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Following the reopening of elective surgery, our division transitioned from inpatient admission to same-day discharge for immediate prosthetic breast reconstruction in an effort to decrease the hospital's clinical burden and minimize potential COVID-19 exposure. This study aims to compare complication rates following this acute transition for patients who had inpatient and outpatient mastectomy with immediate alloplastic reconstruction.A retrospective chart review was performed on patients who underwent mastectomy with immediate prosthetic reconstruction. The outcome of interest was 30-day morbidity. Descriptive statistics were compared for patients with outpatient and inpatient surgeries. Odds ratios were calculated to determine whether any pre-operative factors increased odds of 30-day complications.A total of 115 patients were included in this study. Twenty-six patients had outpatient surgery and 89 stayed inpatient postoperatively. Same-day discharge did not significantly impact the odds of having one or more 30-day complications (OR: 0.275, 95% CI: 0.047-1.618, p = 0.153). Patients with complications had significantly longer median operating times (5.0, IQR 4.0 - 6.0 vs. 4.0, IQR 3.0 - 5.0, p = 0.05), and there was a statistically significant association between length of surgery and odds of complication (OR: 1.596, 95% CI: 1.039-2.451, p = 0.033). Age was independently associated with increased risk of 30-day complication (OR: 1.062, 95% CI: 1.010-1.117, p = 0.020).Our findings support a continuation of same-day discharge strategy which could decrease costs for patients and hospitals without increasing complications.

The aim of this study was to characterize the current state of surgical ergonomics education in the United States.The burden of work-related musculoskeletal disorders (MSDs) in surgeons is high and no overarching strategy for redress exists. Twelve distinct specialties describe an unmet need for surgical ergonomics education (SEE). This study aimed to define the current state of SEE in U.S. surgical training programs.We performed a descriptive analysis of a 20-item questionnaire of ACGME-certified program directors from 14 surgical and interventional medical specialties. Formal SEE was defined as any organized education module that reviewed the occupation-specific burden of common work-related MSDs and described a framework for prevention via occupation-specific applied ergonomics. Program directors were queried regarding SEE provision, characteristics, and perceived trainee attitude toward the education.Questionnaires were received from 130 of 441 (29.5%) program directors. Two (1.5%) provided formal SEE and 33 (25.4%) provided informal SEE, which consisted of unstructured intraoperative directives and isolated lectures. Two programs previously provided SEE but discontinued the effort due to lack of an evidence-based framework and instructors. Trainees appeared to think that learning surgical ergonomics skills was a worthwhile time investment in 100% and 76.7% of current formal and informal SEE, respectively.SEE is rarely provided in any capacity (25.4%), let alone in a consistent or evaluable fashion (1.5%). Impediments to sustainable SEE include lack of an evidence-based framework for education and instructors. An evidence-based, reproducible, and accreditation council-compliant SEE module would be a valuable resource for the surgical and interventional medical communities.

BACKGROUND Integrative medicine (IM) centers are becoming more established nationwide and provide an expansive range of therapeutic services. Given the high prevalence of IM usage among plastic surgery patients, we sought to define referrals rates to IM centers by plastic surgeons to investigate (1) the role of IM in the continuous care process of plastic surgery patients and (2) whether IM centers are being effectively utilized. METHODS Institutions with plastic surgery residency programs were identified using the American Medical Association's Fellowship and Residency Electronic Interactive Database Access System in January 2017. Data on the presence of a named IM center, director/administrator contact information, and types of therapeutic services offered were extracted. The total number of IM services at these centers was summed and tabulated for preliminary analyses. A survey questionnaire was sent to the center to ascertain referral patterns in February 2017. RESULTS Of 96 institutions with plastic and reconstructive surgery residency programs in North America, 49 (51%) provide IM services, and 24 (25%) have affiliated named IM centers of which we attained a survey response from 13 (54.5%). Of these centers, 10 (76.9%) evaluate more than 50 patients per week. Patient referrals to these centers were primarily from the department of medicine (73.8%) as opposed to surgery (13.1%) (P < 0.0001). An average of 0.77% of surgical referrals, or 0.077% of all referrals, arose from plastic and reconstructive surgery. CONCLUSIONS Plastic surgeons appear to infrequently refer patients to IM centers. Given the high prevalence of IM usage among our patient population, IM centers are an underutilized adjunct in the care of our patients. Further study into specific IM services that may benefit our patients would be helpful in increasing IM utilization in our field.

