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Intravascular Ultrasonography Analysis of the Everolimus-Eluting Stent in Coronary Chronic Total Occlusions
(2013-01-22) Navara, Rachita; Brilakis, Emmanouil S.; Rangan, Bavana
PURPOSE: Coronary artery disease (CAD) is consistently the number one cause of death for both men and women worldwide. Of the millions of patients diagnosed with CAD, approximately 1 in 5 is found to have a coronary artery that has been 100% blocked for three months or longer, representing the most formidable subset of atherosclerosis: chronic total occlusion (CTO). While drug-eluting stents have demonstrated success in patients with less severe coronary atherosclerosis, little is known about their efficacy in CTOs, which are currently managed by bare metal stents associated with high rates of restenosis. The present study aims to evaluate the effectiveness of the novel Everolimus-Eluting Stent (EES) in CTOs, using intravascular ultrasonography (IVUS) to assess restenosis. METHODS: One hundred consecutive CTO patients who were successfully treated using EES at the Dallas VAMC between 2009-2012 were enrolled in the AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO trial: NCT01012869). Patients underwent follow-up angiography and IVUS imaging at 8 months and clinical follow-up for up to 12 months. The primary endpoint of this study, binary angiographic restenosis, was defined as >50% minimum lumen diameter stenosis, as assessed by 8-month follow-up quantitative coronary angiography in the treated coronary segment. The primary endpoint of the IVUS analysis was 8-month in-stent neointimal hyperplasia (NIH) volume, defined as the difference between stent and lumen volume. RESULTS: Of the 226 patients who underwent CTO percutaneous coronary intervention (PCI) during the enrollment period, 129 were eligible and 100 agreed to participate. Mean age was 64±7 years, and 99% of the patients were men. Patients had high prevalence of hypertension (91%), hyperlipidemia (90%), diabetes (47%), prior myocardial infarction (51%), and prior PCI (21%). The CTO target vessel was the right coronary artery (70%), left anterior descending artery (16%), circumflex (13%), or left main (1%). The mean number of implanted stents was 3.3±1.3, mean stent diameter was 2.8±1.1 mm, mean stent length was 85±34 mm, and 94 patients had overlapping stents. Binary angiographic restenosis was 45%. Follow-up IVUS analysis of 55 patients revealed low median minimum lumen area (3.3 mm2) and high NIH volume (103.6 mm3). CONCLUSIONS: Everolimus-eluting stent implantation in CTOs is associated with high rates of angiographic restenosis and high NIH volume, suggesting the need for novel therapeutic strategies to improve outcomes in this complex and challenging lesion subgroup.
Obesity and Outcomes Following Burns in the Pediatric Population
(2013-01-22) Ross, Evan; Burris, Agnes; Murphy, Joseph T.
PURPOSE: While obesity is associated with increased mortality and decreased functional outcomes in adult burn patients, the ramifications of larger than average body size in the pediatric burn population are less well understood. Building on the finding that obese pediatric burn patients have a significantly longer length of hospital stay than their lean counterparts, the present study sought to determine whether obesity was associated with poor outcomes following burn injuries. METHODS: Data on patients ≤ 18 years of age who were admitted to a large regional burn unit between the years of 2000 and 2010 and for whom height and weight data was available (n=540) was collected from the hospital's burn database. Using the definition of obesity as ≥ 95thpercentile of weight for height according to the World Health Organization growth charts (< 2 years of age) or BMI for age according to the Centers for Disease Control growth charts (2 to 18 years of age), outcomes were compared between thermally-injured children classified as obese (n=155) and those classified as non-obese (n=385). Outcome parameters examined were total body surface area injury (TBSA), % full thickness injury, days in the ICU, non-ICU hospital days, days requiring mechanical ventilation, incidence of sepsis, pneumonia, number of operations, and overall mortality. All data was collected in accordance with IRB (#STU 032012-032) regulations. RESULTS: Obese and non-obese thermally injured children did not differ significantly with respect to TBSA, percentage of full thickness burn, or overall mortality. However, these groups were significantly different with respect to age (obese=7.26±0.46 years, non-obese=9.36±0.32 years, p=0.00015) and days requiring mechanical ventilation (obese=4.86±1.28 days, non-obese=2.72±0.49 days, p=0.029). When considering only those thermally injured children admitted to the BICU without inhalation injury (n=177), the obese (n=46) and non-obese (n=131) groups did not differ significantly with respect to TBSA, percentage of full thickness burn, or overall mortality. However, significant differences between these groups were noted for number of days spent in the ICU (obese=18.59±5.12 days, non-obese=9.38±1.79 days, p=0.017) and number of days requiring mechanical ventilation (obese=11.65±3.87 days, non-obese=3.87±0.83 days, p=0.002). CONCLUSION: These data show thermally injured obese pediatric patients required longer and more intensive medical support in the form of BICU care and respiratory intervention. Counter to findings in adult populations, differences in mortality were not observed. Collectively, these findings suggest obesity as a risk factor for increased morbidity in the pediatric burn population.
