α- and β-Adrenergic receptor mechanisms in spontaneous contractile activity of rat ileal longitudinal smooth muscle

Gastrointestinal motility is influenced by adrenergic modulation. Our aim was to identify specific subtypes of adrenergic receptors involved in inhibitory mechanisms that modulate gut smooth muscle contractile activity. Muscle strips of rat ileal longitudinal muscle were evaluated for spontaneous contractile activity and for equimolar dose-responses (10-7 to 3 x 10-5 M) to the adrenergic agents norepinephrine (nonselective agonist), phenylephrine (α1-agonist), clonidine (α2-agonist), prenalterol (β1-agonist), ritodrine (β2- agonist), and ZD7114 (β3-agonist) in the presence and absence of tetrodotoxin (nonselective nerve blocker). Norepinephrine (3 x 10-5 M) inhibited 65 ± 6% (mean ± SEM) of spontaneous contractile activity. The same molar dose of ritodrine, phenylephrine, or ZD7114 resulted in less inhibition (46 ±7%, 31 ± 5%, and 39 ± 3%, respectively; P < 0.05). The calculated molar concentration of ZD7114 needed to induce 50% inhibition was similar to that of norepinephrine, whereas higher concentrations of phenylephrine or ritodrine were required. Clonidine and prenalterol had no effect on contractile activity. Blockade of intramural neural transmission by tetrodotoxin affected the responses to ritodrine and phenylephrine (but not to norepinephrine or ZD7114), suggesting that these agents exert part of their effects via neurally mediated enteric pathways. Our results suggest that adrenergic modulation of contractile activity in the rat ileum is mediated primarily by muscular β3-, β2-, and α1 -receptor mechanisms; the latter two also involve neural pathway

Role of Selective α and β Adrenergic Receptor Mechanisms in Rat Jejunal Longitudinal Muscle Contractility

Gut motility is modulated by adrenergic mechanisms. The aim of our study was to examine mechanisms of selective adrenergic receptors in rat jejunum. Spontaneous contractile activity of longitudinal muscle strips from rat jejunum was measured in 5-ml tissue chambers. Dose-responses (six doses, 10−7-3 × 10−5M) to norepinephrine (NE, nonspecific), phenylephrine (PH, α1), clonidine (C, α2), prenalterol (PR, β1), ritodrine (RI, β2), and ZD7714 (ZD, β3) were evaluated with and without tetrodotoxin (TTX, nerve blocker). NE(3 × 10−5M) inhibited 74 ± 5% (mean ± SEM) of spontaneous activity. This was the maximum effect. The same dose of RI(β2), PH(α1), or ZD(β3) resulted in an inhibition of only 56 ± 5, 43 ± 4, 33 ± 6, respectively. The calculated concentration to induce 50% inhibition (EC50) of ZD(β3) was similar to NE, whereas higher concentrations of PH(α1) or RI(β2) were required. C(α2) and PR(β1) had no effect. TTX changed exclusively the EC50 of RI from 4.4 ± 0.2 to 2.7 ± 0.8% (p < 0.04). Contractility was inhibited by NE (nonspecific). PH(α1), RI(β2), and ZD(β3) mimic the effect of NE. TTX reduced the inhibition by RI. Our results suggest that muscular α1, β2, and β3 receptor mechanisms mediate adrenergic inhibition of contractility in rat jejunum. β2 mechanisms seem to involve also neural pathway

Prognostic factors in patients with acute mesenteric ischemia-novel tools for determining patient outcomes

