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Background Visceral pain (VP) following laparoscopic sleeve gastrectomy remains a substantial problem. VP is associated with autonomic symptoms, especially nausea and vomiting, and is unresponsive to traditional pain management algorithms aimed at alleviating somatic (incisional) pain. The present study was performed to evaluate the safety and effectiveness of laparoscopic paragastric autonomic neural blockade (PG-ANB) in managing the symptoms associated with VP following sleeve gastrectomy. Study Design This prospective, double-blinded, randomized clinical trial involved patients undergoing laparoscopic sleeve gastrectomy at two high-volume institutions. The patients were randomized to laparoscopic transversus abdominis plane block with or without PG-ANB. The primary outcome was patient-reported pain scores assessed at 1, 8, and 24 h postoperatively. The secondary outcome measures were analgesic requirements, nausea, vomiting, hiccups, and hemodynamic changes immediately after PG-ANB and postoperatively. Results In total, 145 patients (block group, n = 72; control group, n = 73) were included in the study. The heart rate and mean arterial pressure significantly decreased 10 min after PG-ANB. The visual analog scale score for pain was significantly lower in the PG-ANB than in the control group at 1 h postoperatively (p p p = 0.003) and 8 h postoperatively (p p = 0.298). No complications related to PG-ANB occurred. Conclusion PG-ANB safely and effectively reduces early VP, associated autonomic symptoms, and analgesic requirements after laparoscopic sleeve gastrectomy. Graphical abstract

Choledocholithiasis is commonly encountered. It is frequently managed with laparoscopic common bile duct exploration or endoscopic retrograde cholangiopancreatography (either preoperative, intraoperative, or postoperative relative to laparoscopic cholecystectomy). The purpose of this study is to determine the most cost-effective method to manage inpatient choledocholithiasis.A decision tree model was created to evaluate the cost-effectiveness of laparoscopic common bile duct exploration and preoperative, intraoperative, and postoperative endoscopic retrograde cholangiopancreatography. The primary outcome was incremental cost-effectiveness ratio with a ceiling willingness to pay threshold assumed of $100,000 per quality-adjusted life year. Model parameters were determined through review of published literature and institutional data. Costs were from the perspective of the healthcare system with a time horizon of 1 year. Sensitivity analyses were performed on model parameters.In the base case analysis, laparoscopic common bile duct exploration was cost-effective, resulting in 0.9909 quality-adjusted life years at an expected cost of $18,357. Intraoperative endoscopic retrograde cholangiopancreatography yielded more quality-adjusted life years (0.9912) at a higher cost ($19,717) with an incremental cost-effectiveness ratio of $4,789,025, exceeding the willingness to pay threshold. Both preoperative and postoperative endoscopic retrograde cholangiopancreatographies were eliminated for being both more costly and less effective. Laparoscopic common bile duct exploration remained cost-effective if the probability of successful biliary clearance was above 0.79, holding all other variables constant. If its base cost remained below $18,400 and intraoperative endoscopic retrograde cholangiopancreatography base cost rose above $18,200, then laparoscopic common bile duct exploration remained cost-effective.Laparoscopic common bile duct exploration is the most cost-effective method to manage choledocholithiasis. Efforts to ensure availability of local expertise and resources for this procedure are warranted.

Despite the non-sterile nature of the alimentary tract, percutaneous endoscopic gastrostomy (PEG) procedures are often performed after creating a sterile surgical field to reduce infection risk. Our group has previously demonstrated no statistically significant difference in the rate of surgical site infection (SSI) following PEG performed with or without sterile operative fields. The purpose of this study is to evaluate the cost-effectiveness of working with or without sterile operative fields during PEG.A decision tree model of PEG with and without sterile operative fields was created to evaluate the cost-effectiveness of these two methods. The primary outcome was incremental cost-effectiveness ratio with a ceiling willingness to pay threshold assumed of $100,000 per quality-adjusted life year (QALY). Costs were from the perspective of the healthcare system with a time horizon for the model of 90 days. Sensitivity analyses were performed on all model parameters.In the base case analysis, sterile operative field PEG was cost-effective resulting in 0.2225 QALYs at an expected cost of $2,099. PEG procedures without a sterile operative field yielded less QALYs (0.2224) at a higher cost ($2,199) and were dominated. These procedures became cost-effective when the expected cost was $1618 (e.g., $140 less than sterile operative field PEG) or when the SSI rate was 1.6% (e.g., 0.2% higher than sterile operative field PEG) while holding all other variables constant.PEG procedures performed without a sterile operative field can be cost-effective compared to procedures performed with a sterile operative field if the rates of SSI remain similar. Cost savings from foregoing a sterile operative field appear to be offset if the SSI rate increases 0.2% above that of sterile operative field PEG procedures.

