Differently charged polypeptides and their impact on peritoneal and pleural postoperative adhesion formation

Organization LUND UNIVERSITY Department of Surgery, Clinical Sciences Skånes University Hospital Lund SE-221 85 Lund Sweden Document name DOCTORAL DISSERTATION Date of issue: November 8, 2013 Author(s): Daniel Åkerberg Sponsoring organization Title and subtitle: Differently charged polypeptides and their impact on peritoneal and pleural postoperative adhesion formation Abstract: Abdominal adhesions are formed after previous peritoneal traumas where previous surgery poses the most frequent cause. An increasing number of clinical complications due to adhesions have been detected such as small bowel obstructions, female infertility, and pain. Postoperative adhesions also form in pleura and pericardium after thoracic surgery. Complications include risk of bleeding, organ perforation and prolonged surgery, both in the thorax and abdomen, during reoperations. Previous reports have shown increased healthcare expenditures due to complications of abdominal adhesions. Several prophylactic anti-adhesion devices exist on the market, but none of them are sufficient in every aspect, such as being able to be used during abdominal infections, bleeding and in case of an intestinal anastomosis. The use of two differently charged polypeptides covering the peritoneal wounds during surgery has, in previous studies, shown promising anti-adhesion effects. The aim of this study was to investigate whether the polypeptides in any way affected different important healing aspects of the peritoneum and if the polypeptides may be administered as a spray in an animal study (I). Furthermore, the aim was to elucidate if the administered polypeptides affected important aspects of the healing process during an extended time dynamic pattern (II). It was also investigated whether the polypeptides reduced adhesions after adhesiolysis in the abdomen (III) and pleura (IV), and if there was an impact on peritoneal/pleural healing. In order to investigate the impact of polypeptides, an in vitro cell model was set up (V). A significant decrease in adhesions was seen both in the abdomen and pleura using the polypeptides. A significant decrease in adhesion reformation was seen after adhesiolysis and polypeptide administration. Despite some variation, no significant impact on key parameters of peritoneal and pleural resolving processes were seen after administration of the polypeptides. It was feasible to administer the polypeptides with a spray atomizer. Cell proliferation was decreased when higher concentrations of the polypeptides were administered, indicating a dose response relationship relying on the configuration and amount of charges of the polypeptides. In conclusion, the use of the two differently charged polypeptides to prevent abdominal and pleural adhesions was feasible, reducing adhesions after primary surgery and relaparotomy, without affecting key parameters of the resolving process investigated. Key words: Abdominal adhesions, small bowel obstructions, pain, female infertility, pleural adhesions, peritoneal, pleural, resolving process and key substances. Classification system and/or index terms (if any) Supplementary bibliographical information Language English ISSN and key title 1652-8220 ISBN978-91-87651-18-2 Recipient’s notes Number of pages 150 Price Security classificatio

Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas

Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumorrelated factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer

Toxicity and Dose Response of Intra-Abdominally Administered Poly-L-alpha-Lysine and Poly-L-Glutamate for Postoperative Adhesion Protection.

Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents

Workshop Methods for Troubleshooting the Performance of the After-treatment system

New legislations are constantly arising in Europe that puts stringent restrictions on the emissions coming from heavy-duty vehicles. The latest one is the Euro VI that has tough limits on both nitrogen oxides (NOx) and particulate matter (PM). To be able to cope with these tough limits, many developers of heavy-duty trucks have chosen to mount an after-treatment system after the engine containing several different catalysts. The emissions are monitored by an On-Board Diagnosis (OBD) system during operation, and if the emissions are too high a Malfunction Indicator (MI) lamp is lit and the truck needs to be serviced in a workshop. In the workshop the fault is investigated, which could be caused by several things, one of which may be a performance loss of one of the catalysts.This master thesis investigates different methods for testing the performance of two of these catalysts. The catalysts that were investigated was the Diesel Oxidation Catalyst (DOC) that oxidizes hydrocarbons (HC), carbon monoxide (CO) and nitrogen monoxide (NO), and Selective Catalytic Reduction (SCR) that uses ammonia for the reduction of nitrogen oxides (NOx). A comprehensive literature study was made to get an insight in how the current system works and to be able to develop concepts for future workshop methods. From the literature study, three concepts were developed for each catalyst. These concepts were tested out on Scania’s 13 litre 6-cylinder Euro VI engine with Scania’s Euro VI after-treatment system. The concepts are mainly consisting of three measuring principles that investigates the changes in temperature, NOx-conversion and ammonia storage. The tests resulted in that one concept per catalyst could be used to isolate and measure the performance. The performance of the DOC could be measured with the increase of temperature due to the exothermal reaction when HC is injected into the catalyst, called Measurement of HC-slip. To be able to measure the performance of the SCR, the changes in the maximum ammonia storage that the catalyst could achieve during an ammonia sweep was used, called Measurement of ammonia storage

Workshop Methods for Troubleshooting the Performance of the After-treatment system

