CT angiography effectively evaluates extremity vascular trauma.

Traditionally, conventional arteriography is the diagnostic modality of choice to evaluate for arterial injury. Recent technological advances have resulted in multidetector, fine resolution computed tomographic angiography (CTA). This study examines CTA for evaluation of extremity vascular trauma compared with conventional arteriography. Our hypothesis is that CTA provides accurate and timely diagnosis of peripheral vascular injuries and challenges the gold standard of arteriogram. Traumatic extremity injuries over a 5-year period were identified using a Level I trauma center registry and radiology database. Information collected included patient demographics, mechanism, imaging modality, vascular injuries, management, and follow-up. Two thousand two hundred and fifty-one patients were identified with extremity trauma. Twenty-four patients were taken directly to the operating room for evaluation and management of vascular injuries. Fifty-two underwent vascular imaging. Fourteen patients had conventional arteriograms with 13 abnormal studies: 7 were managed operatively, 2 embolized, and 4 observed. Thirty-eight patients underwent CTA with 17 abnormal scans: 9 were managed operatively, 3 embolized, and 5 observed. There were no false negatives or missed injuries. CTA provides accurate peripheral vascular imaging while additionally offering advantages of noninvasiveness and immediate availability. Secondary to these advantages, CTA has supplanted arteriography for initial radiographic evaluation of peripheral vascular injuries at our Level I trauma center. This study supports CTA as an effective alternative to conventional arteriography in assessing extremity vascular trauma.

Pediatric blunt abdominal injury: age is irrelevant and delayed operation is not detrimental.

BACKGROUND: During the past 40 years, management of solid organ injury in pediatric trauma patients has shifted to highly successful nonoperative management. Our purpose was to characterize children requiring operative intervention. We hypothesized that older children would be more likely to require operative intervention. In particular, we wanted to examine potential outcome disparities between children who were operated upon immediately and those in whom attempted nonoperative management failed. Additionally, we asked whether attempted nonoperative management, when failed, put children at higher risk for mortality or morbidities such as increased blood product transfusions or lengths of stays. METHODS: Retrospective cohorts from seven Level I pediatric trauma centers were identified. Blunt splenic, hepatic, renal, or pancreatic injuries were documented in 2,944 children <1 to 19 years of age from January 1993 to December 2002. Data collected included demographics, hemodynamics, blood transfusions, Glasgow Coma Scale score, Injury Severity Score, hospital length of stay (LOS), intensive care unit (ICU) LOS, and mortality. Analysis involved 140 (4.8%) of 2,944 patients requiring operation. Two cohorts were characterized: (1) immediate operation (IO), defined as laparotomy 3 hours after arrival (n = 59; 42%). RESULTS: Comparing the two cohorts, no age differences were found. Compared with F-NOM, IO had significantly worse hemodynamics, Injury Severity Score, and Glasgow Coma Scale score and was associated with liver injuries. Pancreatic injuries were significantly associated with F-NOM. While controlling for injury severity to compare IO versus F-NOM, linear regression revealed equivalent blood transfusions, ICU LOS, hospital LOS, and mortality rates. CONCLUSION: IO and F-NOM are rare events and independent of age. When operated upon for appropriate physiology, the timing of operation in pediatric solid organ injury is irrelevant and not detrimental with respect to blood transfusion, mortality, ICU and hospital LOS, and resource utilization.

Risk factors for hepatic morbidity following nonoperative management: multicenter study.

