Laura L. McGhee

The ETO (MTG8) gene family

Cloning and characterization of the 8;21 chromosomal breakpoint identified AML1 on chromosome 21 and ETO (MTG8) on chromosome 8, and the resultant chimeric gene product, AML-1/ETO. The ETO gene family now includes three human members encoding proteins composed of four evolutionarily conserved domains termed nervy homology regions (NHR) 1-4. ETO associates with N-CoR/Sin3a/HDAC complexes in vivo and acts as a corepressor for the promyelocytic zinc finger protein. Moreover, ETO is nuclear matrix attached at sites coincident with histone deacetylase enzymes and mSin3a. These data suggest that ETO proteins function as transcriptional corepressors. This review focuses on the ETO gene family in terms of expression and function. Specifically, the role of ETO as a co-repressor will be detailed. Additionally, the impact of this recent discovery on treatment of t(8;21)-containing leukemia will be discussed.

The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members

BACKGROUND Predisposing factors for posttraumatic stress disorder (PTSD) include experiencing a traumatic event, threat of injury or death, and untreated pain. Ketamine, an anesthetic, is used at low doses as part of a multimodal anesthetic regimen. However, since ketamine is associated with psychosomatic effects, there is a concern that ketamine may increase the risk of developing PTSD. This study investigated the prevalence of PTSD in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) service members who were treated for burns in a military treatment center. METHODS The PTSD Checklist-Military (PCL-M) is a 17-question screening tool for PTSD used by the military. A score of 44 or higher is a positive screen for PTSD. The charts of all OIF/OEF soldiers with burns who completed the PCL-M screening tool (2002-2007) were reviewed to determine the number of surgeries received, the anesthetic regime used, including amounts given, the total body surface area burned, and injury severity score. Morphine equivalent units were calculated using standard dosage conversion factors. RESULTS The prevalence of PTSD in patients receiving ketamine during their operation(s) was compared with patients not receiving ketamine. Of the 25,000 soldiers injured in OIF/OEF, United States Army Institute of Surgical Research received 603 burned casualties, of which 241 completed the PCL-M. Of those, 147 soldiers underwent at least one operation. Among 119 patients who received ketamine during surgery and 28 who did not; the prevalence of PTSD was 27% (32 of 119) versus 46% (13 of 28), respectively (p = 0.044). CONCLUSIONS Contrary to expectations, patients receiving perioperative ketamine had a lower prevalence of PTSD than soldiers receiving no ketamine during their surgeries despite having larger burns, higher injury severity score, undergoing more operations, and spending more time in the ICU.

The Effect of Propranolol on Posttraumatic Stress Disorder in Burned Service Members

Posttraumatic stress disorder (PTSD) is reported to affect almost one third of the civilian burn patient population. Predisposing factors for PTSD include experiencing a traumatic event. Of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) soldiers returning home after deployment without injury, 17% reported cognitive symptoms of PTSD. The authors recent study of soldiers burned in OIF/OEF showed a PTSD prevalence of ∼30%, which is similar to civilian studies. Burns are characterized by hypermetabolism and increased catecholamine levels. &bgr;-Adrenergic receptor blocking agents, like propranolol, decrease catecholamine levels. Propranolol may reduce consolidation of memory and a prophylaxis for PTSD. This retrospective study examines the relationship between PTSD prevalence and propranolol administration. After institutional review board approval, propranolol received, number of surgeries, anesthetic/analgesic regimen, TBSA burned, and injury severity score were collected from patients charts. The military burn center received 603 soldiers injured in OIF/OEF, of which 226 completed the PTSD Checklist-Military. Thirty-one soldiers received propranolol and 34 matched soldiers did not. In propranolol patients, the prevalence of PTSD was 32.3% vs 26.5% in those not receiving propranolol (P = .785). These data suggest propranolol does not decrease PTSD development in burned soldiers. The prevalence of PTSD in patients receiving propranolol is the same as those not receiving propranolol. More research is needed to determine the relationship between PTSD and propranolol.

RUNX1 (AML-1) and RUNX2 (AML-3) cooperate with prostate-derived Ets factor to activate transcription from the PSA upstream regulatory region

The RUNX transcription factors (RUNX1, RUNX2, and RUNX3) play essential roles in hematopoiesis and skeletal development. Consistent with these roles in differentiation and cell cycle, the activity of both RUNX1 and RUNX3 is perturbed in cancer. To determine a role for the RUNX factors in prostate biology, we investigated the expression of RUNX factors in prostate epithelial cell lines and normal prostate tissue. RUNX1, RUNX2, and RUNX3 were expressed in both normal prostate tissue and an immortalized, non‐transformed cell line. We found that prostate cancer‐derived cell lines expressed RUNX1 and RUNX2, but not RUNX3. Next, we sought to identify prostate‐specific genes whose expression could be regulated by RUNX proteins. Four consensus RUNX sites are located within the prostate‐specific antigen (PSA) regulatory region. Chromatin immunoprecipitation (ChIP) analysis showed that RUNX1 is specifically bound to the PSA regulatory region in LNCaP cells. RUNX1 and RUNX2 activated the PSA regulatory region alone or cooperatively with prostate‐derived ETS factor (PDEF) and RUNX1 physically associated with PDEF. Taken together, our results suggest that RUNX factors participate in prostate epithelial cell function and cooperate with an Ets transcription factor to regulate PSA gene expression. J. Cell. Biochem.