Background Complication rates after flap coverage for pressure ulcers have been high historically. These patients have multiple risk factors associated with poor wound healing and complications including marginal nutritional status, prolonged immobilization, and a high comorbidities index. This study utilizes the National Surgical Quality Improvement Program (NSQIP) to examine perioperative outcomes of flap coverage for pressure ulcers. Methods Data from the NSQIP database (2005–2015) for patient undergoing flap coverage for pressure ulcers was identified. Demographic, perioperative information, and complications were reviewed. One-way analysis of variance and Pearson chi-square were used to assess differences for continuous variables and nominal variables, respectively. Multivariate logistic regression was performed to identify independent risk factors for complications. Results There were 755 cases identified: 365 (48.3%) sacral ulcers, 321 (42.5%) ischial ulcers, and 69 (9.1%) trochanteric ulcers. Most patients were older male, with some degree of dependency, neurosensory impairment, high functional comorbidities score, and American Society of Anesthesiologists class 3 or above. The sacral ulcer group had the highest incidence of septic shock and bleeding, while the trochanteric ulcer group had the highest incidence of superficial surgical site infection. There was an overall complication rate of 25% at 30-day follow-up. There was no statistical difference in overall complication among groups. Total operating time, diabetes, and non-elective case were independent risk factors for overall complications. Conclusions Despite patients with poor baseline functional status, flap coverage for pressure ulcer patients is safe with acceptable postoperative complications. This type of treatment should be considered for properly selected patients.

Background Hidradenitis suppurativa (HS) is a chronic debilitating cutaneous disorder. The recalcitrant nature of this disease may require surgery in severe cases. We aimed to delineate the types of operations performed, the risk factors associated with these operations, and the surgical services involved based on a national database. Methods Data were collected through the American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2016. Current Procedural Terminology (CPT) and International Classification of Disease, Ninth Revision, (ICD-9) codes were used for data extraction and analysis as type of surgery and complication rates were extracted. Results There were 2594 patients diagnosed with HS: 1405 (54.2%) incision and drainage, 1017 (39.2%) debridement, 31 (1.2%) skin graft, and 141 (5.4%) flap reconstruction. There were significant differences in transfusion rates and operation time among the four procedures. Skin graft and flap reconstruction had the highest complications and longest operation time. Bleeding requiring preoperative transfusion and a number of comorbidities were significant risk factors for postoperative complications. Flap reconstructions by plastic surgeons compared to general surgeons had significantly shorter operation times (134.89 versus 209.82 min, P = 0.022) and lower transfusion rates (2.2% versus 12.8%, P = 0.024). Conclusions The management of HS can be complex and may require a multidisciplinary approach. Bleeding requiring preoperative transfusion and other baseline comorbidities are independent risk factors that should be addressed when definitive surgical treatment of hidradenitis is planned. Appropriate surgical specialty involvement may better optimize the surgical outcomes for HS.

BACKGROUND: Surveys have reported that as high as 80% of plastic surgery patients utilize integrative medicine approaches including natural products (NPs) and mind-body practices (MBPs). Little is known regarding the evidence of benefit of these integrative therapies specifically in a plastic surgery patient population. METHODS: We conducted a systematic review of studies in MEDLINE, PubMed, and EMBASE (inception through December 2016) evaluating integrative medicine among plastic surgery patients. Search terms included 76 separate NP and MBP interventions as listed in the 2013 American Board of Integrative Health Medicine Curriculum. Two independent reviewers extracted data from each study, including study type, population, intervention, outcomes, conclusions (beneficial, harmful, or neutral), year of publication, and journal type. Level of evidence was assessed according to the American Society of Plastic Surgeons Rating Levels of Evidence and Grading Recommendations. RESULTS: Of 29 studies analyzed, 13 studies (45%) evaluated NPs and 16 (55%) studied MBPs. Level II reproducible evidence supports use of arnica to decrease postoperative edema after rhinoplasty, onion extract to improve scar pigmentation, hypnosis to alleviate perioperative anxiety, and acupuncture to improve perioperative nausea. Level Vevidence reports on the risk of bleeding in gingko and kelp use and the risk of infection in acupuncture use. After year 2000, 92% of NP studies versus 44% of MBP studies were published (P = 0.008). CONCLUSIONS: High-level evidence studies demonstrate promising results for the use of both NPs and MBPs in the care of plastic surgery patients. Further study in this field is warranted.

