Military experience in the management of pelvic fractures from OIF/OEF.

INTRODUCTION: Pelvic fractures are a common occurrence in combat trauma. However, the fracture pattern and management within the most recent conflicts, i.e. Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), have yet to be described, especially in the context of dismounted complex blast injury. Our goal was to identify the incidence, patterns of injury and management of pelvic fractures. METHODS: We conducted a retrospective review on all combat-injured patients who arrived at our military treatment hospital between November 2010 and November 2012. Basic demographics, Young-Burgess fracture pattern classification and treatment strategies were examined. RESULTS: Of 562 patients identified within the study time period, 14% (81 of 562) were found to have a pelvic fracture. The vast majority (85%) were secondary to an improvised explosive device. The average Injury Severity Score for patients with pelvic fracture was 31±12 and 70% were classified as open. Of the 228 patients with any traumatic lower extremity amputation, 23% had pelvic fractures, while 30% of patients with bilateral above-knee amputations also sustained a pelvic fracture. The most common Young-Burgess injury pattern was anteroposterior compression (APC) (57%), followed by lateral compression (LC) (36%) and vertical shear (VS) (7%). Only 2% (nine of 562) of all patients were recorded as having pelvic binders placed in the prehospital setting. 49% of patients with pelvic fracture required procedural therapy, the most common of which was placement of a pelvic external fixator (34 of 40; 85%), followed by preperitoneal packing (16 of 40; 40%) and angioembolisation (three of 40; 0.75%). 17 (42.5%) patients required combinations of these three treatment modalities, the majority of which were a combination of external fixator and preperitoneal packing. The likelihood to need procedural therapy was impacted by injury pattern, as 72% of patients with an APC injury, 100% of patients with a VS injury and 25% of patients with an LC injury required procedural therapy. CONCLUSIONS: Pelvic fractures were common concomitant injuries following blast-induced traumatic lower extremity amputations. APC was the most common pelvic fracture pattern identified. While procedural therapy was frequent, the majority of patients underwent conservative therapy. However, placement of an external fixator was the most frequently used modality. Considering angioembolisation was used in less than 1% of cases, in the forward deployed military environment, management should focus on pelvic external fixation±preperitoneal packing. Finally, prehospital pelvic binder application may be an area for further process improvement.

Prediction of venous thromboembolism using clinical and serum biomarker data from a military cohort of trauma patients.

INTRODUCTION: Venous thromboembolism (VTE) is a frequent complication of trauma associated with high mortality and morbidity. Clinicians lack appropriate tools for stratifying trauma patients for VTE, thus have yet to be able to predict when to intervene. We aimed to compare random forest (RF) and logistic regression (LR) predictive modelling for VTE using (1) clinical measures alone, (2) serum biomarkers alone and (3) clinical measures plus serum biomarkers. METHODS: Data were collected from 73 military casualties with at least one extremity wound and prospectively enrolled in an observational study between 2007 and 2012. Clinical and serum cytokine data were collected. Modelling was performed with RF and LR based on the presence or absence of deep vein thrombosis (DVT) and/or pulmonary embolism (PE). For comparison, LR was also performed on the final variables from the RF model. Sensitivity/specificity and area under the curve (AUC) were reported. RESULTS: Of the 73 patients (median Injury Severity Score=16), nine (12.3%) developed VTE, four (5.5%) with DVT, four (5.5%) with PE, and one (1.4%) with both DVT and PE. In all sets of predictive models, RF outperformed LR. The best RF model generated with clinical and serum biomarkers included five variables (interleukin-15, monokine induced by gamma, vascular endothelial growth factor, total blood products at resuscitation and presence of soft tissue injury) and had an AUC of 0.946, sensitivity of 0.992 and specificity of 0.838. CONCLUSIONS: VTE may be predicted by clinical and molecular biomarkers in trauma patients. This will allow the development of clinical decision support tools which can help inform the management of high-risk patients for VTE.

A conceptual time window-based model for the early stratification of trauma patients.

