Individual variation in heat substitution: is activity in the cold energetically cheaper for some individuals than others?

In many endotherms, a potentially important yet often overlooked mechanism to save energy is the use of the heat generated by active skeletal muscles to replace heat that would have been generated by thermogenesis (i.e. 'activity-thermoregulatory heat substitution'). While substitution has been documented numerous times, the extent of individual variation in substitution has never been quantified. Here, we used a home-cage respirometry system to repeatedly measure substitution through the concomitant monitoring of metabolic rate (MR) and locomotor activity in 46 female white-footed mice (Peromyscus leucopus). A total of 117 measures of substitution were taken by quantifying the difference in the slope of the relationship between MR and locomotor activity speed at two different ambient temperatures. Consistency repeatability (±s.e.) of substitution was 0.313 (±0.131); hence, about a third of the variation in substitution occurs at the among-individual level. Body length and heart mass were positively correlated with substitution whereas surface area was negatively correlated with substitution. These three sub-organismal traits accounted for the majority of the among-individual variation (i.e. individual differences in substitution were not significant after accounting for these traits). Overall, our results imply that the energetic cost of activity below the thermoneutral zone is consistently cheaper from some individuals than others, and that the energy saved from substitution might be available to invest in fitness-enhancing activities.

Rare, long-term complication after pancreatoduodenectomy-a case report of cecal volvulus.

Complications after pancreatoduodenectomy are common, and range widely in timing of presentation, relation to pancreatobiliary pathology, and necessity of operative intervention. We present a case of a 74-year-old male with history of pancreatoduodenectomy for pancreatic adenocarcinoma who presented 11 months after index operation with cecal volvulus and required emergent right hemicolectomy. Prior history of pancreatoduodenectomy with mobilization of the right colon likely predisposed him to development of this surgical emergency. Patients have altered gastrointestinal anatomy after pancreatoduodenectomy and special care is necessary to protect the afferent biliopancreatic limb during intraoperative exploration, and particularly if right colectomy is necessary.

The Evolving Landscape of Medical Device Regulation in East, Central, and Southern Africa.

Effective regulatory frameworks, harmonized to international standards, are critical to expanding access to quality medical devices in low- and middle-income countries. This review provides a summary of the state of medical device regulation in the 14 member countries of the College of Surgeons of East, Central, and Southern Africa (COSECSA) and South Africa. Countries were categorized according to level of regulatory establishment, which was found to be positively correlated to gross domestic product (GDP; rs=0.90) and years of freedom from colonization (rs=0.60), and less positively correlated to GDP per capita (rs=0.40). Although most countries mandate medical device regulation in national legislation, few employ all the guidelines set forth by the World Health Organization. A streamlined regulatory process across African nations would simplify this process for innovators seeking to bring medical devices to the African market, thereby increasing patient access to safe medical devices.

Pharmacological prevention of surgery-accelerated metastasis in an animal model of osteosarcoma.

BACKGROUND: Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults. A mainstay of treatment in osteosarcoma is removal of the primary tumor. However, surgical excision itself has been implicated in promoting tumor growth and metastasis, an effect known as surgery-accelerated metastasis. The underlying mechanisms contributing to surgery-accelerated metastasis remain poorly understood, but pro-tumorigenic alterations in macrophage function have been implicated. METHODS: The K7M2-BALB/c syngeneic murine model of osteosarcoma was used to study the effect of surgery on metastasis, macrophage phenotype, and overall survival. Pharmacological prevention of surgery-accelerated metastasis was examined utilizing gefitinib, a receptor interacting protein kinase 2 inhibitor previously shown to promote anti-tumor macrophage phenotype. RESULTS: Surgical excision of the primary tumor resulted in increases in lung metastatic surface nodules, overall metastatic burden and number of micrometastatic foci. This post-surgical metastatic enhancement was associated with a shift in macrophage phenotype within the lung to a more pro-tumor state. Treatment with gefitinib prevented tumor-supportive alterations in macrophage phenotype and resulted in reduced metastasis. Removal of the primary tumor coupled with gefitinib treatment resulted in enhanced median and overall survival. CONCLUSIONS: Surgery-accelerated metastasis is mediated in part through tumor supportive alterations in macrophage phenotype. Targeted pharmacologic therapies that prevent pro-tumor changes in macrophage phenotype could be utilized perioperatively to mitigate surgery-accelerated metastasis and improve the therapeutic benefits of surgery.

Gefitinib Inhibits Invasion and Metastasis of Osteosarcoma via Inhibition of Macrophage Receptor Interacting Serine-Threonine Kinase 2.