BACKGROUND Scholastic productivity has previously been shown to be positively associated with National Institute of Health (NIH) grants and industry funding. This study examines whether society, industry, or federal funding contributes toward academic productivity as measured by scholastic output of academic plastic surgeons. METHODS Institution Web sites were used to acquire academic attributes of full-time academic plastic surgeons. The Center for Medicare and Medicaid Services Open Payment database, NIH reporter, the Plastic Surgery Foundation (PSF), and American Association of Plastic Surgeons (AAPS) Web sites were accessed for funding and endowment details. Bibliometric data of each surgeon were then collected via Scopus to ascertain strengths of association with each source. Multiple linear regression analysis was used to identify significant contributors to high scholastic output. RESULTS We identified 935 academic plastic surgeons with 94 (10.1%), 24 (2.6%), 724 (77.4%), and 62 (6.6%) receiving funding from PSF, AAPS, industry, and NIH, respectively. There were positive correlations in receiving NIH, PSF, and/or AAPS funding (P < 0.001), whereas industry funding was found to negatively associate with PSF (r = -0.75, P = 0.022) grants. The NIH R award was consistently found to be the most predictive of academic output across bibliometrics, followed by the AAPS academic scholarship award. Conventional measures of academic seniority remained predictive across all measures used. CONCLUSIONS Our study demonstrates for the first time interactions between industry, federal, and association funding. The NIH R award was the strongest determinant of high scholastic productivity. Recognition through AAPS academic scholarships seemed to associate with subsequent success in NIH funding.

Objective We have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor–associated kinase 1 (IRAK1). Methods RAW264.7 cells were exposed to LPS (1 μg/mL) for 2 h, followed by treatment with SAHA (10 μM) or geldanamycin (3 μM), an inhibitor of HSP90. Sham (no SAHA, no LPS) macrophages served as a control. The cells were harvested at different time points, and time zero served as the reference point. Results LPS dramatically increased protein expression of myeloid differentiation factor 88 and IRAK1, and stimulated nuclear translocation of nuclear factor κB, leading to an increases of gene expression and protein production of tumor necrosis factor α and interleukin-6. Treatment with SAHA significantly attenuated these LPS-stimulated alterations. LPS or SAHA did not change the levels of HSP90 protein, but immunoprecipitation studies demonstrated that SAHA treatment enhanced acetylation of HSP90, and increased the dissociation of IRAK1, compared to the LPS control. Conclusions SAHA suppresses LPS/Toll-like receptor 4 signaling in LPS-stimulated macrophages through multiple potential mechanisms. It inhibits the function of HSP90 through hyperacetylation of the chaperone protein, which results in dissociation and degradation of the client protein IRAK1 and, at least in part, leads to a decrease in nuclear translocation of nuclear factor κB and attenuation of key proinflammatory cytokine expression.

