS had a longer risk-adjusted length of stay and cost of index hospitalization (Absolute difference [95% CI]: 12.70 [12.14-13.26] and $57,797 [55,415-60,179], respectively]).

Conclusions: Transplant patients fare poorly after developing an EGS condition. The results of this study will help in identifying at-risk patients and determining outcomes.
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http://dx.doi.org/10.1016/j.jss.2019.07.054DOI Listing
January 2020

Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine.

J Trauma Acute Care Surg 2019 11;87(5):1133-1139

From the Department of Surgery (B.E.B., A.M.W., I.S.D., N.J.G., K.C., A.Z.S., R.L.O., U.F.B., B.L., R.M.R., Y.L., H.B.A.), and Department of Clinical Pharmacy (M.P.P.), University of Michigan, Ann Arbor, Michigan.

Background: Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300-400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries.

Methods: Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test.

Results: Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05).

Conclusion: A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects.

Level Of Evidence: Therapeutic, level V.
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http://dx.doi.org/10.1097/TA.0000000000002460DOI Listing
November 2019

Inhibition of Histone Deacetylase 6 Protects Hippocampal Cells Against Mitochondria-mediated Apoptosis in a Model of Severe Oxygen-glucose Deprivation.

Curr Mol Med 2019 ;19(9):673-682

Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States.

Background: Histone deacetylase (HDAC) 6 inhibitors have demonstrated significant protective effects in traumatic injuries. However, their roles in neuroprotection and underlying mechanisms are poorly understood. This study sought to investigate the neuroprotective effects of Tubastatin A (Tub-A), an HDAC6 inhibitor, during oxygenglucose deprivation (OGD) in HT22 hippocampal cells.

Methods: HT22 hippocampal cells were exposed to OGD. Cell viability and cytotoxicity were assessed by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assay. Cellular apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mitochondria membrane potential was detected using JC-1 dye. Expressions of acetylated α-tubulin, α-tubulin, cytochrome c, VDAC, Bax, Bcl- 2, cleaved caspase 3, phosphorylated Akt, Akt, phosphorylated GSK3β and GSK3β were analyzed by Western blot analysis.

Results: Tub-A induced acetylation of α-tubulin, demonstrating appropriate efficacy. Tub-A significantly increased cell viability and attenuated LDH release after exposure to OGD. Furthermore, Tub-A treatment blunted the increase in TUNEL-positive cells following OGD and preserved the mitochondrial membrane potential. Tub-A also attenuated the release of cytochrome c from the mitochondria into the cytoplasm and suppressed the ratio of Bax/Bcl-2 and cleaved caspase 3. This was mediated, in part, by the increased phosphorylation of Akt and GSK3β signaling pathways.

Conclusion: HDAC 6 inhibition, using Tub-A, protects against OGD-induced injury in HT22 cells by modulating Akt/GSK3β signaling and inhibiting mitochondria-mediated apoptosis.
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http://dx.doi.org/10.2174/1566524019666190724102755DOI Listing
August 2020

Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

J Trauma Acute Care Surg 2019 08;87(2):393-401

From the Department of Surgery (A.M.W., U.F.B., B.E.B., N.J.G., K.C., J.Z., I.S.D., R.G.K., C.A.V., R.M.R., Y.L., H.B.A.), University of Michigan Health System, Ann Arbor, Michigan; and Trauma Center, Department of Orthopedics and Traumatology (J.Z.), Peking University People's Hospital, Beijing, China.

Background: Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes.

Methods: Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes.

Results: This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels.

Conclusion: VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.
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http://dx.doi.org/10.1097/TA.0000000000002281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660397PMC
August 2019

Four-extremity amputation following disseminated intravascular coagulation and purpura fulminans.

