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Case: Pseudoaneurysms of the hand are rare among the adult population and even more rare in pediatric patients. We report a case of a 10-month-old boy who presented with a nontraumatic pseudoaneurysm of the deep palmar arch, likely of congenital etiology. Magnetic resonance imaging and angiography identified the growing left hand palmar mass. Surgical excision without the need for vascular reconstruction was performed successfully with no recurrence or complications at 1-year follow-up., Conclusion: Surgical excision is an effective treatment for large or symptomatic palmar pseudoaneurysms of likely congenital origin. Vascular reconstruction after excision must be considered on a case-by-case basis to ensure adequate hand perfusion., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C373)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: A shortage of general surgeons is predicted in the future, with particular impact on rural surgery. This is an exploratory analysis on a rural-focused longitudinal integrated clerkship to determine if such clerkships can be used to increase interest and recruitment in rural general surgery., Methods: An institutional database was reviewed to identify students who became general surgeons after completing a rural-focused longitudinal integrated clerkship. Telephone interviews were conducted on a portion of these surgeons., Results: Fifty-seven students (3.6%) completing the rural-focused longitudinal integrated clerkship became general surgeons. Of those participating in phone interviews, most (90%) decided to become surgeons during their experience while all stated that preclinical years did not influence their specialty decision., Conclusions: A substantial portion of these surgeons went on to practice in rural communities. Pre-existing rural and primary care-focused education could help to address the future projected shortage of rural general surgeons., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The utility of irrigation at the time of appendectomy for acute appendicitis has been debated, with recent studies showing no benefit to irrigation. In our practice, two techniques have been used; one in which irrigation was at the discretion of the surgeon, and one in which irrigation was standardized. The standardized irrigation technique involved large volume (3-12 l) irrigation in small, focused, directed aliquots to achieve optimal dilution. We sought to retrospectively assess whether the standardized large volume irrigation technique was associated with measurably reduced intraabdominal infection. We hypothesized that there would be no difference in intraabdominal infection rate., Methods: Medical records for cases of appendectomies performed for acute appendicitis, years 2007 through 2017, were reviewed (n = 432). Rate of subsequent abdominal infection was compared between patients who underwent the standardized large volume irrigation technique compared to those who did not using Fisher's exact test; p < 0.05 was considered significant., Results: For patients that underwent the standardized large volume irrigation technique there were no (0/140) subsequent abdominal infections within the study period, compared with a rate of 6.2% (18/292) for all other patients (p value 0.001). Among cases that had a perforated appendix (n = 105), the rates were 0% (0/31) compared to 18.9% (14/74; p value 0.009)., Conclusions: Utilization of a standardized large volume irrigation technique with the objective of serial dilution is associated with a significantly lower rate of subsequent abdominal infection, even among cases with a perforated appendix. Prospective studies are needed to evaluate this technique., Level of Evidence: Level III., Type of Study: Treatment study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Gastrojejunostomy (GJ) tubes are frequently used to provide pediatric enteral nutritional support for pediatric patients. Various placement methods have been described, each with attendant advantages and disadvantages., Description of the Operative Technique: We present a technique for primary laparoscopic/fluoroscopic GJ button tube placement designed to avoid delay in placement of the jejunal limb, and difficulties associated with endoscopic-assisted and primary fluoroscopic placement., Results: There were 52 gastrojejunostomy button tubes placed via this technique in patients ranging from 3.8 to 90.3 kg in weight. Three postoperative complications were identified; one bowel perforation on postoperative day two, and two tube dislodgements within 30 days., Conclusion: The described technique was uniformly effective and was associated with a low complication rate (5.8%)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the medical student perception and experience of a 24-hour call requirement, and to learn if improvements can be made to improve the 24-hour call requirement., Design: Medical students completing their required surgical clerkship over 1 academic year at our institution were surveyed prior to their clerkship and on the last week of clerkship regarding their perceptions and experience with 24-hour call., Setting: This study was performed at the University of Minnesota, in Minneapolis, Minnesota, a medical school and tertiary medical center., Participants: Two hundred one medical students were given the option to complete an anonymous survey before and after their required surgical clerkship., Results: Response rate for the preclerkship survey was 70% (n = 140) and 58% (n = 117) for the postclerkship survey. The mean age of respondents was 26 years, and the majority of