Assessment of Risk Factors Correlated with Outcomes of Traumatic Lower Extremity Soft Tissue Reconstruction.

Identifying risk factors for traumatic lower extremity reconstruction outcomes has been limited by sample size. We evaluated patient and procedural characteristics associated with reconstruction outcomes using data from almost four million patients. Methods: The National Trauma Data Bank (2015-2018) was queried for lower extremity reconstructions. Univariable and multivariable analyses determined associations with inpatient outcomes. Results: There were 4675 patients with lower extremity reconstructions: local flaps (77%), free flaps (19.2%), or both (3.8%). Flaps were most commonly local fasciocutaneous (55.1%). Major injuries in reconstructed extremities were fractures (56.2%), vascular injuries (11.8%), and mangled limbs (2.9%). Ipsilateral procedures prereconstruction included vascular interventions (6%), amputations (5.6%), and fasciotomies (4.3%). Postoperative surgical site infection and amputation occurred in 2% and 2.6%, respectively. Among survivors (99%), mean total length of stay (LOS) was 23.2 ± 21.1 days and 46.8% were discharged to rehab. On multivariable analysis, vascular interventions prereconstruction were associated with increased infection [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.05-3.79, P = 0.04], amputation (OR 4.38, 95% CI 2.56-7.47, P < 0.001), prolonged LOS (OR 1.59, 95% CI 1.14-2.22, P = 0.01), and discharge to rehab (OR 1.49, 95% CI 1.07-2.07, P = 0.02). Free flaps were associated with prolonged LOS (OR 2.08, 95% CI 1.74-2.49, P < 0.001). Conclusions: Prereconstruction vascular interventions were associated with higher incidences of adverse outcomes. Free flaps correlated with longer LOS, but otherwise similar outcomes. Investigating reasons for increased complication and healthcare utilization likelihood among these subgroups is warranted.

Bovine versus porcine acellular dermal matrix for abdominal wall herniorrhaphy or bridging.

BACKGROUND: The management of complicated ventral hernias (CVH), namely ventral hernias in actively or recently infected/contaminated operative fields, and open abdomens in which the native fascia cannot be primarily reapproximated, pose a surgical challenge. Fetal Bovine and Porcine Acellular Dermal Matrix (BADM and PADM) biologic meshes are being increasingly used in these scenarios. A comparison, however, of clinically relevant outcomes between the two is lacking. With this investigation, we aim to review and compare clinically relevant outcomes in patients that underwent abdominal wall herniorrhaphy with either BADM or PADM at a tertiary urban academic institution over a 5-year period. METHODS: Patients who had a BADM or PADM implanted during CVH over a 5-year period at a tertiary urban academic hospital were identified. Baseline clinical and hernia characteristics, as well as postoperative outcomes were compared after a retrospective chart review. Phone interviews were also conducted to assess for recurrence, followed by in-person visits as indicated. Cox Proportional Hazard regression was fitted to identify risk factors for recurrence. RESULTS: Of the 140 patients who underwent biologic mesh implantation for CVH, 109 were for ventral hernia repair and 31 for open abdomen bridging. Mean age was 52.7 ± 14.2 and males constituted 57.9% of our sample, while 25.1% had undergone > 5 prior abdominal operations. Thirty percent were active smokers, and another 30% required emergency surgery. Only immunosuppression was a risk factor for recurrence [HR 13.3 (1.04-169.2), p = 0.047] on Cox Proportional Hazard regression, while mesh selection had no effect. CONCLUSIONS: Both BADM and PADM meshes perform well in CVH, with satisfactory recurrence rates, only slightly higher compared to traditional synthetic mesh repairs.

The majority of major amputations after resuscitative endovascular balloon occlusion of the aorta are associated with preadmission trauma.