Background We demonstrated recently that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improved survival in a rodent model of lipopolysaccharide (LPS)-induced endotoxic shock. The precise mechanisms, however, have not been well-defined. The aim of this study was to investigate the impact of SAHA treatment on gene expression profiles at an early stage of shock. Methods Male C57BL/6J mice were treated with or without SAHA (50 mg/kg, IP), followed by a lethal dose of LPS (20 mg/kg, IP) and a second dose of SAHA. Lungs of the animals (LPS and SAHA+LPS groups; n = 3 per group) were harvested 3 hours post-LPS insult. Sham mice (no LPS and no SAHA) served as controls. RNA was isolated from the tissues and gene expression was analyzed using Affymatrix microarray (23,000 genes). A lower confidence bound of fold change was determined for comparison of LPS versus SAHA + LPS, and genes with a lower confidence bound of >2 were considered to be differentially expressed. Reverse transcriptase polymerase chain reaction, Western blotting, and tissue staining were performed to verify the key changes. Network graphs were used to determine gene interaction and biologic relevance. Results The expression of many genes known to be involved in septic pathophysiology changed after the LPS insult. Interestingly, a number of genes not implicated previously in the septic response were also altered. SAHA treatment attenuated expression of several key genes involved in inflammation. It also decreased neutrophil infiltration in lungs and histologic evidence of acute lung injury. Further analysis confirmed genes engaged in the cellular and humoral arms of the innate immune system were specifically inhibited by SAHA. Gene network analysis identified numerous molecules for the potential development of targeted therapies. Conclusion Administration of SAHA in a rodent model of LPS shock rapidly modulates gene transcription, with an attenuation of inflammatory mediators derived from both arms (cellular and humoral) of the innate immune system. This may be a novel mechanism responsible for the survival advantage seen with SAHA treatment.

Background Acute lung injury (ALI) is a complication of hemorrhagic shock (HS). Histone deacetylase inhibitors, such as valproic acid (VPA), can improve survival after HS; however, their effects on late organ injury are unknown. Herein, we have investigated the effects of HS and VPA treatment on ALI and circulating cytokines that may serve as biomarkers for the development of organ injury. Methods Anesthetized Wistar-Kyoto rats (250–300 g) underwent 40% blood volume hemorrhage over 10 minutes followed by 30 minutes of unresuscitated shock and were treated with either VPA (300 mg/kg) or vehicle control. Blood samples were obtained at baseline, after shock, and before death (at 1, 4, and 20 hours; n = 3–4/timepoint/group). Serum samples were screened for possible biomarkers using a multiplex electrochemiluminescence detection assay, and results were confirmed using enzyme-linked immunosorbent assay (ELISA). In addition, lung tissue lysate was examined for chemokine and myeloperoxidase (MPO) levels as a marker for neutrophil infiltration and ALI. Lung cytokine-induced neutrophil chemoattractant-1 (CINC-1; a chemokine belonging to the interleukin-8 family that promotes neutrophil chemotaxis) mRNA levels were measured by real-time polymerase chain reaction studies. Results Serum screening revealed that hemorrhage rapidly altered levels of circulating CINC-1. ELISA confirmed that CINC-1 protein was significantly elevated in the serum as early as 4 hours and in the lung at 20 hours after hemorrhage, without any significant changes in CINC-1 mRNA expression. Lung MPO levels were also elevated at both 4 and 20 hours after hemorrhage. VPA treatment attenuated these changes. Conclusion Hemorrhage resulted in the development of ALI, which was prevented with VPA treatment. Circulating CINC-1 levels rose rapidly after hemorrhage, and serum CINC-1 levels correlated with lung CINC-1 and MPO levels. This suggests that circulating CINC-1 levels could be used as an early marker for the subsequent development of organ inflammation and injury.