students were in their third year of medical school. After completing the clerkship, students interested in surgery more often agreed the 24-hour call requirement should remain (51% versus 31%, p = 0.01). Students rotating at a Level I Trauma Center were also more likely to agree the call requirement should remain (59% versus 33%, p = 0.008). Medical students generally had less concerns (mental health, fatigue, mistakes, and grade performance) related to 24-hour call after completion of the clerkship. Concerns about the effect of 24-hour call on study schedule remained high in both pre and postclerkship groups., Conclusions: Medical students have concerns about the experience prior to the clerkship that diminished by its completion. To improve medical student perceptions and overall experience of 24-hour call, frequency of shifts could be limited and the 24-hour call requirement sites could be shifted to Level I Trauma Centers., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Peritoneal dialysis (PD) is a commonly used method for renal support in pediatric patients and can be associated with the risk of post-surgical complications. We evaluated method of placement of PD catheters with regard to post-surgical complications., Methods: PD catheters placed at two institutions between 2005 and 2017 were reviewed. Complication rates were evaluated based on method of placement, delayed usage, omentectomy, and patient age using Fisher's exact test, two-sided, with significance set at 0.05. Factors influencing complication were evaluated with multivariate logistic regression and Kaplan-Meier survival analysis., Results: There were 130 patients with 157 catheters placed, ranging in age from 1 day to 23 years. There was no significant difference in complication rate by method of placement or delayed usage. Infants were significantly more likely to experience leakage (21% vs 8%, p 0.036) and hernias (15% vs 5%, p 0.030). Patients that underwent an omentectomy were less likely to require a catheter replacement (7% vs 27%, p 0.004), and the catheters had a significantly higher survival rate (p 0.009). We found that laparoscopic intervention resulted in catheter salvage. Lateral exit sites may be a risk factor for catheter migration in some patients., Conclusions: Omentectomy is associated with longer PD catheter survival. Laparoscopic salvage of dysfunctional catheters may be a valuable adjunct in management.

Background: Umbilical hernia is a common congenital anomaly, and can result in the appearance of a protuberant umbilicus. In select cases, inversion of the umbilical skin can be impaired by the presence of thickened dermis or fascial remnants of the umbilical stalk., Description of Operative Technique: After umbilical herniorrhaphy, the skin is everted over the left index finger and radial partial thickness incisions in the fascia and dermis of the undersurface of the umbilicus. The umbilical skin is then inverted and secured to the fascia., Conclusion: This operative technique can allow complete inversion of the umbilical skin creating an aesthetically appealing umbilical hernia repair., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The role of simulation-based education continues to expand exponentially. To excel in this environment as a surgical simulation leader requires unique knowledge, skills, and abilities that are different from those used in traditional clinically-based education., Methods: Leaders in surgical simulation were invited to participate as discussants in a pre-conference course offered by the Association for Surgical Education. Highlights from their discussions were recorded., Results: Recommendations were provided on topics such as building a simulation team, preparing for accreditation requirements, what to ask for during early stages of development, identifying tools and resources needed to meet educational goals, expanding surgical simulation programming, and building educational curricula., Conclusion: These recommendations provide new leaders in simulation with a unique combination of up-to-date best practices in simulation-based education, as well as valuable advice gained from lessons learned from the personal experiences of national leaders in the field of surgical simulation and education., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Children undergoing operative intervention while induced under general anesthesia are at risk for experiencing a significant decrease in core body temperature that can lead to adverse systemic effects. Given that the head contributes an estimated 18% of a child's body surface area, we theorized that a liquid-warming garment applied to the head could control a pediatric patient's core body temperature during surgical procedures., Methods: Patients undergoing elective, non-cranial, general surgical procedures were enrolled in the study. A head garment with an embedded network of tubing was placed on the patient. The garment connected to a computer-controlled water bath that managed the temperature of the water in the tubing through a feedback mechanism., Results: Ten patients with ages ranging from 1 day to 3 years (mean age 10.5 months) were enrolled in this study. The average procedure length was 82.5 min. The mean core body temperature throughout the procedure for all-comers was 36.5 ± 0.9 °C with an overall mean difference in maximum and minimum temperatures of 1.32 ± 1.1 °C., Conclusion: A liquid-warming garment applied to the head of pediatric surgical patients is an innovative and relatively low-cost means to regulate and to maintain the ideal core body temperature of patients undergoing surgical procedures.