HYPOTHESIS: Early risk factors for hepatic-related morbidity in patients undergoing initial nonoperative management of complex blunt hepatic injuries can be accurately identified. DESIGN: Multicenter historical cohort. SETTING: Seven urban level I trauma centers. PATIENTS: Patients from January 2000 through May 2003 with complex (grades 3-5) blunt hepatic injuries not requiring laparotomy in the first 24 hours. INTERVENTION: Nonoperative treatment of complex blunt hepatic injuries. MAIN OUTCOME MEASURES: Complications and treatment strategies. RESULTS: Of 699 patients with complex blunt hepatic injuries, 453 (65%) were treated nonoperatively. Overall, 61 patients (13%) developed 87 hepatic complications including bleeding (38), biliary (bile peritonitis, 7; bile leak, 9; biloma, 11; biliary-venous fistula, 1; and bile duct injury, 1), abdominal compartment syndrome (5), and infections (abscess, 7; necrosis, 2; and suspected abdominal sepsis, 6), which required 86 multimodality treatments (angioembolization, 32; endoscopic retrograde cholangiopancreatography and stenting, 9; interventional radiology drainage, 16; paracentesis, 1; laparotomy, 24; and laparoscopy, 4). Hepatic complications developed in 5% (13 of 264) of patients with grade 3 injuries, 22% (36 of 166) of patients with grade 4 injuries, and 52% (12 of 23) of patients with grade 5 injuries. Univariate analysis revealed 24-hour crystalloid, total and first 24-hour packed red blood cells, fresh frozen plasma, platelet, and cryoprecipitate requirements and liver injury grade to be significant but only liver injury grade (grade 4 odds ratio, 4.439; grade 5 odds ratio, 12.001) and 24-hour transfusion requirement (odds ratio, 6.446) predicted complications by multivariable analysis. CONCLUSIONS: Nonoperative management of high-grade liver injuries is associated with significant morbidity and correlates with grade of liver injury. Screening patients with transfusion requirements and high-grade injuries may result in earlier diagnosis and treatment of hepatic-related complications.

Stem cells: tissue regeneration and cancer.

Regenerative medicine is the promised paradigm of replacement and repair of damaged or senescent tissues. As the building blocks for organ development and tissue repair, stem cells have unique and wide-ranging capabilities, thus delineating their potential application to regenerative medicine. The recognition that consistent patterns of molecular mechanisms drive organ development and postnatal tissue regeneration has significant implications for a variety of pediatric diseases beyond replacement biology. The observation that organ-specific stem cells derive all of the differentiated cells within a given tissue has led to the acceptance of a stem cell hierarchy model for tissue development, maintenance, and repair. Extending the tissue stem cell hierarchical model to tissue carcinogenesis may revolutionize the manner in which we conceptualize cancer therapeutics. In this review, the clinical promise of these technologies and the emerging concept of "cancer stem cells" are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the accompanying research in this area with the potential for clinical application.

Donor-derived, liver-specific protein expression after bone marrow transplantation.

BACKGROUND: Bone marrow transplantation (BMT) may represent a novel mechanism to deliver a functional gene to a deficient liver. Bone marrow-derived hepatocytes are rare and without a defined contribution to liver function. Consequently, the clinical significance of BMT to treat liver disease is unclear. We sought to quantify bone marrow-derived hepatocyte protein expression after BMT and determine whether the process is inducible with liver injury. METHODS: Mice transgenic for human alpha-1 antitrypsin (hAAT) under a hepatocyte-specific promoter were used as bone marrow donors. Adenoviral transduction of modified urokinase plasminogen activator (Ad-muPA) was used to induce liver injury. Eight weeks after lethal irradiation and BMT, recipients were stratified into two groups: BMT alone (n = 5) and BMT + Ad-muPA (n= 10). Both groups of animals were bled before (t = 0) and at 2, 4, 8, and 16 weeks after Ad-muPA administration, and the serum samples were assessed for hAAT by enzyme-linked immunosorbent assay. RESULTS: Transgenic donor mice expressed 5 to 10 mg/mL of hAAT. Recipients of BMT alone expressed less than 80 ng/mL of hAAT over all time periods. Animals receiving BMT + Ad-muPA showed sustained and stable hAAT expression of approximately 200 ng/mL. Differences were statistically significant at each time point. CONCLUSION: Serum protein levels from liver-specific transgene expression are detectable and persist after BMT. Expression is low, but inducible with liver injury. We are currently developing strategies to augment donor-derived, liver-specific protein expression after BMT.