A Quantitative Study of Parathyroid (1-34) and Bone Morphogenetic Protein-2 on Spinal Fusion Outcomes in a Rabbit Model of Lumbar Dorsolateral Intertransverse Process Arthrodesis
(2013-01-22) Hwang, Lee; Santiago-Dieppa, David; Lina, John; Liauw, Jason; Witham, Timothy
INTRODUCTION: Lumbar spinal fusion is a common neurosurgical procedure. Over 250,000 lumbar spinal fusion operations are performed annually in the U.S. and, by far, dorsolateral intertransverse process arthrodesis (DIPA) is the most common type of fusion technique performed in the lumbar spine. Unfortunately, the rate of non-fusion (pseudoarthrosis) has been reported to be as high as 35%. Pseudoarthrosis is also one known cause of Failed Back Surgery Syndrome (FBSS), which is characterized by chronic back pain that is often unbearable and debilitating to the patient. In the following study, our goal was to explore methods of improving the rate of fusion by first establishing an accurate animal model - more specifically the New Zealand White rabbit model, which has a pseudoarthrosis rate nearly identical to that of humans as well as similar spinal anatomy. We also aimed to assess the effects of osteoinductive agents PTH (1-34) and rhBMP-2 on bone turnover after DIPA spinal fusion in the rabbit model. We hypothesize that the use of both PTH (1-34) and rhBMP-2 has a synergistic effect on stiffness and composition of the bone fusion mass. METHODS: To elucidate the potential relationship between PTH (1-34) and rhBMP-2, 24 NZW rabbits will be assigned to each of the following 4 groups: spinal fusion with iliac crest autograft and saline-based injections (control); spinal fusion with rhBMP-2 matrix alone; spinal fusion with iliac crest autograft and PTH (1-34) injections alone; spinal fusion with rhBMP-2 matrix and PTH (1-34) injections. Each specimen will undergo manual palpation, radiographic analysis, four-point non-destructive biomechanical testing, and histological analysis. PRELIMINARY RESULTS: Based on the CT reconstructions, the spine fusion rates for the control group (n = 9) and the PTH (1-34) group (n = 5) were 44% and 60%, respectively. Although manual palpation is used as the standard measure of fusion, radiographic analysis proved more effective in differentiating fused masses based on bone, not fibrous tissue. In both the PTH (1-34) and control groups, lateral bending in both the right and left orientations proved to be the stiffest testing orientation. CONCLUSIONS: Preliminary data suggests that PTH (1-34) may enhance both the composition and mechanical properties of L5-L6 fusion in rabbits. As demonstrated by biomechanical testing, the enhanced bone formation in the PTH (1-34) group may be responsible for an increase in stiffness. We expect that data from the additional two groups will allow for further investigation of individual efficacies as well as any synergistic effects of PTH (1-34) and rhBMP-2.
Severe Remote Burn Injury Results in Early, Elevated Markers of Alzheimer's Disease
(2013-01-22) Suleman, Leyya; Gatson, Joshua; Maass, David; Warren, Victoria; Wolf, Steven; Minei, Joseph; Pepe, Paul; Idris, Ahamed; Wigginton, Jane
BACKGROUND: Prior studies have found that patients with severe burns may suffer neurocognitive decline. While these observations are frequently attributed to psycho-social causes, our lab recently reported that remote burn injury is associated with significant brain changes, including new data revealing a substantial, rapid and sustained (30 min - 45 day) increase in rat brain inflammation following remote burns. Other acute brain injury processes, such as traumatic brain injury and stroke have been associated with an accelerated accumulation of Aβ40, Aβ42,, and Tau, and ultimately a clinical picture of early-onset Alzheimer's disease (AD). We hypothesized that similar AD-like processes may be triggered in the brain following remote, severe burn injury. METHODS: In this study, 44 male rats received a 3° 40% TBSA back/flank scald burn by immersion (divided into 6 harvest time points), with an additional 8 receiving a sham burn (immersion in room temperature water), totaling 52 rats. Brains of those burned were harvested at 1, 6, 12, 24 hours, 7 days (n=8/each time point) and 45 days (n=4/time point) after injury. Brain tissue IL-6, TNF-α, IL-1β, Aβ40, Aβ42, total Tau and phosphorylated Tau were measured using ELISA methods. RESULTS: Burned animals had significantly increased markers of inflammation and AD at each time point measured compared with those receiving a sham burn injury (see table for data at 1 hour and 45 days). CONCLUSIONS: Severe remote burn injury not only results in early, robust, and sustained neuroinflammation, but also significantly increases brain levels of Aβ40, Aβ42, and Tau. This novel finding may pave the way for future brain-preserving interventional trials in burn patients, as well as provide a more rapid and effective testing-ground for new therapies aimed at slowing and/or preventing AD.
Discordance in OR Safety Attitudes: Does Safety Lie in the Eye of the Beholder?
(2013-01-22) Clayton, Joshua; Bernstein, Ira H.; Chen, Li Ern
BACKGROUND: Efforts to improve operating room (OR) safety can be optimized if we understand the safety attitudes of those who work in the OR. We sought to describe the safety attitudes of current OR personnel. METHODS: Survey: The Safety Attitudes Questionnaire (OR Version) was modified to develop a shorter, 23-item anonymous electronic survey to measure attitudes toward OR safety. Respondents were also asked to rate the quality of their communication with other providers who care for surgical patients. Participants: Surgeons and proceduralists, anesthesia providers, and nurses who worked in perioperative services and on the surgical wards. Data: Respondents' demographic information was collected. Survey responses were on a 5-point Likert scale, where a higher score reflected a better safety attitude or higher quality communication, as appropriate. Analysis: Classical test theory and factor analysis. ANOVA was used to compare responses between surgeons/proceduralists, anesthesia providers and nurses. Results are reported as mean (SD). RESULTS: Survey: The 23 survey items reliably measured attitudes toward OR safety (α=0.92). Respondents: 170 staff responded to the survey (55 surgeons, 29 anesthesia providers, and 86 nurses). Mean age of respondents was 40.1 (10.9) years. Median duration of experience was 8 years (range: <1 to 42). Attitudes toward OR safety culture: The mean score on the 23-item survey for all respondents was 3.95(0.68). Scores differed significantly among provider groups (p=0.0009). Surgeons' mean score was 0.57 higher than anesthesia providers' (p<0.05), and 0.33 higher than nurses' (p<0.05). Quality of communication: The surgeons' perception of the quality of their communication with nurses was higher than the nurses' perception of the quality of their communication with surgeons (3.95 vs. 3.05, p<0.0001). Similarly, surgeons' perception of the quality of their communication with anesthesia providers was higher than the anesthesia providers' perception of their communication with surgeons (4.43 vs. 3.81, p=0.0015). However, the anesthesia providers' perception of the quality of their communication with nurses did not differ from the nurses' perception of the quality of their communication with anesthesia providers (3.62 vs. 3.68, p=0.77). CONCLUSION: The abbreviated questionnaire is a reliable measure of OR safety attitudes. Surgeons had the most positive OR safety attitude, but there was consistent discrepancy in the way surgeons rated their communication with other provider groups - surgeons reported that the quality of their communication with anesthesia providers and nurses was better than how these other groups rated their communication with surgeons. This finding calls to question the validity of the surgeons' survey scores, and whether they truly had the best safety attitude.
