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APSA's Right Child/Right Surgeon Initiative addresses issues concerning patient access to appropriate pediatric surgical care and workforce distribution. The APSA Workforce Committee sought to understand the experiences and motivations of recent graduates of Pediatric Surgery Training Programs entering the workforce.Using APSA membership databases, we identified members who completed fellowship training from 2010 to 2019. An online survey was created using Survey Monkey, and invitations to participate were sent via email.144 of 447 invited participants responded (32% response rate). 91% of respondents participated in dedicated research prior to fellowship, but only 64% perform research during their employment. 23% completed an additional clinical fellowship, but only 54% currently practice within the second field. When asked to identify the top three factors used to choose a position, the most common responses were "location or geography" (71%), "available mentorship" (53%), and "compensation and benefits" (37%). Describing their first position, 77% reported working in an academic institution, 78% reported working in a metropolitan/urban area, and 55% reported working in a free-standing children's hospital. 94% participate in General Surgery resident education, and 49% are faculty within a Pediatric Surgery fellowship. Overall, 92% of respondents were able to find the type of employment position that they had wanted.In our survey the overwhelming majority of young pediatric surgeons found the type of job they desired. Most report beginning their practice in more populated, urban areas within academic institutions. Geographic location and work environment played heavily into their employment decisions. These preferences could contribute to continued disparity in access to pediatric surgeons between urban and rural America and to dilution of experience for urban surgeons. Possible solutions include alternative incentive programs for employment in less populated areas or new training models for general surgeons in rural areas to train in fundamentals of Pediatric Surgery.

Surgical training includes the development of technical and nontechnical skills. While technical skills are more easily quantified, nontechnical skills such as situation awareness (SA) are more difficult to measure and quantify. This study investigated the relationships between different SA elements and expertise.Twenty attending and resident surgeons rated their anticipation of an impending adverse event while watching 20 videos of laparoscopic cholecystectomies with and without adverse events. After watching each video, they assessed surgeon skills and self-assessed their anticipation ratings. All participants answered a general confidence questionnaire before and after the study.Videos with adverse events led to significantly higher anticipation of adverse events (P 0.001), lower surgeon skill rating (P 0.001), and higher self-assessment in their anticipation ratings (P 0.001) across both participant groups. General confidence was significantly lower for residents than that for attending surgeons (P 0.001). Compared with the residents, attendings exhibited stronger and more stable correlations between measurements of SA. When viewing videos with adverse events, attendings showed significantly higher correlation between anticipation of an impending adverse event and skill assessment of the surgeon (P = 0.005).This study investigated how different elements of SA and their relationships were influenced by experience. The results indicated that attendings had stronger and more stable correlations between SA elements than residents, demonstrating how measurement correlations could be meaningful and sensitive indicators of expertise and autonomy readiness.

Introduction Nonoperative management of hemodynamically stable patients with blunt splenic and/or hepatic injury has been widely accepted in the pediatric population. However, variability exists in the utilization and timing of repeat imaging to assess for delayed complications during index hospitalization. Recent level-IV evidence suggests that repeat imaging in children should be performed based on a patient’s clinical status rather than on a routine basis. The aim of this study is to examine the rate of delayed complications and interventions in pediatric trauma patients with blunt splenic and/or hepatic injuries who undergo repeat imaging prompted either by a clinical change (CC) or non-clinical change (NCC). Methods A 9-year (2011-2019), retrospective, dual-institution study was performed of children (0-17 years) with blunt splenic and/or hepatic injuries. Patients were grouped based on reason for repeat imaging: CC or NCC. The rate of organ-specific delayed complications and interventions was examined by reason for scan. Results A total of 307 injuries were included in the study period (174 splenic, 113 hepatic, and 20 both). Of 194 splenic injuries, 30(15.5%) underwent repeat imaging (CC = 19; NCC = 11). Of 133 hepatic injuries, 27(20.3%) underwent repeat imaging (CC = 21; NCC = 6). There was no difference in the incidence of organ-specific delayed complications between the CC and NCC groups. Of the 4 patients with complications necessitating intervention, only one was identified based on NCC. Conclusions Our data suggest routine repeat imaging is unnecessary in children with blunt splenic and/or hepatic injuries; therefore, practitioners may rely on a patient’s clinical change.

Objective With recent changes to graduate medical education, the balance between resident autonomy and need for supervision impacts the educational and training experience of residents. The objective of this study was to understand the relationship between the confidence of attendings and residents and their different perspectives of perceived educational experience and autonomy in the operating room (OR). We hypothesized that the attending's confidence in the resident would be an important factor in improving the educational experience and resident's autonomy in the OR. Design Self-reported confidence-rating and operative experience surveys were administered to teams of post-graduate year (PGY 1) through PGY 5 surgical residents and attendings in two temporal sets (Early: Sept-Dec 2015, n = 20; Late: Jan-Apr 2016, n = 22). A second “end-of-year” survey was distributed to residents (n = 9, 37.5% response) and attendings (n = 10, 35% response) asking questions regarding their educational experience and operative experience during the past year. Setting Large rural teaching hospital. Participants Nineteen general surgery residents (PGY 1 - 5) and 14 general surgery attendings. Results Resident perception of confidence differs from junior to senior residents, and that there was discordance between resident's confidence and skill as perceived by attendings, particularly in senior residents. Results also showed that attending's confidence in residents was positively correlated with attending's perceived educational experience in the OR. Residents and attendings both indicated attending's confidence in residents as an important factor in increasing resident autonomy in the OR, thus the attending's confidence in residents could have a positive impact on resident autonomy and educational experience in the OR. Conclusions We have demonstrated a relationship between self-confidence for residents and improved confidence from attendings in residents’ capabilities. Based on these findings, we would propose identifying methods to expand resident's awareness of surgical situations and develop attending's confidence in residents.