Progress in the testing of therapies targeting the immune response following trauma, a leading cause of morbidity and mortality worldwide, has been slow. We propose that the design of interventional trials in trauma would benefit from a scheme or platform that could support the identification and implementation of prognostic strategies for patient stratification. Here, we propose a stratification scheme based on defined time periods or windows following the traumatic event. This 'time-window' model allows for the incorporation of prognostic variables ranging from circulating biomarkers and clinical data to patient-specific information such as gene variants to predict adverse short- or long-term outcomes. A number of circulating biomarkers, including cell injury markers and damage-associated molecular patterns (DAMPs), and inflammatory mediators have been shown to correlate with adverse outcomes after trauma. Likewise, several single nucleotide polymorphisms (SNPs) associate with complications or death in trauma patients. This review summarizes the status of our understanding of the prognostic value of these classes of variables in predicting outcomes in trauma patients. Strategies for the incorporation of these prognostic variables into schemes designed to stratify trauma patients, such as our time-window model, are also discussed.

Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood. Here we demonstrate for the first time that adipose-derived stromal/stem cells (ASCs) induced to an adipogenic or osteogenic lineage have differences in strand preference (-3p and -5p) for miRNAs originating from the same primary transcript. Furthermore, evaluation of miRNA expression in ASCs demonstrates alterations in both miRNA strand preference and 5'seed site heterogeneity. Additionally, we show that during stem cell differentiation there are alterations in expression of genes associated with the miRNA biogenesis pathway. Quantitative RT-PCR demonstrated changes in the Argonautes (AGO1-4), Drosha, and Dicer at intervals of ASC adipogenic and osteogenic differentiation compared to untreated ASCs. Specifically, we demonstrated altered expression of the AGOs occurring during both adipogenesis and osteogenesis, with osteogenesis increasing AGO1-4 expression and adipogenesis decreasing AGO1 gene and protein expression. These data demonstrate changes to components of the miRNA biogenesis pathway during stromal/stem cell differentiation. Identifying regulatory mechanisms for miRNA processing during ASC differentiation may lead to novel mechanisms for the manipulation of lineage differentiation of the ASC through the global regulation of miRNA as opposed to singular regulatory mechanisms.

The development of a rat model to investigate the formation of blast-related post-traumatic heterotopic ossification.

Currently, there is no animal model in which to evaluate the underlying physiological processes leading to the heterotopic ossification (HO) which forms in most combat-related and blast wounds. We sought to reproduce the ossification that forms under these circumstances in a rat by emulating patterns of injury seen in patients with severe injuries resulting from blasts. We investigated whether exposure to blast overpressure increased the prevalence of HO after transfemoral amputation performed within the zone of injury. We exposed rats to a blast overpressure alone (BOP-CTL), crush injury and femoral fracture followed by amputation through the zone of injury (AMP-CTL) or a combination of these (BOP-AMP). The presence of HO was evaluated using radiographs, micro-CT and histology. HO developed in none of nine BOP-CTL, six of nine AMP-CTL, and in all 20 BOP-AMP rats. Exposure to blast overpressure increased the prevalence of HO. This model may thus be used to elucidate cellular and molecular pathways of HO, the effect of varying intensities of blast overpressure, and to evaluate new means of prophylaxis and treatment of heterotopic ossification.

Amnion-derived multipotent progenitor cells support allograft tolerance induction.

Donor-specific immunological tolerance using high doses of bone marrow cells (BMCs) has been demonstrated in mixed chimerism-based tolerance induction protocols; however, the development of graft versus host disease remains a risk. Here, we demonstrate that the co-infusion of limited numbers of donor unfractionated BMCs with human amnion-derived multipotent progenitor cells (AMPs) 7 days post-allograft transplantation facilitates macrochimerism induction and graft tolerance in a mouse skin transplantation model. AMPs + BMCs co-infusion with minimal conditioning led to stable, mixed, multilineage lymphoid and myeloid macrochimerism, deletion of donor-reactive T cells, expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(regs)) and long-term allograft survival (>300 days). Based on these findings, we speculate that AMPs maybe a pro-tolerogenic cellular therapeutic that could have clinical efficacy for both solid organ and hematopoietic stem cell transplant applications.

Ethical dilemmas in patient selection for a new kidney transplant program in Guyana, South America.