Folate Receptor Beta Targeting for In Vivo Optical Imaging of Head and Neck Squamous Cell Carcinoma
(2013-01-22) Sun, Joel; Thibodeaux, Joel; Huang, Gang; Wang, Yiguang; Gao, Jinming; Low, Philip S.; Sumer, Baran D.
OBJECTIVE: The folate receptor (FR) is a high-affinity folic acid binding endocytic receptor uncommonly expressed in normal tissues. The α isoform (FR-α) is overexpressed in a variety of epithelial neoplastic cells. In contrast, functional expression of the β isoform (FR-β) is limited to activated macrophages. Importantly, in many malignancies FR serves as a target for the delivery of tumor specific drugs and imaging markers. Folic acid conjugated fluorescent dyes have been used to guide tumor resection in mouse models and humans. However, their potential utility in head and neck squamous cell carcinoma (HNSCC) is unclear due an incomplete characterization of FR expression in such tumors. We hypothesized that tumor infiltrating macrophages expressing FR-β could allow fluorescent visualization of HNSCC tumors using folate conjugated dyes even when FR expression in cancer cells is low. SUBJECTS AND METHODS: Immunohistochemistry was performed on a tissue microarray (TMA) containing primary tumor tissue and matched tumor free surgical margins from 22 patients who underwent HNSCC resection. Primary tumor sites included the oral tongue, base of tongue, tonsil, supraglottic larynx, glottic larynx and hypopharynx. We evaluated the expression of FR-α, FR-β, TGF-β, CD68 and arginase-1. To examine the use of folate targeting for image guided surgery, orthotopic xenograft HNSCC tumor models were generated from nude mice. The mice received 0.8 mg/kg intravenous injections of fluorescein isothiocyanate conjugated folate (Folate-FITC) and were imaged for fluorescent emission under 495nm light two hours later. RESULTS: No FR-α expression was observed in any TMA tumor specimen. All tumor samples demonstrated positive FR-β expression. Cellular morphology and CD68 expression identified the FR-β expressing cells as tumor infiltrating macrophages. No association was observed between FR-β staining and either TGF-β or arginase-1 staining. In tumor xenograft mouse models, tumors showed strong fluorescence in vivo after folate-FITC injection. Normal salivary glands and surrounding neck muscles did not demonstrate significant fluorescence. Histologic examination of the xenografts revealed that fluorescence within the tumors was confined to areas of inflammatory cell infiltration, consistent with our TMA data. Conclusion: HNSCC tumors contain a significant population of FR-β expressing macrophages. In contrast to many other carcinomas, the HNSCC tumor cells in our TMA did not express FR-α. By targeting tumor infiltrating macrophages, the folate linked delivery of fluorescent dyes can facilitate image guided HNSCC resection even when the tumor cells themselves do not express FR.
A Study of Trauma Memory in Survivors of the 9/11 Attacks Using the Deese-Roediger-McDermott (DRM) Memory Paradigm
(2013-01-22) Yangirova, Dinara; North, Carol S.; Zarkin, Andrea; Roediger, Henry L., III
BACKGROUND. PTSD has been found to be associated with abnormalities in memory function. This relationship has not previously been studied with the Deese-Roediger-McDermott (DRM) paradigm in disaster-exposed populations. The DRM paradigm uses semantically related and unrelated intrusions in an immediate test of recited word lists. It was hypothesized that PTSD would be associated with false alarms to critical lures in the DRM paradigm. METHODS. Approximately three years after the 9/11 attacks, a volunteer sample (N=379) was recruited from members of eight participating agencies (three agencies in the WTC towers and one nearby agency, three agencies that provided 9/11 disaster recovery services, and an airline that lost personnel and property in the attacks). This sample was assessed for individual disaster experience and related psychiatric status using a fully structured diagnostic interview to assess full DSM-IV-TR criteria. At the end of the interview, the DRM paradigm was administered to test participants' recognition of words. RESULTS. No associations were found between PTSD or other psychopathology and DRM memory variables. The only predictor of false alarms to critical lures was direct exposure to 9/11 trauma, which was not associated with correct identification of recited words or with false alarms to unrelated lures. DISCUSSION. The study's hypothesis that PTSD would be associated with false alarms to critical lures was not supported. The finding that direct 9/11 endangerment was associated with critical lures was unexpected. The results suggest that neural processing of trauma exposure may involve associative processes of overgeneralization in cognitive processing coupled with insufficient inhibition of responses to associated but harmless stimuli. The findings of this study also support the importance of differentiating psychopathology such as PTSD from normal physiologic fight-or-flight responses to trauma in studies of memory and neurobiological investigations of trauma and its effects in future research.
Analysis of Free Flap Breast Reconstruction Failures: Are Specific Patient Characteristics Associated with Free Flap Failure?
(2013-01-22) Sciano, Natalie M.; Farkas, Jordan; Cortez, Robert; Miller, Travis; Davis, Kathryn; Kenkel, Jeffrey M.
PURPOSE: This study was performed to gain insight on the patients who have undergone free flap breast reconstructive surgery. Recognizing certain patient variables, as risk factors for developing free flap failure, is invaluable. This knowledge can provide surgeons the benefit of foresight when assessing patients pre and postoperatively. The goal was to identify specific characteristics that predisposed patients to developing flap failure. METHODS: A retrospective chart review was completed on patients who had received free flap breast reconstructive surgery during January 2008 to January 2012. A cohort of 124 patients receiving free flap reconstruction was identified using the Current Procedural Technology (CPT) code 19364. A number of patient variables which include general characteristics, comorbidities, and surgical characteristics were analyzed to determine their contribution toward a patient's development of free flap failure. Patients were categorized into two groups- those without and those with flap failure. A comparison of the means and proportions was performed to determine statistical significance between the two groups. The level of statistical significance for this univariate analysis was set at a P < 0.05. RESULTS: All of the 124 patients identified were female. The overall flap success rate was 91.94 percent, with only ten patients experiencing flap failure. Of the factors analyzed in this study, there was not an identified patient characteristic that predisposed a patient to developing free flap failure. CONCLUSIONS: Flap failure is an unfortunate risk of reconstructive surgery that needs to be minimized at all costs. No specific patient variables were identified as predisposing risk factors that could contribute to free flap failure. Institutions should strive to educate all breast reconstruction candidates on their options and risks which can help increase the volume of patients acquiring reconstruction. In the future, other investigations with a larger sample size should be done to yield more beneficial information for the physician and patient.