BACKGROUND The purpose of this study was to determine the relationship between timing and volume of crystalloid before blood products and mortality, hypothesizing that earlier transfusion and decreased crystalloid before transfusion would be associated with improved outcomes. METHODS A multi-institutional prospective observational study of pediatric trauma patients younger than 18 years, transported from the scene of injury with elevated age-adjusted shock index on arrival, was performed from April 2018 to September 2019. Volume and timing of prehospital, emergency department, and initial admission resuscitation were assessed including calculation of 20 ± 10 mL/kg crystalloid boluses overall and before transfusion. Multivariable Cox proportional hazards and logistic regression models identified factors associated with mortality and extended intensive care, ventilator, and hospital days. RESULTS In 712 children at 24 trauma centers, mean age was 7.6 years, median (interquartile range) Injury Severity Score was 9 (2-20), and in-hospital mortality was 5.3% (n = 38). There were 311 patients(43.7%) who received at least one crystalloid bolus and 149 (20.9%) who received blood including 65 (9.6%) with massive transfusion activation. Half (53.3%) of patients who received greater than one crystalloid bolus required transfusion. Patients who received blood first (n = 41) had shorter median time to transfusion (19.8 vs. 78.0 minutes, p = 0.005) and less total fluid volume (50.4 vs. 86.6 mL/kg, p = 0.033) than those who received crystalloid first despite similar Injury Severity Score (median, 22 vs. 27, p = 0.40). On multivariable analysis, there was no association with mortality (p = 0.51); however, each crystalloid bolus after the first was incrementally associated with increased odds of extended ventilator, intensive care unit, and hospital days (all p < 0.05). Longer time to transfusion was associated with extended ventilator duration (odds ratio, 1.11; p = 0.04). CONCLUSION Resuscitation with greater than one crystalloid bolus was associated with increased need for transfusion and worse outcomes including extended duration of mechanical ventilation and hospitalization in this prospective study. These data support a crystalloid-sparing, early transfusion approach for resuscitation of injured children. LEVEL OF EVIDENCE Therapeutic, level IV.

Esophageal atresia is the most common congenital anomaly of the esophagus. Treatment optimally includes primary tension-free anastomosis of the upper and lower aspects of the esophagus. Distance between the upper and lower esophagus predisposes the anastomosis to tension, increasing the risk of anastomotic stricture. Esophageal stricture has historically been managed with repeated endoscopic balloon dilations. Multiple failed attempts at endoscopic balloon dilation requires surgical revision of the anastomosis. Stenting of esophageal stricture has been used in the adult population but has not been described for children. This case report demonstrates the placement of biliary stents in a 2-month-old infant with esophageal stricture following repair of a long gap Type C tracheoesophageal fistula. Successful stenting procedure averted the need for surgical revision.

Eye-gaze metrics derived from areas of interest (AOIs) have been suggested to be effective for surgical skill assessment. However, prior research is mostly based on static images and simulated tasks that may not translate to complex and dynamic surgical scenes. Therefore, eye-gaze metrics must advance to account for changes in the location of important information during a surgical procedure. We developed a dynamic AOI generation technique based on eye gaze collected from an expert viewing surgery videos. This AOI updated as the gaze of the expert moved with changes in the surgical scene. This technique was evaluated through an experiment recruiting a total of 20 attendings and residents to view 10 videos associated with and another 10 without adverse events. Dwell time percentage (i.e., gaze duration) inside the AOI differentiated video type (U = 13508.5, p

Thoracoscopic surgery has been increasingly utilized in treating pediatric congenital lung malformations (CLM). Comparative studies evaluating 30-day outcomes between thoracoscopic and open resection of CLM are lacking.There were 258 patients identified in pediatric NSQIP with a CLM and pulmonary resection in 2012-2013. Comparisons of patient characteristics and outcomes between surgical approaches were made using standard univariate statistics. In addition, a propensity score match was performed to evaluate outcomes in similar patient cohorts.One-hundred twelve patients (43.4%) received thoracoscopic resections and 146 patients (56.6%) received open resections. Patients undergoing open resections were more likely to be less than 5 months of age and have a comorbidity/preoperative condition (47.3% vs. 25.0%, p0.001). The extent of resection was a lobectomy in 84.8% of thoracoscopic and 92.5% of open resection patients. Median operative time was similar between both groups (thoracoscopic 172 vs. open 153.5 minutes). On univariate analysis, thoracoscopic resection was associated with decreased postoperative complications (9.8% vs. 25.3%, p=0.001) and LOS (3 vs. 4 days, p0.001). However, after adjusting for similar patient and operative characteristics, no significant differences were encountered between techniques.Thoracoscopic and open resection provide comparable 30-day outcomes and safety in the management of congenital lung malformations.

BACKGROUND Operation Iraqi Freedom and Operation Enduring Freedom have seen the highest rates of combat casualties since Vietnam. These casualties often require massive transfusion (MT) and immediate surgical attention to control hemorrhage. Clinical practice guidelines dictate ratio-driven resuscitation (RDR) for patients requiring MT. With the transition from crystalloid to blood product resuscitation, we have seen fewer open abdomens in combat casualties. We sought to determine the effect RDR has on achieving early definitive abdominal fascial closure in combat casualties undergoing exploratory laparotomy. METHODS Records of 1,977 combat casualties admitted to a single US military hospital from April 2003 to December 2011 were reviewed. Patients receiving an MT and laparotomy in theater constituted the study cohort. The cohort was divided into RDR, defined as a ratio of 0.8-U to 1.2-U packed red blood cells to 1-U fresh frozen plasma, and No-RDR groups. Age, injury patterns, mechanism of injury, injury severity, blood products, number of laparotomies, and days to fascial closure were collected. Assessed outcomes were number of days (early ≤ 2 days) and number of laparotomies to achieve fascial closure. RESULTS The mean age of the study cohort (n = 172) was 24.0 years, and mean Injury Severity Score (ISS) was 24.8. Improvised explosive device blast was the most common mechanism of injury (74.4%). The cohort was divided into RDR patients (n = 73) and no RDR (n = 99). There was no difference in mean age, mean ISS, or rate of nontherapeutic exploratory laparotomies between the groups. RDR patients had a significantly lower abdominal injury rate (34.2% vs. 72.7%, p < 0.01), had fewer laparotomies (2.7 vs. 4.3, p = 0.003), and achieved primary fascial closure faster (2.4 days vs. 7.2 days, p = 0.004). On multivariate analysis, RDR (2.74; 95% confidence interval, 1.44-5.2) was an independent predictor for early fascial closure. CONCLUSION Adherence to RDR guidelines resulted in significantly decreased number of abdominal operations and was identified as an independent predictor for early fascial closure. Further investigation is warranted to validate these findings. LEVEL OF EVIDENCE Therapeutic study, level III.

