L-arginine: A unique amino acid for improving depressed wound immune function following hemorrhage

Objective: To determine whether L-arginine has any salutary effects on wound immune cell function following trauma-hemorrhage. Background. Depressed wound immune function contributes to an increased incidence of wound infections following hemorrhage. Although administration of L-arginine has been shown to restore depressed cell-mediated immune responses following hemorrhage potentially by maintaining organ blood flow, it remains unknown whether Larginine has any salutary effects on the depressed local immune response at the wound site. Methods: Male mice were subjected to a midline laparotomy and polyvinyl sponges were implanted subcutaneously in the abdominal wound prior to hemorrhage (35 +/- 5 mm Hg for 90 min and resuscitation) or sham operation. During resuscitation mice received 300 mg/kg body weight L-arginine or saline (vehicle). Sponges were harvested 24 h thereafter, wound fluid collected and wound immune cells cultured for 24 h in the presence of LPS. Pro- (IL-1beta, IL-6) and anti-inflammatory (IL-10) cytokines were determined in the supernatants and the wound fluid. In addition, wounds were stained for IL-6 immunohistochemically. In a separate set of animals, skin and muscle blood flow was determined by microspheres. Results: The capacity of wound immune cells to release IL-1beta and IL-6 in vitro was significantly depressed in hemorrhaged mice receiving vehicle. Administration of L-arginine, however, improved wound immune cell function. In contrast, in vivo the increased IL-6 release at the wound site was decreased in L-arginine-treated mice following hemorrhage. Moreover, IL-10 levels were significantly increased in the wound fluid in hemorrhaged animals receiving L-arginine compared to vehicle-treated mice. In addition, the depressed skin and muscle blood flow after hemorrhage was restored by L-arginine. Conclusions: Thus, L-arginine might improve local wound cell function by decreasing the inflammatory response at the wound site. Since L-arginine protected wound immune cell function this amino acid might represent a novel and useful adjunct to fluid resuscitation for decreasing wound complications following hemorrhage. Copyright beta 2002 S. Karger AG, Basel

Recent advances in minimally invasive colorectal cancer surgery

Laparoscopy has improved surgical treatment of various diseases due to its limited surgical trauma and has developed as an interesting therapeutic alternative for the resection of colorectal cancer. Despite numerous clinical advantages (faster recovery, less pain, fewer wound and systemic complications, faster return to work) the laparoscopic approach to colorectal cancer therapy has also resulted in unusual complications, i.e. ureteral and bladder injury which are rarely observed with open laparotomy. Moreover, pneumothorax, cardiac arrhythmia, impaired venous return, venous thrombosis as well as peripheral nerve injury have been associated with the increased intraabdominal pressure as well as patient's positioning during surgery. Furthermore, undetected small bowel injury caused by the grasping or cauterizing instruments may occur with laparoscopic surgery. In contrast to procedures performed for nonmalignant conditions, the benefits of laparoscopic resection of colorectal cancer must be weighed against the potential for poorer long-term outcomes of cancer patients that still has not been completely ruled out. In laparoscopic colorectal cancer surgery, several important cancer control issues still are being evaluated, i.e. the extent of lymph node dissection, tumor implantation at port sites, adequacy of intraperitoneal staging as well as the distance between tumor site and resection margins. For the time being it can be assumed that there is no significant difference in lymph node harvest between laparoscopic and open colorectal cancer surgery if oncological principles of resection are followed. As far as the issue of port site recurrence is concerned, it appears to be less prevalent than first thought (range 0-2.5%), and the incidence apparently corresponds with wound recurrence rates observed after open procedures. Short-term (3-5 years) survival rates have been published by a number of investigators, and survival rates after laparoscopic surgery appears to compare well with data collected after conventional surgery for colorectal cancer. However, long-term results of prospective randomized trials are not available. The data published so far indicate that the oncological results of laparoscopic surgery compare well with the results of the conventional open approach. Nonetheless, the limited information available from prospective studies leads us to propose that minimally invasive surgery for colorectal cancer surgery should only be performed within prospective trials