Impact of Ethnicity in Upper Gastrointestinal Hemorrhage
(2013-01-22) Wollenman, Casey; Chason, Rebecca; Reisch, Joan S.; Rockey, Don C.
BACKGROUND AND AIMS: Upper gastrointestinal hemorrhage (UGIH) is a serious condition, with considerable morbidity and mortality. Thus, we aimed to examine the role of ethnicity in UGIH outcomes. METHODS: We analyzed 2196 consecutive patients admitted with acute UGIH between January 2006 and February 2012. Data (including complete demographic and clinical data) was gathered prospectively and entered into our GI Bleed Registry, which captures multiple demographic and clinical variables. Results were analyzed using the Chi-square analyses and the analysis of variance techniques with Tukey multiple comparisons. RESULTS: Among 2196 patients, 620 (28%) were Black, 625 (29%) White, 881 (40%) Hispanic, and 70 (3%) were members of other ethnic groups. Males outnumbered females by approximately 2:1 (p=0.01). ASA (18%; p<0.001) and NSAID (17% p=0.007) use was common across ethnic groups. Smoking and illicit drug use was highest in Whites (63% and 31%), and Blacks (62% and 31%). Alcohol use was highest in Hispanics (63%) and Whites (63%). The most frequently identified causes of UGIH include gastric and duodenal ulcers (25%), esophageal varices (25%), and esophagitis (12%). Among the 3 main ethnicities, Blacks frequently had UGIH due to gastroduodenal ulcers (32%), while Hispanics most commonly bled from esophageal varices (34%). Ulcer disease and esophageal varices in Whites were found equally (25%). Causative bleeding varied with age. More Black (50%) and White patients (44%) bled between 50-64 years, while 40% of Hispanics bled between 35-49. The most common cause of bleeding in patients younger than 35 or older than 65 years was gastroduodenal ulcer disease. Overall, rebleeding rates were significantly lower in Whites (5.8%) than in Hispanics (9.9%) or Blacks (8.7%) (p = 0.02). Looking at outcomes in patients with variceal or gastroduodenal ulcers, Blacks had a higher mortality rate (7% and 11%), while Whites had a lower mortality rate (5% and 5%). Hispanics with varices had higher rebleeding rates (13%) but the lowest mortality (6%). CONCLUSIONS: By examining an ethically large and diverse population, we conclude that the etiology and outcome of UGIH has specific trends across age and ethnic groups. Hispanics were more likely to have esophageal varices and higher rebleeding rates, while Blacks were more likely to have ulcers and the highest mortality overall. Whites were equally likely to have ulcers or varices, but a lower rate of rebleeding. UGIH frequently occurs between the ages of 34-49; however, patients over 65 were more likely to have ulcers.
Barbed Sutures and Wound Complications in Plastic Surgery
(2013-01-22) Cortez, Roberto; Kenkel, Jeffrey M.; Farkas, Jordan; Lazcano, Eric; Hein, Rachel; Miller, Travis; Sciano, Natalie; Constantine, Ryan; Anigian, Kendall; Jewell, James
GOALS: Technological advancements, along with their refinements, have substantially increased the amount of wound closure tools at the disposal of the surgeon. Barbed sutures, with a unique design containing circumferentially located barbs, could potentially decrease operation time and facilitate wound healing by eliminating the need to tie knots and providing even tension distribution across the wound. This study was conducted: 1) to determine whether using a barbed suture device in wound closure showed an increase, decrease, or no difference in wound complication development when compared to conventional non-barbed sutures 2) to analyze complication rates observed within the barbed suture population (Angiotech QuillTM SRS vs. Covidien V-LocTM) to test for any significant difference between the two competing brands. METHODS: An IRB-approved retrospective chart review identified 1709 patients undergoing plastic surgery procedures from January of 2008 to January of 2012. In our database, a barbed suture device was used in a total of 372 cases and the type used (Angiotech QuillTM SRS vs. Covidien V-LocTM) was recorded in each case. The QuillTM SRS device was used in 106 cases, while the V-LocTM device was used in 266 total cases. Outcomes following these procedures were compared to outcomes of the same CPT codes where a barbed suture device was not used. Wound complications were defined as one or more of the following: infection, dehiscence, erythema, necrosis, seroma, hematoma, and delayed wound healing. RESULTS: Using multivariate analysis, barbed sutures appear to be associated with an increased incidence of wound complications (p=0.012), to include dehiscence (p=0.007), erythema (p=0.008), and necrosis (p=0.03) when compared to their non-barbed counterparts. Further exploration within the barbed suture population found the Covidien brand associated with an increased incidence of wound complications (p=0.03), particularly dehiscence (p=0.009), while the Quill brand was found to have a higher association with erythema (p=0.001) along the incision site. CONCLUSIONS: Barbed sutures appear to be associated with an increased incidence of wound complications in plastic and reconstructive surgery procedures, with the Covidien V-LocTM device showing a higher incidence of wound complication development compared to Angiotech QuillTM SRS device.