Circulating proteins may serve as biomarkers for the early diagnosis and treatment of shock. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced septic shock. Preliminary proteomic data showed that LPS-induced shock altered a number of proteins in circulation, including histone H3 (H3) and citrullinated histone H3 (Cit H3). The present study was designed to confirm these findings and to test whether the pro-survival phenotype could be detected by an early alteration in serum biomarkers.Three experiments were performed. In experiment I, Western blotting was performed on serum samples from male C57B1/6J mice (n = 9, 3/group) that belonged to the following groups: (a) LPS (20 mg/kg)-induced septic shock, (b) SAHA-treated septic shock, and (c) sham (no LPS, no SAHA). In experiment II, HL-60 granulocytes were cultured and treated with LPS (100 ng/m1) in the absence or presence of SAHA (10 μmol/L). Sham (no LPS, no SAHA) granulocytes served as controls. The medium and cells were harvested at 3 hours, and proteins were measured with Western blots. In experiment III, a large dose (LD, 35 mg/kg) or small dose (SD, 10 mg/kg) of LPS was injected intraperitoneally into the C57B1/6J mice (n = 10 per group). Blood was collected at 3 hours, and serum proteins were determined by Western blots or enzyme-linked immunosorbent assay (ELISA). All of the Western blots were performed with antibodies against H3, Cit H3, and acetylated H3 (Ac H3). ELISA was performed with antibody against tumor necrosis factor (TNF)-α. Survival rates were recorded over 7 days.In experiment I, intraperitoneal (IP) injection of LPS (20 mg/kg) significantly increased serum levels of H3, which was prevented by SAHA treatment. In experiment II, LPS (100 ng/mL) induced expression and secretion of Cit H3 and H3 proteins in neutrophilic HL-60 cells, which was decreased by SAHA treatment. In experiment III, administration of LPS (LD) caused a rise in serum H3 and Cit H3 but not Ac H3 at 3 hours, and all of these animals died within 23 hours (100% mortality). Decreasing the dose of LPS (SD) significantly reduced the mortality rate (10% mortality) as well as the circulating levels of Cit H3 (non detectable) and H3. An increase in serum TNF-α was found in both LPS (LD) and (SD) groups, but in a non-dose-dependent fashion.Our results reveal for the first time that Cit H3 is released into circulation during the early stages of LPS-induced shock. Moreover, serum levels of Cit H3 are significantly associated with severity of LPS-induced shock. Therefore, Cit H3 could serve as a potential protein biomarker for early diagnosis of septic shock, and for predicting its lethality.

Background: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, and spray-dried plasma (SDP) improve early survival after lethal hemorrhage and polytrauma, but their effect on long-term survival and organ function remains untested. Methods: Yorkshire swine (n = 27; 6―8/group) underwent a protocol simulating different phases of trauma care: (1) prehospital—rib fracture, soft-tissue injury, hemorrhage (50% blood volume), 30 minutes of shock, and infusion of 0.9% saline (3× shed blood); (2) early hospital/treatment—grade IV liver (partial amputation of the median lobe) and grade V splenic (transection of spleen into three pieces) injuries to simulate rupture of contained hematomas, followed by 30 minutes of uncontrolled hemorrhage. Animals were treated with (a) Hextend (6% hetastarch), (b) fresh whole blood (FWB), (c) SDP, and (d) VPA (300 mg/kg) plus Hextend. VPA was given during the prehospital phase, and the volumes of Hextend, FWB and SDP (reconstituted in water) matched shed blood; (3) repair/resuscitation—liver injury was controlled by suture control of the transected edge, and splenic injury was treated by partial splenectomy; 1 hour after repair of injuries, surviving animals were fully resuscitated with packed red blood cells; and (4) monitoring—survival was monitored for 7 days (primary endpoint), and blood samples were drawn serially to measure organ function. Results: Only 25% of the Hextend-treated animals survived. Addition of VPA improved survival to only 50% (p = 0.28), whereas treatment with SDP and FWB increased survival significantly to 83% and 100%, respectively (p < 0.05). Surviving animals showed no long-term organ dysfunction, postoperative hemorrhage, and delayed complications. Conclusions: In a clinically relevant lethal polytrauma model, administration of SDP significantly improves survival without any long-term organ dysfunction or complications.