OBJECTIVE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potentially life-saving intervention. However, recent reports of associations with limb loss and mortality have called its safety into question. We aimed to evaluate patient and hospital characteristics associated with major amputation and in-hospital mortality among patients undergoing REBOA for trauma. METHODS: The National Trauma Data Bank (2015-2017) was queried for patients presenting to trauma centers and treated with REBOA. We included REBOA performed on hospital day 1 in patients who survived 6 or more hours from presentation. Univariable and multivariable analyses evaluated associations with major amputation and in-hospital mortality. RESULTS: A total of 316 patients underwent REBOA and survived in the acute period after presentation. Overall, mean age was 45 ± 20 years and the majority were male (73%) and White (56%). Most patients presented to level I trauma centers (72%) after blunt injuries (79%) with an average Injury Severity Score (ISS) of 31 ± 15, indicating major trauma. In 15 patients (5%), there were 18 major amputations-7 above knee and 11 below knee. A subgroup of 11 amputations were either traumatic amputations (73%) or mangled limbs requiring amputation within 24 hours (27%). Of the remaining amputations, 71% were associated with ipsilateral vascular or orthopedic lower extremity injuries of serious to severe Abbreviated Injury Scale severity. Comparing patients with amputations with those without amputations, there were no significant differences in patient demographics, comorbidities, or hospital characteristics. During hospitalization, patients requiring amputation more frequently received open peripheral vascular interventions (40% vs 10%; P = .002), underwent similar numbers of endovascular interventions (6.7% vs 4.7%; P = .5), and more often developed compartment syndrome (13% vs 2%; P = .04). Overall, there were 110 deaths (35%). The major amputation prevalence was similar between patients who died vs those who survived (3.6% vs 5.3%; P = .5). In multivariable analysis, prehospital cardiac arrest (odds ratio [OR], 8.47; 95% confidence interval [CI], 1.47-48.66; P = .02), penetrating vs blunt trauma (OR, 5.5; 95% CI, 1.05-28.82; P = .04), decreased Glasgow Coma Scale score (OR, 1.18; 95% CI, 1.05-1.32; P = .01), older age (OR, 1.06; 95% CI, 1.03-1.10; P < .001), and increased Injury Severity Score (OR, 1.05; 95% CI, 1.0-1.1; P = .03) were associated with higher mortality. CONCLUSIONS: The majority of major amputations in patients undergoing REBOA were secondary to the initial traumatic mechanism. Injury type and severity, as well as initial hemodynamic derangements, are associated with mortality after REBOA. Despite concerns about prohibitive limb complications of REBOA, baseline injuries seem to be the primary cause of limb loss, but further prospective analysis is needed.

Clinical diagnostic phenotypes in hospitalizations due to self-inflicted firearm injury.

BACKGROUND: . Hospitalized self-inflicted firearm injuries have not been extensively studied, particularly regarding clinical diagnoses at the index admission. The objective of this study was to discover the diagnostic phenotypes (DPs) or clusters of hospitalized self-inflicted firearm injuries. METHODS: . Using Nationwide Inpatient Sample data in the US from 1993 to 2014, we used International Classification of Diseases, Ninth Revision codes to identify self-inflicted firearm injuries among those ≥18 years of age. The 25 most frequent diagnostic codes were used to compute a dissimilarity matrix and the optimal number of clusters. We used hierarchical clustering to identify the main DPs. RESULTS: . The overall cohort included 14072 hospitalizations, with self-inflicted firearm injuries occurring mainly in those between 16 to 45 years of age, black, with co-occurring tobacco and alcohol use, and mental illness. Out of the three identified DPs, DP1 was the largest (n=10,110), and included most common diagnoses similar to overall cohort, including major depressive disorders (27.7%), hypertension (16.8%), acute post hemorrhagic anemia (16.7%), tobacco (15.7%) and alcohol use (12.6%). DP2 (n=3,725) was not characterized by any of the top 25 ICD-9 diagnoses codes, and included children and peripartum women. DP3, the smallest phenotype (n=237), had high prevalence of depression similar to DP1, and defined by fewer fatal injuries of chest and abdomen. LIMITATIONS: . Claims data. CONCLUSIONS: . There were three distinct diagnostic phenotypes in hospitalizations due to self-inflicted firearm injuries. Further research is needed to determine how DPs can be used to tailor clinical care and prevention efforts.

Quality improvement in tracheostomy care: A multidisciplinary approach to standardizing tracheostomy care to reduce complications.

PURPOSE: Develop a model for quality improvement in tracheostomy care and decrease tracheostomy-related complications. METHODS: This study was a prospective quality improvement project at an academic tertiary care hospital. A multidisciplinary team was assembled to create institutional guidelines for clinical care during the pre-operative, intra-operative, and post-operative periods. Baseline data was compiled by retrospective chart review of 160 patients, and prospective tracking of select points over 8 months in 73 patients allowed for analysis of complications and clinical parameters. RESULTS: Implementation of a quality improvement team was successful in creating guidelines, setting baseline parameters, and tracking data with run charts. Comparison of pre- and post-guideline data showed a trend toward decreased rate of major complications from 4.38% to 2.74% (p = 0.096). Variables including time to tracheotomy for prolonged intubation, surgical technique, day of first tracheostomy tube change, and specialty performing surgery did not show increased risk of complications. There were increased tracheostomy-related complications in cold months (p = 0.04). CONCLUSIONS: An interdisciplinary quality improvement team can improve tracheostomy care by identifying system factors, standardizing care among specialties, and providing continuous monitoring of select data points.