The Radiation Footprint on the Pediatric Trauma Patient
(2013-01-22) Farzal, Zainab; Fischer, Anne C.; Wilson, Sarah; Brown, Erica; Burkhalter, Lorrie
BACKGROUND: Overuse of radiation in patients has recently become an important topic of discussion within the medical community. Pediatric patients are most at risk. A recent study has proven the incidence of 1 brain tumor for every 10,000 head computed tomography (CT) scans among patients under the age of 10 in the ten years following a single scan1. Although there have been attempts to limit radiation dosage, there is no published data on the quantity of imaging done on the pediatric trauma patient. The high index of suspicion in trauma has created a paradigm of comprehensive imaging independent of symptoms. Our hypothesis was to identify the current amount of radiation used in a pediatric trauma patient for one visit and correlate the levels of imaging with trauma activation status in order to identify the subset of pediatric trauma patients most at risk for over-radiation. METHODS: This IRB-approved retrospective review of pediatric trauma patients at an ACS verified Level 1 independent children's hospital reviewed three levels of trauma activation (Stats, Alerts, Consults) from June 2010 to January 2011. Charts were analyzed for demographics, mechanism of injury, injury severity score (ISS), imaging modalities, and radiation dosages. Our study included the total number of Stats with representative cohorts from Alerts and Consults. 215 patients (N=1050) met inclusion criteria with complete dosimetry data available. RESULTS: The demographics include: gender (143M, 72F); age range <1-16 years (median 5.5), and activation status with average ISS score (Consults, 7.7 ± 9; Alerts, 8.8 ± 7; and Stats, 17 ± 14, respectively). Non-accidental trauma (NAT) and Stat activations exceeded all others in radiation exposure. Per Stat the number of CTs ranged from 0-10 with 2-3 CTs in 35% and 4-10 CTs in 40% for one admission. The studies most often repeated were head CTs (45%), face/sinus CTs (13.8%) and neck CTs (10%). The majority (66%) of outside CTs delivered more radiation, of which 50.0% of the doses were at least double the dosage delivered at the children's hospital. CONCLUSION: This study is the first to correlate the amount of radiation exposure with trauma activation status. Most of the repetitive imaging was utilized in Stat activations and NATs and used 2-3 times as many CT scans. The identified factors associated with the most radiation include suspected NATs, Stat activations, and outside imaging. To minimize the radiation footprint, we may need to change the current practice of imaging to identify all possible injuries regardless of symptoms.
NF-kB Mediates Cartilage Degradation induced by Trauma Injury and IL-1
(2013-01-22) Carter, Kristen; Kashyap, Meghana; Sauer, Brent C.; Chen, Christopher T.
BACKGROUND: IL-1 is one of the major pro-inflammatory cytokines responsible for cartilage degradation. Several studies have shown that IL-1 mediates the upregulation of tissue degradation through the NF-κB and Mitogen-activated protein kinase (MAPK, p38) pathways, but its role in cartilage degradation after blunt trauma injury is not clear. The objective of this study was to determine the roles of NF-κB and p38 in IL-1- induced cell death, proteoglycan (PG) degradation, nitric oxide (NO) production, and related gene upregulation in cartilage after blunt injury. METHODS: Full-thickness cartilage plugs were obtained from mature bovine knees (>18 mo) and pre-cultured in DMEM. The signaling pathways (p38 and NF-kB) were inhibited by pretreatment with 10μM SB202190 for p38 (p38i) and 50μM BAY117085 for NF-κB (IκBi) for 1 hour. Samples in Injury and Injury+IL-1 groups received impact injury with impact energy of 15J/cm2. IL-1 and Injury+IL-1 groups were treated with 1 ng/ml IL-1. Cell viability was assessed using fluorescein diacetate and propidium iodine. The mRNA from cartilage was isolated using Trizol and RNeasy Mini kit (Qiagen), reverse transcribed, and analyzed using qPCR to determine pro-inflammatory cytokine and tissue remodeling genes (IL- 6, MMP-3, TIMP-3). All gene expression was normalized to GAPDH. The medium was analyzed for proteoglycan (PG) release/loss and nitric oxide (NO) production using dimethylmethylene blue (DMMB) and Greiss assays, respectively. RESULTS: Increased cell death was found in the Injury and Injuy+IL-1 groups. Increase of PG loss was found in IL-1, Injury and Injury+IL-1 treated groups (37%, 104% and 126%, respectively). Significant decreases (69-73%) of PG loss were found in all IκBi treated groups, while little or no changes were found in the p38 groups. Results from the qPCR analysis supported the findings. IκBi treatment reduced MMP-3 upregulation induced by IL-1 and Injury, while there was minimal change with the p38 inhibitor. Similarly, NO production was also decreased in the IκBi treated groups. DISCUSSION and CONCLUSION: Our study suggests that the NF-κB signaling pathway plays a greater role than p38 in IL-1 mediated PG loss and NO production in cartilage after trauma injury. Future studies are needed to determine the time-course response and specific NF-κB mediators for downstream regulation, as well as the effects in long-term therapeutic treatment to ameliorate the progress of post traumatic osteoarthritis.
Evolving Characteristics of HIV Infected Pregnancies at a Single Institution
(2013-01-22) Cooper, Sara J.; Stewart, Robert D.; Duryea, Elaine L.; McIntire, Donald D.; Roberts, Scott W.; McElwee, Barbara; Sheffield, Jeanne S.
OBJECTIVE: Over the past 26 years, significant advances have been made in the understanding and management of patients infected with HIV. We sought to determine if these changes in HIV care have had an impact on the characteristics of pregnant women with HIV and their pregnancies in a large cohort of HIV infected women at a single institution. STUDY DESIGN: This was a retrospective review of all pregnancies infected with HIV who presented for prenatal care at our institution from January 1986 through November 2012. Medical records were reviewed, and maternal, neonatal, and delivery data were ascertained. The data were divided into three cohorts representing different levels of antiretroviral therapy and analyzed for trends. Cohort 1 (pre-HIV interventions) includes data from 1986-1991, Cohort 2 (introduction of ZDV) includes data from 1992-2002, and Cohort 3 (multi-drug therapy) comprises the remaining data from 2003-2012. RESULTS: During the 26 year study period 1005 HIV infected pregnancies were identified. The incidence of HIV in pregnancy has remained stable at 0.2 -0.3% of all deliveries. The vast majority of our HIV infected obstetric population receives prenatal care and the number of patients receiving no prenatal care has decreased over time (27% to 6%, p<0.001). There has been a significant increase in maternal age and number of prenatal visits during the study period. The estimated gestational age at delivery has remained steady throughout the entire data set and there have been no changes in birthweight, 5-minute APGAR <7, prematurity, stillbirth, or neonatal deaths. The rate of cesarean section doubled (24% to 55%, p<0.001) for deliveries after 2000 following the release of guidelines recommending scheduled c-section for patients with viral loads >1000 copies/mL. Median maternal viral load and CD4 count have not changed significantly throughout the cohorts, with HIV viral load usually becoming non-detectable by delivery. CONCLUSION: Over the past two decades, HIV infected women have presented for prenatal care at an older age, entered prenatal care earlier with more frequent visits and overall have decreased maternal viral copy number at delivery with antiretroviral therapy. Despite increased maternal age, pregnancy outcomes remain excellent. This study highlights the fact that appropriate prenatal care is associated with excellent pregnancy outcome in this high risk population.