BMJ Case Rep 2019 Mar 20;12(3). Epub 2019 Mar 20.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Purpura fulminans (PF) is a rare but serious complication of septic shock in adults. The complex disease course makes it challenging to manage the condition. Here, we present the case of a healthy young woman who presented with sepsis and new-onset erythematous lesions 4 days after the vaginal delivery of a healthy baby. The infectious source could not be identified, and the patient was started on antibiotics and resuscitated. However, her condition worsened, and she developed disseminated intravascular coagulation and PF. The septic episode slowly decreased in severity, but she sustained extensive ischaemic injuries to her extremities, for which she underwent four-limb amputation.
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http://dx.doi.org/10.1136/bcr-2018-228028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453384PMC
March 2019

The impact of intraoperative fluid management during laparoscopic donor nephrectomy on donor and recipient outcomes.

Clin Transplant 2019 06 29;33(6):e13542. Epub 2019 Apr 29.

Division of Transplantation, Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: Intraoperative fluid management during laparoscopic donor nephrectomy (LDN) may have a significant effect on donor and recipient outcomes. We sought to quantify variability in fluid management and investigate its impact on donor and recipient outcomes.

Methods: A retrospective review of patients who underwent LDN from July 2011 to January 2016 with paired kidney recipients at a single center was performed. Patients were divided into tertiles of intraoperative fluid management (standard, high, and aggressive). Donor and recipient demographics, intraoperative data, and postoperative outcomes were analyzed.

Results: Overall, 413 paired kidney donors and recipients were identified. Intraoperative fluid management (mL/h) was highly variable with no correlation to donor weight (kg) (R = 0.017). The aggressive fluid management group had significantly lower recipient creatinine levels on postoperative day 1. However, no significant differences were noted in creatinine levels out to 6 months between groups. No significant differences were noted in recipient postoperative complications, graft loss, and death. There was a significant increase (P < 0.01) in the number of total donor complications in the aggressive fluid management group.

Conclusions: Aggressive fluid management during LDN does not improve recipient outcomes and may worsen donor outcomes compared to standard fluid management.
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http://dx.doi.org/10.1111/ctr.13542DOI Listing
June 2019

Histone Deacetylase Inhibition Attenuates Cardiomyocyte Hypoxia-Reoxygenation Injury.

Curr Mol Med 2018 ;18(10):711-718

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, United States.

Background: Cardiac reperfusion injury can have devastating consequences. Histone deacetylase (HDAC) inhibitors are potent cytoprotective agents, but their role in the prevention of cardiac injury remains ill-defined.

Objective: We sought to determine the therapeutic potential of HDAC inhibitors in an in vitro model of cardiomyocyte hypoxia-reoxygenation (H/R).

Method: H9c2 cardiomyocytes were subjected to H/R and treated with various classspecific and pan-HDAC inhibitors in equal concentrations (5µM). Biological activity of inhibitors was determined, as a proxy for concentration adequacy, by Western blot for acetylated histone H3 and α-tubulin. Cell viability and cytotoxicity were measured by methyl thiazolyl tetrazolium and lactate dehydrogenase assays, respectively. Mechanistic studies were performed to better define the effects of the most effective agent, Tubastatin-A (Tub-A), on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway effectors, and on the degree of autophagy.

Results: All inhibitors acetylated well-known target proteins (histone H3 and α-tubulin), suggesting that concentrations were adequate to induce a biological effect. Improved cell viability and decreased cell cytotoxicity were noted in cardiomyocytes exposed to Tub-A, whereas the cytoprotective effects of other HDAC inhibitors were inconsistent. Pro-survival mediators in the PI3K/mTOR pathway were up-regulated and the degree of autophagy was significantly attenuated in cells that were treated with Tub-A.

Conclusion: HDAC inhibitors improve cell viability in a model of cardiomyocyte H/R, with Class IIb inhibition (Tub-A) demonstrating superior cellular-level potency and effectiveness. This effect is, at least in part, related to an increased expression of prosurvival mediators and a decreased degree of autophagy.
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http://dx.doi.org/10.2174/1566524019666190208102729DOI Listing
October 2019

Valproic Acid and Neural Apoptosis, Inflammation, and Degeneration 30 Days after Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma in a Swine Model.