BACKGROUND Acute mesenteric ischemia (AMI) is a devastating disease with poor prognosis. Due to the multitude of underlying factors, prediction of outcomes remains poor. We aimed to identify factors governing diagnosis and survival in AMI and develop novel prognostic tools. METHODS This monocentric retrospective study analyzed patients with suspected AMI undergoing imaging between January 2014 and December 2019. Subgroup analyses were performed for patients with confirmed AMI undergoing surgery. Nomograms were calculated based on multivariable logistic regression models. RESULTS Five hundred and thirty-nine patients underwent imaging for clinically suspected AMI, with 216 examinations showing radiological indication of AMI. Intestinal necrosis (IN) was confirmed in 125 undergoing surgery, 58 of which survived and 67 died (median 9 days after diagnosis, IQR 22). Increasing age, ASA score, pneumatosis intestinalis, and dilated bowel loops were significantly associated with presence of IN upon radiological suspicion. In contrast, decreased pH, elevated creatinine, radiological atherosclerosis, vascular occlusion (versus non-occlusive AMI), and colonic affection (compared to small bowel ischemia only) were associated with impaired survival in patients undergoing surgery. Based on the identified factors, we developed two nomograms to aid in prediction of IN upon radiological suspicion (C-Index = 0.726) and survival in patients undergoing surgery for IN (C-Index = 0.791). CONCLUSION As AMI remains a condition with high mortality, we identified factors predicting occurrence of IN with suspected AMI and survival when undergoing surgery for IN. We provide two new tools, which combine these parameters and might prove helpful in treatment of patients with AMI

Combining staged laparoscopic colectomy with robotic completion proctectomy and ileal pouch-anal anastomosis (IPAA) in ulcerative colitis for improved clinical and cosmetic outcomes: a single-center feasibility study and technical description

Robotic proctectomy has been shown to lead to better functional outcomes compared to laparoscopic surgery in rectal cancer. However, in ulcerative colitis (UC), the potential value of robotic proctectomy has not yet been investigated, and in this indication, the operation needs to be adjusted to the total colectomy typically performed in the preceding 6 months. In this study, we describe the technique and analyze outcomes of a staged laparoscopic and robotic three-stage restorative proctocolectomy and compare the clinical outcome with the classical laparoscopic procedure. Between December 2016 and May 2021, 17 patients underwent robotic completion proctectomy (CP) with ileal pouch-anal anastomosis (IPAA) for UC. These patients were compared to 10 patients who underwent laparoscopic CP and IPAA, following laparoscopic total colectomy with end ileostomy 6 months prior by the same surgical team at our tertiary referral center. 27 patients underwent a 3-stage procedure for refractory UC (10 in the lap. group vs. 17 in the robot group). Return to normal bowel function and morbidity were comparable between the two groups. Median length of hospital stay was the same for the robotic proctectomy/IPAA group with 7 days [median; IQR (6-10)], compared to the laparoscopic stage II with 7.5 days [median; IQR (6.25-8)]. Median time to soft diet was 2 days [IQR (1-3)] vs. 3 days in the lap group [IQR 3 (3-4)]. Two patients suffered from a major complication (Clavien-Dindo ≥ 3a) in the first 90 postoperative days in the robotic group vs. one in the laparoscopic group. Perception of cosmetic results were favorable with 100% of patients reporting to be highly satisfied or satisfied in the robotic group. This report demonstrates the feasibility of a combined laparoscopic and robotic staged restorative proctocolectomy for UC, when compared with the traditional approach. Robotic pelvic dissection and a revised trocar placement in staged proctocolectomy with synergistic use of both surgical techniques with their individual advantages will likely improve overall long-term functional results, including an improved cosmetic outcome

Morbus Crohn: zeitgemässe Therapie von perianalen Fisteln

Perianale Fisteln beeinträchtigen die Lebensqualität von Patienten mit Morbus Crohn stark. Wenngleich in den letzten Jahren deutliche Fortschritte in der Effizienz der medikamentösen und chirurgischen Therapieverfahren erzielt werden konnten, sind die Ansprechraten nach wie vor suboptimal und Rezidive des Fistelleidenshäufig. Ein Therapieerfolg ist in den meisten Fällen möglich, verlangt jedoch eine gute Zusammenarbeit von Chirurgen und Gastroenterologen

Impact of Preoperative Bevacizumab on Complications After Resection of Colorectal Liver Metastases: Case-Matched Control Study