Parameters that Predict for High Grade Rectal Toxicity in Prostate Cancer Patients Undergoing Stereotactic Body Radiation Therapy- Analysis of Phase I/II at UT Southwestern
(2013-01-22) Straka, Christopher; Kim, D. Nathan; Pistenmaa, David; Lotan, Yair; Xie, Xian-Jin; Timmerman, Robert
INTRODUCTION: Conventional radiation therapy (CRT) is a well-accepted option for PCa treatment with high disease control rate, and low (< 3-5%) risk of rectal toxicity. SBRT, unlike CRT, delivers higher doses of radiation in 1-5 fractions, reducing treatment time significantly (from 8-9 weeks to ~ 2 weeks). Benefits of SBRT include improved patient convenience, significant healthcare cost reduction, and it has strong biologic rationale. A dose escalation phase I study (Boike et. al, JCO 2011) established 45-50 Gy in 5 treatments as effective and safe. Phase II study at 50 Gy was recently completed. Interim analysis unexpectedly revealed a significant number of grade 3+ delayed rectal events. We performed a rigorous analysis to determine potential etiology and methods to avoid occurrence of such rectal events. METHODS: Clinical parameters evaluated include tumor stage, Gleason grade, prostate volume, comorbid conditions (diabetes, smoking history, immunosuppression), race, age, and baseline bowel function score. Treatment planning parameters collected and evaluated included rectal wall volume receiving high doses of radiation, target volume size, rectal wall size, and degree of circumferential radiation to the rectal wall. Uni/multivariate analysis and correlative studies were conducted. RESULTS: 59 low/intermediate risk Pca patients were enrolled in this phase I/II study at UTSW. Median follow-up for all patients is 25.5 months. Tumor control rate is 99% to date. No patients experienced high grade rectal toxicity at 45 and 47.5 Gy, but at 50 Gy 10.8% experienced ≥ grade 3 rectal toxicity. Significant parameters were rectal volume receiving 50 Gy, HR of 2.67 (1.25, 5.71), p=.0113; rectal circumference irradiated by 24 Gy, 39 Gy and 50 Gy, HR of 1.1 (1.01,1.2) (p=.03), 1.2 (1.01, 1.38) (p=.04), and 1.22 (1.01, 1.47) (p=.04) respectively; and possibly diabetes HR 6.86 (0.83, 56.8) (p=.074). All 4 patients with grade 3+ rectal toxicity had > 3.5 cm3 rectal wall irradiated by 50 Gy. All patients without rectal toxicity had < 3.5 cm3 rectal wall irradiated by 50 Gy. DISCUSSION: We have determined the absolute threshold dose volume constraint to avoid rectal toxicity for SBRT of Pca. These findings contribute significantly to the radiobiology of bowel tolerance. If anatomy does not permit safe rectal dose constraints, dose reduced SBRT or alternatively CRT should be considered. When rectal constraints are met, or when 45-47.5 Gy prescription dose is used, SBRT seems to be a potent, safe, convenient and cost effective treatment for patients with low/intermediate risk PCa.
AB1-42 Antibody Producing Plasma Cells in DNA AB42 Trimer Immunized Mice Reside Predominantly in the Bone Marrow
(2013-01-22) Zacharias, Tresa; Langworthy, Suzanna; Fu, Min; Anderson, Larry; Stuve, Olaf; Rosenburg, Roger; Lambracht-Washington, Doris
Alzheimer's disease (AD) is the most common form of age-related dementia and affects nearly 40 million people worldwide. Immunotherapy provides a possible avenue for prophylaxis of AD, but a clinical trial (AN1792) in which patients with early AD were immunized with Aβ1-42 peptide was halted after the occurrence of meningoencephalitis in 6% of the immunized people which was attributed to a T cell autoimmune response. DNA vaccination has been shown to have a polarized Th2 immune response that lacks many of the features responsible for inflammation seen in peptide immunizations. In this study, we show a new feature of the DNA Aβ42 trimer elicited B cell immune response and present data for the presence of a long lived plasma cell pool residing within the bone marrow in DNA immunized mice but not in peptide immunized mice. Two groups of mice were analyzed: one group of B6C3F1 mice (n=20) were studied 4 months after the last DNA vaccination, and a second group of BALB/c mice (n=14), which received DNA or peptide immunizations, were analyzed 10 days following the last immunization. The comparison of antibody producing cells in bone marrow and spleen for the DNA and peptide immunized mice with an Antibody Forming Cell (AFC) ELISPOT assay and subsequent ELISAs showed that bone marrow plasma cells from DNA immunized mice produced more anti-Aβ42 IgG producing cells and higher levels of secreted IgG antibodies. In peptide immunized mice, more IgG antibody producing cells were found to reside in the spleen. These data indicate that the bone marrow may be an important reservoir for B cells following DNA Aβ42 immunization and is in line with studies showing that the bone marrow represents an excellent niche for the survival of long lived plasma cells and a lifetime source for antibody producing B cells which are independent of continuous antigen specific stimulation. Further studies are needed to show whether it is possible to define additional phenotypic characteristics for the antigen specific B cell immune response in DNA Aβ42 trimer immunized mice or differences in the TH subsets directly involved in initial signaling events to B cells in the germinal center reactions.