Hernias spanning both chest and abdominal walls are uncommon and associated with chest wall trauma, coughing and obesity. This study describes the radiographic appearance of these hernias to guide proper identification and operative planning. Proposed standardized reporting patterns are also presented.The cross sectional imaging of patients presenting with thoracoabdominal hernias was reviewed. Radiographic reports were supplemented by surgeon imaging review and operative findings during repair. Defect dimensions, hernia content, level of herniation, presence of osseous or cartilaginous disruption of the chest wall and degree of rib displacement were collected. Disruption of myofascial planes was also noted.Six patients were identified. All hernias occurred below the 9th rib and were associated with complete intercostal muscle disruption. The transversus abdominis was disrupted in all hernias and the internal oblique was disrupted in five of the hernias. The majority (83%) had caudal rib displacement (median 6.8 cm compared to contralateral side). Median hernia width was 10.35 cm (1.6-19.1 cm) and median length was 10.2 cm (1.8-14.3 cm). Five patients had associated bone/cartilage injuries: two with 11th rib fractures, two with combined bone and cartilaginous fractures and one with a surgical rib resection.The typical injury pattern of thoracoabdominal hernias includes disruption of the intercostal muscles, transversus abdominis, and commonly the internal oblique with an intact external oblique. Inferior rib displacement by hernia contents and unopposed pull of the abdominal musculature is common. Osseous or cartilaginous disruption always occurs unless the defect is bounded on at least one side by a floating rib.

Patients with severe obesity and complex abdominal wall hernias (CAWH) present a challenging clinical dilemma. Their body mass index (BMI) is often prohibitive of successful ventral hernia repair (VHR) and the CAWH presents technical challenges when pursuing bariatric surgery. Our hernia center policy is to refer patients with severe obesity for evaluation with the surgical weight loss program. This study describes outcomes of laparoscopic sleeve gastrectomy (LSG) in patients with both severe obesity and CAWH.A retrospective analysis was performed on data prospectively collected between 2014 and 2020. CAWH patients referred for and undergoing LSG were included. Revisional bariatric surgery patients were excluded. The dataset was augmented with operative time, BMI changes, length of stay (LOS), hernia characteristics, postoperative complications, time from referral to weight loss surgery, and time from LSG to VHR.Twenty patients (10 males, mean age 54.3 years) met inclusion criteria. Mean BMI at LSG was 45.6 ± 6.1 kg/mLSG can be performed successfully even in patients with CAWH. Outcomes do not appear to differ significantly from typical patients undergoing LSG. Further study with larger cohorts is warranted to better delineate complication rates in this population as well as to determine long-term outcomes.

Endoscopic management of full-thickness gastrointestinal tract defects (FTGID) has become an attractive management strategy, as it avoids the morbidity of surgery. We have previously described the short-term outcomes of over-the-scope clip management of 22 patients with non-acute FTGID. This study updates our prior findings with a larger sample size and longer follow-up period.A retrospective analysis of prospectively collected data was conducted. All patients undergoing over-the-scope clip management of FTGID between 2013 and 2019 were identified. Acute perforations immediately managed and FTGID requiring endoscopic suturing were excluded. Patient demographics, endoscopic adjunct therapies, number of endoscopic interventions, and need for operative management were evaluated. Success was strictly defined as complete FTGID closure.We identified 92 patients with 117 FTGID (65 fistulae and 52 leaks); 27.2% had more than one FTGID managed simultaneously. The OTSC device (Ovesco Endoscopy, Tubingen, Germany) was utilized in all cases. Additional closure attempts were required in 22.2% of defects. With a median follow-up period of 5.5 months, overall defect closure success rate was 66.1% (55.0% fistulae vs. 79.6% leaks, p = 0.007). There were four mortalities from causes unrelated to the FTGID. Only 14.9% of patients with FTGID underwent operative management. There were no complications related to endoscopic intervention and no patients required urgent surgical intervention.Over-the-scope clip management of FTGID represents a safe alternative to potentially morbid operative intervention. When strictly defining success as complete closure of all FTGID, endoscopy was successful in 64.4% of patients with only a small minority of patients ultimately requiring surgery.