INTRODUCTION: We describe ethical/moral issues in patient selection in a new living donor kidney transplant program in Guyana, South America. CASE REPORTS: Over 3 years, we screened 450 patients with chronic kidney disease among which 70 were suitable for kidney transplantation. There were five patients whose evaluations raised possible ethical dilemmas: one had nonadherence to dialysis; two of Guyanese origin living abroad wished to have the transplant performed in Guyana; a minor wished to donate to her mother; and another subject was considering commercialization of the transplant process. RESULTS: Since inception of the renal replacement program in 2008, we have completed 13 living kidney transplantations, 17 peritoneal dialysis placements, and 20 vascular access procedures. In the five patients wherein faced ethical dilemmas, three were rejected for consideration despite having living donors: one was nonadherent, the second excluded due to an attempt to commercialize the process, and the third, a minor who wished to donate to the mother. The other two patients were considered Guyanese ex-patriots acceptable for the program. DISCUSSION: The consequence of kidney failure in Guyana prior to introduction of renal replacement therapy was a virtual death sentence. These cases illustrate ethical dilemmas serving to throw into stark relief the implications of decisions made in a developing country versus those in a developing country.

Development of a Bayesian model to estimate health care outcomes in the severely wounded.

BACKGROUND: Graphical probabilistic models have the ability to provide insights as to how clinical factors are conditionally related. These models can be used to help us understand factors influencing health care outcomes and resource utilization, and to estimate morbidity and clinical outcomes in trauma patient populations. STUDY DESIGN: Thirty-two combat casualties with severe extremity injuries enrolled in a prospective observational study were analyzed using step-wise machine-learned Bayesian belief network (BBN) and step-wise logistic regression (LR). Models were evaluated using 10-fold cross-validation to calculate area-under-the-curve (AUC) from receiver operating characteristics (ROC) curves. RESULTS: Our BBN showed important associations between various factors in our data set that could not be developed using standard regression methods. Cross-validated ROC curve analysis showed that our BBN model was a robust representation of our data domain and that LR models trained on these findings were also robust: hospital-acquired infection (AUC: LR, 0.81; BBN, 0.79), intensive care unit length of stay (AUC: LR, 0.97; BBN, 0.81), and wound healing (AUC: LR, 0.91; BBN, 0.72) showed strong AUC. CONCLUSIONS: A BBN model can effectively represent clinical outcomes and biomarkers in patients hospitalized after severe wounding, and is confirmed by 10-fold cross-validation and further confirmed through logistic regression modeling. The method warrants further development and independent validation in other, more diverse patient populations.

Room temperature pulsatile perfusion of renal allografts with Lifor compared with hypothermic machine pump solution.

This pilot study compared the use of the Lifor Organ Preservation Medium (RTLF) at room temperature with hypothermic Belzer machine preservation solution (CMPS) and room in vitro temperature Belzer machine preservation solution (RTMPS) in a porcine model of uncontrolled donation after cardiac death (DCD). In this study, 5 porcine kidneys for each perfusate group were recovered under a DCD protocol. The kidneys were recovered, flushed, and placed onto a renal preservation system following standard perfusion procedures. The average flow rate for CMPS was 36.2 +/- 7.2549 mL/min, RTMPS was 90.2 +/- 9.7159 mL/min, and RTLF was 103.1 +/- 5.1108 mL/min. The average intrarenal resistance for CMPS was 1.33 +/- 0.1709 mm Hg/mL per minute, RTMPS was 0.84 +/- 0.3586 and RTLF was 0.39 +/- 0.04. All perfusion parameters were statistically significant (P < .05) at all time points for the CMPS when compared with both RTMPS and RTLF. All perfusion parameters for RTMPS and RTLF were equivalent for the first 12 hours; thereafter, RTLF became significantly better than RTMPS at 18 and 24 hours. It appears that both RTMPS and RTLF have equivalent perfusion characteristic for the initial 12 hours of perfusion, but LF continues to maintain a low resistance and high flow up to 24 hours. The results of this pilot study indicate that RTLF may represent a better alternative to pulsatile perfusion with CMPS and requires validation in an in vivo large animal transplant model.