Absence of the p53 tumor suppressor gene promotes osteogenesis in mesenchymal stem cells.

OBJECTIVE: Osteosarcoma arises predominantly in the metaphyseal growth plate of children during the growth spurt years. These tumors develop during physiological growth from an expanding cell population, suggesting that the transformed cell is a bone-forming progenitor. An absence of the p53 oncogene has been implicated in the origin and progression of osteosarcoma, and because mesenchymal stem cells (MSCs) are the physiological osteogenic progenitor cell population, we hypothesized that a p53-/- mutation would enhance bone differentiation of MSC in a mouse model of in vitro osteogenesis. METHODS: Clonal MSC populations were derived from p53-/- mice. P53-/- and wild-type cells were placed in osteogenic culture and assessed via Alizarin Red quantification and alkaline phosphatase staining. The osteogenic marker genes Cbfa1, osteopontin, and osteocalcin were assessed by quantitative real time polymerase chain reaction during differentiation. RESULTS: Bone nodule formation and alkaline phosphatase staining was accelerated and enhanced in the p53-/- cells. The early and intermediate osteogenic markers, Cbfa1 and osteopontin, were upregulated in p53-/- MSCs compared with wild-type cells during osteogenesis. The terminal osteogenic marker gene osteocalcin was paradoxically lower in p53-/- MSCs indicating impaired terminal differentiation. CONCLUSION: The p53-/- mutation enhances and accelerates early osteogenesis in MSCs, but prevents terminal differentiation toward a mature osteocyte phenotype. These findings may have important implications for the regulation of the MSC compartment during the derivation of osteosarcoma in children.

Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor.

BACKGROUND: Chronic inflammation is a characteristic feature of abdominal aortic aneurysms (AAAs), but the molecular signals responsible for recruiting monocytes into the outer aortic wall are unresolved. The purpose of this study was to examine whether AAA tissues elaborate chemotactic activity for mononuclear phagocytes and to determine whether this activity is attributable to interactions between elastin degradation peptides (EDPs) and their cell surface receptor, the 67-kD elastin binding protein (EBP). MATERIAL AND METHODS: Soluble proteins were extracted from human AAA tissues, and chemotactic activity for differentiated U937 mononuclear phagocytes was measured by use of a modified Boyden chamber. Chemotactic activity induced by N -formyl-Met-Leu-Phe was used as a positive control and checkerboard analysis was used to distinguish chemotaxis from chemokinesis. Inhibition of chemotaxis was tested by peptide competition, blocking antibodies and galactosugar-mediated dissociation of the 67-kD EBP. RESULTS: AAA extracts stimulated a concentration-dependent increase in monocyte migration that reached up to 24% of the maximal effect induced by N -formyl-Met-Leu-Phe. Checkerboard analysis demonstrated that AAA extracts stimulated chemotaxis without a chemokinetic effect. AAA-derived chemotactic activity was eliminated by competition with Val-Gly-Val-Arg-Pro-Gly (VGVAPG), a repetitive peptide found in human elastin that binds to cellular elastin receptors, and decreased nearly 40% in the presence of BA-4, an antielastin monoclonal antibody that can block EDP-mediated chemotactic activity. Monocyte chemotaxis in response to both VGVAPG and AAA extracts was abolished in the presence of lactose, a galactosugar that specifically dissociates the 67-kD EBP, but it was unaffected by either glucose, fructose, or mannose. CONCLUSIONS: These findings indicate that soluble EDPs released within human AAA tissue can subsequently attract mononuclear phagocytes through ligand-receptor interactions with the 67-kD EBP, thereby providing a plausible molecular mechanism to explain the inflammatory response that accompanies aneurysmal degeneration. Better understanding of factors regulating inflammatory cell recruitment may lead to novel forms of therapy for early stages of aneurysmal degeneration.