Survey of American College of Surgeons Committee on trauma members on firearm injury: Consensus and opportunities.

BACKGROUND: In the United States, there is a perceived divide regarding the benefits and risks of firearm ownership. The American College of Surgeons Committee on Trauma Injury Prevention and Control Committee designed a survey to evaluate Committee on Trauma (COT) member attitudes about firearm ownership, freedom, responsibility, physician-patient freedom and policy, with the objective of using survey results to inform firearm injury prevention policy development. METHODS: A 32-question survey was sent to 254 current U.S. COT members by email using Qualtrics. SPSS was used for χ exact tests and nonparametric tests, with statistical significance being less than 0.05. RESULTS: Our response rate was 93%, 43% of COT members have firearm(s) in their home, 88% believe that the American College of Surgeons should give the highest or a high priority to reducing firearm-related injuries, 86% believe health care professionals should be allowed to counsel patients on firearms safety, 94% support federal funding for firearms injury prevention research. The COT participants were asked to provide their opinion on the American College of Surgeons initiating advocacy efforts and there was 90% or greater agreement on 7 of 15 and 80% or greater on 10 of 15 initiatives. CONCLUSION: The COT surgeons agree on: (1) the importance of formally addressing firearm injury prevention, (2) allowing federal funds to support research on firearms injury prevention, (3) retaining the ability of health care professionals to counsel patients on firearms-related injury prevention, and (4) the majority of policy initiatives targeted to reduce interpersonal violence and firearm injury. It is incumbent on trauma and injury prevention organizations to leverage these consensus-based results to initiate prevention, advocacy, and other efforts to decrease firearms injury and death. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level I; therapeutic care, level II.

Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance.

BACKGROUND: Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS. METHODS: ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid. RESULTS: VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma. CONCLUSION: Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.

Association Between Inferior Vena Cava Filter Insertion in Trauma Patients and In-Hospital and Overall Mortality.

Importance: Trauma patients admitted to the hospital are at increased risk of bleeding and thrombosis. The use of inferior vena cava (IVC) filters in this population has been increasing, despite a lack of high-quality evidence to demonstrate their efficacy. Objective: To determine if IVC filter insertion in trauma patients affects overall mortality. Design, Setting, and Participants: This retrospective cohort study used stratified 3:1 propensity matching to select a control population similar to patients who underwent IVC filter insertion at Boston Medical Center (a level I trauma center at Boston University School of Medicine) between August 1, 2003, and December 31, 2012. Among patients with an IVC filter and matched controls, age, sex, race/ethnicity, and Injury Severity Score were entered into a multivariable logistic regression model to calculate a propensity score. Matching was stratified by the date of injury. Main Outcomes and Measures: Multivariable logistic regression was used to compare hospital mortality across both groups, adjusting for age, sex, race/ethnicity, Injury Severity Score, and brain injury severity using the head and neck Abbreviated Injury Score. To determine any significant difference in mortality, patient characteristics and mortality data from the National Death Index were analyzed in all patients and in those who survived 24, 48, and 72 hours after injury, as well as at hospital discharge. Results: Among 451 trauma patients with an IVC filter and 1343 matched controls without an IVC filter, the mean (SD) age was 47.4 (21.5) years. The median Injury Severity Score overall was 24 (range, 1-75). Based on a mean follow-up of 3.8 years (range, 0-9.4 years), there was no significant difference in overall mortality or cause of mortality in patients with vs without an IVC filter who survived more than 24 hours from the time of injury, independent of the presence or absence of deep vein thrombosis or pulmonary embolism at the time of IVC filter placement. Additional analyses at shorter intervals of 6 months and 1 year after discharge also showed no significant difference between the 2 groups of patients. Eight percent (38 of 451) of the IVC filters were removed at Boston Medical Center during the follow-up period. Conclusions and Relevance: The research herein demonstrates no significant difference in survival in trauma patients with vs without placement of an IVC filter, whether in the presence or absence of venous thrombosis. The use of IVC filters in this population should be reexamined because filter removal rates are low and there is increased risk of morbidity in patients with filters that remain in place.