Background. Despite global efforts to improve the treatment of sepsis, it remains a leading cause of morbidity and mortality in intensive care units. We have previously shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, markedly improves survival in a murine model of lipopolysaccharide (LPS)-induced shock. SAHA has anti-inflammatory properties that have not been fully characterized. The liver plays an important role in the production of acute phase reactants involved in the inflammatory cascade and is also one of the major organs that can become dysfunctional in septic shock. The purpose of this study was to assess the effect of SAHA treatment on MAP kinases and associated inflammatory markers in murine liver after LPS-induced injury. Methods. C57B1/6J mice were randomly divided into three groups: (A) experimental-given intraperitoneal (i.p.) SAHA (50 mg/kg) in dimethyl sulfoxide (DMSO) vehicle solution (n = 12); (B) control- given vehicle only (n = 12), and; (C) sham-given no treatment (n = 7). Two hours later, experimental and control mice were injected with LPS (20 mg/kg, i.p.) and experimental mice received a second dose of SAHA. Livers were harvested at 3, 24, and 48 h for analysis of inflammatory markers using Western Blot, Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) techniques. Results. After 3 h, the livers of animals treated with SAHA showed significantly (P < 0.05) decreased expression of the pro-inflammatory MAP kinases phosphorylated p38, phosphorylated ERK, myeloperoxidase and interleukin-6, and increased levels of the anti-inflammatory interleukin-10 compared with controls. Phospho-p38 expression remained low in the SAHA treated groups at 24 and 48 h. Conclusion. Administration of SAHA is associated with attenuation of MAPK activation and alteration of inflammatory and anti-inflammatory markers in murine liver after a lethal LPS insult. The suppression of MAPK activity is rapid (within 3 h), and is sustained for up to 48 h post-treatment. These results may in part account for the improvement in survival shown in this model.

Hemorrhage is the leading cause of preventable trauma-related deaths, and histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following lethal hemorrhage. HDACI acetylate proteins, and acetylation regulates many cellular functions. Here we have investigated the effects of VPA treatment on extracellular signal-regulated kinase 1/2 (ERK) activation, as ERK is well known to modulate cell death, gene expression, and inflammation.Anesthetized Wistar-Kyoto rats were subjected to lethal (60%) blood loss, and then randomized (n = 5-6/group) to (1) VPA 300 mg/kg or (2) vehicle control. Survival was monitored for 24 h. A separate group of rats were subjected to sublethal (40%) hemorrhage and were treated with VPA or vehicle. Rats were sacrificed at 1, 4, and 20 h, and lung tissue was assessed for the degree of acetylation of histone 3, and activation (phosphorylation) of ERK. Sham animals served as normal controls.Sixty percent hemorrhage resulted in severe shock. Only 17% of the vehicle-treated animals survived (most died within 1 h), whereas 80% of the VPA-treated animals survived (P0.05). Hemorrhage resulted in a significant increase in phosphorylated ERK (activated form) compared with sham at the 1 and 4 h time points, but not at the 20 h time point. VPA treatment significantly attenuated these changes, while increasing histone protein acetylation.VPA treatment significantly improves survival following lethal hemorrhagic shock. Hemorrhage induces ERK activation, which is significantly attenuated by VPA treatment. This may represent one mechanism through which VPA promotes survival in otherwise lethal hemorrhagic shock.

INTRODUCTION We have previously demonstrated that induction of profound hypothermia improves long-term survival in animal models of complex injuries/lethal hemorrhage. However, the precise mechanisms have not been well defined. The aim of this high-throughput study was to investigate the impact of profound hypothermia on gene expression profiles. METHODS Wistar-Kyoto rats underwent 40% blood volume arterial hemorrhage over 10 minutes and were randomized into two groups based on core body temperatures (n = 7 per group): hypothermia (H, 15 degrees C) and normothermia (N, 37 degrees C). Hypothermia was induced by infusing cold isotonic solution using a cardiopulmonary bypass (CPB) setup. After reaching target body temperature, low-flow state (CPB flow rate of 20 mL x kg x min) was maintained for 60 minutes. Hypothermic rats were rewarmed to baseline temperature, and all rats were resuscitated on CPB and monitored for 3 hours. The N group underwent identical CPB management. Sham rats (no hemorrhage and no instrumentation) were used as controls. Blood samples were collected serially, and hepatic tissues were harvested after 3 hours. Affymatrix Rat Gene 1.0 ST Array (27,342 genes, >700,000 probes) was used to determine gene expression profiles (n = 3 per group), which were further analyzed using GeneSpring (Agilent Technologies, Santa Clara, CA) and GenePattern (Broad Institute, Cambridge, MA) programs. Data were further queried using network analysis tools including Gene Ontology, and Ingenuity Pathway Analysis (Ingenuity Systems). Key findings were verified using real-time polymerase chain reaction and Western blots. RESULTS Induction of hypothermia significantly (p < 0.05) decreased the magnitude of lactic acidosis and increased the survival rates (100% vs. 0% in normothermia group). Five hundred seventy-one of 23,000 genes had altered expression in response to the induction of hypothermia: 382 were up-regulated and 187 were down-regulated. Twelve key pathways were specifically modulated by hypothermia. Interleukin-6, interleukin-10, p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells, glucocorticoids, and other signaling pathways involved with acute phase reactants were up-regulated. Multiple metabolic pathways were down- regulated. The largest change was in the peroxisome proliferator-activated receptor gamma gene that codes for a transcriptional coactivator, which in turn controls mitochondrial biogenesis, glycerolipid, and other metabolic pathways in the liver. Apoptotic cell death cascades were activated in response to blood loss (H and N groups), but multiple specific anti-apoptotic genes (baculoviral Inhibitor of apoptosis protein repeat-containing 3, BCL3L1, NFKB2) displayed an increased expression specifically in the hypothermia treated animals, suggesting an overall pro-survival phenotype. CONCLUSIONS Profound hypothermia increases survival in a rodent model of hemorrhagic shock. In addition to decreasing tissue oxygen consumption, induction of hypothermia directly alters the expression profiles of key genes, with an overall up-regulation of pro-survival pathways and a down- regulation of metabolic pathways.

