NFAT regulates the expression of AIF-1 and IRT-1: Yin and yang splice variants of neointima formation and atherosclerosis.

Aims Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1). Here we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype.Methods and results Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity. Pharmacological inhibition of NFAT or targeting of NFATc3 with siRNA lowers the AIF-1/IRT-1 ratio and favors an anti-proliferative outcome. NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque.Conclusions Inhibition of NFAT signaling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis

O2 consumption, aerobic glycolysis and tissue phosphagen content during activation of the Na+/K+ pump in rat portal vein

Oxygen consumption, lactate production and tissue contents of ATP, phosphocreatine (PCr) and lactate were measured following readdition of K+ to K+-depleted rat portal veins, in order to study the energy turnover associated with Na+/K+ pumping. During incubation in K+-free medium at 37 degrees C spontaneous contractions disappeared in 10-20 min. Readdition of K+ (5.9 mM) after 40 min K+-free incubation caused hyperpolarization of the cell membrane for the first 5-10 min and then gradual depolarization with return of spontaneous action potentials and contractions by 10-20 min. During the first 4-6 min after K+ readdition aerobic lactate production was about doubled and then gradually returned to the original level (0.17 mumol/min g) at about 20 min. The increase in glycolytic rate was prevented by 1 mM ouabain. In contrast, O2 consumption (in K+-free medium, 0.38 mumol/min g) rose by about 10% when K+ was added and this increase lasted about 5 min. By 8 min after K+ addition the increased glycolysis and oxidative phosphorylation had accounted for each about the same amount of extra ATP generation over that extrapolated from the steady rate before K+ addition. The average total increase in ATP turnover in the first 8 min was 15%. During this period there was no change in the cellular content of ATP, PCr, or extractable ADP. The results indicate that Na+/K+ pumping utilizes a relatively small share of the total energy turnover in the vascular smooth muscle but is to a large extent dependent on aerobic glycolysis and therefore a major site of carbohydrate usage

Defunctioning stoma in anterior resection for rectal cancer does not impact anastomotic leakage: a national population-based cohort study

Abstract Background Anterior resection (AR) is considered the gold standard for curative cancer treatment in the middle and upper rectum. The goal of the sphincter-preserving procedure, such as AR, is vulnerable to anastomotic leak (AL) complications. Defunctioning stoma (DS) became the protective measure against AL. Often a defunctioning loop-ileostomy is used, which is associated with substantial morbidity. However, not much is known if the routine use of DS reduces the overall incidence of AL. Methods Elective patients subjected to AR in 2007–2009 and 2016-18 were recruited from the Swedish colorectal cancer registry (SCRCR). Patient characteristics, including DS status and occurrence of AL, were analyzed. In addition, independent risk factors for AL were investigated by multivariable regression. Results The statistical increase of DS from 71.6% in 2007–2009 to 76.7% in 2016–2018 did not impact the incidence of AL (9.2% and 8.2%), respectively. DLI was constructed in more than 35% of high-located tumors ≥ 11 cm from the anal verge. Multivariable analysis showed that male gender, ASA 3–4, BMI > 30 kg/m2, and neoadjuvant therapy were independent risk factors for AL. Conclusion Routine DS did not decrease overall AL after AR. A selective decision algorithm for DS construction is needed to protect from AL and mitigate DS morbidities

Outcomes Following Exenteration for Gynecological Neoplasms

The primary treatment of gynecological malignancies has considerably evolved over the last century, with a move to less aggressive procedures when appropriate. However, gynecological malignancies comprise a heterogeneous group, with varying treatment options. The choice of reconstructive method for urinary and fecal diversion is crucial, as most patients have been irradiated with high doses or had prior surgery for their primary neoplasm. Patient characteristics, such as age and comorbidity, also affect the choice of urinary diversion, especially when opting for a continent reconstruction in the setting of an anterior exenteration for a gynecological cancer. For patients with advanced gynecological tumors requiring both urinary and fecal diversion, that is, two stomas, a double-barreled colostomy has been popularized. The optimal localization of the urinary stoma is an integral part of the preoperative preparation and of critical importance to avoid postoperative difficulties with stoma accessories or emptying a continent cutaneous diversion