Simulation-based training (SBT) over the last 10 years has become a mainstay for surgical education at the graduate medical education (GME) level. More recently, however, the technique has rapidly become the standard for early efficient teaching of surgical skills and decision making at the undergraduate medical education (UME) level. The described benefits of SBT include its ability to compartmentalize education, to combine immediate assessment and feedback, and to accelerate knowledge and skill acquisition for the young learner. Consequently, SBT is now being adopted in multiple national medical student surgical educational initiatives., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Using simulation to teach and assess learners represents a powerful approach to training, but one that comes with hidden costs in terms of faculty time, even if programs adopt existing curricula. Some simulators are built to be used independently by learners, but much of the surgical simulation curricula developed for cognitive and psychomotor tasks requires active faculty involvement and low learner-to-faculty teaching ratios to ensure sufficient practice with feedback. The authors hypothesize that the added teaching demands related to simulation have resulted in a significant financial burden to surgery training programs. To date, the effect of simulation-based training on faculty workload has not been estimated objectively and reported in the literature., Methods: To test their hypothesis, the authors analyzed data from 2 sources: (1) changes over time (2006-2014) in formal teaching hours and estimated faculty costs at the University of Minnesota, General Surgery Department and (2) a 2014 online survey of general surgery program directors on their use of simulation for teaching and assessment and their perceptions of workload effects., Results: At the University of Minnesota, the total number of hours spent by department faculty in resident and student simulation events increased from 81 in annual year 2006 to 365 in annual year 2013. Estimated full-time equivalent faculty costs rose by 350% during the same period. Program directors (n = 48) of Association of Program Directors in Surgery reported either a slight (60%) or a significant (33%) increase in faculty workload with the advent of simulation, and moderate difficulty in finding enough instructors to meet this increase. Calling upon leadership for support, using diverse instructor types, and relying on "the dedicated few" represent the most common strategies., Conclusion: To avoid faculty burnout and successfully sustain faculty investment in simulation-based training over time, programs need to be creative in building, sustaining, and managing the instructor workforce., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Rural longitudinal integrated clerkship (LIC) programs for third-year medical students provide strong educational curricula and can nurture interest in rural surgical practice. Students learn technical skills in an apprenticeship model. Variability in instruction and patient experiences across sites, coupled with a lack of simulation facilities, raise some concerns about technical skill development. To explore the adequacy of skills acquisition for students in the University of Minnesota Rural Physician Associate Program (RPAP), this study compared RPAP students' performance on a scenario-based Objective Structured Assessment of Technical Skills (OSATS) with that of traditional surgery block clerkship students (Course 7500)., Design, Setting, and Participants: This is a nonexperimental post-only study. All enrolled students (n = 254) completed the OSATS examination. Students in the Course 7500 (n = 222) completed 15 hours of simulation skills training and supervised practice during their 6-week clerkship. RPAP students (n = 32) completed 3 hours of skills training before their 9-month rural assignment. Both groups had access to comprehensive online materials. Mean OSATS checklist, global rating, and total scores were compared at the end of training using t tests (p < 0.05). Self-reported OR and clinical experiences were explored., Results: Both groups did well on the OSATS. There were no statistical differences in completion time, checklist scores, mean global ratings, or total scores. RPAP students reported significantly more days in the OR, surgery cases, and first assists. Experience with OSATS tasks reported by RPAP students during clinical rotations correlated with their OSATS performance., Conclusion: This study supports the viability of the LIC model for fundamental skills acquisition when augmented with introductory simulation skills training and online resources. It also suggests that simulation fills a training gap for students in a traditional surgery block clerkship program. It opens a dialog about the potential partnership of surgery departments with rural LICs to address rural general surgery shortages. Further research in this aspect is needed., (© 2013 Association of Program Directors in Surgery Published by Association of Program Directors in Surgery All rights reserved.)