Summary: Abdominal-based free flaps are commonly used for breast reconstruction, and the internal mammary or thoracodorsal vessels are typically used as recipient sites. Conversely, free tissue transfer is less commonly used for chest wall reconstruction in the setting of chest wall recurrence, in part, because of a paucity of recipient vessels. Here, we describe a case of a 68-year-old female smoker with metastatic breast cancer, who presented with a chest wall recurrence. There was a large area of chronic ulceration with foul smelling drainage, in addition to radiation-induced tissue injury, and palliative resection was performed. The area was reconstructed with a free transverse rectus abdominis myocutaneous flap using lumbar perforators as recipient vessels, because conventional recipient sites were unavailable because of scarring from radiation and residual tumor. This case demonstrates that uncommon recipient vessels such as lumbar perforators may allow for successful palliative chest wall reconstruction. We hypothesize that the tumor burden, previous surgeries, and radiation may have rendered the recipient field relatively ischemic, thereby inducing hypertrophy of the lumbar perforators, similar to a delay phenomenon.

Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. We have previously shown that treatment with histone deacetylase inhibitors (HDACIs) significantly improves survival in lethal models (60% blood loss) of hemorrhage. The aim of the current study was to examine whether these protective effects were due to attenuation of mitogen activated protein kinase (MAPK) signaling pathways, which are known to promote inflammation and apoptosis.Wistar-Kyoto rats (250-300 g) were subjected to 40% blood loss and randomized to treatment with: (1) HDACI valproic acid (VPA 300 mg/kg i.v.; volume = 0.75 mL/kg), or (2) vehicle control (0.75 mL/kg of 0.9% saline). Animals were sacrificed at 1, 4, and 20 h (n = 3-4/group/timepoint), and lung samples were analyzed by Western blotting for expression of active (phosphorylated) and inactive forms of c-Jun N-terminal Kinase (JNK) and p38 MAPK. Myeloperoxidase (MPO) activity was measured in lung tissue 20 h after hemorrhage as a marker of neutrophil infiltration. Normal animals (n = 3) served as shams.Hemorrhaged animals demonstrated significant increases in phosphorylated p38 at 1 h, phosphorylated JNK at 4 h, and increased MPO activity at 20 h (P0.05 compared with sham). VPA treatment significantly (P0.05) attenuated all of these changes.Hemorrhagic shock activates pro-inflammatory MAPK signaling pathways and promotes pulmonary neutrophil infiltration, affects that are significantly attenuated by VPA treatment. This may represent a key mechanism through which HDACIs decrease organ damage and promote survival in hemorrhagic shock.

We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model.C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay.All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P.001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations.We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.