Perineal wound healing after abdominoperineal resection for rectal cancer : a retrospective cohort study

Purpose: Delayed perineal wound healing is a common complication after abdominoperineal resection (APR) in rectal cancer. The primary aim of this study was to evaluate the number of patients with delayed wound healing after APR. Secondary aims were to identify risk factors, and describe treatment. Methods: Prospectively collected data from the Swedish Colorectal Cancer Registry (SCRCR) was used for retrospective analysis of APR performed at Skåne University Hospital Malmö between 2013 and 2018. Medical charts were retrospectively reviewed. Delayed healing was defined as non-healed perineal wound 30 days postoperatively. Patients undergoing extralevator APR requiring reconstruction were excluded. Statistical analysis was made using SPSS. Risk factors for impaired wound healing were analyzed using a multivariable model. Results: A total of 162 patients were included, of which 114 underwent standard APR (sAPR) and 48 patients intersphincteric APR (isAPR). In the total population, 69% (111/162) were male, with median age 71 (26–87). The overall healing rate was 52% (85/162); 44% (50/114) in sAPR vs 73% (35/48) in isAPR (P 30 (OR 7.0; CI 95% 1.8–26.2, P = 0.004), reoperation (OR 7.9; CI 95% 1.6–39.8, P = 0.013), neoadjuvant radiotherapy (OR 5.2; CI 95% 1.02–25.1, P = 0.047) and sAPR (OR 2.598; CI 95% 1.05–6.41, P = 0.038). Eight percent (13/162) required an intervention (Clavien-Dindo ≥ 3). Conclusion: Delayed perineal wound healing is a frequent complication after APR but the majority could be treated conservatively. Several risk factors were identified. Further studies aiming at interventions reducing delayed perineal wound healing after APR are warranted

Circumferential resection margin and local recurrence after rectal cancer surgery: a population-based study cohort

Aim: Studies have suggested that there is a difference in risk of local recurrence(LR) with circumferential resection margins (CRM) less than 1.0 mm. We aimed toexamine how exact resection margins affect LR risk.Method: Data from the Swedish Colorectal Cancer Registry (SCRCR) were usedfor retrospective analysis of resected rectal cancers between 2005 and 2013. Primaryendpoint was LR.Results: 12146 cases were identified of which 8666 cases were analysed after exclusion. 388 cases had CRM < 1.0 mm and 8278 cases CRM ≥ 1.0 mm. There were 42LR (11.4%) when CRM < 1.0 mm and 280 LR (3.5%) when CRM ≥ 1.0 mm. LRrate was 17% (n = 27/159), 7.1% (n = 15/210), 5.5% (n = 26/473) and 3.4%(n = 254/7550) when CRM was 0.0 mm, 0.1–0.9 mm, 1.0–1.9 mm andCRM ≥ 2 mm respectively. LR risk at CRM 0.0 mm was significantly increased compared to all other groups. No significant difference in LR between CRM 1.0–1.9 mm and ≥ 2 mm was observed. LR was diagnosed earlier when CRM < 1.0 mm.Conclusion: LR risk is related with accuracy to the surgical circumferential resec-tion margin distance. There was no difference in LR risk above CRM 1.0 mm.Most LRs occurred within two years after surgery when CRM was below 1.0 m

Rektalcancer: : Risk för lokalt recidiv är beroende av RESEKTIONSMARGINAL

Rektalcancer är en sjukdom där behandlingsresultaten förbättrats kraftigt de senaste decennierna. Behandling för ändtarmscancer sker med antingen endast kirurgi eller kirurgi i kombination med onkologisk neoadjuvant behandling. Kirurgisk radikalitet, mikroskopisk marginal mellan tumörvävnad och frisk vävnad, är av stor betydelse för att minska risken för lokalrecidiv och öka överlevnade