Surgery

Objective: Thoracic aortic injuries following blunt trauma mechanisms are associated with high mortality rates. For survivors transported to a hospital, Chest X-Rays (CXR) have traditionally been used as a "screening modality" to decide on the need for further diagnostic testing. The liberal use of Spiral Chest CT angiography (CTA) following high speed crashes regardless of CXR findings has been advocated by some. We set to determine the adequacy of utilizing CXR alone as a screening tool for Blunt thoracic aortic injury (BTAI) at a level I Trauma Center. Methods: All patients with BTAI diagnosed clinically or at autopsy admitted to a Level I Trauma Center between Jan1998 and Dec 2004 were identified. The CXRs of these patients and those of a cohort of Blunt trauma patients with an ISS Ͼ 15 (control group) in the same time period were reviewed at a single session by 4 active Trauma surgeons who were blinded to the diagnosis. Each of the trauma surgeons decided based on each film viewed if they would have proceeded to chest CTA, conventional aortic angiography or required no further studies to rule out BTAI. Results: In the 7 year period, there were 83 patients with BTAI. CXRs were available for 47 patients -all motor vehicle crash victims. The CXRs of these patients and those of 49 controls were reviewed. A total of 96 CXRs were viewed by the 4 surgeons (24 each). Of the 47 patients with BTAI, the surgeons chose to proceed to Chest CTA in 38 patients (81%), conventional aortography in 2 patients (4%) and no further testing in 7 patients (15%). A widened mediastinum was the most common CXR feature chosen to decide the need for further studies -34/47(72%). Loss of AP window (38%), indistinct aortic knob (28%) and pleural capping (4%) were other reasons. Patients with BTAI were more likely to have a positive CXR -40/47 when compared with the controls-25/49 -statistically significant by ?2 testing (pϽ .001). CXR sensitivity was 85.1%, specificity -51%, positive predictive value -62.5% and negative predictive value -78.1%. Conclusions: CXR is sensitive as a sole screening test for BTAI but failed to identify up to 15% of patients with injuries. The liberal use of Chest CTA especially following high speed motor vehicle crashes is highly recommended to minimize the incidence of missed thoracic aortic injuries. A widened mediastinum was the most frequent criterion used to indicate a positive CXR.

BACKGROUND: Thoracic needle decompression is lifesaving in tension pneumothorax. However, performance of subsequent tube thoracostomy is questioned. The needle may not enter the chest, or the diagnosis may be wrong. The aim of this study was to test the hypothesis that routine tube thoracostomy is not required.

Background: Primary closure after trauma celiotomies is not always accomplished. We reviewed our experience with delayed closure in trauma patients. Methods: Prospective data were collected on patients who had damage-control celiotomy and were discharged with open abdomens. The time to closure, repair methods, and complication data also were compiled. Results: In the 6-year period, 84 patients underwent damage-control celiotomy. Thirty-one patients died and 33 patients had early closure. Twenty patients had closure during a subsequent hospitalization (mean time to delayed closure, 193 days): 8 patients (40%) had component separation, 3 (15%) had component separation with mesh, 4 (20%) had mesh alone, and primary closure occurred in 5 (25%). Nine patients (45%) had complications such as wound and mesh infections, hernias, and fistulas. Repair before or after 6 months showed no statistically significant difference for the presence of complications or enterotomies (P ϭ .64 and .5743, respectively). Conclusions: Open-abdomen reconstruction presents significant challenges. Closure within 6 months is possible; the presence of complications is not affected by early repair.

The theoretical efficacy of hypertonic saline (HS) resuscitation for hemorrhagic shock purportedly stems from the osmolar extraction of intracellular fluid into the plasma. This hypothesis presumes a concomitant expansion of the interstitial fluid space. Colloid resuscitation, in theory, expands the plasma volume by extracting interstitial fluid. These hypotheses were tested in a canine-modified Wigger's model of hemorrhagic shock. Forty, male, splenectomized dogs were anesthetized and instrumented. Animals underwent a baseline equilibration period followed by shock for 120 minutes. Each animal was randomized to one of four groups and received equal amounts of Na+ either as lactated Ringer's (LR) solution, 10% dextran 40 (Dex) in normal saline, 7.5% saline (HS), or 7.5% saline plus Dex (HSD). Parameters measured at baseline, shock, and at postresuscitation 30 minutes, 60 minutes, 90 minutes, and 120 minutes, included: mean pressure (MAP), output, pulmonary capillary wedge pr...

Anthrax lethal toxin is one of the fundamental components believed to be responsible for the virulence of Bacillus anthracis. In order to find novel compounds with anti-lethal toxin properties, we used a cell-based assay to screen a collection of approximately 500 small molecules. Nineteen compounds that blocked lethal toxinmediated killing of RAW 264.7 macrophages were identified, and we report here on the characterization of the two most potent antitoxic compounds, amiodarone and bepridil. These drugs are used to treat cardiac arrhythmia or angina in humans at doses similar to those that provide protection against lethal toxin in vitro. Our results support a model whereby the antitoxic properties of both drugs result from their ability to block endosomal acidification, thereby blocking toxin entry. Amiodarone was tested in vivo and found to significantly increase survival of lethal toxin-challenged Fischer rats.

Viral protein R (Vpr), one of the human immunodeficiency virus type 1 (HIV-1) accessory proteins, contributes to multiple cytopathic effects, G 2 cell cycle arrest and apoptosis. The mechanisms of Vpr have been intensely studied because it is believed that they underlie HIV-1 pathogenesis. We here report a cell-based small molecule screen on Vpr induced cell death in the context of HIV-1 infection. From the screen of 504 bioactive compounds, we identified damnacanthal (Dam), a component of noni fruit, as an inhibitor of Vpr induced cell death. Our studies illustrate a novel efficient platform for drug discovery and development in anti-HIV therapy which should also be applicable to other viruses.