Background: Simulation can enhance learning effectiveness, efficiency, and patient safety and is engaging for learners., Methods: A survey was conducted of surgical clerkship directors nationally and medical students at 5 medical schools to rank and stratify simulation-based educational topics. Students applying to surgery were compared with others using Wilcoxon's rank-sum tests., Results: Seventy-three of 163 clerkship directors (45%) and 231 of 872 students (26.5%) completed the survey. Of students, 28.6% were applying for surgical residency training. Clerkship directors and students generally agreed on the importance and timing of specific educational topics. Clerkship directors tended to rank basic skills, such as examination skills, higher than medical students. Students ranked procedural skills, such as lumbar puncture, more highly than clerkship directors., Conclusions: Surgery clerkship directors and 4th-year medical students agree substantially about the content of a simulation-based curriculum, although 4th-year medical students recommended that some topics be taught earlier than the clerkship directors recommended. Students planning to apply to surgical residencies did not differ significantly in their scoring from students pursuing nonsurgical specialties., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: New surgical interns may be unprepared for job-related tasks and harbor anxiety that could interfere with job performance. To address these problems, we extended our intern orientation with the principal aim of demonstrating the need for expanded instruction on execution of daily tasks. Additionally, we sought to show that an enriched orientation curriculum durably augments intern confidence., Methods: Twenty-one surgical interns participated in an extended orientation program, consisting of interactive didactics, case scenario presentations, and small group discussions. Evaluations collected at completion of orientation and 1-month follow-up assessed self-reported confidence levels on job-related tasks before, immediately afterward, and 1-month after orientation. Statistical analyses were performed using Student t tests (P < .05 significant)., Results: Self-reports of confidence on job-related tasks before the orientation sessions were low; however, program participation resulted in immediate confidence increases in all areas. Evaluations at 1-month follow-up showed persistence of these gains., Conclusion: Interns reported considerable anxiety in all job-related tasks before orientation. After the sessions, confidence levels were significantly and durably improved in all areas. Our findings suggest the need for specific instruction on job-related tasks of surgical internship and demonstrate the effectiveness of an expanded orientation in improving intern confidence in execution of these tasks., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Given the investment that programs make to simulation training, it is important to evaluate its effects on student learning. Tasks (e.g., gowning and gloving, suturing) are typically taught in isolation over a series of linked sessions. This study assessed students' ability to integrate such tasks while executing an unrehearsed procedure before and after a new simulation curriculum was introduced., Methods: An Objective Structured Assessment of Technical Skill (OSATS) was administered to 26 students in the 2007 clerkship who received a 3-hour orientation to the operating room followed by a 3-hour animate laboratory, and to 167 students in the 2008 clerkship who received a 9-hour simulation skills curriculum. The OSATS task involved a live volunteer "patient" with an arm laceration. Students had 40 minutes to explain the procedure, start an intravenous line, administer a local anesthetic, prepare the wound (pig's foot), gown and glove, and suture the wound. The OSATS was scored by trained raters using a tool with 57 checklist and 7 global rating items. Its internal consistency reliability was 0.82. Independent sample t tests were used to analyze differences between "pre" and "post" groups., Results: Mean scores were significantly higher for the post group for the checklist score (83% vs 62%, p < 0.001), the average global item score (3.62 vs 3.07, p = 0.003) and the OSATS total score (79% correct vs 62%, p < 0.001). Students from both groups were weakest in maintaining a sterile field, motion, and flow. Although superior, post group students still struggled with organizing a plan of action when faced with an unrehearsed procedure., Conclusions: The revised curriculum had a positive impact on students' mastery of basic surgical skills, despite the loss of the animal laboratory. Implications for instruction include greater use of discovery-learning techniques to teach productive versus reproductive