Background The benefit of Ladd's procedure for malrotation at a Children's Hospital (CH) has not previously been established. Our aim was to characterize the potential variations in management and outcomes between CH and Non-Children's Hospitals (NCH) in the treatment of malrotation with Ladd's procedure. Methods There were 2827 children identified with malrotation and complete information from the Kids' Inpatient Database (2003, 2006, 2009). Outcomes were compared between CH and NCH and evaluated with logistic and linear regressions. Additional propensity score matching was used to balance covariates between CH and NCH. Results There were 2261 (80.0%) children with malrotation undergoing Ladd's procedures treated at CH; 566 (20.0%) were treated at NCH. In multivariate analysis, CH was associated with a 39% lower odds of resection ( p =0.004), with no differences observed for mortality, morbidity and LOS. Comparison of a propensity score matched cohort confirmed these findings, as well as demonstrated no significant differences in associated costs. Conclusions The majority of pediatric intestinal malrotation is managed at CH. While measured outcomes of mortality, morbidity, LOS, and costs were not different at NCH, CH was less likely to perform intestinal resection during Ladd's procedure.

After a decade of war in Iraq and Afghanistan, we have observed an increase in combat-related injury survival and a paradoxical increase in injury severity, mainly because of the effects of blasts. These severe injuries have a devastating effect on each patient's immune system resulting in massive upregulation of the systemic inflammatory response. By examining inflammatory mediators, preliminary data suggest that it may be possible to correlate complications such as wound failure and heterotopic ossification (HO) with distinct systemic and local inflammatory profiles, but this is a relatively new topic.We asked whether systemic or local markers of inflammation could be used as an objective means, independent of demographic and subjective factors, to estimate the likelihood of (1) HO and/or (2) wound failure (defined as wounds requiring surgical débridement after definitive closure, or wounds that were not closed or covered within 21 days of injury) in patients sustaining combat wounds.Two hundred combat wounded active-duty service members who sustained high-energy extremity injuries were prospectively enrolled between 2008 and 2012. Of these 200 patients, 189 had adequate followups to determine the presence or absence of HO, and 191 had adequate followups to determine the presence or absence of wound failure. In addition to injury-specific and demographic data, we quantified 24 cytokines and chemokines during each débridement. Patients were followed clinically for 6 weeks, and radiographs were obtained 3 months after definitive wound closure. Associations were investigated between these markers and wound failure or HO, while controlling for known confounders.The presence of an amputation (p0.001; odds ratio [OR], 6.1; 95% CI. 1.63-27.2), Injury Severity Score (p = 0.002; OR, 33.2; 95% CI, 4.2-413), wound surface area (p = 0.001; OR, 1.01; 95% CI, 1.002-1.009), serum interleukin (IL)-3 (p = 0.002; OR, 2.41; 95% CI, 1.5-4.5), serum IL-12p70 (p = 0.01; OR, 0.49; 95% CI, 0.27-0.81), effluent IL-3 (p = 0.02; OR, 1.75; 95% CI, 1.2-2.9), and effluent IL-13 (p = 0.006; OR, 0.67; 95% CI, 0.50-0.87) were independently associated with HO formation. Injury Severity Score (p = 0.05; OR, 18; 95% CI, 5.1-87), wound surface area (p = 0.05; OR, 28.7; 95% CI, 1.5-1250), serum procalcitonin ([ProCT] (p = 0.03; OR, 1596; 95% CI, 5.1-1,758,613) and effluent IL-6 (p = 0.02; OR, 83; 95% CI, 2.5-5820) were independently associated with wound failure.We identified associations between patients' systemic and local inflammatory responses and wound-specific complications such as HO and wound failure. However, future efforts to model these data must account for their complex, time dependent, and nonlinear nature.Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Combat casualties have endured an increase in traumatic lower extremity amputations secondary to improvised explosive devices. Often surgical control of the proximal vasculature is required. We evaluate the safety profile of exploratory laparotomy (EXLAP) for proximal control (PC) in combat-injured patients.Records of 845 combat casualties from June 2009 to December 2011 were reviewed. Patients undergoing EXLAP were divided by indication into PC and non-PC groups. Demographics, Injury Severity Score, mechanism of injury, transfusion requirements, EXLAP findings, reoperation rates, and abdominal-related complications were recorded.44 patients were identified as PC and 91 as non-PC. Age was similar (23.7 ± 4.1 vs. 24.0 ± 4.6, p = 0.7138), and all were male. Improvised explosive devices blast was the most common mechanism of injury. Injury Severity Score (25.8 ± 8.2 vs. 21.4 ± 9.1, p = 0.0075), lower extremity amputation (93.1% vs. 28.6%, p = 0.0001), and transfusion requirements were different. Days to fascial closure (1.8 ± 1.9 vs. 1.7 ± 2.8, p = 0.8308) and number of EXLAPs were similar (2.4 ± 1.3 vs. 2.1 ± 1.5, p = 0.2581). PC had higher complications (43.1% vs. 24.2%, p = 0.0292).PC demonstrated an increase in abdominal complications. The reason for this remains unclear. Alternative approaches of achieving proximal vascular control may avoid the morbidity associated with laparotomy, and predeployment training of such procedures should be considered for the general surgeon. Further studies are warranted to determine best practices for these patients.

Objective:The Haitian earthquake of January 12, 2010, was a disaster essentially unprecedented in the Western Hemisphere's recorded history. TheUSNS Comfortdeparted from Baltimore, Maryland, within 72 hours of the earthquake and arrived in Port-au-Prince harbor on January 19. During the subsequent 40 days, the ship provided one of the largest relief efforts in the US Navy's history.Methods:The data analyzed included all patients evaluated and treated by theUSNS Comfortbetween January 19 and February 27, 2010. A medical chart with a unique identifier was created for each patient on admission. A patient database was created from these records and used for this analysis.Results:A total of 872 patients and 185 patient escorts were processed aboard the ship. Ages ranged from younger than 1 day to 89 years: 635 were adults and 237 were children. Of those admitted, 817 of the patients were admitted for longer than 24 hours; the average length of stay was 8.0 days. The need for surgery was substantial: 454 patients went to the operating room (OR) 843 times for 927 cumulative procedures. A total of 58 patients underwent amputations.Conclusions:Haiti was almost completely reliant on foreign medical teams for trauma care. Analysis of the data illustrates the challenges of triage and treatment in a humanitarian mass-casualty response. The remarkable coordination and cooperation among the Haitian Ministry of Health, nongovernmental humanitarian aid organizations, and the US military highlighted the responders' respective capabilities and demonstrated the importance of collaboration in future disaster response efforts.(Disaster Med Public Health Preparedness. 2012;6:370–377)

Introduction: The aim of our study was to apply longitudinal force to the small bowel to increase the length of intestine in juvenile rats. Methods: Fifty juvenile rats had double barrelled, blind loop ostomies created using an isolated segment of bowel. Our intestinal lengthening device was inserted into one of the loops and the second loop served as a control. Once the device was deployed, the experimental, control, and in situ segments of bowel were evaluated for length, weight, histology, and disaccharidase enzyme activity. Results: Mechanical tension increased intestinal length by 149%. The lengthened bowel also exhibited a greater total weight (218%), greater mucosal weight (122%), and increased protein mass (164%) compared with the control limb of bowel. Histologically, there was a markedly increased thickness of the muscularis propria in the lengthened bowel (200% increase compared with the control limb). Functionally, we found increased total disaccharidase activity in the lengthened bowel (between 47% and 350%, depending on the particular enzyme tested; p Conclusion: Mechanical tension induces intestinal growth by increasing length, weight of the bowel and mucosa, and protein mass. Histological changes, such as increases in Paneth cells, suggest that increased proliferation and reorganisation of the mucosa and muscularis propria are a response to mechanical tension. Functionally, increased intestinal length corresponds with increased disaccharidase activity, thus implying potential increased absorptive capacity of the lengthened bowel.