The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brain-derived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redox-mediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair.

Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, N-arachidonoyl dopamine, N-oleoyldopamine (OLDA), and N-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types. Mol Cancer Ther; 10(10); 1818-28. Ó2011 AACR.

Oct4 is a key component of the molecular circuitry which regulates embryonic stem cell proliferation and differentiation. It is essential for maintenance of undifferentiated, pluripotent cell populations, and accomplishes these tasks by binding DNA in multiple heterodimer and homodimer configurations. Very little is known about how formation of these complexes is regulated, or the mechanisms through which Oct4 proteins respond to complex extracellular stimuli which regulate pluripotency. Here, we provide evidence for a phosphorylation-based mechanism which regulates specific Oct4 homodimer conformations. Point mutations of a putative phosphorylation site can specifically abrogate transcriptional activity of a specific homodimer assembly, with little effect on other configurations. Moreover, we performed bioinformatic predictions to identify a subset of Oct4 target genes which may be regulated by this specific assembly, and show that altering Oct4 protein levels affects transcription of Oct4 target genes which are regulated by this assembly but not others. Finally, we identified several signaling pathways which may mediate this phosphorylation and act in combination to regulate Oct4 transcriptional activity and protein stability. These results provide a mechanism for rapid and reversible alteration of Oct4 transactivation potential in response to extracellular signals.

Background. The purpose of this study was to review our 15-year experience in the treatment of blunt splenic injury in adults. Our hypothesis was that the implementation of a change in practice, with stress on splenic preservation and splenic artery embolization for the management of splenic injury, would result in improved splenic salvage rates without negatively affecting mortality rates. Methods. A retrospective cohort analysis was performed on all consecutive adults with blunt splenic injury who were admitted to a Level One Trauma Center. The cohorts were defined by 2 separate 7.5-year periods (1991-1998 and 1998-2005). Results. Six hundred twenty-five patients with blunt splenic trauma were identified; 403 patients who were treated from 1998 to 2005 were compared with 222 patients whose cases had been reviewed previously (1991 to 1998). The present cohort differed in age (35 vs 40 years; P Ͻ .001) and injury severity score (27 vs 21; P Ͻ .0001). Nonoperative treatment was implemented in 136 patients (61%) in the initial cohort and 344 patients (85%) in the present cohort. The frequency of splenic artery embolization increased from 2.7% to 22.6% (P Ͻ .001). The success of nonoperative management increased from 77% to 96% (P Ͻ .001); the splenic salvage rate for all patients improved from 57% to 88% (P Ͻ .0001). Hospital mortality rates decreased from 12% to 6% (P Ͻ .001), and the mean hospital length of stay decreased from 15 to 9 days (P Ͻ .001). Conclusion. These results demonstrate that the success of nonoperative management and the splenic preservation for blunt injury has improved over time. This improvement correlated with a greater use of splenic artery embolization. (Surgery 2006;140:625-32.)

A medical imaging technique known as Indocyanine Green (ICG) fluorescence cholangiography can potentially improve safety and reduce cost in minimally invasive surgery, but is not widely used. Refinement of existing ICG imaging prototypes would facilitate more widespread use of the technology. The goal of this research was to optimize the display of an ICG imaging prototype, post-hoc. Images produced by the prototype were systematically manipulated by altering brightness and contrast levels, and corresponding changes in perceived image quality were measured. Results showed that perceived image quality increased when either brightness or contrast of the original image was increased by 10% and 20%, respectively. With high quality images, similar manipulations of brightness or contrast did not improve the perceived image quality, nor did they degrade the perceived image quality significantly. These adjustments are expected to increase the overall clinical utility of the prototype as the perceived quality of the images most in need of improvement was enhanced.

standing emotions and managing emotions. The four subscales of the WLEIS are self-perception of emotions, other-perceptions of emotions, understanding emotions, and regulation of emotions. Results: Of the 247 students approached, 152 agreed to participate (response rate 62%). The mean age was 24 (standard deviation [sd]ϭ3), 61 (40%) were male, and 75 (49%) were White. The MSCEIT provides scores on a normative scale, where the normative mean is 100 and the normative sd is 15 on all subcales and on the overall scale. Thus, we expected to find medical student means greater than 100. Instead, medical student means were similar to the general population on all 4 subscales and overall (means 98.31 -100.54), although medical students were less variable than the general population (sds ranged from 7.9 to 12.9). The WLEIS does not have extensive norms. However, medical student scores tended to be higher than available comparison groups (overall mean 5.06 vs 4.63), and again, variance of medical student scores was lower. Although both the MSCEIT and the WLEIS purport to measure emotional intelligence, the correlations between the MSCEIT and WLEIS were lower than expected in the subscales (range 0.00 -0.24), and the correlation between overall scores was 0.18. The MSCEIT was developed as an ability test (e.g., what is the person in this picture feeling?), but the WLEIS was developed as a direct self-report measure (e.g., how good are you at controlling your emotions?). Because of this difference in item types, it is perhaps not too surprising that the scores on the two tests show a small correlation. Conclusion: By two measurements, medical students appear similar to the general population in terms of emotional intelligence. This finding was particularly strong for the MSCEIT, which does not depend on a direct self-evaluation of emotional intelligence. Research is needed to understand the impact of emotional intelligence on performance in the third and fourth year of medical school, and also on how to better elucidate emotional intelligence of medical students.