Most patients with osteosarcoma have subclinical pulmonary micrometastases at diagnosis. Mounting evidence suggests that macrophages facilitate metastasis. As the EGFR has been implicated in carcinoma-macrophage cross-talk, in this study, we asked whether gefitinib, an EGFR inhibitor, reduces osteosarcoma invasion and metastatic outgrowth using the K7M2-Balb/c syngeneic murine model. Macrophages enhanced osteosarcoma invasion in vitro, which was suppressed by gefitinib. Oral gefitinib inhibited tumor extravasation in the lung and reduced the size of metastatic foci, resulting in reduced metastatic burden. Gefitinib also altered pulmonary macrophage phenotype, increasing MHCII and decreasing CD206 expression compared with controls. Surprisingly, these effects are mediated through inhibition of macrophage receptor interacting protein kinase 2 (RIPK2), rather than EGFR. Supporting this, lapatinib, a highly specific EGFR inhibitor that does not inhibit RIPK2, had no effect on macrophage-promoted invasion, and RIPK2-/- macrophages failed to promote invasion. The selective RIPK2 inhibitor WEHI-345 blocked tumor cell invasion in vitro and reduced metastatic burden in vivo In conclusion, our results indicate that gefitinib blocks macrophage-promoted invasion and metastatic extravasation by reprogramming macrophages through inhibition of RIPK2.

The incidence of Marfan syndrome and cardiac anomalies in patients presenting with pectus deformities.

PURPOSE: The incidence of Marfan syndrome in the general population is 0.3%. Two-thirds of patients with Marfan syndrome have concurrent pectus deformity. However, incidence of Marfan syndrome and cardiac abnormalities in patients presenting with an isolated pectus deformity remains unknown. We sought to establish the degree of association between pectus deformities and these abnormalities, and whether referral of these patients for cardiac and genetic workup is warranted. METHODS: Our pediatric surgery group refers patients with pectus deformities for genetic and cardiac evaluation. We examined 415 records from 2009 to 2016, and identified 241 patients with a chief complaint of a pectus deformity. Patient characteristics, echocardiogram results, Haller indices, and genetic results were analyzed. RESULTS: The frequency of Marfan syndrome in our study was 5.3%. The incidence of Marfan was highest among patients with combined type pectus deformity (20%). Cardiac anomalies showed an overall incidence of 35%. Of those diagnosed with Marfan, 84% had cardiac abnormalities. CONCLUSION: More than 5% of patients presenting with a chief complaint of pectus deformity will have a diagnosis of Marfan syndrome, compared to 0.3% in the general population. Approximately a third of this population will have cardiac abnormalities. Referral of patients with pectus deformities for evaluation for Marfan syndrome and cardiac abnormalities is appropriate. LEVEL OF EVIDENCE: Level IV.

The Impact of Pathological Criteria on Pediatric Negative Appendectomy Rate.

INTRODUCTION: Negative appendectomy rate (NAR) is a quality metric used in the surgical management of appendicitis. The rates of negative appendectomy (NA) in children range anywhere from 1% to 40% in the literature. Many reports do not provide clear pathological definitions for either appendicitis or NA on which they base their calculation of NAR. We reviewed our experience with pediatric appendectomy and the pathological spectrum encompassed within our definition of a NA and examined how the pathologic definition impacts our hospital's NAR. METHODS: A retrospective review from 2012 to 2016 in a single institution identified 1676 children that underwent appendectomy. Average age was 11.4 (2-18 years). Patient demographics, clinical outcomes and pathological findings were collected. At our institution, appendicitis is defined as the presence of transmural acute inflammation in the appendix and those patients without this finding have been considered to have had a negative appendectomy. RESULTS: 1435 patients underwent appendectomy for presumed appendicitis. The rate of pathologically diagnosed appendicitis was 91.1% (1307/1435) and as such, the NAR was 8.9% (128/1435). Review of the pathology of the NA cohort identified 67/128 (52.3%) patients with completely normal pathology. The remaining 61 patients displayed some sort of pathological abnormality including malignancy (n = 2), fecaliths (n = 9), pinworms (n = 3), granuloma (n = 2), fibrous obliteration (n = 4), isolated periappendiceal inflammation (n = 1), and acute inflammation confined to the mucosa (n = 40). Exclusion of these patients with abnormal pathology decreased the NAR to 4.6%. Patients with pathological abnormalities of the appendix other than transmural inflammation had a higher rate of 30-day readmission than patients with acute appendicitis (8.2% versus 4.5% p < 0.01). CONCLUSION: Pediatric NAR is dependent upon the pathological definition of appendicitis and negative appendectomy. Institutional variation in definition may explain discrepancies in the literature. By example, including only those that show "the absence of inflammation or other appendiceal pathology" would decrease our NAR by 50%. This study calls into question the interpretation of interhospital NAR and the use of NAR as a quality metric in the management of appendicitis. Retrospective comparative study: Level III evidence.