The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage

Objective: Trauma-hemorrhage results in depressed immune responses of antigen-presenting cells (APCs) and T-cells. Recent studies suggest a key role of depressed T-cell derived interferon (IFN)-g in this complex immune cell interaction. The aim of this study was to elucidate further the underlying mechanisms responsible for dysfunctional T-cells and their interaction with APCs following trauma-hemorrhage. Design: Adult C3H/HeN male mice were subjected to trauma-hemorrhage (3-cm midline laparotomy) followed by hemorrhage (blood pressure of 35�5mmHg for 90 min and resuscitation) or sham operation. At 24 h thereafter, spleens were harvested and T-cells (by Microbeads) and APCs (via adherence) were Isolated. Co-cultures of T-cells and APCs were established for 48 h and stimulated with concanavalin A and lipopolysaccharide. T-Cell specific cytokines known to affect APC function (i.e. interleukin(IL)-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were measured in culture supernatants by Multiplex assay. The expression of MHC class II as well as co-stimulatory surface molecules on T-cells and APCs was determined by flow cytometry. Results: The release of IL-4 and GM-CSF by T-cells was suppressed following trauma-hemorrhage, irrespective of whether sham or trauma-hemorrhage APCs were present. Antigen-presenting cells from animals subjected to trauma-hemorrhage did not affect T-cell derived cytokine release by sham T-cells. In contrast, T-cells from traumahemorrhage animals depressed MHC class II expression of CD11c(þ) cells, irrespective of whether APCs underwent sham or trauma-hemorrhage procedure. Surprisingly, co-stimulatory molecules on APCs (CD80, CD86) were not affected by trauma-hemorrhage. Conclusions: These results suggest that beside IFN-g other T-cell derived cytokines contribute to immunosuppression following trauma-hemorrhage causing diminished MHC II expression on APCs. Thus, T-cells appear to play an important role in this interaction at the time-point examined. Therapeutic approaches should aim at maintenance of T-cell function and their interaction with APCs to prevent extended immunosuppression following trauma-hemorrhage

GSH Attenuates Organ Injury and Improves Function after Transplantation of Fatty Livers

Ischemia-reperfusion injury (IRI) is increased after transplantation of steatotic livers. Since those livers are increasingly used for transplantation, protective strategies must be developed. Reactive oxygen species (ROS) play a key role in hepatic IRI. In lean organs, glutathione (GSH) is an efficient scavenger of ROS, diminishing IRI. The aim of this study was to evaluate whether GSH also protects steatotic allografts from IRI following transplantation. Fatty or lean livers were explanted from 10-week-old obese or lean Zucker rats and preserved (obese 4 h, lean 24 h) in hypothermic University of Wisconsin solution. Arterialized liver transplantation was then performed in lean syngeneic Zucker rats. Recipients of fatty livers were treated with GSH (200 mu mol/h/kg) or saline during reperfusion (2 h, n = 5). Parameters of hepatocellular damage and bile flow were measured. Transplantation of steatotic livers enhanced early reperfusion injury compared to lean organs as measured by increased aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase plasma levels. Bile flow was also reduced in steatotic grafts. Intravenous administration of GSH effectively decreased liver damage in fatty allografts and resulted in improved bile flow. Intravenous application of GSH effectively reduces early IRI in steatotic allografts and improves recovery of these marginal donor organs following transplantation. Copyright (C) 2010 S. Karger AG, Base

Effect of platelet inhibition with perioperative aspirin on survival in patients undergoing curative resection for pancreatic cancer: a propensity score matched analysis

BACKGROUND The importance of platelets in the pathogenesis of metastasis formation is increasingly recognized. Although evidence from epidemiologic studies suggests positive effects of aspirin on metastasis formation, there is little clinical data on the perioperative use of this drug in pancreatic cancer patients. METHODS From all patients who received curative intent surgery for pancreatic cancer between 2014 and 2016 at our institution, we identified 18 patients that took aspirin at time of admission and continued to throughout the inpatient period. Using propensity score matching, we selected a control group of 64 patients without aspirin intake from our database and assessed the effect of aspirin medication on overall, disease-free, and hematogenous metastasis-free survival intervals as endpoints. RESULTS Aspirin intake proved to be independently associated with improved mean overall survival (OS) (46.5 vs. 24.6 months, *p = 0.006), median disease-free survival (DFS) (26 vs. 10.5 months, *p = 0.001) and mean hematogenous metastasis-free survival (HMFS) (41.9 vs. 16.3 months, *p = 0.005). Three-year survival rates were 61.1% in patients with aspirin intake vs. 26.3% in patients without aspirin intake. Multivariate cox regression showed significant independent association of aspirin with all three survival endpoints with hazard ratios of 0.36 (95% CI 0.15-0.86) for OS (*p = 0.021), 0.32 (95% CI 0.16-0.63) for DFS (**p = 0.001), and 0.36 (95% CI 0.16-0.77) for HMFS (*p = 0.009). CONCLUSIONS Patients in our retrospective, propensity-score matched study showed significantly better overall survival when taking aspirin while undergoing curative surgery for pancreatic cancer. This was mainly due to a prolonged metastasis-free interval following surgery