The relationship between hospital volume and outcomes needs to be further elucidated for low-risk procedures such as surgical therapy of localized breast cancer. The objective of this investigation was to assess the relationship between hospital volume and outcomes for breast cancer surgery.A total of 233,247 patients who underwent breast-conserving therapy (BCT) and breast-ablative therapy (BAT) for localized breast cancer were extracted from 13 years (1988-2000) of the Nationwide Inpatient Samples. Hospital volume was classified as low (30 cases/year), intermediate (or =30 to70 cases/year), and high (or =70 cases/year). Multiple linear and logistic regression analyses were used to assess the risk-adjusted association between hospital volume and outcomes.In risk-adjusted analyses, patients operated on at low-volume hospitals were 3.04 (p = 0.03) times more likely to die after BCT compared with patients operated on at high-volume hospitals. Similarly, low-volume hospitals had a significantly higher likelihood of postoperative complications (odds ratio [OR] = 1.73, p = 0.01 for BCT; OR = 1.44, p0.001 for BAT) compared with high-volume hospitals. Compared with low-volume hospitals, length of hospital stay was significantly shorter and nonroutine patient discharge significantly lower for high-volume providers for both BCT and BAT (all p0.001). Patients were also significantly less likely to undergo BCT if operated on in a low- or intermediate-volume hospital compared with a high-volume provider (p0.001).High-volume hospitals had significantly lower nonroutine patient discharge, postoperative morbidity and mortality, shorter length of hospital stay, and higher likelihood of performing BCT. Referral of patients with localized breast cancer to high-volume hospitals may be justified.

The aim of this study was to examine the association between E-cadherin expression and markers of Wilms' tumor aggression, including metastasis and recurrence.Forty Wilms' tumor samples from the National Wilms' Tumor Study Group underwent immunohistochemical staining for E-cadherin. Tumor stage at diagnosis, recurrence, and loss of heterozygosity at 16q status was known for each of the tumor samples. E-Cadherin cell staining was defined as high (33%) or low (33%), and values were assigned by a pathologist blinded to the tumor characteristics. Five stage IV tumors were ineligible for assay because of lack of a tubular component. To identify a mechanism of downregulation, we screened tumor DNA for genetic mutations in exons 1-16 using a combination of WAVE and sequence analysis. To assess the functional significance of the identified mutations, the authors compared amino acid homology across multiple species. Finally, they performed reverse transcriptase-polymerase chain reaction for those tumors with intronic single nucleotide polymorphisms (SNPs) to evaluate for mRNA splice variants.Wilms' tumors presenting with metastatic (stage IV) disease demonstrated decreased levels of E-cadherin expression compared with localized tumors (stage I) (Fisher's Exact test, P.01). In a search for the mechanism of the downregulation of E-cadherin, we identified 5 different mutations in 7 high stage tumors (7/15) and 1 mutation in a low stage tumor (1/20). The mutations occurred in amino acids that were conserved across multiple species. Additionally, 11 of 15 high stage tumors contained an intronic SNP located within 6 bp of the 5 intronic splice junction immediately downstream of exon 1. However, examination of 5 of these tumors using reverse transcriptase-polymerase chain reaction showed that this intronic SNP does not appear to disrupt the assembly of full-length E-cadherin transcripts. Lastly, no correlation was identified between E-cadherin expression and recurrence of disease.In this study, the authors have found an association between decreased E-cadherin expression and metastatic Wilms' tumor. Mutations identified may help identify a mechanism for downregulation. The functional significance of these mutations is supported by the conserved nature of the amino acids across multiple species. The authors believe these findings support the involvement of E-cadherin in the evolution of Wilms' tumor.

The function of the ear depends in part on its absolute size and internal proportions. Thus, in both young individuals and small species, the middle ear is expected to be allometrically enlarged despite its smaller absolute size. Here we aim to compare the ontogenetic allometry of relevant middle-ear structures as observed within gecko (gekkonomorph lizards) species, with the evolutionary allometry observed interspecifically. These observations also provide middle-ear data for future evaluation of variation in auditory sensitivity. The material comprised 84 museum specimens of geckos, representing nine species of three gekkonomorph subfamilies. The results of dissections and measurements show that different reports notwithstanding, the middle-ear ossicular chain is indeed structured as described for geckos by Werner and Wever (J Exp Zool 1972;179:1–16) and Wever (The reptile ear, 1978). Some sexual dimorphism is indicated, but this requires further study. During postnatal ontogeny, the allometric growth in the ratio of the columellar footplate area to body length differed between the intraspecific and interspecific levels, hence species differences in the middle ear do not merely result from animal size. The ratio of the tympanic membrane area to the columellar footplate area increased during ontogeny. In this, geckos resemble birds and probably also mammals. Similarly, when the comparison was among adults representing different species, the ratio of the tympanic membrane area to the columellar footplate area increased with body size. In this, however, the geckos differed from birds and mammals, in which this ratio varied taxonomically, irrespective of body size. It would thus seem that middle-ear proportions have evolved among geckos to produce small interspecific differences, but among amniote tetrapods they have evolved according to different principles in the classes reptiles, birds, and mammals. © 2005 Wiley-Liss, Inc.