Curcumin: a novel therapeutic for burn pain and wound healing

Introduction: Managing burn injury-associated pain and wounds is a major unresolved clinical problem. Opioids, nonsteroidal antiinflammatory drugs (NSAIDs), antidepressants and anticonvulsants remain the most common forms of analgesic therapy to treat burn patients. However, prolonged treatment with these drugs leads to dose escalation and serious side effects. Additionally, severe burn wounds cause scarring and are susceptible to infection. Recent encouraging findings demonstrate that curcumin, a major bioactive component found in turmeric, is a natural pharmacotherapeutic for controlling both severe burn pain and for improved wound healing. Areas covered: This article covers current pr-clinical and clinical studies on the analgesic and wound healing effects. Particular emphasis has been placed on studies aimed at developing improved curcumin delivery vehicles that increase its bioavailability. Based on the available evidence, a hypothesis is proposed that the dual beneficial effects of curcumin, analgesia and enhanced wound healing are mediated through common anti-inflammatory mechanisms. Expert opinion: Emerging studies have demonstrated that curcumin is a promising investigational drug to treat both pain and wounds. The adequate control of severe burn pain, particularly over the long courses required for healing, as well improvements in burn wound healing are unmet clinical needs.

The Relationship of Early Pain Scores and Posttraumatic Stress Disorder in Burned Soldiers

Early acute pain after injury has been linked to long-term patient outcomes, including the development of posttraumatic stress disorder (PTSD). Several studies have identified a negative correlation between early anesthetic/analgesic usage and subsequent development of PTSD. This retrospective study examined the relationship between early acute pain and severity of PTSD symptoms in soldiers with burn injuries. Of the soldiers injured in Overseas Contingency Operations who had pain scores recorded at admission to the Emergency Department, 113 had burn injuries. Of those transferred to the military burn center, 47 were screened for PTSD using the PTSD checklist-military (PCL-M) survey at least 1 month after injury. Soldiers with mild, moderate, and severe pain scores had similar Injury Severity Scores and TBSA burned (P = .339 and .570, respectively). However, there were significant differences in PCL-M scores between the mild and severe pain groups (P = .017). The pain levels positively correlated with the PCL-M score (rho = 0.41, P = .004) but not with injury severity markers (Injury Severity Score and TBSA). These data suggest that early acute pain may be related to increased PCL-M score and PTSD symptoms. The intensity of pain was not related to the injury severity, and these data also show no association between pain intensity and physiological measures, including blood pressure and heart rate. However, this is a small sample size, and many other factors likely influence PTSD development. Further study is necessary to explore the relationship between early acute pain and subsequent development of PTSD symptoms.

The Relationship of Intravenous Midazolam and Posttraumatic Stress Disorder Development in Burned Soldiers

BACKGROUND Midazolam, a short-acting benzodiazepine, is administered preoperatively and intraoperatively for amnesia and anxiolysis. Subsequently, patients often do not recall events which occurred while they were sedated. Recent studies have also reported retrograde facilitation after midazolam exposure. Posttraumatic stress disorder PTSD is based on memory of a traumatic event. Because of the concern that midazolam may enhance memory of the traumatic event in which soldiers were injured, we investigated the prevalence of PTSD in those burned soldiers who received perioperative midazolam and those who did not. We also investigated the intensity of the memories related to the traumatic event. METHODS After institutional review board approval, all charts of US soldiers who completed the PTSD Checklist-Military (PCL-M) screening tool (2004-2008) after admission to US Army Institute of Surgical Research were reviewed to determine the number of operations, the anesthetic regime, total body surface area (TBSA) burned, and Injury Severity Score (ISS). RESULTS The PCL-M was completed by 370 burned soldiers from Operation Iraqi Freedom/Operation Enduring Freedom. During surgery, 142 received midazolam, whereas 69 did not. The prevalence of PTSD was higher in soldiers receiving midazolam as compared with those who did not (29% vs. 25%) (p = 0.481). Both groups had similar injuries based on TBSA and ISS. Patients who received midazolam also had similar scores on PCL-M questions related to memory of the event. CONCLUSIONS Rates of PTSD are not statistically different in combat casualties receiving midazolam during intraoperative procedures. Intraoperative midazolam is not associated with increased PTSD development or with increased intensity of memory of the traumatic event. Patients receiving midazolam had similar injuries (TBSA and ISS) and underwent a similar number of operations as those not receiving midazolam.