The Diagnostic Dilemma of Identifying Perforated Appendicitis
(2013-01-22) Farzal, Zehra; Fischer, Anne C.; Khan, Nudrat
BACKGROUND: Despite 61 clinical trials on pediatric appendicitis in the Cochrane database over the last decade, a defined best clinical pathway for acute versus complicated appendicitis remains lacking. The lack of accuracy in the classification of appendicitis can affect the therapeutic course and associated costs since the average cost per case of complicated appendicitis at USD 12,300 which is twice as expensive as uncomplicated appendicitis at USD 6,355 per case1. We hypothesize that the variability in the diagnosis of complicated appendicitis results in a discordance. METHOD: An IRB-approved retrospective review of appendectomies (N=1311) from a 16-month period from 2010 and 2011, excluding interval or incidental appendectomies and including CT imaging, was analyzed for demographics, length of stay (LOS), post-operative antibiotics, and radiological (R), pathologic (P), and operative (O) reports. The classification of appendicitis as "perforated" was compared in a 3-way analysis between radiology (R), pathology (P), and operative reports (O) to identify the incidence of discordance. Classification was compared to LOS, to determine if the diagnosis was consistent with being "acute" (A) 0-48 hours admission or "perforated" (P) >48 hours. RESULTS: 1241 appendectomies met criteria to enter the three study sets: P+O, O+R, and P+R, (N= 1241, 550, and 550, respectively). In study subsets with radiology (P+R and O+R), 47% had a CT with a definite radiologic diagnosis in 44%. The discordance in diagnosis in P+O, P+R, O+R was 11%, 15.7% and 16.6%, respectively. Pathology and operative reports had the most consistent diagnoses with a concordance of 89%. The O+R group had 16.6% discordance, of which 35% of cases were intraoperatively determined to be perforated, but actually 38.9% of those cases had a LOS <48hrs, consistent with being acute nonperforated. The LOS in the >48 hours group was nontrivial with a median of 88 hours (range 50-272). CONCLUSION: There is a substantial discrepancy between operative, radiologic, and pathologic reports with the greatest discordance occurring between radiologic and operative diagnoses. The variation in the LOS confirms this discordance. Although, the diagnostic classification of complicated and uncomplicated appendicitis are not standardized which contributes to the discordance, the consequences are substantial in terms of medical costs and patient length of stay. Standardizing the criteria for the classification of the type of appendicitis across specialties may improve diagnostic accuracy needed for meaningful clinical trials and to identify best practices for optimal use of hospital resources and health care costs that continue to be elusive.
Argon Laser Trabeculoplasty (ALT): Predictors of Failure
(2013-01-22) Chang, Eric; Markel, Nathan; Kooner, Karanjit; Adams-Huet, Beverley; Li, Xilong
PURPOSE. ALT is widely used to control intraocular pressure (IOP) in glaucoma. We wished to determine predictive factors for long term success of ALT performed by supervised residents in training on patients at a local VA Hospital in Dallas. METHODS. Charts of patients with primary open angle glaucoma who underwent ALT between 2001 and 2011 were reviewed retrospectively. Those with follow up < 3 months, prior ALT/SLT, filtering procedure or inadequate data were excluded. The dependent variable was time to failure after ALT. Failure was defined as any additional medication, ALT/SLT or glaucoma filtering surgery. All patients were treated with 360 ° ALT. Logistic regression and receiver operating characteristic (ROC) analysis was performed to assess correlation between time to failure after ALT and age, pre-op IOP, C/D ratio, visual field defect, family history, refractive error, hypertension, diabetes, number of medications, laser energy used, central corneal thickness. RESULTS. Evaluable data was obtained on 206 patients; mean age 65, 98% male, and 61% black. 40.8% (84/206) were classified as ALT failures. Failure and non-failure patients had equal follow-up duration of median 2 yr. Pre-ALT LogMar (mean (SD) 0.25 (.3) vs. 0.35 (.3)), no. of glaucoma medications (2.9 (1.0) vs. 3.3 (1.0)), and myopia (46% vs. 61%) differed, respectively, between ALT failures and non-failures (p<0.05). In multivariable logistic regression models, after adjusting for age, hypertension, and diabetes, we found that myopia was protective (odds ratio (OR) =0.39, 95% CI 0.21-0.78, p=0.005) but that higher laser energy ((OR=1.6 for a 20k increase in energy, 95% CI: 1.1-2.4, p=0.005) was associated with increased risk associated for ALT failure; model ROC AUC = 0.70 (95% CI: 0.63-0.78). DISCUSSION. Our VA patients were mainly males but had good ethnical diversity. Better response in myopia may be related to thickness of trabecular meshwork while poorer response to increased laser energy may be from thermal damage. Patients using more than three meds were on systemic carbonic anhydrase inhibitors CONCLUSIONS. ALT results were better in patients who used more than 3 meds, were myopic and required less laser energy.