Neural tissue has limited capacity for intrinsic repair after injury, and the identification of alternate sources of neuronal stem cells has broad clinical potential. Preliminary studies have demonstrated that adipose-derived adult stromal (ADAS) cells are capable of differentiating into mesenchymal and non-mesenchymal cells in vitro, including cells with select characteristics of neuronal/glial tissue. In this study, we extended these observations to test the hypothesis that murine (mu) ADAS cells can be induced to exhibit characteristics of neuronal and glial tissue by exposure to a cocktail of induction agents. We characterized the differentiation of muADAS cells in vitro using immunohistochemistry and immunoblotting, and examined whether these cells respond to the glutamate agonist N-methyl-D-aspartate (NMDA). We found that induced muADAS cells express proteins indicative of neuronal/glial cells, including nestin, GFAP, S-100, NeuN, MAP2, tau, and beta-III tubulin. Induced muADAS cells express gamma-aminobutyric acid (GABA), the NR-1 and NR-2 subunits of the glutamate receptor, GAP-43, synapsin I, and voltage-gated calcium channels. Finally, induced muADAS cells demonstrate decreased viability in response to NMDA. These findings suggest that muADAS cells can be induced to exhibit several phenotypic, morphologic, and excitotoxic characteristics consistent with developing neuronal and glial tissue.

The aim of this study was to more precisely map the region of 16q loss of heterozygosity (LOH) in Wilms' tumors and to examine the expression of putative tumor suppressor.We performed polymerase chain reaction-based LOH analysis on the 185 sample pairs from 21 to 80 megabases (Mb) on chromosome 16q. Expression of two candidate tumor suppressor genes located within the identified consensus region of 16q LOH was examined by immunohistochemistry.We identified 16q LOH in 7 (4%) of 185 Wilms' tumors not previously thought to demonstrate such genetic loss. The smallest common region of genetic loss was located between 67.3 and 74.0 Mb on chromosome 16. Within this 6.7-Mb region, there reside only three recognized tumor suppressor genes: E-cadherin, P-cadherin, and E2F4. E-cadherin demonstrates statistically significantly reduced expression in Wilms' tumors with 16q LOH.We have localized the consensus region of 16q LOH in Wilms' tumor to a 6.7-Mb locus and have identified three candidate Wilms' tumor suppressor genes within this narrowed region. Our data support E-cadherin as a candidate tumor suppressor gene in Wilms' tumor; however, further studies are needed to definitively prove its role as the tumor suppressor gene associated with 16q LOH.

The identification of cells capable of neuronal differentiation has great potential for cellular therapies. We examined whether murine and human adipose-derived adult stem (ADAS) cells can be induced to undergo neuronal differentiation. We isolated ADAS cells from the adipose tissue of adult BalbC mice or from human liposuction tissue and induced neuronal differentiation with valproic acid, butylated hydroxyanisole, insulin, and hydrocortisone. As early as 1-3 h after neuronal induction, the phenotype of ADAS cells changed towards neuronal morphology. Following neuronal induction, muADAS cells displayed immunocytochemical staining for GFAP, nestin and NeuN and huADAS cells displayed staining for intermediate filament M, nestin, and NeuN. Following neuronal induction of murine and human ADAS cells, Western blot analysis confirmed GFAP, nestin, and NeuN protein expression. Pretreatment with EGF and basic FGF augmented the neuronal differentiation of huADAS cells. The neuronal differentiation of stromal cells from adipose tissue has broad biological and clinical implications.

Background . Paediatric trauma system development in Alaska is complicated by a vast geographic coverage area, wide regional variations in environment and culture, and a lack of available published data. Objective . To provide a detailed description of paediatric trauma mechanisms, high-risk injury patterns and outcomes in Alaska. Design . This retrospective study included all children aged 17 years or younger in the State of Alaska Trauma Registry database admitted with traumatic injury between 2001 and 2011. Each injury record was reviewed individually and assigned a mechanism based on Centers for Disease Control E-codes. Geographic definitions were based on existing Emergency Medical Services regions. Mechanisms were compared by geographic region, patient demographics, injury characteristics and outcome. Subgroup analysis of fatal injuries was performed to identify causes of death. Results . Of 5,547 patients meeting inclusion criteria, the most common mechanisms of injury were falls (39%), motor vehicle collisions (10%) and all-terrain vehicle (ATV) accidents (9%). The overall case fatality rate was 2%. Mechanisms with the greatest risk of death were gunshot wounds (21%), pedestrians struck by motorized vehicles (9%) and motor vehicle collisions (5%). These 3 mechanisms accounted for 15% of injuries but 60% of deaths in the overall cohort. Injury patterns involving combined central nervous system (CNS) and torso injuries were unusual but especially lethal, occurring in 3% of patients but carrying a case fatality rate of 18%. Although the distribution of mechanisms was generally similar for each geographic region, ATV and snowmobile injuries were significantly more common in remote areas (23% remote vs. 7% non-remote, p < 0.0001). Conclusions . Mechanisms of paediatric trauma in Alaska have widely varying impacts on outcome and show some variation by region. Highest-risk mechanisms include gunshot wounds and motorized vehicle-related accidents. Prevention efforts should give special attention to CNS injury prevention, ATV and snowmobile safety in remote areas, and optimization of management of multisystem trauma. Further studies should investigate predictors of outcome in greater detail. Keywords: Alaska; injury; epidemiology; youth; resource utilization (Published: 6 August 2014) Citation: Int J Circumpolar Health 2014, 73 : 25066 - http://dx.doi.org/10.3402/ijch.v73.25066

The aim of this study was to determine the incidence, risk factors, and proper management for asymptomatic cholelithiasis in children undergoing bone marrow transplantation (BMT).The authors reviewed retrospectively the records of 575 children who underwent bone marrow transplantation at a University bone marrow transplantation unit (BMT) unit between February 1991 and October 1999. Of these patients, 235 underwent abdominal ultrasonography for evaluation of jaundice, sepsis, abdominal pain, or metastasis. To identify risk factors for cholelithiasis, the authors stratified the patients based on their disease and treatment regimen. Finally, the authors analyzed the natural history and management of BMT children with cholelithiasis.The authors identified 20 cases of cholelithiasis (8.5%) in the 235 BMT patients who underwent ultrasonography. Children who underwent BMT to treat bone marrow failure showed a significantly increased risk of cholelithiasis compared with children treated for malignancy (27% v 7.4%; P.01). Most children (85%) with gallstones did not require surgical intervention. Specifically, 9 (45%) died from their primary disease, 5 (25%) showed sonographic resolution of their gallstones, and 3 (15%) underwent follow-up nonoperatively with persistent cholelithiasis. Three of the 20 patients with gallstones (15%) had signs of acute cholecystitis and underwent surgery. There were no surgical complications or deaths in the operative group.Cholelithiasis occurs at a high incidence in pediatric bone marrow transplant patients. Children undergoing BMT for bone marrow failure are at higher risk of having gallstones than those being treated for malignancy. Finally, these data support a strategy of nonoperative management for asymptomatic cholelithiasis in this highly selected group of patients.