J Am Coll Surg 2019 03 9;228(3):265-275. Epub 2019 Jan 9.

Department of Surgery, University of Michigan Health System, Ann Arbor, MI. Electronic address:

Background: A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated.

Study Design: Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume = 3× hemorrhaged volume) or NS + VPA (150 mg/kg) (n = 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated.

Results: For apoptosis, VPA treatment significantly decreased (p < 0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-β, and phosphorylated-Tau protein were significantly attenuated (p < 0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p < 0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p < 0.05) and cytosolic IκBα expression was increased significantly (p < 0.05) in the VPA-treated animals compared with the NS group.

Conclusions: Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.
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http://dx.doi.org/10.1016/j.jamcollsurg.2018.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589830PMC
March 2019

The heavy price of conversion from laparoscopic to open procedures for emergent cholecystectomies.

Am J Surg 2019 04 21;217(4):732-738. Epub 2018 Dec 21.

Department of Surgery, Howard University Hospital and College of Medicine, Washington, DC, USA. Electronic address:

Background: Laparoscopic cholecystectomy (LC) is the standard operative intervention for gallbladder disease. Complications may necessitate conversion to an open cholecystectomy (OC). This study aims to determine the cost-consequences of laparoscopic-to-open conversion using a nationally-representative sample.

Methods: Using the National Inpatient Sample (2007-2011), adult patients undergoing emergent LC were identified. Patients undergoing secondary-conversion to OC were subsequently identified. Multivariable regression analyses, accounting for differences in propensity-quintile, mortality, length of stay, and hospital-level factors were then performed to assess for differences in the odds of conversion and total predicted mean costs per index-hospitalization.

Results: Of 225,805 observations, conversion to open occurred in 1.86% (n = 4203) of cases. Increased age, African-American ethnicity, public-insurance and teaching-hospital status were associated with a higher likelihood of conversion (p < 0.05) after risk-adjustment. Risk-adjusted odds of conversion increased by 34% (95%CI:1.33-1.36) for each day surgery was delayed. Risk-adjusted costs, were 259% higher (absolute-difference $23,358,p < 0.05) with conversion. Mortality was higher amongst patients undergoing conversion to open (4.98% vs 0.34%,p < 0.001).

Conclusion: Patients undergoing conversion from laparoscopic to open cholecystectomy are at an increased risk of receiving disparate care and increased mortality.
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http://dx.doi.org/10.1016/j.amjsurg.2018.12.038DOI Listing
April 2019

Traumatic brain injury may worsen clinical outcomes after prolonged partial resuscitative endovascular balloon occlusion of the aorta in severe hemorrhagic shock model.

J Trauma Acute Care Surg 2019 03;86(3):415-423

From the Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: The use of partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) in combined hemorrhagic shock (HS) and traumatic brain injury (TBI) has not been well studied. We hypothesized that the use of pREBOA in the setting of TBI would be associated with worse clinical outcomes.

Methods: Female Yorkshire swine were randomized to the following groups: HS-TBI, HS-TBI-pREBOA, and HS-pREBOA (n = 5/cohort). Animals in the HS-TBI group were left in shock for a total of 2 hours, whereas animals assigned to pREBOA groups were treated with supraceliac pREBOA deployment (60 minutes) 1 hour into the shock period. All animals were then resuscitated, and physiologic parameters were monitored for 6 hours. Further fluid resuscitation and vasopressors were administered as needed. At the end of the observation period, brain hemispheric swelling (%) and lesion size (mm) were assessed.

Results: Mortality was highest in the HS-TBI-pREBOA group (40% [2/5] vs. 0% [0/5] in the other groups, p = 0.1). Severity of shock was greatest in the HS-TBI-pREBOA group, as defined by peak lactate levels and pH nadir (p < 0.05). Fluid resuscitation and norepinephrine requirements were significantly higher in the HS-TBI-pREBOA group (p < 0.05). No significant differences were noted in brain hemispheric swelling and lesion size between the groups.