skills., (Copyright (c) 2010 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Despite success of several techniques described for pectus excavatum repair, a minority of patients require multiple reoperations for recurrence or other complications. We aimed to review our experience in reoperative pectus excavatum repairs and to identify features correlating with need for additional reoperations., Methods: Charts were reviewed of all patients undergoing reoperative pectus excavatum repair for 3 years at a university-based children's hospital. Number and type of previous repairs, time between operations, lengths of stay, analgesia, and complications were recorded., Results: From February 2004 to December 2007, 170 pectus excavatum repairs were performed. Among these, 27 were reoperative. Overall, 18.2% of reoperative patients required subsequent additional reoperations. 21.1% of patients undergoing repeat open repairs and 33.3% of patients undergoing repeat minimally invasive repairs required further operative interventions. There was no need for additional repairs among patients who had open repairs after minimally invasive repairs, nor for any patients who had minimally invasive repairs after open repairs., Conclusions: We conclude that patients with failed open repairs will have better success with minimally invasive reoperations, whereas patients with failed minimally invasive repairs will have better success with open reoperations. When faced with reoperative pectus excavatum, we recommend consideration of an alternative operative approach from the initial procedure., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background/purpose: Pectus excavatum is a common chest wall deformity, and several procedures have been developed for its correction. We allow patients to choose among Leonard, Nuss, and Ravitch procedures. This study aimed to determine which procedure most patients select and the resultant outcomes., Methods: Charts were reviewed of all pectus excavatum repairs performed for 4 years by a practice covering a university-based children's hospital. Procedure choice, operative time, length of stay, analgesia, fees, and complications were recorded., Results: The Ravitch procedure was chosen by 60.9% of our patients, Leonard procedure by 23.9%, and Nuss procedure by 15.2%. Operative times were not significantly different among the groups. The mean length of stay was 2.2 days (Ravitch), 1.5 days (Leonard), and 3.9 days (Nuss) (P < .005). Epidural analgesia/patient-controlled analgesia pump requirements were 50% (Ravitch), 5% (Leonard), and 100% (Nuss). The mean charges were $27,414 (Ravitch), $18,094 (Leonard), and $43,749 (Nuss) (P < .05). The overall complication rate was 16.3%. The complications among each group were as follows: Ravitch, 14.3%; Leonard, 9.1%; and Nuss, 35.7%., Conclusions: We allow patients to choose among Leonard, Ravitch, and Nuss procedures for repair of pectus excavatum. Most select the Ravitch procedure. Length of stay, fees, analgesic needs, and complication rate were highest among patients in the Nuss group; all of these variables were lowest in the Leonard group.

Introduction: Complications from previously published techniques for laparoscopic gastrostomy tube placement include skin pressure necrosis and extraluminal migration. We developed a modified technique utilizing subcutaneous stay-sutures in order to minimize such complications. This study aimed to identify, quantify, and characterize complications of the modified procedure., Materials and Methods: Charts were reviewed of all pediatric patients undergoing laparoscopic gastrostomy tube placement over 79 months. Complications requiring reoperation, readmission, or outpatient treatment were identified and classified as major or minor., Results: Laparoscopic gastrostomy tubes were placed via modified procedure in 82 patients. Two (2.44%) high-risk patients with significant comorbidities were readmitted for wound infections, two (2.44%) received outpatient antibiotics for cellulitis, and three (3.66%) developed stitch abscesses which resolved with local care. None of the patients had initial intraperitoneal placement, intraperitoneal location upon tube replacement, extraluminal migration, tube-related pressure necrosis, or procedure-related death., Conclusion: Subcutaneous placement of absorbable stay-sutures for laparoscopic gastrostomy tubes offers significant benefits. We eliminated complications associated with presence of external sutures, as well as those associated with early suture removal. This modified technique avoids additional visits for suture removal, avoids pressure necrosis from external stay-sutures, and provides improved adherence of stomach to abdominal wall, thereby preventing extraluminal migration and intraperitoneal tube replacement.