Gekkonoid lizards increase in body size throughout life, and the present study investigates whether changes in auditory function accompany these increases. Middle-ear structures in four groups of animals, adults and juveniles of two gekkonoid species (Eublepharis macularius and Oedura marmorata), were examined. Tympanic membrane velocity and phase were also measured in all four groups. An indication of peripheral auditory function was obtained for each group by measuring compound action potentials (CAPs) from the round window membrane. The middle-ear contribution to CAP thresholds was obtained by comparing threshold levels of the CAP response with and without an intact middle-ear system. The results from these studies indicated that significant changes occurred in middle-ear structure, tympanic membrane velocity and CAP threshold between the younger and older animals. In addition, the adults of both species exhibited better auditory function when the acoustic stimulus was delivered to the tympanic membrane than when it was delivered to the columella footplate. The findings show clearly that increased body size (or age) is accompanied by functional changes in the auditory periphery.

Background: Pancreaticoduodenal artery aneurysms (PDAs) are rare, accounting for only 2% of all visceral artery aneurysms. The majority of reported cases of patients with PDA have presented subsequent to rupture. Presentation without rupture also has been reported and is often associated with abdominal discomfort or diagnosed incidentally on radiologic studies. PDA rupture is associated with a high mortality rate, with fatal bleeding into the retroperitoneal space, intraperitoneal cavity, or gastrointestinal tract. Methods: This article reports two cases of ruptured PDA, both presenting as catastrophic intraabdominal bleeding and both treated successfully at celiotomy. In addition, the literature concerning PDA is reviewed. Results: Only 11 cases of PDA associated with sudden, severe abdominal pain and shock have been described. The mortality rate in these 11 cases was 36%, with half the patients not reaching the operating room alive. Successful management includes rapid resuscitation and control of the bleeding site with minimal pancreatic dissection, angiography for confirmation of vascular control and anatomic localization, and further definitive treatment if obliteration is incomplete. Conclusions: The aneurysm should be obliterated whenever possible to avoid both rebleeding and local complications related to mass effect such as pancreatic duct obstruction or erosion of the mass into neighboring structures. With appropriate and expeditious treatment, these gravely ill patients can be managed effectively and good outcomes obtained. (Surgery 1998;123:8-12.)

Background Intraoperative laparoscopic determination of intestinal viability is currently limited to subjective visible cues. Adjunctive modalities are neither widely available nor practical. Three–charge coupled device (3-CCD) imaging directly correlates the amount of light detected by CCDs to tissue oxygenation. We hypothesize that application of 3-CCD image enhancement detects bowel ischemia in a pediatric laparoscopic appendectomy model. Methods We recorded 10 laparoscopic appendectomies for appendicitis. Offline analysis involved selecting regions of interest (ROIs) in the appendix, adjacent colon, and nonappendiceal fat and calculating mean intensity values in selected images before and after division of the mesoappendix. The colon was used as a control, and the intensity values were normalized to fat. Results As an indicator of decreased perfusion, the mean appendix ROI intensity values decreased over time ( R 2 = 0.92) compared with the colon mean ROI intensity values, which remained stable. There was a statistically significant difference between fat-normalized intensity values for ischemic and nonischemic appendix after 1 minute. Conclusion We have demonstrated proof of principle for the determination of bowel ischemia using 3-CCD image enhancement. By quantitatively identifying areas of ischemia, this technique has the potential to significantly change the management of ischemic bowel in the future.

Background On January 12, 2010, Haiti experienced the western hemisphere's worst-ever natural disaster. Within 24 hours, the United States Naval Ship Comfort received orders to respond, and a group of more than 500 physicians, nurses, and staff undertook the largest and most rapid triage and treatment since the inception of hospital ships. Methods These data represent pediatric surgical patients treated aboard the United States Naval Ship Comfort between January 19 and February 27, 2010. Prospective databases managed by patient administration, radiology, blood bank, laboratory services, and surgical services were combined to create an overall patient care database that was retrospectively reviewed for this analysis. Results Two hundred thirty-seven pediatric surgical patients were treated, representing 27% of the total patient population. These patients underwent a total of 213 operations composed of 243 unique procedures. Orthopedic procedures represented 71% of the total caseload. Patients returned to the operating room up to 11 times and required up to 28 days for completion of surgical management. Conclusions This represents the largest cohort of pediatric surgical patients in an earthquake response. Our analysis provides a model for anticipating surgical caseload, injury patterns, and duration of surgical course in preparing for future disaster response missions. Moreover, we propose a 3-phased response to disaster medicine that has not been previously described.

Surgical organizations have begun to focus their efforts on providing humanitarian assistance in international communities. Most surgeons do not have previous international experience and lack an understanding of what is expected and what care they can provide. The unknown factors include case types, patient volume, postoperative care, and equipment. This abstract presents humanitarian assistance mission and highlights the importance of preparation, host nation involvement, and understanding the local politics of each country.In April to July 2009, the USNS (United States Naval Ship) Comfort deployed to provide humanitarian assistance to 7 countries through Central and South America. Data collected included numbers and types of procedures, rate of rejection of patients for operation, patient age, American Society of Anesthesiology (ASA) score, and length of procedure.These data represent the total mission of Continuing Promise 2009 including a total of 1137 surgical procedures of which 340 were pediatric (18 years old). The average number of pediatric cases for each country in 7 days was 48.3 ± 21.4, with a range of 24 to 84. The average age was 7.5 years (range, 1 month to 18 years). In partnership with host physicians, preoperative screening occurred over 2 to 3 days for every 7 operative days. We maintained a low threshold for rejection (rate of 43%; range, 21%-62%) and average ASA score of 1.3. Including all pediatric subspecialties, the most frequent procedures were inguinal (23%) and umbilical (14%) hernias. Although these were the most frequent procedure, the range and variety of cases varied widely. We had a very low early complication rate (1.2%), including 3 wound infections and 1 early hernia recurrence.Our data represent the largest collection to date on the pediatric surgical care of children in a humanitarian effort. Our experience can be used to identify the most likely types of cases in South and Central America and as a model for the safe and efficient treatment of children in a developing country.

Modern war wounds are complex and primarily involve extremities. They require multiple operative interventions to achieve wound closure and begin rehabilitation. Current assessment of the suitability of surgical wound closure is based upon subjective methods coupled with a semiquantitative determination of the wound bacterial burden. Measurement of the systemic and local response to injury using inflammatory biomarkers may allow for accelerated wound closure and treatment of other combat-related morbidity. This article presents the introduction of personalized medicine into combat casualty care.