Repeated lipopolysaccharide exposure leads to placental endotoxin tolerance.

PROBLEM: Placental infection induces increased levels of pro-inflammatory cytokines, which have been implicated in the pathogenesis of pre-term labor. Endotoxin tolerance is a phenomenon in which exposure to a dose of endotoxin makes tissue less responsive to subsequent exposures. The objective of our study was to determine whether repeated exposure to endotoxin will induce a tolerant phenotype in normal human second-trimester placental tissue. METHODS OF STUDY: Human second-trimester placental explants from elective termination of pregnancy were cultured and exposed to endotoxin (LPS). After 24 hours, the media was collected for analysis, and the explants were re-exposed to LPS after adding fresh media for another 24 hours. This process was repeated for a total of 4 LPS doses. The media was collected from each day and analyzed for cytokine levels. RESULTS: The first LPS treatment stimulated the secretion of the pro-inflammatory cytokines IL-1ß and TNF-α. However, their production was significantly diminished with repeated LPS doses. Production of the anti-inflammatory cytokines, IL-1ra and IL-10, was also stimulated by the first LPS treatment, but secretion was more gradually and moderately decreased with repeated LPS doses compared to the pro-inflammatory cytokines. The ratios of the anti-inflammatory/pro-inflammatory mediators (IL-1ra/IL-1ß and IL-10/TNF-α) indicate a progressively more anti-inflammatory milieu with repeated LPS doses. CONCLUSION: Repeated LPS exposure of human second-trimester placental tissues induced endotoxin tolerance. We speculate that endotoxin tolerance at the maternal-fetal interface will protect the fetus from exaggerated inflammatory responses after repeated infectious exposure.

Management of pilonidal disease.

PURPOSE OF REVIEW: Pilonidal disease, and the treatment associated with it, can cause significant morbidity and substantial burden to patients' quality of life. Despite the plethora of surgical techniques that have been developed to treat pilonidal disease, discrepancies in technique, recurrence rates, complications, time to return to work/school and patients' aesthetic satisfaction between treatment options have led to controversy over the best approach to this common acquired disease of young adults. RECENT FINDINGS: The management of pilonidal disease must strike a balance between recurrence and surgical morbidity. The commonly performed wide excision without closure has prolonged recovery, while flap closures speed recovery time and improve aesthetics at the expense of increased wound complications. Less invasive surgical techniques have recently evolved and are straightforward, with minimal morbidity and satisfactory results. SUMMARY: As with any surgical intervention, the ideal treatment for pilonidal disease would be simple and cost-effective, cause minimal pain, have a limited hospital stay, low recurrence rate and require minimal time off from school or work. Less invasive procedures for pilonidal disease may be favourable as an initial approach for these patients reserving complex surgical treatment for refractory disease.

Intratibial Injection Causes Direct Pulmonary Seeding of Osteosarcoma Cells and Is Not a Spontaneous Model of Metastasis: A Mouse Osteosarcoma Model.