Association between depression and nonadherence in recipients of kidney transplants: analysis of the United States renal data system.

INTRODUCTION: In our previous prospective single-center study, using validated self-administered instruments, we demonstrated correlation between depression and nonadherence in recipients of kidney transplants. The purpose of this study was to confirm our finding that depression was associated with nonadherence in a large database of transplant recipients for which we used the United States Renal Data System (USRDS). METHODS: We conducted a retrospective cohort study of 32,757 Medicare primary renal transplant recipients in the USRDS who underwent transplantation from January 1, 2000 to July 31, 2004 and were followed up through December 31, 2004, assessing Medicare claims showing depression and nonadherence based on codes of the International Classification of Diseases, 9th Revision. RESULTS: Logistic regression analysis (adjusted hazards ratio 1.69 with 95% confidence interval, 1.48-1.92) and log rank test (P < .0005) showed that there was a strong association of depression and nonadherence. Depression was associated with nonadherence, irrespective of the time of depression, whether it was pretransplantation (P < .001) or posttransplantation (P < .001). Nonadherence was also associated with black race (P < .001), younger age (P < .001), less HLA mismatch (P < .005), recipients of living kidneys and patients who underwent transplantation a longer time ago (P < .001). Furthermore, patients with 12 or less years of education were more nonadherent (P < .001). Among the transplant donor factors we investigated, donor black race (P < .001) and expanded criteria donor kidneys were strongly associated with nonadherence (P < .001). However, donor age and delayed graft function were not significantly associated with nonadherence. CONCLUSIONS: Future clinical trials of immunosuppressive therapy should assess the impact of depression on graft survival.

Evaluation of lyophilized platelets as an infusible hemostatic agent in experimental non-compressible hemorrhage in swine.

INTRODUCTION: Human lyophilized platelets hold promise as a novel hemostatic infusion agent for the control of traumatic hemorrhage. Rehydrated, lyophilized platelets (Stasix) were investigated as an infusible hemostatic agent in experimental non-compressible hemorrhage, using a porcine liver injury model. METHODS: Yorkshire swine underwent a grade III liver injury and uncontrolled bleeding. After 15 min, animals were infused with Stasix (n = 10) or normal saline vehicle (n = 10). At 2 h, the liver was repaired, and the animals were monitored for another4 h. Resuscitation, including blood transfusion, was administered during the hospital phase. Laboratory data, including arterial blood gas, complete blood count, thromboelastography (TEG), and coagulation parameters, were collected. All animals underwent necropsy with complete histopathologic examination. RESULTS: Overall survival in the Stasix group [8/10 (80%)] was significantly higher than in the control group [2/10 (20%)] (P = 0.023). Mean total blood loss index (g kg(-1)) was lower in Stasix-treated animals (22.2 +/- 3.5) than in control animals (34.7 +/- 3.4) (P = 0.019). Hemodynamic parameters were improved in the Stasix group, and a trend towards higher hemoglobin and lower lactate was observed. Coagulation and TEG parameters were not different between the groups. One surviving animal in the Stasix group had evidence of thrombi on necropsy. CONCLUSIONS: This is the first reported study to evaluate rehydrated, lyophilized platelets as an infusible hemostatic agent for non-compressible hemorrhage. Stasix improved survival and reduced blood loss in a liver injury porcine model. However, evidence of thrombotic complications warrants further investigation prior to human use in the setting of traumatic hemorrhage.

Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates.