Voluntary Exercise Alters Adaptive Immunity Prior to Injury
(2013-01-22) McPartlin, Angelica; Stowe, Anne M.; Poinsatte, Katherine; Mouti, Mariam; Ireland, Sarah J.; Li, Min
OBJECTIVE: Exercise provides a neuroprotective role in the setting of cerebral infarct. However, the exact mechanism for this protection is unclear. This study established an exercise preconditioning protocol to test the hypothesis that exercise mediates protection from stroke by altering the immune profile prior to injury to reduce inflammation post-infarct. MATERIALS/METHODS: In our first trial, a three week exercise preconditioning protocol was established using nine C57 mice that endogenously expressed green fluorescent protein (GFP) under the PLP promoter. This biomarker was used to identify oligodendrocyte precursor cells (OPC) to qualify their relationship with voluntary exercise. Exercise activity was recorded and tissues were collected for histological and serological analysis. Analysis of histological sections acquired through Nanozoomer imaging was performed using an unbiased quantification (Stereo Investigator). Ten Swiss Webster (SW) mice with no endogenous fluorescence were used in the subsequent trial. Following sacrifice of the SW mice, samples of the spleen and peripheral blood were collected and analyzed by flow cytometry and microarray was used to analyze resident B cell expression (IPA software). Standard ELISA analysis of peripheral blood was also used for all trials. Significance was determined using t-test or ANOVA. RESULTS: Voluntary exercise in PLP-EGFP mice correlated with a trend increase in OPCs as well as a trend increase in cortical angiogenesis (p=0.06). However, voluntary exercise did not increase hippocampal neuron counts. Voluntary exercise in SW mice showed decreases in percent and raw number of splenic neutrophils and CD8+ T cells (both p<0.01), with a concomitant increase in B cell representation (p<0.05). Peripheral blood samples demonstrated a decrease in percent CD4+ T cells (p<0.01) and decrease in CCL2 (p<0.05) and VEGF (p<0.01) protein. Microarray showed a significant upregulation of 1844 genes and significant downregulation of 1333 genes in the resident splenic B cells of SW exercise mice over the sedentary controls. CONCLUSION: Three weeks of voluntary exercise in mice results in a change in the immune profile prior to an injury occurring. Downregulation of neutrophils, cytotoxic T cells, and CCL2 suggest that this alteration in immunity is anti-inflammatory. Microarray analysis of isolated B cells showed an upregulation of genes associated with lymphocyte maturation and differentiation, with simultaneous downregulation of genes responsible for apoptosis and B cell death. Further studies will determine the significance of these immune adaptations and their mechanistic role in decreased deficits following neurovascular injury.
Automated Analysis of Electroglottographic Signal in Adductor Spasmodic Dysphonia
(2013-01-22) Somanath, Keerthan; Mau, Ted
INTRODUCTION: The human voice can be evaluated by a variety of methods. Electroglottographic (EGG) signal is produced when vocal fold vibrations produce cyclic fluctuation in the electrical impedance across the larynx. The EGG signal thus reflects the degree of contact between the vocal folds during voice production and provides a measure of voice quality based on phonatory physiology. However, the utility of EGG has been limited because existing methods of EGG signal analysis focus on the evaluation of 2-3 parameters in a segment of sustained vowel production, which does not reflect pathologies more apparent in conversational speech. We hypothesize that the EGG signal can capture perceptually relevant information from continuous speech in adductor spasmodic dysphonia (ADSD), an enigmatic speech disorder. OBJECTIVES: 1. To develop an automated computer algorithm to analyze the EGG signal in continuous dysphonic speech. 2. To identify EGG waveform features that correlate with the perceived quality of vocal strain in ADSD. METHODS: A computer program was created and refined in MATLAB to display and analyze EGG data via a graphical user interface (GUI). An automated peak-detection algorithm was developed using the differentiated EGG signal and used to perform simultaneous multi-parameter analysis on the EGG signal from normal speech and speech in patients with ADSD. Between-group comparisons were made using two-tailed Student's t test. Also, intrasubject comparison was made between strained and less-strained syllables in ADSD speech. RESULTS: A program was successfully written to allow the display and automated analysis of EGG data from samples of continuous dysphonic speech. The program was found to generate data with good internal consistency. Application to normal and ADSD subjects showed that the open quotient parameter was able to distinguish between strained and less-strained syllables with statistical significance (p=0.04). DISCUSSION/CONCLUSION: We have developed a method to analyze EGG signal from samples of continuous dysphonic speech. The numerical and graphical data obtained support the utility of EGG as an objective means to clinically highlight the speech differences between normal subjects and subjects with ADSD. Further testing to establish normative values for the analyzed EGG parameters and their subsequent comparison with patient EGG data is required to affirm their utility for routine clinical voice assessment.
Anti-VEGF Induced Reduction in Microvessel Density Does Not Correlate with Anti-Tumor Repsonse in Lung Cancer Xenografts
(2013-01-22) Jacob, Antonia J.; Sullivan, Laura A.; Toombs, Jason E.; Minna, John D.; Brekken, Rolf A.
Vascular endothelial growth factor-A (VEGF) is a primary stimulant of angiogenesis in pathological conditions including tumor progression. Strategies to block VEGF activity prevent or slow tumor growth in preclinical settings; however, clinical studies with bevacizumab, a monoclonal antibody (mAb) specific for VEGF have resulted in only modest benefit to a subset of patients with lung cancer. Previous studies in our laboratory defined the therapeutic efficacy of bevacizumab and an alternative anti-VEGF mAb (r84) in 12 non-small cell lung cancer (NSCLC) xenografts. Three NSCLC xenografts (Calu-6, A549 and Calu-3) showed intrinsic resistance to bevacizumab therapy. In the present study we evaluated whether microvessel density (MVD) could be used to 1) demonstrate if the anti-VEGF mAbs were effective at reducing VEGF-driven angiogenesis and 2) if MVD changes induced by bevacizumab or r84 correlated with overall therapeutic efficacy as determined by tumor size after chronic therapy. 3-5 tumors from animals bearing NSCLC xenografts treated with a control mAb (XTLl, bevacizumab or r84 were evaluated by immunohistochemistry for endothelial cells as a measure of microvessel density. Two independent endothelial cell markers were used, endomucin and CD31. In 11 of the 12 xenografts treatment with bevaclzumab or r84 significantly reduced MVD compared to XTL treatment, suggesting that bevacizumab and r84 do reduce VEGF-driven angiogenesis. However, the reduction in MVD induced by anti-VEGF therapy did not correlate with overall tumor response to therapy. These results strongly implicate resistance to anti-VEGF therapy is not mediated by activation af alternative angiogenic programs to compensate for VEGF blockade. Further the results suggest that tumor cell adaptation to therapy-induced hypoxia underlies poor therapeutic response to anti-VEGF strategies. Microarray of gene expression analysis of control treated tumors revealed several genes associated with metabolism, proliferation, and metastasis were significantly increased in tumors that displayed intrinsic resistant to bevacizumab. We conclude that response of tumor cells to therapy-induced hypoxia is a critical feature that drives the overall efficacy of anti-VEGF strategies.

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