BACKGROUND: Although metastasis is the major cause of mortality in patients with osteosarcoma, little is known about how micrometastases progress to gross metastatic disease. Clinically relevant animal models are necessary to facilitate development of new therapies to target indolent pulmonary metastases. Intratibial injection of human and murine osteosarcoma cell lines have been described as orthotopic models that develop spontaneous pulmonary metastasis over time. However, there is variability in reported injection techniques and metastatic efficiency. QUESTIONS/PURPOSES: We aimed to characterize a widely used murine model of metastatic osteosarcoma, determine whether it is appropriate to study spontaneous pulmonary metastasis by establishing a reliable volume for intratibial injection, determine the incidence of primary tumor and metastatic formation, determine the kinetics of pulmonary metastatic seeding and outgrowth, and the contribution of the primary tumor to subsequent development of metastasis. METHODS: The metastatic mouse osteosarcoma cell line K7M2 was injected into the tibia of mice. The maximum volume that could be injected without leakage was determined using Evan's blue dye (n = 8 mice). Primary tumor formation and metastatic efficiency were determined by measuring the incidence of primary tumor and metastatic formation 4 weeks after intratibial injection (n = 30). The kinetics of metastatic development were determined by performing serial euthanasia at 1, 2, 3, and 4 weeks after injection (n = 24; five to six mice per group). Number of metastatic foci/histologic lung section and metastatic burden/lung section (average surface area of metastatic lesions divided by the total surface area of the lung) was calculated in a blinded fashion. To test the contribution of the primary tumor to subsequent metastases, amputations were performed 30 minutes, 4 hours, or 24 hours after injection (n = 21; five to six mice per group). Mice were euthanized after 4 weeks and metastatic burden calculated as described previously, comparing mice that had undergone amputation with control, nonamputated mice. Differences between groups were calculated using Kruskal-Wallis and one-way analysis of variance. RESULTS: The maximum volume of cell suspension that could be injected without leakage was 10 µL. Intratibial injection of tumor cells led to intramedullary tumor formation in 93% of mice by 4 weeks and resulted in detectable pulmonary metastases in 100% of these mice as early as 1 week post-injection. Metastatic burden increased over time (0.88% ± 0.58, week 1; 6.6% ± 5.3, week 2; 16.1% ± 12.5, week 3; and 40.3% ± 14.83, week 4) with a mean difference from week 1 to week 4 of -39.38 (p < 0.001; 95% confidence interval [CI], -57.39 to -21.37), showing pulmonary metastatic growth over time. In contrast, the mean number of metastatic foci did not increase from week 1 to week 4 (36.4 ± 33.6 versus 49.3 ± 26.3, p = 0.18). Amputation of the injected limb at 30 minutes, 4 hours, and 24 hours after injection did not affect pulmonary metastatic burden at 4 weeks, with amputation as early as 30 minutes post-injection resulting in a metastatic burden equivalent to tumor-bearing controls (48.9% ± 6.1% versus 40.9% ± 15.3%, mean difference 7.96, p = 0.819; 95% CI, -33.9 to 18.0). CONCLUSIONS: There is immediate seeding of the metastatic site after intratibial injection of the K7M2 osteosarcoma cell line, independent of a primary tumor. This is therefore not a model of spontaneous metastasis. CLINICAL RELEVANCE: This model should not be used to study the early components of the metastatic cascade, but rather used as an experimental model of metastasis. Improved understanding of this commonly used model will allow for proper interpretation of existing data and inform the design of future studies exploring the biology of metastasis in osteosarcoma.

Ultrasound-guided bilateral rectus sheath block vs. conventional local analgesia in single port laparoscopic appendectomy for children with nonperforated appendicitis.

INTRODUCTION: Despite its minimally invasive approach, laparoscopic surgery can cause considerable pain. Regional analgesic techniques such as the rectus sheath block (RSB) offer improved pain management following elective umbilical hernia repair in the pediatric population. This effect has not been examined in laparoscopic single-incision surgery in children. We sought to compare the efficacy of bilateral ultrasound-guided RSB versus local anesthetic infiltration (LAI) in providing postoperative pain relief in pediatric single-incision transumbilical laparoscopic assisted appendectomy (TULA) with same-day discharge. METHODS: We retrospectively reviewed 275 children, ages 4 to 17 years old, who underwent TULA for uncomplicated appendicitis in a single institution from August 2014 to July 2015. We compared those that received preincision bilateral RSB (n=136) with those who received LAI (n=139). The primary outcome was narcotic administration. Secondary outcomes included initial and mean scores, time from anesthesia induction to release, operative time, time to rescue dose of analgesic in the PACU and time to PACU discharge. RESULTS: Total narcotic administration was significantly reduced in patients that underwent preincision RSB compared to those that received conventional LAI, with a mean of 0.112 mg/kg of morphine versus 0.290 mg/kg morphine (p<0.0001). Patients undergoing RSB reported lower initial (0.38 vs. 2.38; p<0.0001) and mean pain scores (1.26 vs. 1.77; p<0.015). Time to rescue analgesia was prolonged in patients undergoing RSB compared to LAI (58.93min vs. 41.56min; p=0.047). CONCLUSION: Preincision RSB for TULA in uncomplicated appendicitis in children is associated with decreased opioid consumption and lower pain scores compared with LAI. As the addition of this procedure only added 6.67min to time under anesthesia, we feel that it is a viable option for postoperative pain control in pediatric single-incision laparoscopic surgery. RETROSPECTIVE COMPARATIVE STUDY: LEVEL III EVIDENCE.

The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation.

Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.

Pancreatic retransplantation is associated with poor allograft survival: an update of the United Network for Organ Sharing database.