Expression Patterns of TOP2A and SIRT1 Are Predictive of Survival in Patients with High-Risk Soft Tissue Sarcomas Treated with a Neoadjuvant Anthracycline-Based Chemotherapy

Simple Summary High-risk soft tissue sarcomas (HR-STS) account for less than 1% of all malignancies in adults. Despite optimal local treatment, almost half of patients will die within five years of their diagnosis. Chemoresistance is a major responsible mechanism for treatment failure in advanced tumor stages. In contrast to other cancer types, molecular predictors of response to chemotherapy and survival have not been identified and put into clinical practice by now. We analyzed the predictive value of two molecules involved in the working and resistance mechanisms to doxorubicin, TOP2A and SIRT1, in a large cohort of locally advanced HR-STS who underwent a neoadjuvant anthracycline-based chemotherapy with a long-term follow-up. Our results show sarcoma subtype-specific patterns of TOP2A and SIRT1 expression. We demonstrate significant differences in overall survival according to the TOP2A and SIRT1 expression status. Both markers can be used as clinically significant predictive indicators for HR-STS patients scheduled for neoadjuvant anthracycline-based chemotherapy. Abstract Molecular predictors of response to chemotherapy and survival have not been put into clinical practice in high-risk soft tissue sarcomas (HR-STS) by now. The expression of TOP2A and SIRT1 has implications for the mechanism of action of doxorubicin, which is the backbone of chemotherapy in HR-STS. Pre-treatment samples of 167 patients with HR-STS were collected. Protein expression levels of TOP2A and SIRT1 were evaluated with tissue microarrays and immunohistochemistry and correlated with clinicopathological parameters, including overall survival (OS). The expression of TOP2A and SIRT1 was seen in 47% and 60% of patients with HR-STS, respectively. TOP2A expression was associated with higher tumor grading and shorter 5-year OS. The expression of SIRT1 was correlated with a better 5- and 10-year OS. The combination of high SIRT1 and low TOP2A (“Top survivors”) significantly predicted a better OS compared to other biomarker combinations. A multivariate analysis confirmed the expression of SIRT1 and the “Top survivor” biomarker combination as independent predictive factors of OS. This is the first study to associate SIRT1 overexpression with a statistically significant prolongation of OS in HR-STS. Both individual markers and their combination can be used as predictive indicators for HR-STS patients scheduled for neoadjuvant anthracycline-based chemotherapy

Auditory distraction during reading: A Bayesian meta-analysis of a continuing controversy

Everyday reading occurs in different settings, such as on the train to work, in a busy cafeteria, or at home, while listening to music. In these situations, readers are exposed to external auditory stimulation from nearby noise, speech, or music that may distract them from their task and reduce their comprehension. Although many studies have investigated auditory distraction effects during reading, the results have proved to be inconsistent and sometimes even contradictory. Additionally, the broader theoretical implications of the findings have not always been explicitly considered. In the present study, we report a Bayesian meta-analysis of 65 studies on auditory distraction effects during reading and use meta-regression models to test predictions derived from existing theories. The results showed that background noise, speech, and music all have a small, but reliably detrimental effect on reading performance. The degree of disruption in reading comprehension did not generally differ between adults and children. Intelligible speech and lyrical music resulted in the biggest distraction. While this last result is consistent with theories of semantic distraction, there was also reliable distraction by noise. It is argued that new theoretical models are needed that can account for distraction by both background speech and noise

Genetic diversity and population structure of Peronosclerospora sorghi isolates of Sorghum in Uganda