Epithelial scattering occurs when cells disassemble cell-cell junctions, allowing individual epithelial cells to act in a solitary manner. Epithelial scattering occurs frequently in development, where it accompanies epithelial-mesenchymal transitions and is required for individual cells to migrate and invade. While migration and invasion have received extensive research focus, how cell-cell junctions are detached remains poorly understood. An open debate has been whether disruption of cell-cell interactions occurs by remodeling of cell-cell adhesions, increased traction forces through cell substrate adhesions, or some combination of both processes. Here we seek to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/scatter factor-induced EMT. We find that HGF signaling does not alter the strength of cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion strength might not accompany epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role, as cell-substrate adhesions are stronger in cells treated with HGF and since rapid scattering in cells treated with HGF and TGFβ is associated with a dramatic increase in focal adhesions. Increases in the pliability of the substratum, reducing cells ability to generate traction on the substrate, alter cells׳ ability to scatter. Further consistent with changes in substrate adhesion being required for cell-cell detachment during EMT, scattering is impaired in cells expressing both active and inactive RhoA mutants, though in different ways. In addition to its roles in driving assembly of both stress fibers and focal adhesions, RhoA also generates myosin-based contractility in cells. We therefore sought to examine how RhoA-dependent contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely an inhibition of cell scattering following HGF treatment. Interestingly, restoration of myosin-based contractility in blebbistatin-treated cells results in cell scattering, including global actin rearrangements. Scattering is reminiscent of HGF-induced epithelial scattering without a concomitant increase in cell migration or decrease in adhesion strength. This scattering is dependent on RhoA, as blebbistatin-induced scattering is reduced in cells expressing dominant-negative RhoA mutants. This suggests that induction of myosin-based cellular contractility may be sufficient for cell-cell detachment during epithelial scattering.

Understanding patterns of geothermal and volcanic activity at many of Iceland's most active volcanic systems is hampered by thick overlying ice, which prevents direct observation and complicates interpretation of geophysical signals. Katla is a prime example, being a large and restless volcanic system covered by the 740m thick Mýrdalsjökull ice cap, whose eruptions have triggered some of the most powerful known meltwater floods in historical times. To shed new light on geothermal and subglacial hydrological processes at Katla, we have determined the sulphate isotopic composition of a series of glacial meltwater samples discharged from Sólheimajökull, a valley glacier of Mýrdalsjökull, between 2009 and 2012. Dual isotopic analysis of δ34S and δ18O in dissolved sulphate allows identification of source mixing processes and chemical evolution during subglacial meltwater transport. Strikingly, meltwater δ18OSO4 signatures indicate redox conditions at the glacier bed, which are inverse to those normally encountered at Arctic and Alpine glaciers. Discharge of reduced, anoxic meltwater in summer, rather than winter, points towards seasonal release of geothermally derived volatile gases. We attribute this to headward expansion of the channelized subglacial drainage system during the summer melt season, accessing key areas of geothermal activity within the Katla caldera. Volatile release may be further enhanced by unloading of overburden pressure due to snowpack melting in the summer season. In winter, restriction of subglacial channels to lower elevations effectively seals geothermal fluids and dissolved gases beneath the ice cap, with only sporadic release permitted by periodic increases in subglacial water pressure. When the subglacial drainage configuration permits access to key geothermal areas, sulphate isotopic signatures thereby form sensitive indicators of geothermal activity occurring deep beneath the Mýrdalsjökull ice cap.