Evaluating three methods to encourage mentally competent older adults to assess their driving behavior.

BACKGROUND: Fourteen percent (43.1 million) of the population in the United States was 65 years and older in 2012. This population is projected to reach 20% (88.5 million) by 2050. Older adults accounted for 17% of all traffic fatalities and 9% of all vehicle occupant injuries in 2012. We explored the effectiveness of three interventions to help older adults assess their current driving behaviors at a Level 1 trauma center. METHODS: During 2010 to 2012, 1,216 inpatients 70 years and older admitted for surgical and medical services were screened for eligibility, and 120 were enrolled. Participants completed a driving assessment and preintervention questionnaires and were subsequently randomized to one of the following interventions: (1) brief negotiated interview plus an educational kit by the American Automobile Association about older driving plus an accompanying list of Web-based resources for older adult drivers; (2) American Automobile Association document and a list of Web-based resources; (3) online referral sheet of the list of Web-based resources only. A 3-month postintervention follow-up questionnaire was administered over the telephone to measure changes in (1) driving-related knowledge, attitudes, and beliefs as well as (2) driving-related behaviors and intended behaviors. RESULTS: A total of 113 randomized patients were included in the analysis. The mean (SD) age was 76.8 (5.23) years; majority of patients were white (64%), followed by black African American (33%); and 51% were males and 49% were females. Multivariate analysis showed that older adults' driving knowledge, attitudes, and beliefs (p < 0.0001, R = 0.37) as well as behaviors and intentions (p < 0.0001, R = 0.27) toward driving were positively correlated, controlling for other predictors in the model. Intervention assignment did not affect changes in outcomes, although outcomes improved across experimental conditions. CONCLUSION: Our pilot study suggests that older adults are likely to make changes in their driving behavior on the basis of minimal hospital-based intervention.

Addition of tranexamic acid to a traumatic injury massive transfusion protocol.

PURPOSE: The development of eligibility criteria and use of tranexamic acid in conjunction with a massive transfusion protocol (MTP) are described. SUMMARY: The trauma surgery and pharmacy departments collaborated to operationalize tranexamic acid administration in trauma patients for whom an MTP was activated. The MTP at Boston Medical Center, an urban, tertiary, academic medical center, is activated by the attending physician when the patient is expected to require at least 10 units of packed red blood cells in 24 hours. Tranexamic acid was considered in MTP trauma patients who arrived at the medical center within 8 hours of traumatic injury, were 15 years of age or older, and weighed at least 40 kg. Eligible patients were to receive a loading dose of tranexamic acid 1 g i.v. over 10 minutes followed by a maintenance dose of 1 g infused over 8 hours. To ensure that tranexamic acid use was limited to trauma patients, both its location of use and physician-ordering privileges were restricted by the pharmacy department. A 16-month assessment revealed that 16 patients received tranexamic acid, 13 (81%) of whom met all criteria for use. Tranexamic acid was used in 13 (38%) of 34 eligible MTP patients. Barriers to the use of tranexamic acid include a lack of familiarity with the medication among staff, drug availability, the complexity of administration, and the critical setting of MTP activation. CONCLUSION: Multidisciplinary collaboration and standardization of tranexamic acid use in conjunction with an MTP promoted use of the drug within a trauma population.

Nutritional considerations for head and neck cancer patients: a review of the literature.

PURPOSE: Approximately 35% to 60% of all patients with head and neck cancer are malnourished at the time of their diagnosis because of tumor burden and obstruction of intake or the anorexia and cachexia associated with their cancer. The purpose of this article is to provide a contemporary review of the nutritional aspects of care for patients with head and neck cancer. MATERIALS AND METHODS: A literature search was performed in Medline, Cochrane, and other available databases from 1990 through 2012 for the clinical effectiveness of nutritional support, treatment modalities, and methods of delivery in relation to patients with head and neck malignancies. Human studies published in English and having nutritional status and head and neck cancer as a predictor variable were included. Randomized controlled trials, meta-analyses, prospective clinical studies, and systemic reviews were selected based on their relevance to the abovementioned subtitles. The resultant articles were analyzed and summarized into the definition, impact, assessment, treatment, and modes of administration of nutrition on the outcome of patients with head and neck cancer. RESULTS: Articles were reviewed that focused on the etiology and assessment of malnutrition and current nutritional treatments for cancer-induced anorexia and cachexia. Two hundred forty-eight articles were found: 2 clinical trials, 10 meta-analyses, 210 review studies, and 26 systematic reviews. Because of the lack of prospective data, a summative review of the conclusions of the studies is presented. CONCLUSION: Nutritional interventions should be initiated before cancer treatment begins and these interventions need to be ongoing after completion of treatment to ensure optimal outcomes for patients. A nutritional assessment must be part of all comprehensive treatment plans for patients with head and neck cancer. Alternative medical interventions, such as immune-enhancing nutrients or anticytokine pharmaceutical agents, also may be effective as adjuvant therapies, but more research is needed to quantify their clinical effect.