Background: Chemotherapy may increase postoperative morbidity and mortality after liver surgery. Especially bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), could have a detrimental effect. To assess the impact of neoadjuvant bevacizumab on clinical outcome after hepatectomy for colorectal liver metastases (CRLMs) this case-matched control study was initiated. Methods: The multicentric data collection was performed in the Swiss HPB Center of the University Hospital Zurich (CH), the Department of Digestive Surgery and Transplantation Strasbourg (F), and the Division of Hepato-biliary-pancreatic surgery of "Josep Tureta” Hospital Girona (E). Consecutive patients operated onbetween July 2005 and December 2007 due to CRLMs who received neoadjuvant chemotherapy were assessed. Patients were divided in two groups: group A had neoadjuvant chemotherapy with bevacicumab, and group B had it without bevacizumab. Results: No differences in overall morbidity (56 vs. 40% in the bevacizumab and control groups, respectively, p=0.23) or mortality could be documented. Similarly, the incidence of severe postoperative complications was not statistically different between the bevacizumab and control groups (31 and 18%, respectively, p=0.31). Wound complications were comparable (11% in the bevacizumab group compared and 9% in the control group, p=1.00). However, bevacizumab was associated with a significantly decreased incidence of postoperative hepatic insufficiency (7 vs. 20%, p=0.03). Conclusions: No impact on the incidence or severity of complications by bevacizumab could be shown. Bevacizumab may even reduce the incidence of liver failure after liver surger

Effect of closed and permanent stoma on disease course, psychological well-being and working capacity in Swiss IBD cohort study patients

BACKGROUND Little is known about the impact of ostomy formation in inflammatory bowel disease patients on course of disease, psychological well-being, quality of life and working capacity. METHODS We analyzed patients over a follow-up of up to 16 years in the Swiss inflammatory bowel disease cohort study (SIBDCS) with prospective data collection. We compared Ulcerative colitis and Crohn's disease patients with and without ostomy as well as permanent and closed stoma formation before and after surgery, investigating disease activity, psychological wellbeing and working capacity in a case-control design. RESULTS Of 3825 SIBDCS patients, 176 with ostomy were included in the study and matched with 176 patients without ostomy using propensity score, equaling 352 patients for the analysis. As expected, we observed a lower mean and maximal disease activity in patients after stoma surgery compared with control patients without stoma. Overall, psychological wellbeing in patients with stomas vs. controls as well as patients with permanent vs. closed stoma was similar in terms of disease-specific quality of life (total score of the Inflammatory Bowel Disease Quality of Life questionnaire), psychological distress (total score of the Hospital Anxiety and Depression Scale), and stress at work (effort-reward-imbalance ratio), with the exception of a higher Posttraumatic Diagnostic Scale total score in patient with vs. without stoma. Compared to IBD patients without stoma, the adverse impact on working capacity in overall stoma IBD patients appeared to be modest. However we observe a significantly higher reduction in working capacity in permanent vs. closed stoma in CD but not UC patients. CONCLUSION As to be expected, IBD patients may benefit from closed and permanent stoma application. Stoma surgery appears to only modestly impact working capacity. Importantly, stoma surgery was not associated with adverse psychological outcomes, with comparable psychological well-being regardless of presence and type of stoma

Protein tyrosine phosphatase non-receptor type 2 controls colorectal cancer development

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC) as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. Particularly, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T-cells and increased PTPN2 levels negatively correlated with PD1, CTLA4, STAT1 and granzyme A. In vivo, T-cell and dendritic cell-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T-cells, as well as CD8+ T-cell infiltration and cytotoxicity into the tumor. In direct relevance to CRC treatment, T-cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced anti-tumor memory formation upon tumor re-challenge in vivo. Our data suggest a role for PTPN2 in suppressing anti-tumor immunity and promoting tumor development in CRC patients. Our in vivo results uncover PTPN2 as a key player in controlling immunogenicity of CRC, with the strong potential to be exploited to promote cancer immunotherapy

Das kolorektale Karzinom

Kolorektale Karzinome sind zu Beginn meist asymptomatisch und werden in 20% der Fälle erst im metastasierten Stadium entdeckt. Durch frühzeitige Erkennung und Therapie kann das Mortalitätsrisiko deutlich gesenkt werden, weshalb der Vorsorgeberatung durch den Hausarzt und dem Einsatz von Screening-Untersuchungen entscheidende Bedeutung zukommt