Differential expression of protein kinase C isoforms in coronary arteries of diabetic mice lacking the G-protein Gα11

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus counts as a major risk factor for developing atherosclerosis. The activation of protein kinase C (PKC) is commonly known to take a pivotal part in the pathogenesis of atherosclerosis, though the influence of specific PKC isozymes remains unclear. There is evidence from large clinical trials suggesting excessive neurohumoral stimulation, amongst other pathways leading to PKC activation, as a central mechanism in the pathogenesis of diabetic heart disease. The present study was therefore designed to determine the role of G_q-protein signalling via Gα₁₁in diabetes for the expression of PKC isozymes in the coronary vessels.</p> <p>Methods</p> <p>The role of Gα₁₁in diabetes was examined in knockout mice with global deletion of Gα₁₁compared to wildtype controls. An experimental type 1-diabetes was induced in both groups by injection of streptozotocin. Expression and localization of the PKC isozymes α, βII, δ, ε, and ζ was examined by quantitative immunohistochemistry.</p> <p>Results</p> <p>8 weeks after induction of diabetes a diminished expression of PKC <b>ε </b>was observed in wildtype animals. This alteration was not seen in Gα₁₁knockout animals, however, these mice showed a diminished expression of PKCζ. Direct comparison of wildtype and knockout control animals revealed a diminished expression of PKC δ and ε in Gα₁₁knockout animals.</p> <p>Conclusion</p> <p>The present study shows that expression of the nPKCs δ and <b>ε </b>in coronary vessels is under control of the g-protein Gα₁₁. The reduced expression of PKC ζ that we observed in coronary arteries from Gα₁₁-knockout mice compared to wildtype controls upon induction of diabetes could reduce apoptosis and promote plaque stability. These findings suggest a mechanism that may in part underlie the therapeutic benefit of RAS inhibition on cardiovascular endpoints in diabetic patients.</p

Clinical features and prediction of long-term survival after surgery for perihilar cholangiocarcinoma

Introduction:The treatment of perihilar Cholangiocarcinoma (pCCA) poses specific challenges not only due to its high perioperative complication rates but also due its dismal long-term prognosis with only a few long-term survivors (LTS) among the patients. Therefore, in this analysis characteristics and predictors of LTS in pCCA patients are investigated. Material and methods:In this single center analysis, patients undergoing curative-intent liver resection for pCCA between 2010 and 2022 were categorized into long-term and short-term survivors (STS) excluding perioperative mortality. Binary logistic regression was used to determine key differences between the groups and to develop a prognostic composite variable. This composite variable was subsequently tested in the whole cohort of surgically treated pCCA patients using Cox Regression analysis for cancer-specific survival (CSS). Results:Within a cohort of 209 individuals, 27 patients were identified as LTS (median CSS = 125 months) and 55 patients as STS (median CSS = 16 months). Multivariable analysis identified preoperative portal vein infiltration (OR = 5.85, p = 0.018) and intraoperative packed red blood cell (PRBC) transfusions (OR = 10.29, p = 0.002) as key differences between the groups. A prognostic composite variable based on these two features was created and transferred into a Cox regression model of the whole cohort. Here, the composite variable (HR = 0.35, p&lt;0.001), lymph node metastases (HR = 2.15, p = 0.001) and postoperative complications (HR = 3.06, p&lt;0.001) were identified as independent predictors of CSS. Conclusion: Long-term survival after surgery for pCCA is possible and is strongly negatively associated with preoperative portal vein infiltration and intraoperative PRBC transfusion. As these variables are part of preoperative staging or can be modulated by intraoperative technique, the proposed prognostic composite variable can easily be transferred into clinical management to predict the oncological outcome of patients undergoing surgery for pCCA.</p

Oxygen Persufflation in Liver Transplantation Results of a Randomized Controlled Trial