The role of microRNAs in hepatocyte nuclear factor-4alpha expression and transactivation.

Hepatocyte nuclear factor (HNF)-4α is a key member of the transcription factor network regulating hepatocyte differentiation and function. Genetic and molecular evidence suggests that expression of HNF-4α is mainly regulated at the transcriptional level. Activation of HNF-4A gene involves the interaction of distinct sets of transcription factors and co-transcription factors within enhancer and promoter regions. Here we study the inhibitory effect of microRNAs (miRNAs) on the 3'-untranslated region (3'-UTR) of HNF-4A mRNA. The potential recognition elements of a set of miRNAs were identified utilizing bioinformatics analysis. The family members of miR-34 and miR-449, including miR-34a, miR-34c-5p and miR-449a, share the same target elements located at two distinct locations within the 3'-UTR of HNF-4A. The over-expression of miR-34a, miR-34c-5p or miR-449a in HepG2 cells led to a significant decrease in the activity of luciferase reporter carrying 3'-UTR of HNF-4A. The repressive effect on reporter activity was partially or fully eliminated when one or two of the binding site(s) for miR-34a/miR-34c-5p/miR-449a were deleted within the 3'-UTR. The protein level of HNF-4α was dramatically reduced by over-expression of miR-34a, miR-34c-5p and miR-449a, which correlates with a decrease in the binding activity of HNF-4α and transactivation of HNF-4α target genes. These results suggest that the recognition sites of miR-34a, miR-34c-5p and miR-449a within 3'-UTR of HNF-4A are functional. The mechanism of down-regulation of the binding activity and transactivation of HNF-4α by the miRNAs involves the decrease in HNF-4α protein level via miRNAs selectively targeting HNF-4A 3'-UTR, leading to the translational repression of HNF-4α expression.

Chest X-ray after tracheostomy is not necessary unless clinically indicated.

BACKGROUND: Chest radiography is routinely used post-tracheostomy to evaluate for complications. Often, the chest X-ray findings do not change clinical management. The present study was conducted to evaluate the utility of post-tracheostomy X-rays. METHOD: This retrospective review of 255 patients was performed at a single-center, university, level I trauma center. All patients underwent tracheostomy and were evaluated for postprocedure complications. RESULTS: Of the 255 patients, 95.7% had no change in postprocedure chest X-ray findings. New significant chest X-ray findings were found in 4.3% of patients, including subcutaneous emphysema, pneumothorax, and new significant consolidation. Only three of these patients required change in clinical management, and all changes were based on clinical presentation alone. CONCLUSIONS: Routine chest X-ray following tracheostomy fails to provide additional information beyond clinical examination. Therefore radiographic examination should be performed only after technically difficult procedures or if the patient experiences clinical deterioration. Significant cost savings and minimization of radiation exposure can be achieved when chest radiography after tracheostomy is performed exclusively for clinical indications.

Injury-induced changes in liver specific transcription factors HNF-1α and HNF-4α.