Exsanguinating hemorrhage is a common clinical feature of multisystem trauma that results in death or severe disability. Cardiovascular collapse resulting from hemorrhage is unresponsive to conventional methods of cardiopulmonary resuscitation. Even when bleeding is controlled rapidly, adequate circulation cannot be restored in time to avoid neurologic consequences that appear after only 5 mins of cerebral ischemia and hypoperfusion. Reperfusion adds further insult to injury. A novel solution to this problem would be to institute a therapy that makes cells and organs more resistant to ischemic injury, thereby extending the time they can tolerate such an insult. Hypothermia can attenuate some effects of ischemia and reperfusion. Accumulating preclinical data demonstrate that hypothermia can be induced safely and rapidly to achieve emergency preservation for resuscitation during lethal hemorrhage. Hypothermia may be an effective therapeutic approach for otherwise lethal traumatic hemorrhage, and a clinical trial to determine its utility is warranted.

We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.

Background The initial management of a poly-trauma patient requires evaluation for potential hemorrhage and ongoing monitoring to assess the efficacy of treatment and avoid complications related to massive blood loss. Certain serum protein levels may be altered in response to hemorrhagic shock, and may serve as useful biomarkers to guide diagnosis, prognosis, and therapeutics in traumatic hemorrhagic shock (HS). Treatment with valproic acid (VPA) has been shown to up-regulate various survival pathways and improve outcome. Here we determine whether these changes would result in altered serum biomarkers. Methods Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss) followed by treatment with or without VPA (300 mg/kg). Using surface enhanced laser desorption-time of flight mass spectrometry (SELDI or SELDI-TOF MS) technology, we screened serum samples obtained from five rats at different time points (baseline, post-hemorrhagic shock, and post-VPA treatment) in a lethal model of hemorrhagic shock (HS). Additionally, we used isobaric tag labeling for relative quantitation (iTRAQ) to identify potential biomarkers in the serum. Western blots were performed to validate iTRAQ-identified biomarker from independent serum samples, and to analyze protein biomarker levels in the intestine during hemorrhagic shock and treatment. Results HS and treatment with VPA affected serum levels of many proteins. One such protein with a mass spectrum around 22.7 kDa was detected in all five rats. The same serum samples subjected to iTRAQ resulted in our identification of claudin-3, a 23 kDa tight junction protein. HS elevated serum claudin-3 protein levels, which was reversed by VPA treatment in a pattern similar to the SELDI-TOF MS studies. Further validation with independent serum and intestine samples from individual rats by Western blots confirmed that HS increased the protein level of claudin-3 in serum and decreased its level in the intestine. Treatment with VPA reversed the hemorrhagic shock-induced alteration in claudin-3 to sham levels. Conclusions HS causes an acute rise in serum claudin-3 protein levels and a concurrent decrease in intestinal claudin-3 protein expression. VPA treatment attenuates these alterations and stabilizes intestinal claudin-3 levels. Our results demonstrate for the first time that claudin-3 is a potential biomarker in HS and treatment.

Recent studies suggest that gamma-aminobutyric acid type B (GABA(B)) receptors located on dopaminergic cells in the ventral tegmental area (VTA) regulate mesolimbic dopaminergic (A10) activity. In the current study, we identified GABA(B) receptor subtypes in the area of the VTA and examined their role in modulating acute opiate actions. We studied the effects of intra-VTA infusions of the selective GABA(B) agonist baclofen on morphine-induced locomotor stimulation and A10 neuronal activation. Drug treatments were followed by ambulatory activity monitoring for 180 min. Intra-VTA baclofen treatment produced a 70% inhibition of morphine-stimulated locomotor activity. Furthermore, functional activation of A10 neurons was assessed by immunohistochemical staining of c-Fos in the nucleus accumbens (NAc), where A10 neurons terminate. We found that morphine treatment increased the levels of Fos-positive nuclei in the NAc, while intra-VTA baclofen treatment reversed morphine's effects. Finally, GABA(B) receptor subtypes and isoforms were identified in the ventromedial mesencephalon using immunoblotting. We demonstrated the presence of GABA(B)R1a (130 kDa), GABA(B)R1b (100 kDa), and GABA(B)R2 (120 kDa) receptor subtypes in this region. These results suggest that GABA(B) receptor isoforms are found in the VTA and their activation results in the blockade of behavioral effects of opiates via inhibition of dopaminergic neurotransmission.