Oxygen persufflation has shown experimentally to favorably influence hepatic energy dependent pathways and to improve survival after transplantation. The present trial evaluated oxygen persufflation as adjunct in clinical liver preservation. A total of n = 116 adult patients (age: 54 (23&#8722;68) years, M/F: 70/46), were enrolled in this prospective randomized study. Grafts were randomized to either oxygen persufflation for &#8805;2 h (O2) or mere cold storage (control). Only liver grafts from donors &#8805;55 years and/or marginal grafts after multiple rejections by other centers were included. Primary endpoint was peak-aspartate aminotransferase (AST) level until post-operative day 3. Standard parameters including graft- and patient survival were analyzed by uni- and multivariate analysis. Both study groups were comparable except for a longer ICU stay (4 versus 3 days) of the donors and a higher recipient age (57 versus 52 years) in the O2-group. Serum levels of TNF alpha were significantly reduced after oxygen persufflation (p &lt; 0.05). Median peak-AST values did not differ between the groups (O2: 580 U/l, control: 699 U/l). Five year graft- and patient survival was similar. Subgroup analysis demonstrated a positive effect of oxygen persufflation concerning the development of early allograft dysfunction (EAD), in donors with a history of cardiopulmonary resuscitation and elevated ALT values, and concerning older or macrosteatotic livers. This study favors pre-implantation O2-persufflation in concrete subcategories of less than optimal liver grafts, for which oxygen persufflation can be considered a safe, cheap and easy applicable reconditioning method

Lymph Node Staging in Perihilar Cholangiocarcinoma: The Key to the Big Picture

Klatskin tumors have a bad prognosis despite aggressive therapy. The role and extent of lymph node dissection during surgery is a matter of discussion. This retrospective study analyzes our current experience of surgical treatments in the last decade. Patients and Methods: A retrospective single-center analysis of patients (n = 317) who underwent surgical treatment for Klatskin tumors. Univariable and multivariable logistic regression and Cox proportional analysis were performed. The primary endpoint was to investigate the role of lymph node metastasis for patient survival after complete tumor resection. The secondary endpoint was the prediction of lymph node status and long-term survival from preoperatively available parameters. Results: In patients with negative resection margins, a negative lymph node status was the prognosis-determining factor with a 1-, 3-, and 5-year survival rate of 87.7%, 37%, and 26.4% compared with 69.5%, 13.9%, and 9.3% for lymph-node-positive patients, respectively. Multivariable logistic regression for complete resection and negative lymph node status demonstrated only Bismuth type 4 (p = 0.01) and tumor grading (p = 0.002) as independent predictors. In multivariate Cox regression analysis, independent predictors of survival after surgery were the preoperative bilirubin level (p = 0.03), intraoperative transfusion (p = 0.002), and tumor grading (G) (p = 0.001). Conclusion: Lymph node dissection is of utmost importance for adequate staging in patients undergoing surgery for perihilar cholangiocarcinoma. In spite of extensive surgery, long-term survival is clearly associated with the aggressiveness of the disease

High MELD score and extended operating time predict prolonged initial ICU stay after liver transplantation and influence the outcome

<div><p>Background</p><p>The aim of the present study is to determine the incidence of a prolonged (>3 days) initial ICU-stay after liver transplantation (LT) and to identify risk factors for it.</p><p>Patients and methods</p><p>We retrospectively analyzed data of adult recipients who underwent deceased donor first-LT at the University Hospital Essen between 11/2003 and 07/2012 and showed a primary graft function.</p><p>Results</p><p>Of the 374 recipients, 225 (60.16%) had prolonged ICU-stay. On univariate analysis, donor INR, high doses of vasopressors, “rescue-offer” grafts, being hospitalized at transplant, high urgency cases, labMELD, alcoholic cirrhosis, being on renal dialysis and length of surgery were associated with prolonged ICU-stay. After multivariate analysis, only the labMELD and the operation’s length were independently correlated with prolonged ICU-stay. Cut-off values for these variables were 19 and 293.5 min, respectively. Hospital stay was longer for patients with a prolonged initial ICU-stay (p<0.001). Survival rates differed significantly between the two groups at 3 months, 1-year and 5-years after LT (p<0.001).</p><p>Conclusions</p><p>LabMELD and duration of LT were identified as independent predictors for prolonged ICU-stay after LT. Identification of recipients in need of longer ICU-stay could contribute to a more evidenced-based and cost-effective use of ICU facilities in transplant centers.</p></div