BACKGROUND: Allogeneic skin transplantation remains a rigorous test of any immune intervention designed to prevent allograft rejection. To date, no single, clinically available immunosuppressant has been reported to induce long-term primary skin allograft survival in primates. We have previously shown that treatment with the humanized CD154-specific monoclonal antibody, humanized 5C8 (hu5C8), induces long-term renal allograft survival in nonhuman primates. In this study, we evaluated the efficacy of hu5C8 in preventing primary skin allograft rejection in rhesus monkeys. METHODS: Ten rhesus monkeys were transplanted with full-thickness skin allografts mismatched at both class I and class II major histocompatibility loci. Of these, two were given no treatment, five were treated with hu5C8 alone, and three received hu5C8 combined with whole blood donor-specific transfusion (DST). All recipients also received skin autografts for comparison. Animals were followed by inspection, serial biopsy, mixed lymphocyte culture, and alloantibody determination. RESULTS: Treatment with hu5C8 alone or hu5C8 plus DST greatly prolonged allograft survival. Rejection occurred in the untreated group within 7 days. Mean allograft survival in the monotherapy hu5C8 group was >236 days and in the DST group was >202 days; these differences were not significant. Rejection eventually occurred in most animals. Allograft survival was not correlated with the development of T cell hyporesponsiveness in mixed lymphocyte culture. Rejection was not predicted by the development of donor-specific alloantibody. CONCLUSION: These results show that treatment with the CD154-specific monoclonal antibody, hu5C8, greatly delays the onset of acute skin allograft rejection.

Induction therapy with monoclonal antibodies specific for CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates.

CD80 and CD86 (also known as B7-1 and B7-2, respectively) are both ligands for the T cell costimulatory receptors CD28 and CD152. Both CD80 and CD86 mediate T cell costimulation, and as such, have been studied for their role in promoting allograft rejection. In this study we demonstrate that administering monoclonal antibodies specific for these B7 ligands can delay the onset of acute renal allograft rejection in rhesus monkeys. The most durable effect results from simultaneous administration of both anti-B7 antibodies. The mechanism of action does not involve global depletion of T or B cells. Despite in vitro and in vivo evidence demonstrating the effectiveness of the anti-B7 antibodies in suppressing T cell responsiveness to alloantigen, their use does not result in durable tolerance. Prolonged therapy with murine anti-B7 antibodies is limited by the development of neutralizing antibodies, but that problem was avoided when humanized anti-B7 reagents are used. Most animals develop rejection and an alloantibody response although still on antibody therapy and before the development of a neutralizing antibody response. Anti-B7 antibody therapy may have use as an adjunctive agent for clinical allotransplantation, but using the dosing regimens we used, is not a tolerizing therapy in this non-human primate model.

Upper cervical chiropractic management of a patient with Parkinson's disease: a case report.

OBJECTIVE: To discuss the use of upper cervical chiropractic management in managing a single patient with Parkinson's disease and to describe the clinical picture of the disease. CLINICAL FEATURES: A 60-year-old man was diagnosed with Parkinson's disease at age 53 after a twitch developed in his left fifth finger. He later developed rigidity in his left leg, body tremor, slurring of speech, and memory loss among other findings. INTERVENTION AND OUTCOME: This subject was managed with upper cervical chiropractic care for 9 months. Analysis of precision upper cervical radiographs determined upper cervical mis-alignment. Neurophysiology was monitored with paraspinal digital infrared imaging. This patient was placed on a specially designed knee-chest table for adjustment, which was delivered by hand to the first cervical vertebrae, according to radiographic findings. Evaluation of Parkinson's symptoms occurred by doctor's observation, the patient's subjective description of symptoms, and use of the Unified Parkinson's Disease Rating Scale. Reevaluations demonstrated a marked improvement in both subjective and objective findings. CONCLUSION: Upper cervical chiropractic care aided by cervical radiographs and thermal imaging had a successful outcome for a patient with Parkinson's disease. Further investigation into upper cervical injury as a contributing factor to Parkinson's disease should be considered.

Potential of costimulation-based therapies for composite tissue allotransplantation.

Clinical success has not been routinely achieved for composite tissue allotransplantation (CTA). Although most of the technical details of CTA have been overcome, the immunological aspects of these procedures have proved complex. Many traumatic conditions requiring CTA contraindicate acute global immunosuppression. Moreover, the risk of long-term immunosuppression is difficult to reconcile with non-life-threatening defects that can be adequately palliated. Recently, several successful immunomodulating strategies have been introduced for solid organ transplantation. They include therapies that alter costimulatory signals at engraftment. One approach, using treatment with a monoclonal antibody directed against CD154, has shown promise in rodent and nonhuman primate models and is discussed as a potential strategy for CTAs.

Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro.

The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL-60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.