Although diseases of the thyroid and parathyroid glands are relatively uncommon in children, the implications of missed diagnoses can be severe. This review describes the embryology, anatomy, and physiology of the thyroid and parathyroid glands, and focuses on significant benign and malignant pathologies of these glands.

Aim The availability of large clinical databases allows for careful evaluation of surgical practices, indicators of quality improvement, and cost. We used a large clinical database to compare the effect of surgeon and hospital volume for the care of children with hypertrophic pyloric stenosis (HPS). Methods Patients with International Classification of Diseases-9 codes for HPS and pyloromyotomy were selected from the 1994 to 2000 National Inpatient Samples database. Multiple and logistic regression models were used to evaluate the risk-adjusted association between provider volume and outcomes. Results Postoperative complications occurred in 2.71% of patients. Patients operated on by low- and intermediate-volume surgeons were more likely to have complications compared with those operated on by high-volume surgeons (95% confidence interval [CI], 1.25-3.78 and 95% CI, 1.25-2.69, respectively). Patients operated at low-volume hospitals were 1.6 times more likely to have complications compared with those operated at intermediate- or high-volume hospitals (95% CI, 1.19-2.20). Procedures performed at high-volume hospitals were less expensive than those at intermediate-volume hospitals by a margin of $910 (95% CI, $443-$1377). Conclusions These data represent the largest study to date on the epidemiology, complication rate, and cost for care for HPS. Patients treated by both high-volume surgeons and at high-volume hospitals have improved outcomes at less cost.

We generated a line of transgenic mice using a yeast artificial chromosome containing the Ret mutation responsible for the multiple endocrine neoplasia type 2B syndrome (MEN 2B). The resulting animals did not develop any of the expected neoplasms associated with MEN 2B. Transgenic animals were then bred with animals lacking murine Ret (Ret(M)) to further evaluate the function of human mutated Ret (Ret(H)(2B)) in the murine context. Whereas mice lacking Ret(M) exhibit intestinal aganglionosis and the absence of kidneys with other genitourinary anomalies, expression of the Ret(H)(2B) transgene in Ret(M)-deficient mice allowed significant renal development with a partial rescue of the enteric nervous system. These Ret(H)(2B)-positive/Ret(M)-deficient mice exhibit normal Ret expression and survive longer than Ret(M)-deficient mice, but still die at 3 to 5 days of age with evidence of enterocolitis. We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in mice. Although the gene is normally expressed in the appropriate target tissues, there is incomplete phenotypic rescue in mice lacking murine Ret. These results suggest important interspecies differences between humans and mice in the function of the Ret oncogene.

Iodine 131-meta-iodobenzylguanidine ((131)I-MIBG) has been applied to the palliative treatment of metastatic pheochromocytoma in small studies. We report our institutional experience for the treatment of metastatic pheochromocytoma and paraganglioma.We performed a retrospective review of 33 patients with metastatic pheochromocytoma (n=22) and paraganglioma (n=11) treated at our institution with (131)I-MIBG over a 10-year period.Patients received a mean dose of 388+/-131 mCi (131)I-MIBG. Median survival after treatment was 4.7 years. Most patients experienced a symptomatic response leading to an improved survival (4.7 years vs 1.8 years, P.01). Patients with a measurable hormone response demonstrated an increased survival in comparison to those with no response (4.7 years vs 2.6 years, P=.01). Patients who received a high dose (500 mCi) as their initial therapy also had improved survival (3.8 years vs 2.8 years, P=.02).These data support (131)I-MIBG treatment for select patients with metastatic pheochromocytoma. In our experience, prolonged survival was best predicted by symptomatic and hormone response to (131)I-MIBG treatment. An initial dose of 500 mCi may be optimal. The benefit of (131)I-MIBG treatment for metastatic pheochromocytoma must also be weighed against its side effects.

Castleman disease usually presents in children as a localized mass with prominent feeding vessels. The mainstay of treatment of Castleman disease is surgical resection; historically, resection is associated with excessive blood loss. These tumors are well known to have large feeding vessels and, thus, are amenable to preoperative arteriography with embolization. The authors present a case of Castleman disease treated with preoperative embolization as an adjunct to operative management.

Background . Off-road motorized vehicle crashes are a common source of trauma among Alaska children. Injury morbidity is worse in Alaska Native children than non-Native children, but the reasons are unclear. Objective . To evaluate the differences in helmet use between the Native and the non-Native children, and to assess the impact of helmet use on injury patterns and outcomes. Design . This retrospective cohort study identified patients aged 17 or younger admitted after all-terrain vehicle, snowmobile or motorbike injury between 2001 and 2011 from the Alaska Trauma Registry. Helmeted and non-helmeted patients were compared with respect to demographics, central nervous system (CNS) injury and the overall risk of death or permanent disability. Logistic regression was used to evaluate predictors of helmet use and the effects of ethnicity and helmet use on outcomes. Results . Of the 921 injured children, 51% were Alaska Native and 49% were non-Native. Helmet use was lower among Native versus non-Native patients on unadjusted comparison (24% vs. 71%) and multivariable logistic regression (OR 0.17, 95% CI 0.11–0.27, p

Abstract —Heat shock proteins (HSPs) are a family of highly conserved proteins, essential to cell survival, that are induced during times of physiological stress. These proteins, when induced, can provide tolerance to subsequent injury. Several studies have documented that HSPs play an important role in the response of vascular cells to injury or stress. Whether the vasculature itself can be effectively preconditioned before arterial injury is unknown. Vascular HSP induction by whole-body hyperthermia (WBH) was evaluated with regard to its effects on the vascular response to balloon injury. WBH treatment of Sprague-Dawley rats (colonic temperatures of 41 to 42°C for 15 minutes) resulted in maximal arterial HSP expression within 8 to 12 hours. Rats (male, 300 g, n=59) were randomly assigned to undergo either WBH or no treatment 8 hours before standard carotid balloon injury. At 14 (n=26) and 90 (n=21) days after balloon injury, histomorphometric analysis revealed a significant limitation of intimal accumulation in preconditioned arteries as compared to controls (intimal/medial area ratios±SEM: 14 days, 0.57±0.07 versus 0.86±0.08, P =0.01; 90 days, 0.78±0.12 versus 1.19±0.14, P P P

Pulmonary hyalinizing granuloma (PHG) is a rare benign pulmonary nodular lesion of unknown etiology. We present a case of a 5-year-old boy who was found to have a chest mass while being evaluated for abdominal pain. He underwent a CXR and CT scan that showed popcorn calcifications in the right posterior mediastinum and within the hilum of right lung. These lesions were suspicious for benign calcified lymph nodes and follow-up chest CT after 3.5 months showed no interval changes in the calcified mediastinal masses. Extensive testing ruled out infectious diseases and malignancies. Given the unknown etiology of the lesions, he underwent VATS biopsy that demonstrated a nodular lesion characterized by a peripheral rim of fibrous tissue and central zone of necrosis and calcification, findings consistent with hyalinizing granuloma. PHG is extremely rare in pediatric age group. Although diagnosis of this condition is made by radiological and histopathological findings, it is important to rule out other causes of chest masses. Most of the patients usually have good prognosis with this rare disorder.