New legislations are constantly arising in Europe that puts stringent restrictions on the emissions coming from heavy-duty vehicles. The latest one is the Euro VI that has tough limits on both nitrogen oxides (NOx) and particulate matter (PM). To be able to cope with these tough limits, many developers of heavy-duty trucks have chosen to mount an after-treatment system after the engine containing several different catalysts. The emissions are monitored by an On-Board Diagnosis (OBD) system during operation, and if the emissions are too high a Malfunction Indicator (MI) lamp is lit and the truck needs to be serviced in a workshop. In the workshop the fault is investigated, which could be caused by several things, one of which may be a performance loss of one of the catalysts.This master thesis investigates different methods for testing the performance of two of these catalysts. The catalysts that were investigated was the Diesel Oxidation Catalyst (DOC) that oxidizes hydrocarbons (HC), carbon monoxide (CO) and nitrogen monoxide (NO), and Selective Catalytic Reduction (SCR) that uses ammonia for the reduction of nitrogen oxides (NOx). A comprehensive literature study was made to get an insight in how the current system works and to be able to develop concepts for future workshop methods. From the literature study, three concepts were developed for each catalyst. These concepts were tested out on Scania’s 13 litre 6-cylinder Euro VI engine with Scania’s Euro VI after-treatment system. The concepts are mainly consisting of three measuring principles that investigates the changes in temperature, NOx-conversion and ammonia storage. The tests resulted in that one concept per catalyst could be used to isolate and measure the performance. The performance of the DOC could be measured with the increase of temperature due to the exothermal reaction when HC is injected into the catalyst, called Measurement of HC-slip. To be able to measure the performance of the SCR, the changes in the maximum ammonia storage that the catalyst could achieve during an ammonia sweep was used, called Measurement of ammonia storage

Factors influencing receipt of adjuvant chemotherapy after surgery for pancreatic cancer : a two-center retrospective cohort study

Objective: The addition of adjuvant chemotherapy after surgical resection has improved survival rates for patients with pancreatic ductal adenocarcinoma (PDAC). However, outside clinical trials, many operated patients still do not receive adjuvant chemotherapy due to clinical and tumor-related factors. The aim of this study was to investigate factors that may influence the receipt of adjuvant chemotherapy and the effect on long-term survival. Materials and methods: Patients undergoing macroscopically curative resection for PDAC at the University Hospitals in Lund and Linköping, Sweden, between 1 January 2007 and 31 December 2015, were retrospectively reviewed. Clinical and pathological data were compared between adjuvant and non-adjuvant chemotherapy groups and factors affecting chemotherapy receipt were analyzed by multiple logistic regression. Multivariable Cox regression analysis was performed to select predictive variables for survival. Results: A total of 233 patients were analyzed. Adjuvant chemotherapy was administered to 167 patients (71.7%). The likelihood of receiving adjuvant chemotherapy decreased with age, OR 0.91, 95% CI 0.86–0.95, p < .001. Moreover, patients with severe postoperative complications (Clavien–Dindo grade ≥ III) were less likely to receive adjuvant chemotherapy, OR 0.31, 95% CI 0.14–0.71, p = .005. The presence of lymph node metastases on histopathological reporting was associated with increased likelihood of initiating adjuvant chemotherapy, OR 2.19, 95% CI 1.09–4.40, p = .028. Adjuvant chemotherapy was an independent factor for prolonged survival on multivariable Cox regression analysis, HR 0.45 (95% CI 0.31–0.65), p < .001. Conclusions: Age, postoperative complications and the presence of lymph node metastases affect the likelihood of receiving adjuvant chemotherapy after PDAC surgery

Early postoperative fluid retention is a strong predictor for complications after pancreatoduodenectomy

Background: Perioperative fluid overload has been reported to increase complications after a variety of operative procedures. This study was conducted to investigate the incidence of fluid retention after pancreatic resection and its association with postoperative complications. Methods: Data from 1174 patients undergoing pancreatoduodenectomy between 2010 and 2016 were collected from the Swedish National Pancreatic and Periampullary Cancer Registry. Early postoperative fluid retention was defined as a weight gain ≥2 kg on postoperative day 1. Outcome measures were overall complications, as well as procedure-specific complications. Results: The weight change on postoperative day 1 ranged from −1 kg to +9 kg. A total of 782 patients (66.6%) were considered to have early fluid retention. Patients with fluid retention had significantly higher rates of total complications (p = 0.002), surgical complications (p = 0.001), pancreatic anastomotic leakage (p = 0.018) and wound infection (p = 0.023). Multivariable logistic regression confirmed early fluid retention as an independent risk factor for total complications (OR 1.46; p = 0.003), surgical complications (OR 1.49; p = 0.002), pancreatic anastomotic leakage (OR 1.48; p = 0.027) and wound infection (OR 1.84; p = 0.023). Conclusions: Fluid retention is common after elective pancreatic resection, and its associated with an increased rate of postoperative complications

Treatment of acute pancreatitis: focus on medical care.

Acute pancreatitis has an incidence of about 300 per 1 million individuals per year, of which 10-15% of patients develop the severe form of the disease. Novel management options, which have the potential to improve outcome, include initial proper fluid resuscitation, which maintains microcirculation and thereby potentially decreases ischaemia and reperfusion injury. The traditional treatment concept in acute pancreatitis, fasting and parenteral nutrition, has been challenged and early initiation of enteral feeding in severe pancreatitis and oral intake in mild acute pancreatitis is both feasible and provides some benefits. There are at present no data supporting immunonutritional supplements and probiotics should be avoided in patients with acute pancreatitis. There is also no evidence of any benefits provided by prophylactic antibacterials in patients with predicted severe acute pancreatitis. A variety of specific medical interventions have been investigated (e.g. intense blood glucose monitoring by insulin) but none has become clinically useful. Lessons can probably be learned from critical care in general, but studies are needed to verify these interventions in acute pancreatitis

Cationic polypeptides in a concept of oppositely charged polypeptides as prevention of postsurgical intraabdominal adhesions

Two differently charged polypeptides, α-poly-L-lysine and poly-L-glutamate, have previ- ously been shown to effectively reduce postoperative intraabdominal adhesions. Though α-poly-L-lysine showed toxicity in doses too close to the lowest the-rapeutic dose, the aim in the present study was to investigate the possible antiadhesive effect of another four cationic polypeptides