Sorghum is the third most important staple cereal crop in Uganda after maize and millet. Downy mildew disease is one of the most devastating fungal diseases which limits the production and productivity of the crop. The disease is caused by an obligate fungus, Peronosclerospora sorghi (Weston & Uppal) with varying symptoms. Information on the genetic diversity and population structure of P.sorghi in sorghum is imperative for the screening and selection for resistant genotypes and further monitoring possible mutant(s) of the pathogen. Isolates of P. sorghi infecting sorghum are difficult to discriminate when morphological descriptors are used. The use of molecular markers is efficient, and reliably precised for characterizing P. sorghi isolates. This study was undertaken to assess the level of genetic diversity and population structure that exist in P. sorghi isolates in Uganda. A total of 195 P. sorghi isolates, sampled from 13 different geographic populations from 10 different regions (agro-ecological zones) was used. Eleven (11) molecular markers, comprising of four Random amplified microsatellite (RAM) and seven (7) Inter-Simple Sequence Repeat (ISSR) markers were used in this study. The analysis of molecular variation (AMOVA) based on 11 microsatellite markers showed significant (P < 0.001) intra-population (88.9 %, PhiPT = 0.111) and inter-population (8.4 %, PhiPR = 0.083) genetic variation, while the genetic variation among regions (2.7 %, PhiRT = 0.022) was not significant. The highest genetic similarity value (0.987 = 98.7 %) was recorded between Pader and Lira populations and the lowest genetic similarity (0.913 = 91.3 %) was observed between Namutumba and Arua populations. The mean Nei's genetic diversity index (H) and Shannon Information Index (I) were 0.308 and 0.471 respectively. Seven distinct cluster groups were formed from the 195 P. sorghi isolates based on their genetic similarity. Mantel test revealed no association between genetic differentiation and geographical distance (R2 = 0.0026, p = 0.02) within the 13 geographic populations

Amine functionalization of cholecyst-derived extracellular matrix with generation 1 PAMAM dendrimer

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Biomacromolecules, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/pdf/10.1021/bm701055k.A method to functionalize cholecyst-derived extracellular matrix (CEM) with free amine groups was established in an attempt to improve its potential for tethering of bioactive molecules. CEM was incorporated with Generation-1 polyamidoamine (G1 PAMAM) dendrimer by using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and N-hydroxysuccinimide cross-linking system. The nature of incorporation of PAMAM dendrimer was evaluated using shrink temperature measurements, Fourier transform infrared (FTIR) assessment, ninhydrin assay, and swellability. The effects of PAMAM incorporation on mechanical and degradation properties of CEM were evaluated using a uniaxial mechanical test and collagenase degradation assay, respectively. Ninhydrin assay and FTIR assessment confirmed the presence of increasing free amine groups with increasing quantity of PAMAM in dendrimer-incorporated CEM (DENCEM) scaffolds. The amount of dendrimer used was found to be critical in controlling scaffold degradation, shrink temperature, and free amine content. Cell culture studies showed that fibroblasts seeded on DENCEM maintained their metabolic activity and ability to proliferate in vitro. In addition, fluorescence cell staining and scanning electron microscopy analysis of cell-seeded DENCEM showed preservation of normal fibroblast morphology and phenotype

Moon phases and moon signs do not influence morbidity, mortality and long-term survival, after living donor kidney transplantation

Background: Approximately 11% of the German population are convinced that certain moon phases and moon signs may impact their health and the onset and clinical course of diseases. Before elective surgery, a considerable number of patients look to optimize the timing of the procedure based on the lunar cycle. Especially patients awaiting living donor kidney transplantation (LDKT) commonly look for an adjustment of the date of transplantation according to the moon calendar. This study therefore investigated the perioperative and long-term outcome of LDKT dependent on moon phases and zodiac signs. Methods: Patient data were prospectively collected in a continuously updated kidney transplant database. Two hundred and seventy-eight consecutive patients who underwent LDKT between 1994 and December 2009 were selected for the study and retrospectively assigned to the four moon phases (new-moon, waxing-moon, full-moon, and waning-moon) and the corresponding zodiac sign (moon sign Libra), based on the date of transplantation. Preexisting comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. Results: Of all LDKT procedures, 11.9, 39.9, 11.5, and 36.5% were performed during the new, waxing, full, and waning moon, respectively, and 6.2% during the moon sign Libra, which is believed to interfere with renal surgery. Survival rates at 1, 5, and 10 years after transplantation were 98.9, 92, and 88.7% (patient survival) and 97.4, 91.6, and 80.6% (graft survival) without any differences between all groups of lunar phases and moon signs. Overall perioperative complications and early graft loss occurred in 21.2 and 1.4%, without statistical difference (p > 0.05) between groups. Conclusion: Moon phases and the moon sign Libra had no impact on early and long-term outcome measures following LDKT in our study. Thus, concerns of patients awaiting LDKT regarding the ideal time of surgery can be allayed, and surgery may be scheduled independently of the lunar phases