Purpose: A variety of procedures have been described for the treatment of total colonic aganglionosis (TCA); however, there is no consensus as to a superior operative method. The objective of this review is to evaluate the operative methods used to treat TCA and their effectiveness with respect to morbidity, mortality, rates of enterocolitis, and functional outcomes., Methods: We searched Medline (1950-2007) and the Cochrane Library for studies reporting the operative treatment of TCA. Search terms used were "aganglionosis," "Hirschsprung's disease," "total colonic," and "long-segment." Studies evaluated were limited to those that solely discussed the operative outcomes for the treatment of TCA. A meta-analysis was then performed for morbidity outcomes in those studies describing a single operative procedure., Results: The search yielded 271 articles related to TCA. One hundred twenty-two articles discussed operative treatment of Hirschsprung's disease, and only 26 of these articles discussed operative management of TCA. Nineteen articles were isolated for statistical analysis on the basis of results for perioperative outcomes for a single procedure. These procedures included Martin (4), colonic patch modifications (4), Duhamel (2), endorectal pull-through (1), Kimura (2), Boley (2), Rehbein (2), Soave (1), and J-pouch ileoanal anastomosis (1). Overall mortality was 1.9%. Meta-analysis revealed morbidity rates ranging from 10% to 64% depending on procedure category without significant outliers. Higher morbidity rates were found for the Martin-type procedure using the descending colon but with noted higher within-group variance due to small sample sizes. Enterocolitis was noted in 7 studies with a mean of 22%., Conclusions: There is no superior operative method for the treatment of TCA with respect to perioperative morbidity, mortality, enterocolitis, and functional outcomes. The operative technique performed should be selected on center and surgeon familiarity and expertise.

Objectives: The presence of anemia and/or hypoxia in cancer patients have both been correlated with worse outcomes. While some retrospective data suggest an improvement in outcomes in cervical cancer patients whose anemia has been corrected, the critical level to which hemoglobin should be raised and the issue of whether raising hemoglobin translates into a survival advantage remain controversial. This debate has more recently expanded to concerns over how we raise hemoglobin, with 2 recent randomized trials suggesting impaired survival outcomes in the groups who received poietic proteins to correct hemoglobin levels to normal and above values., Methods: A comprehensive literature search was performed utilizing combinations of the key search words anemia, hypoxia, radiotherapy, HIF-1alpha, angiogenesis, and erythropoietin., Results: The preponderance of evidence suggest a correlation between both anemia and worse outcome as well as hypoxia and worse outcome; however the relationship between anemia and hypoxia remains complex. A critical review of molecular changes associated with hypoxia that drive the molecular process, anemia correction and the data on the use of poietic proteins, and a review of future directions of research which focus on the opportunity of therapies correcting hypoxia or hypoxia-relevant targets is also presented., Conclusions: Anemia and hypoxia remain biologically plausible targets for improving therapy. The potential benefit of raising hemoglobin will depend on whether anemia can influence treatment resistance and whether anemia plays a reversible role in driving the molecular milieu contributing to malignant clonogen survival and dissemination.

Background: The aim of the study was to describe current treatment and trends in surgical management of pediatric inguinal hernias (IHs), specifically contralateral exploration., Methods: Surveys were sent to 599 Surgical Section members. Questions paralleled the 1993 American Academy of Pediatrics survey and addressed recent controversial topics. Statistical analysis by chi2 was performed., Results: Three hundred ninety-five (66%) surveys returned. For full-term boys with reducible IH, 79% (82%) repair electively, regardless of age or weight. For full-term girls with reducible ovary, 49% (27%) repair electively, 36% (59%) next available slot, 5% (10%) emergently (P < .01). In former premature infants, 53% (65%) repair reducible IH when convenient, regardless of age. For unilaterally presenting IH, 44% (65%) routinely explore contralateral groins in boys 2 years or younger (P < .01); 47% (84%) routinely explore girls 4 years or younger (P < .01). No significant association between routine exploration patterns and years in practice, region of country, or training program affiliation was found. Laparoscopic evaluation for contralateral IH was reported by 37% (6%), (P < .01) 1993 results italicized., Conclusion: Reports of routine contralateral inguinal exploration had absolute decreases of 21% for boys 2 years or younger, 37% for girls 4 years or younger. There has been a shift toward elective repair for girls with reducible ovaries. Use of laparoscopy for diagnostic contralateral evaluation has increased dramatically.