The intraoperative administration of ketamine to burned U.S. service members does not increase the incidence of post-traumatic stress disorder.

AIM Patients with severe burns typically undergo multiple surgeries, and ketamine is often used as part of the multimodal anesthetic regimen during such surgeries. The anesthetic ketamine is an N-methyl-D-aspartate receptor antagonist that also provides analgesia at subanesthetic doses, but the psychoactive side effects of ketamine have caused concern about its potential psychological effects on a combat-wounded population. Post-traumatic stress disorder (PTSD) affects approximately 30% of burned U.S. service members injured in Operation Iraqi Freedom/Operation Enduring Freedom. A preliminary analysis by our research group reported that patients who received perioperative ketamine had a significantly lower prevalence of PTSD than those injured service members who did not receive ketamine. We have now expanded this research to examine the relationship between ketamine and PTSD development in a much larger population. METHODS A retrospective analysis on data from service members being treated for burns at the San Antonio Military Medical Center was conducted. Collected data included drugs received, injury severity score (ISS), total body surface area (TBSA) burned, length of hospital stay (LOS), number of intensive care unit days, number of surgeries, and PTSD Checklist-Military (PCL-M) scores and administration dates. Subjects were grouped based on intraoperative receipt of ketamine, and the groups were compared. The groups were binary for ketamine (yes or no), and dose of ketamine administered was not included in data analyses. Propensity score matching based on ISS and TBSA was performed to control for individual differences in burn severity. RESULTS Two hundred eighty-nine burned U.S. service members received the PCL-M at least 30 days after injury. Of these subjects, 189 received intraoperative ketamine, and 100 did not. Despite significantly greater injuries, as evidenced by significantly higher TBSA burned and ISS (p < 0.01), patients who received ketamine did not screen positive for PTSD at a different rate than those patients who did not (24% vs. 26.98%, p = 0.582). Patients receiving intraoperative ketamine also underwent a significantly greater number of surgeries, spent more time in the hospital, spent more days in the ICU, and received more morphine equivalent units (p < 0.0001). Propensity score matching based on ISS and TBSA resulted in a total subject number of 130. In the matched samples, subjects who received ketamine still underwent significantly more surgeries and experienced longer hospital stays (p < 0.0001). Again, there was no statistically significant difference in the incidence of a positive screen for PTSD based upon the receipt of ketamine (28% vs. 26.15%, p = 0.843). CONCLUSIONS Ketamine is often used in burn patients to reduce opioid usage and decrease the hemodynamic and respiratory side effects. Although this study does not show a benefit of ketamine on PTSD development that was identified in previous work with a smaller sample number, it does support the conclusion that ketamine does not increase PTSD development in burned service members.

State of the Science Review: Advances in Pain Management in Wounded Service Members over a Decade at War

Abstract The pain conditions and comorbidities experienced by injured service members and the challenge of pain management by the military medical system offer a unique opportunity to inform pain management and medical research. In this article, acute and chronic pain issues, current treatment options and limitations, as well as novel approaches to pain management are discussed within the context of combat casualty care, from the battlefield to hospitalization and rehabilitation. This review will also highlight the current pain management limitations that need to be addressed in future clinical and basic science research to improve care for our nation’s injured service members.

Use of Ultra Rapid Opioid Detoxification in the Treatment of Us Military Burn Casualties

BACKGROUND The purpose of this case series was to review the management of burn patients who requested ultrarapid opioid detoxification under anesthesia after extended duration of narcotic use for chronic pain related to burn injury. METHODS The treatment plan of six opioid-dependent burn patients was analyzed to assess the effectiveness of our detoxification practice to date. Demographic and clinical information was used to characterize the patient population served: age, burn size, injury severity, duration of narcotic use before detoxification intervention, and length of hospitalization stay. Daily narcotic consumption, in morphine equivalent units, was noted both before and after detoxification. RESULTS Six burn patients (average age, 31 years) underwent detoxification at the Burn Center during a hospitalization lasting between 1 day and 2 days. Average burn size was 38% total body surface area (range, 17-65); average Injury Severity Score was 30 (range, 25-38). Mean duration of narcotic use was 672 days (range, 239-1,156 days); average use of narcotics at time of detoxification was >200 units daily. Mean outpatient consumption for opioids after the intervention was minimal (<25 units/d). No complications were noted during any procedures. CONCLUSIONS The results of ultrarapid opioid detoxification under anesthesia suggests that it is safe and effective for treating opioid addiction in military burn casualties when a coordinated, multidisciplinary approach is used. Safety and effectiveness to date validate current practice and supports incorporation into clinical practice guidelines. Further clinical research is warranted to identify those patients who may benefit most from detoxification and to determine the timing of such treatment.