Leptin may have a role in the initiation of puberty and the regulation of subsequent weight gain, but this hypothesis has not been tested by longitudinal study. We report data from 40 normal children (20 boys and 20 girls) followed from 8-16 yr of age with hormone measurements and auxology every 6 months. Before the onset of puberty, leptin levels were similar in boys and girls: G1, mean (95% confidence interval), 2.63 (2.17-3.20) ng/mL; B1, 2.47 (2.08-2.94) ng/mL (P = 0.64) and increased with age in both sexes (B, 0.107 +/- 0.042; P = 0.02). With the onset of puberty, leptin levels increased in girls (B2-B5, P < 0.0005), but decreased in boys (G2-G5, P < 0.0005). Similar positive independent relationships were seen between leptin and fat mass in girls (B, 0.106 +/- 0.022; P < 0.0005) and boys (B, 0.121 +/- 0.020; P < 0.0005), and negative relationships were found with fat-free mass [girls: B, -1.104 +/- 0.381 (P < 0.005); boys: B, -1.288 +/- 0.217 (P < 0.0005)]. Girls gained more fat mass than boys, whereas boys gained more fat-free mass, and this explained the sex difference in leptin levels. Leptin levels correlated significantly with a large number of other hormones, but none was independent of changes in body composition. In girls, but not in boys, low leptin levels during prepuberty (B1) predicted subsequent gains in the percent body fat during puberty (r = -0.75; P = 0.005). The sexual dimorphism in leptin levels during puberty reflects differential changes in body composition. Prepubertal leptin levels in girls also predict gains in the percent body fat.

Cell-cell junction remodeling is associated with dramatic actin reorganizations. Several actin regulatory systems have been implicated in actin remodeling events as cell-cell contacts are assembled and disassembled, including zyxin/LPP-VASP complexes. These complexes facilitate strong cell-cell adhesion by maintaining actin-membrane connections. It has been proposed that zyxin and LPP localize to cell-cell junctions via a well-defined interaction with alpha-actinin. This was recently confirmed for LPP, but zyxin localization at cell-cell contacts occurs independently of alpha-actinin binding. Here we seek to map the zyxin sequence responsible for localization to cell-cell contacts and identify the protein that docks zyxin at this cellular location. Previous results have shown that a zyxin fragment excluding the alpha-actin binding site and the LIM domains (amino acids 51-392) can independently localize to cell-cell contacts. Here, expression of smaller zyxin fragments show that zyxin localization requires amino acids 230-280. A yeast-two-hybrid screen, using the central region of zyxin as bait, resulted in the identification of the cell-cell adhesion receptor nectin-4 as a zyxin binding partner. Further demonstrating zyxin-nectin interactions, zyxin binds the intracellular domain of nectin-2 in vitro. Depletion of nectin-2 from L cells expressing E-cadherin results in a loss of zyxin localization to cell-cell contacts, demonstrating that the zyxin-nectin interaction plays a critical role in zyxin targeting to these sites.

Insulin-like growth factors (IGF)-I, -II and IGF binding protein-2 (IGFBP-2) have been measured in plasma of children with Wilms' tumour. The mean levels for total serum IGF-I and -II were not significantly altered in Wilms' tumour as compared with normal control plasma. However, the chromatographic profiles for IGF-I and -II in these groups were different with regard to the presence of IGF binding proteins and high molecular weight forms of IGFs; the high molecular weight form (9–15 kD) of IGF-II was significantly reduced in Wilms' tumour. Levels of IGFBP-2 were substantially elevated in serum from Wilms' tumour patients (1025 ± 112 ng/ml compared with 416 ± 44 ng/ml in controls), and inversely correlated with the levels of high molecular weight forms of IGF-II. We suggest that IGFBP-2 measurements might be of value as a marker for monitoring this type of tumour, either as an adjunct to diagnosis or surveillance of tumour growth during therapy.

Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8–17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean ± sem) was greater by 1.45 ± 0.69 kg/m2 in girls and 1.46 ± 0.55 kg/m2 in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 ± 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 ± 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes.

In this study we have investigated the effect on the bioactivity of pituitary-derived human growth hormone (hGH) and recombinant bovine (b) GH after the addition of various concentrations of the water soluble cross-linking agent 1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC; 6.25-100 mg/ml). The biological activity of resulting cross-linked reactions were determined by its ability to promote incorporation of 35SO4(2-) into costal cartilage of hypopituitary Snell dwarf mice in vivo. Administration of EDC-treated hGH solutions resulted in a significant enhancement of hormone activity in vivo compared with non-cross-linked samples. A similar significant enhancement of bGH activity in vivo was also observed when solutions containing recombinant bGH were cross-linked using EDC. For both hGH and bGH the degree of enhancement appears to be dose-dependent for the concentration of EDC (6.25-100 mg/ml for hGH; 6.25-50 mg/ml for bGH) present in the cross-linking reactions. SDS-PAGE analysis of EDC cross-linked solutions containing hGH and bGH spiked with 125I-hGH and 125I-bGH respectively revealed that dimeric GH was the primary cross-linked component. Increasing the concentration of EDC in cross-linking reactions resulted in increased formation of dimeric hGH and bGH. There was a significant correlation between the amount of GH dimer present and the increase in biological activity, suggesting that GH dimers were responsible for the enhanced biological activity. This was confirmed by the enhanced biological activity of a purified preparation of EDC cross-linked dimeric hGH. In conclusion, covalently cross-linked GH dimers reported here have enhanced bioactivity in vivo. However, since naturally occurring GH dimers are known to have reduced biological activity, this work suggests that the structure of EDC cross-linked GH dimers differs fundamentally from that of native dimeric hGH.