Background: Bactericidal permeability increasing protein (BPI) binds to and neutralizes lipopolysaccharide (LPS, endotoxin). Small synthetic peptides based on the amino acid sequence of the LPS binding domain of BPI neutralize LPS, albeit inefficiently. Although the LPS binding domain of native BPI possesses a beta-turn secondary structure, this structure is not present in small derivative peptides. The purpose of this study was to determine whether the addition of a beta-turn to a BPI-derived peptide is associated with more potent endotoxin antagonism., Methods: We generated a hybrid peptide (BU3) on the basis of (1) a portion of the LPS binding domain from BPI and (2) amino acids known to initiate a beta-turn. BU3 folds with a beta-turn, and we tested its effects on LPS neutralization and LPS-induced tumor necrosis factor-alpha secretion, comparing it with BPI-derived peptide BG22 that lacks a beta-turn and to an irrelevant peptide (BG16)., Results: Compared with BG22, BU3 demonstrated enhanced LPS neutralization and inhibition of LPS-induced tumor necrosis factor-alpha secretion in vitro and a similar diminution of endotoxemia and tumor necrosis factor-alpha secretion in a murine model of endotoxemia., Conclusions: These data demonstrate the potential for enhancing the biologic activity of a BPI-derived peptide endotoxin antagonist via manipulation of its conformational structure.

Candida albicans has been isolated with increasing frequency during intraabdominal infection; yet its role as a pathogen or copathogen remains controversial. A recent experimental study of its effect during polymicrobial peritonitis indicated that it did not enhance mortality when added to an Escherichia coli challenge, but that study used fecal or mucin-based adjuvants which are known to markedly potentiate the lethality of intraperitoneal bacteria. Therefore, we sought to examine the hypothesis that C. albicans and E. coli are synergistic copathogens that act in concert to increase mortality rates in experimental models of polymicrobial peritonitis, irrespective of the presence of growth adjuvant. To test this hypothesis, we assessed the mortality rates of previously healthy Swiss-Webster mice (20 g) that were challenged intraperitoneally (i.p.) with E. coli, C. albicans, or both, in either the presence or the absence of hemoglobin-mucin. In the absence of hemoglobin-mucin, E. coli plus C. albicans resulted in 83.3% mortality (P < 0.02) compared to either E. coli (0%) or C. albicans (0%) alone. In the presence of hemoglobin-mucin, the synergistic effect was not observed, lower numbers of E. coli alone (62.5%), C. albicans alone (75%), or both organisms together (100%, P > 0.05) provoked high lethality. These data demonstrate that in the absence of adjuvant, E. coli plus C. albicans provoked synergistic lethality. However, in the presence of hemoglobin-mucin the synergistic effect was no longer observed. Therefore, this study provides support for the contention that C. albicans is capable of acting as a copathogen during experimental peritonitis, but that this effect may be obscured by the presence of an adjuvant substance that itself markedly potentiates microbial growth.

We developed 9H1.B11, an anti-idiotypic anti-deep core/lipid A (DCLA), murine monoclonal antibody (mAb) that mimics the conserved DCLA region of lipopolysaccharide (LPS). It recognizes an epitope in the variable region of an DCLA mAb, binds to the murine macrophage cell surface, and inhibits LPS-induced macrophage cytokine secretion. We hypothesized that (1) active immunization with mAb 9H1.B11 would be associated with the development of anti-DCLA antibodies and (2) immunization would protect against subsequent gram negative bacterial challenge. Mice were immunized for 8 weeks before intraperitoneal (ip) challenge with Escherichia coli O111:B4 bacteria. Control animals were immunized with an irrelevant IgM antibody 8133 (negative control) or with LPS derived from Salmonella minnesota Re bacteria (positive control). Sera from immunized mice were collected, and titers against the core region of LPS (Re) and against LPS derived from the infecting E. coli strain were determined. Mice immunized with mAb 9H1.B11 developed measurable titers against S. minnesota Re LPS but not against the challenge strain of E. coli. However, immunization with 9H1.B11 on S. minnesota Re LPS protected against subsequent infection due to E. coli O111:B4 (100% survival). The group of mice immunized with IgM 8133 exhibited only 25% survival. The development of an anti-S. minnesota Re LPS titer after immunization with 9H1.B11 provides further evidence that a portion of 9H1.B11 mimics the conserved DCLA region of LPS. We believe that this approach holds considerable promise and plan further studies to define the mechanism by which protective capacity occurs.