Conclusion: Prolonged application of pREBOA in the setting of TBI does not contribute to early worsening of brain lesion size and edema. However, the addition of TBI to HS-pREBOA may worsen the severity of shock. Providers should be aware of the potential physiologic sequelae induced by TBI.
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http://dx.doi.org/10.1097/TA.0000000000002149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715315PMC
March 2019

Histone Deacetylase Inhibitors: A Novel Strategy in Trauma and Sepsis.

Shock 2019 09;52(3):300-306

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Trauma remains a leading cause of morbidity and mortality among all age groups in the United States. Hemorrhagic shock and traumatic brain injury (TBI) are major causes of preventable death in trauma. Initial treatment involves fluid resuscitation to improve the intravascular volume. Although crystalloids may provide volume expansion, they do not have any pro-survival properties. Furthermore, aggressive fluid resuscitation can provoke a severe inflammatory response and worsen clinical outcomes. Due to logistical constraints, however, definitive resuscitation with blood products is often not feasible in the prehospital setting-highlighting the importance of adjunctive therapies. In recent years, histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. In this review, we discuss the role of histone deacetylases (HDACs) and pharmacologic agents that inhibit them (HDACis). We also highlight the therapeutic effects and mechanisms of action of HDACis in hemorrhagic shock, TBI, polytrauma, and sepsis. With further investigation and translation, HDACis have the potential to be a high-impact adjunctive therapy to traditional resuscitation.
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http://dx.doi.org/10.1097/SHK.0000000000001308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588509PMC
September 2019

Inhibition of histone deacetylase 6 attenuates intestinal inflammation and apoptosis in a rodent model of hemorrhagic shock.

J Trauma Acute Care Surg 2019 05;86(5):874-880

From the Trauma Medicine Center (P.C.), Peking University People's Hospital, Beijing, China; and Department of Surgery (P.C., U.F.B., A.M.W., I.S.D., B.L., Y.L., H.B.A.), University of Michigan Health System, Ann Arbor, Michigan.

Background: Intestinal inflammation is a mediator of multiorgan failure in trauma. We have previously shown that histone deacetylase (HDAC6) inhibitors, including ACY1083, improve survival and preserve intestinal tight junction integrity in a rodent model of hemorrhagic shock (HS). However, mechanisms leading to this alleviation in intestinal injury remain poorly defined. In this study, we sought to determine whether HDAC6 inhibition by ACY1083 can attenuate intestinal inflammation and apoptosis in rats subjected to HS.

Methods: Sprague Dawley rats were subjected to hemorrhage (40% of total blood volume) followed by intravenous injection of either ACY1083 (30 mg/kg) dissolved in cyclodextrin or cyclodextrin only (vehicle group). Three hours after hemorrhage, blood samples were collected, and small bowel was harvested. Histological effects of ACY1083 on small bowel were examined. Myeloperoxidase (MPO) levels were assessed as a marker for neutrophil infiltration. Whole cell lysates were analyzed for acetylated α-tubulin, metalloproteinase (ADAM) 17, TNF-α, IL-6, and cleaved caspase 3 using Western blot. The levels of ADAM17, TNF-α, and IL-6 in serum were also examined using enzyme-linked immunosorbent assay.

Results: ACY1083 treatment significantly attenuated HS-induced intestinal injury and MPO production. Both systemic and intestinal TNF-α and IL-6 levels were attenuated following ACY1083 administration. Increased acetylation of α-tubulin was observed in rats treated with ACY1083, along with a significantly decreased expression of cleaved caspase 3 following hemorrhage.

Conclusion: Inhibition of HDAC6 with ACY1083 provides intestinal protection by attenuating both the inflammatory and apoptotic responses during HS.
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http://dx.doi.org/10.1097/TA.0000000000002169DOI Listing
May 2019