Metastasis requires shedding and migration of individual cells from the tumor. In tumors of epithelial origin, cells often maintain strong cell-cell interactions that must be disassembled prior to cell detachment. Remodeling of cell-cell adhesions occurs during epithelial-mesenchymal transition (EMT), a developmental process where individual cells are triggered to detach and migrate to distant sites by developmental signaling programs. It is thought that inappropriate activation of EMT drives metastasis, particularly by allowing detachment and migration of cancer cells. While much is known about migration and invasion, how cell-cell junctions are detached remains poorly understood. Here we sought to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/ scatter factor-induced EMT. We find that HGF signaling actually increases cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion are not enough to drive epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role. Cell-substrate adhesion increases upon HGF stimulation and alterations in the pliability of the subtratum alter cells' ability to undergo scattering. Interestingly, scattering is impaired in cells expressing both active and inactive RhoA mutants. While this also indicates a role for important changes in cell-substrate adhesion during cell-cell detachment, RhoA also affects myosin-based contractility. We sought to examine how myosin-based contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely initiation of cell spreading and an inability to rupture cell-cell adhesions in response to HGF treatment. Interestingly, when cell spreading is induced by transient treatment of cells with blebbistatin, blebbistatin washout results in cellular events that closely resemble HGF-induced epithelial scattering. This suggests that global suppression and subsequent induction of myosin II activity may be sufficient to rupture cell-cell adhesions. Such experiments also suggest a role for RhoA, as blebbistatin-induced scattering is not fully completed in cells expressing a dominant-negative RhoA mutant. Taken together, these results suggest that cell-cell detachment is controlled by contractility, with a contribution by RhoA-mediated changes in cell adhesion. Citation Format: Jacob Peter Hoj, Kendra Fullmer, John Davis, David Morrell, MDH Hansen. Detachment of epithelial cells is driven by myosin-based contractility and RhoA. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C55.

Myelination by Schwann cells is likely to be regulated in vivo by positive and negative epigenetic factors. In vitro, the positive regulation of myelin differentiation, in particular expression of the major myelin protein Po, can be mimicked by cAMP elevating agents, while serum, transforming growth factor (TGF) beta s, and fibroblast growth factor (FGF)2 have been shown to exert a negative effect on this differentiation. Growth factors which promote Po induction have not, however, been identified previously. Using a forskolin concentration (0.4 microM) which alone produces little Po mRNA or protein induction, we show that insulin-like growth factor (IGF)-I, IGF-II and high concentrations of insulin promote high levels of Po induction, although in the absence of forskolin they have no effect. Another event related to Schwann cell differentiation, induction of galactocerebroside expression in response to cAMP analogues, is also potentiated by IGFs. In a different context, IGFs regulate Schwann cell DNA synthesis. We find that in defined medium forskolin plus FGF2, TGF beta or platelet-derived growth factor (PDGF) BB causes minimal DNA synthesis in the absence of IGFs and that IGFs act as potent mitogens under these conditions. IGFs also potentiate DNA synthesis induced by beta isoforms of neu-differentiation factors (NDFs), although in this case considerable DNA synthesis occurs even in the absence of IGF. These results show that IGFs can act as powerful stimulators of both proliferation and differentiation in Schwann cells, and that the total growth factor input determines which of these pathways IGFs will promote.

Method and apparatus for determining the length of a tubular member such as a pipe are disclosed. A burst of acoustical pulses are emitted from a sending unit and are received by a reference acoustical transducer and by a slave acoustic transducer. The slave transducer emits a return pulse which is used to compute the duration of the sound propagation interval between the ends of the pipe. A phase angle compensation factor is computed by measuring the phase shift of the signal received by the reference transducer with respect to the signal emitted by the master transducer.