Objective: To determine the effect of targeted disruption of the cellular receptors of either tumor necrosis factor alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta) during experimental gram-negative bacterial infection and endotoxemia., Design: Transgenic (knockout [KO]) mice deficient in either the p55 TNF receptor (TNF RI) or the p80 IL-1 receptor (IL-1 RI) were challenged with intravenous lipopolysaccharide (endotoxin) or intraperitoneal live Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Serum endotoxin levels and quantitative blood cultures were monitored at multiple times during infection., Setting: Surgical infectious disease research laboratory., Main Outcome Measures: Mortality, results of quantitative blood cultures, and serum endotoxin levels., Results: Both TNF and IL-1 RI KO mice were resistant to endotoxin challenge (0% mortality for both groups) compared with control mice (100% mortality [P < .01]). In contrast, only the IL-1 RI KO mice were resistant to infection caused by viable gram-negative bacteria (43% mortality) compared with control mice (100% mortality [P < .01]). Infection led to 100% mortality in TNF RI KO mice. The IL-1 RI KO mice exhibited less bacteremia and diminished endotoxemia compared with control and TNF RI KO mice 18 and 24 hours after infection., Conclusion: The absence of either the TNF or the IL-1 RI receptor prevents cellular activation by each respective cytokine. Absence confers protection against intravenous endotoxin, which stimulates massive rapid release of cytokines into the systemic circulation. However, bacterial infection within the peritoneal cavity is known to cause more delayed cytokine release, and cytokines may act at the site of infection to enhance host defenses. We believe that IL-1 signaling may be more critical in provoking lethal systemic toxic effects than TNF signaling. However, TNF signaling may be an important component of host defense enhancement at the local site of infection.

Objectives: To generate a recombinant fusion protein (FP) based on the endotoxin-binding domain of bactericidal/permeability-increasing protein (BPI) and the constant domain of IgG and to test its ability to inhibit lipopolysaccharide (LPS)-induced macrophage tumor necrosis factor alpha (TNF-alpha) secretion., Design: A murine macrophage cell line, RAW 264.7, was transfected with a BPI-IgG FP before incubation with LPS. The amount of LPS-induced TNF-alpha protein secreted was measured and compared with that secreted by cells transfected with a control construct., Setting: Basic science research laboratory., Main Outcome Measures: Secreted TNF-alpha protein concentration., Results: After transfection, RAW 264.7-cell FP expression was detected in cell lysates and supernatants. At each LPS dose tested, cells transfected with the FP gene secreted less TNF-alpha than did cells transfected with a control construct., Conclusions: The FP possesses substantial antiendotoxin activity, as delineated by inhibition of LPS-induced TNF-alpha secretion by murine macrophages transfected with the fusion gene construct. In the future, such FP may be used as a clinical reagent to reduce the morbidity and mortality associated with serious gram-negative bacterial infections in surgical patients.

Twenty-seven amino acid peptides with sequences corresponding to a proposed endotoxin binding region of bactericidal permeability increasing protein (BPI):1) inhibit lipopolysaccharide induced macrophage tumor necrosis factor-alpha (TNF-alpha) secretion, 2) have bactericidal activity against gram-negative bacteria, and 3) protect mice from a lethal lipopolysaccharide (LPS) challenge. Unfortunately, peptides have a short halflife in vivo. Therefore, we have chemically conjugated the BPI based peptide, BG38, to a larger carrier protein, keyhole limpet hemocyanin (KLH), and characterized its ability: 1) to inhibit LPS induced macrophage TNF-alpha secretion and 2) to decrease plasma endotoxin and TNF-alpha levels following an i.v. injection of E. coli 0111:B4 LPS. BG38-KLH inhibited cultured macrophage TNF-alpha secretion in response to LPS derived from four pathogenic strains of gram-negative bacteria in a dose dependent manner (>90% inhibition at 50 microgram/ml, P < 0.05 Student's t test). BG38-KLH also decreased serum endotoxin (>90%, P < 0.05 Student's t test) and peak TNF-alpha levels (>30% inhibition, P < 0.05 Student's t test) following E. coli LPS challenge in a murine gram-negative bacterial sepsis model. Novel endotoxin antagonists based upon a small domain of BPI represent promising reagents for the treatment of serious gram-negative bacterial infections.