BACKGROUND: The hepatic acute phase response(APR) is an organ-specific response to a diverse array of insults and is largely under transcriptional control. Liver-specific transcription factors, hepatic nuclear factors (HNFs)-1α and 4α play important roles in maintenance of liver phenotype and function and their binding activity changes early after injury. However, their roles in modulation of the liver's response over time are not defined. MATERIALS AND METHODS: C57/BL6 mice were anesthetized and exposed to 95°C water for 10 s to create a 15% body surface area full-thickness burn. At specific time points, the mice were sacrificed. An ELISA for IL-6 was performed on serum and hepatic mRNA levels for fibrinogen-γ and serum amyloid A(SAA)-3 were obtained through polymerase chain reaction (PCR). Transcriptional factor binding activity was assessed with electrophoretic mobility shift assays. RESULTS: Serum IL-6 levels peaked at 3 h and fibrinogen-γ and SAA mRNA levels increased more than 6-fold at 12 h before returning to control levels at 48 h. The binding activity of HNF-4α and HNF-1α rapidly declined after injury (1.5 h) but recovered to near control level at 24 and 6 h, respectively. CONCLUSIONS: Changes in HNF-4α and HNF-1α binding occurred before changes in acute phase protein mRNA levels and were preceded by the peak in IL-6 levels. The rapid suppression and reconstitution of liver-specific transcription factor binding after injury may represent a mechanism that allows the normal liver phenotype to change and an injury-response phenotype to prevail. This mechanism in the liver's adaptive response to injury suggests a central role for both HNF-4α and HNF-1α in transcriptional regulation of the hepatic APR.

Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α.

BACKGROUND: Hepatocyte nuclear factor 4α (HNF4α), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4α in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4α knock-down in HepG2 cells. RESULTS: The expression of over five thousand genes in HepG2 cells is significantly changed with the dramatic reduction of HNF4α concentration compared to the cells with native levels of HNF4α. Over two thirds (71%) of genes that exhibit differential expression in response to cytokine treatment also reveal differential expression in response to HNF4α knock-down. In addition, we found that a number of HNF4α target genes may be indirectly mediated by an ETS-domain transcription factor ELK1, a nuclear target of mitogen-activated protein kinase (MAPK). CONCLUSION: The results indicate that HNF4α has an extensive impact on the regulation of a large number of the liver-specific genes. HNF4α may play a role in regulating the cytokine-induced inflammatory response. This study presents a novel function for HNF4α, acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver.

The effects of injury magnitude on the kinetics of the acute phase response.

BACKGROUND: The acute-phase response (APR) is critical to the body's ability to successfully respond to injury. A murine model of closed unilateral femur fractures and bilateral femur fracture were used to study the effect of injury magnitude on this response. METHODS: Standardized unilateral femur fracture and bilateral femur fracture in mice were performed. The femur fracture sites, livers, and serum were harvested over time after injury. Changes in mRNA expression of cytokines, hepatic acute-phase proteins, and serum cytokines overtime were measured. RESULTS: There was a rapid and short-lived hepatic APR to fracture injuries. The overall pattern in both models was similar. Both acute-phase proteins' mRNA (fibrinogen-γ and serum amyloid A-3) showed increased mRNA expression over baseline within the first 48 hours and their levels positively correlated with the extent of injury. However, increased severity of injury resulted in a delayed induction of the APR. A similar effect on the gene expression of cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-α) at the fracture site was seen. Serum IL-6 levels increased with increased injury and showed no delay between injury models. CONCLUSIONS: Greater severity of injury resulted in a delayed induction of the liver's APR and a diminished expression of cytokines at the fracture site. Serum IL-6 levels were calibrated to the extent of the injury, and changes may represent mechanisms by which the local organ responses to injury are regulated by the injury magnitude.

Hepatocyte nuclear factor-4α interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression.

Transthyretin is a negative acute phase protein whose serum level decreases during the acute phase response. Transthyretin gene expression in the liver is regulated at the transcriptional level, and is controlled by hepatocyte nuclear factor (HNF)-4α and other HNFs. The site-directed mutagenesis of HNF-4, HNF-1, HNF-3 and HNF-6 binding sites in the transthyretin proximal promoter dramatically decreases transthyretin promoter activity. Interestingly, the mutation of the HNF-4 binding site not only abolishes the response to HNF-4α, but also reduces significantly the response to other HNFs. However, mutation of the HNF-4 binding site merely affects the specific binding of HNF-4α, but not other HNFs, suggesting that an intact HNF-4 binding site not only provides a platform for specific interaction with HNF-4α, but also facilitates the interaction of HNF-4α with other HNFs. In a cytokine-induced acute phase response cell culture model, we observed a significant reduction in the binding of HNF-4α, HNF-1α, HNF-3ß and HNF-6α to the transthyretin promoter, which correlates with a decrease in transthyretin expression after injury. These findings provide new insights into the mechanism of the negative transcriptional regulation of the transthyretin gene after injury caused by a decrease in the binding of HNFs and a modulation in their coordinated interactions.