UNLABELLED: The aim of the study was to assess outcomes of pancreas retransplantation versus primary pancreas transplantation. METHODS: Data from the United Network for Organ Sharing database on all adult (age, ≥18 years) subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 20,854). The subjects were analyzed in the following 2 groups: retransplant (n = 1149) and primary transplant (n = 19,705). RESULTS: Kaplan-Meier analysis demonstrated significantly different patient survival (P < 0.0001) and death-censored graft survival (P < 0.0001) between the primary transplant versus retransplant subjects. Allograft survival was significantly poorer in the retransplantation group. Patient survival was greater in the retransplant group. CONCLUSIONS: The results of our study differ from previous studies, which showed similar allograft survival in primary and secondary pancreas transplants. Further studies may elucidate specific patients who will benefit from retransplantation. At the present time, it would appear that pancreas retransplantation is associated with poor graft survival and that retransplantation should not be considered for all patients with primary pancreatic allograft failure.

The use of venous jump grafts in pancreatic transplantation - no difference in patient or allograft outcomes - an update of the UNOS database.

Venous jump grafts are used in pancreas transplantation to salvage a pancreas with a short portal vein or to facilitate an easier anastomosis. There have been no large studies evaluating the safety of venous jump grafts in pancreas transplantation. We analyzed the UNOS database to determine whether venous jump grafts are associated with graft loss or patient death. Data from UNOS on all adult pancreas transplant recipients 1996-2012 were analyzed. Venous extension grafts were used in 2657 cases; they were not in 18 124. Kaplan-Meier/product-limit estimates analysis demonstrated similar patient survival (p < 0.641) and death-censored graft survival (p < 0.351) at one, three, five,10, and 15 yr between subjects with and without venous jump grafts. There was a statistically significant difference in one-yr unadjusted patient survival between the venous extension graft (94.9%) and the no-venous extension graft (95.8%) groups (p < 0.045) and a borderline difference in one-yr graft survival between the venous extension graft (84.1%) and the no-venous extension graft (82.6%) groups (p < 0.055). There was no significant difference in patient survival or allograft survival at the three-, five-, 10-, and 15-yr intervals. The use of venous jump grafts is not associated with increased graft loss or mortality.

An analysis of pancreas transplantation outcomes based on age groupings--an update of the UNOS database.

INTRODUCTION: Previously, increasing age has been a part of the exclusion criteria used when determining eligibility for a pancreas transplant. However, the analysis of pancreas transplantation outcomes based on age groupings has largely been based on single-center reports. METHODS: A UNOS database review of all adult pancreas and kidney-pancreas transplants between 1996 and 2012 was performed. Patients were divided into groups based on age categories: 18-29 (n = 1823), 30-39 (n = 7624), 40-49 (n = 7967), 50-59 (n = 3160), and ≥60 (n = 280). We compared survival outcomes and demographic variables between each age grouping. RESULTS: Of the 20 854 pancreas transplants, 3440 of the recipients were 50 yr of age or above. Graft survival was consistently the greatest in adults 40-49 yr of age. Graft survival was least in adults age 18-29 at one-, three-, and five-yr intervals. At 10- and 15-yr intervals, graft survival was the poorest in adults >60 yr old. Patient survival and age were found to be inversely proportional; as the patient population's age increased, survival decreased. CONCLUSION: Pancreas transplants performed in patients of increasing age demonstrate decreased patient and graft survival when compared to pancreas transplants in patients <50 yr of age.

Pancreas transplantation from donors after cardiac death: an update of the UNOS database.

OBJECTIVE: There is reluctance to use donation after cardiac death (DCD) organs for fear of worse outcomes due to increased warm ischemia time. Extensive evidence to confirm the quality of DCD pancreas transplants is not manifest. METHODS: A united network for organ sharing database review of pancreas transplants performed between 1996 and 2012 was conducted. We compared outcomes and all demographic variables between donors after cardiac death and donors after brain death in pancreas transplantation. RESULTS: There were 320 DCD pancreas transplants and 20,448 donation after brain death pancreas transplants performed in the United States between 1996 and 2012. There was no statistically significant difference in graft survival or patient survival in pancreas transplantation in DCD versus donation after brain death donors measured at 1-year, 3-year, 5-year, 10-year, and 15-year intervals. There was no significant difference between donor and recipient age, race, sex, and body mass index (BMI) between the groups. There was no significant difference between the recipient ethnicity or time on wait list between the groups. CONCLUSIONS: Pancreata procured by DCD have comparable outcomes to those procured after brain death. Donation after cardiac death pancreas transplant is a viable method of increasing the donor pool, decreasing wait list mortality, and improving the quality of life for type 1 diabetic patients.