Purpose: The purpose of this study was to determine whether endogenous basic fibro-blast growth factor (bFGF) production contributes to the intimal hyperplastic response to injury in a model of rabbit femoral artery balloon injury. Inhibition of de novo production of bFGF protein was targeted by intramural adenoviral gene transfer of antisense bFGF (Ad.ASbFGF) RNA. The adenovirus was delivered locally intraluminally at the time of arterial injury. Methods: New Zealand White rabbits underwent balloon injury of the superficial femoral artery, followed by intraluminal delivery of an adenoviral vector encoding a rat antisense bFGF ( ASbFGF ) transcript at a concentration of 1 × 10 10 plaque-forming units per milliliter. Control animals were treated in a similar fashion, using either an adenovirus encoding the lac Z reporter gene (Ad.lacZ) or phosphate-buffered saline solution (PBS; vehicle) alone. Two weeks after balloon injury, rabbits were killed and perfusion fixed. Femoral arteries were harvested for histomorphometric analysis. Intimal and medial wall thickness was measured at eight points around the vessel perimeter, and mean intimal/medial (I/M) thickness ratios were compared by analysis of variance and Student's t test. In addition, medial cell proliferation in Ad.ASbFGF and Ad.lacZ treated arteries was evaluated 4 days and 2 weeks after balloon injury by 5-Bromo-2'-deoxyuridine labeling. Results: At 14 days (n = 25) after balloon injury, histomorphometric analysis revealed a significant inhibition of intimal thickening in Ad.ASbFGF-treated arteries as compared with Ad.lacZ-treated and PBS-treated controls (I/M thickness ratios ± SD, 0.43 ± 0.22 for Ad.ASbFGF vs 1.03 ± 0.28 for Ad.lacZ and 0.86 ± 0.19 for PBS; p p = 0.004, respectively). There was no significant difference in the I/M thickness ratios of Ad.lacZ-treated and PBS-treated vessels ( p = 0.27). Although there was no significant difference in the proliferation index of Ad.ASbFGF-treated and Ad.lacZ-treated vessels 4 days after injury, an increase in apoptosis was noted in the Ad.ASbFGF-treated vessels 4 days after balloon injury. Conclusions: The use of ASbFGF RNA gene transfer, designed to inhibit de novo bFGF synthesis after balloon injury, results in a significant inhibition of neointimal formation. This suggests that continued bFGF synthesis contributes to the arterial response to injury in rabbits. ASbFGF gene transfer may be an effective strategy in limiting the intimal hyperplastic response after vascular reconstructive procedures. (J Vasc Surg 1998;27:126-34.)

Purpose: To determine whether synthesis of endogenous basic fibroblast growth factor (bFGF) after arterial injury is critical to the intimal thickening response, intraluminal adenoviral gene transfer of an antisense bFGF (Ad.ASbFGF) transgene was used to inhibit the subsequent synthesis of bFGF protein after injury.Methods: Sprague-Dawley rats underwent balloon catheter carotid artery injury and in vivo gene transfer. Isolated segments of rat common carotid artery were infected with an adenoviral vector encoding an antisense bFGF transcript at concentrations of 2 × 109, 1 × 1010, or 1 × 1011 pfu/ml. Control rats were treated with either a control adenovirus encoding the β-galactosidase gene, (Ad.lacZ), at 1 × 1010, or 1 × 1011 pfu/ml, or phosphate-buffered saline solution (vehicle). Two weeks after injury the rats were killed and perfusion-fixed. Cross-sectional areas of the carotid arterial intima and media were measured by planimetry, and the intima/media ratio (I/M) was calculated for each vessel.Results: The mean I/M for each Ad.ASbFGF group and controls were compared and the significance assessed by analysis of variance. At two weeks after injury, the highest dose of Ad.ASbFGF, 1 × 1011 pfu/ml, resulted in a near total inhibition of thickening (I/M = 0.14 ± 0.04, mean ± SEM) when compared with phosphate-buffered saline solution alone (I/M = 0.99 ± 0.07), or Ad.lacZ 1 × 1010 pfu/ml (I/M = 1.01 ± 0.10) control treatments (p < 0.01). A tenfold lower dose of Ad.ASbFGF, 1 × 1010 pfu/ml, also caused significant reduction in intimal thickening (I/M = 0.39 ± 0.07, p < 0.01). Treatment with 2 × 109 pfu/ml Ad.ASbFGF did not significantly limit intimal thickening (I/M = 0.72 ± 0.12).Conclusions Inhibition of bFGF synthesis in vivo using an antisense RNA strategy significantly inhibits intimal thickening after arterial balloon injury. This study suggests that continued bFGF synthesis contributes to intimal thickening after arterial injury, and that antisense bFGF may represent an effective strategy in limiting restenosis after angioplasty. (J Vasc Surg 1997;25:320-5.)

In animal models, kidney formation is known to be controlled by the proteins RET, GDNF, and GFRA1; however, no human studies to date have shown an association between abnormal kidney development and mutation of these genes. We hypothesized that stillborn fetuses with congenital renal agenesis or severe dysplasia would possess mutations in RET, GDNF, or GFRA1. We assayed for mutations in these genes in 33 stillborn fetuses that had bilateral or unilateral renal agenesis (29 subjects) or severe congenital renal dysplasia (4 subjects). Mutations in RET were found in 7 of 19 fetuses with bilateral renal agenesis (37%) and 2 of 10 fetuses (20%) with unilateral agenesis. In two fetuses, there were two different RET mutations found, and a total of ten different sequence variations were identified. We also investigated whether these mutations affected RET activation; in each case, RET phosphorylation was either absent or constitutively activated. A GNDF mutation was identified in only one fetus with unilateral agenesis; this subject also had two RET mutations. No GFRA1 mutations were seen in any fetuses. These data suggest that in humans, mutations in RET and GDNF may contribute significantly to abnormal kidney development.