Pub Date : 2022-01-01Epub Date: 2021-10-22DOI: 10.1159/000519666
Tamás Szabó, Viktória Kormos, Zoltán Rékási, Balázs Gaszner
Background: In Dupuytren's surgery, limited fasciectomy is still the gold-standard treatment. A relatively high risk of iatrogenic nerve injury has been observed especially when the spiral cords of the Dupuytren's tissue pull digital nerves away from their normal anatomical location. Intraoperative neural marking could facilitate locating the potentially displaced nerves. Hence, surgery could be undertaken more quickly with a lower risk of iatrogenic nerve injury.
Objectives: We hypothesize that digital nerves may be stained with methylene blue (MB) in vivo providing a visual aid to distinguish them from Dupuytren's tissue. We aim to (a) test an in vivo nerve staining technique using MB in a rat sciatic nerve model and to (b) assess the safety of epineural MB injection.
Methods: Three experiments were performed: first, the effects of (a) sham surgery, (b) epineural needle insertion, and (c) 40 μL epineural saline injection were tested in the rat sciatic nerve. Second, we determined the (a) histoanatomical localization of the epineurally injected 40 µL 1 m/m% MB stock solution and (b) we tested which saline dilution (i.e., 1:40, 1:80, and 1:160) of the stock solution does provide optimal blue color upon 40 µL epineural injection. Third, the functional and morphological effect of 40 µL 1:80 diluted MB injection was compared with that of saline, injected into the contralateral sciatic nerve. The functional effects were tested by assessing the pain threshold by using a dynamic plantar esthesiometer (DPA) and by examination of the animal's gate and paw posture. Sciatic nerves were subjected to histological examination and morphometry to test structural damage.
Results: Neither epineural needle insertion nor saline injection caused any functional or morphological changes. Histological examination revealed that the MB stained the epineural compartment. Epineural injection of 40 μL 1:80 diluted MB into the sciatic nerve stained an 18.18-mm segment of the nerve distal to the puncture point. DPA revealed unchanged pain threshold values on the plantar surface of the limbs. Normal gait and foot posture suggested normal motor functions in all groups. No histological changes were seen in the stained nerves, and the nerve fiber density remained unchanged.
Conclusion: We demonstrated that in vivo nerve staining with MB is a suitable method to mark nerves without causing detectable negative effect to the stained nerve. Human trials are required to prove the efficacy of the technique in Dupuytren's disease.
{"title":"Epineural Methylene Blue Injection May Aid Localization of Digital Nerves in Dupuytren's Surgery.","authors":"Tamás Szabó, Viktória Kormos, Zoltán Rékási, Balázs Gaszner","doi":"10.1159/000519666","DOIUrl":"https://doi.org/10.1159/000519666","url":null,"abstract":"<p><strong>Background: </strong>In Dupuytren's surgery, limited fasciectomy is still the gold-standard treatment. A relatively high risk of iatrogenic nerve injury has been observed especially when the spiral cords of the Dupuytren's tissue pull digital nerves away from their normal anatomical location. Intraoperative neural marking could facilitate locating the potentially displaced nerves. Hence, surgery could be undertaken more quickly with a lower risk of iatrogenic nerve injury.</p><p><strong>Objectives: </strong>We hypothesize that digital nerves may be stained with methylene blue (MB) in vivo providing a visual aid to distinguish them from Dupuytren's tissue. We aim to (a) test an in vivo nerve staining technique using MB in a rat sciatic nerve model and to (b) assess the safety of epineural MB injection.</p><p><strong>Methods: </strong>Three experiments were performed: first, the effects of (a) sham surgery, (b) epineural needle insertion, and (c) 40 μL epineural saline injection were tested in the rat sciatic nerve. Second, we determined the (a) histoanatomical localization of the epineurally injected 40 µL 1 m/m% MB stock solution and (b) we tested which saline dilution (i.e., 1:40, 1:80, and 1:160) of the stock solution does provide optimal blue color upon 40 µL epineural injection. Third, the functional and morphological effect of 40 µL 1:80 diluted MB injection was compared with that of saline, injected into the contralateral sciatic nerve. The functional effects were tested by assessing the pain threshold by using a dynamic plantar esthesiometer (DPA) and by examination of the animal's gate and paw posture. Sciatic nerves were subjected to histological examination and morphometry to test structural damage.</p><p><strong>Results: </strong>Neither epineural needle insertion nor saline injection caused any functional or morphological changes. Histological examination revealed that the MB stained the epineural compartment. Epineural injection of 40 μL 1:80 diluted MB into the sciatic nerve stained an 18.18-mm segment of the nerve distal to the puncture point. DPA revealed unchanged pain threshold values on the plantar surface of the limbs. Normal gait and foot posture suggested normal motor functions in all groups. No histological changes were seen in the stained nerves, and the nerve fiber density remained unchanged.</p><p><strong>Conclusion: </strong>We demonstrated that in vivo nerve staining with MB is a suitable method to mark nerves without causing detectable negative effect to the stained nerve. Human trials are required to prove the efficacy of the technique in Dupuytren's disease.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39550736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-01Epub Date: 2021-11-24DOI: 10.1159/000521036
Clotilde Fuentes-Orozco, Ruben Agredano-Jiménez, Andrea Socorro Alvarez-Villaseñor, Roberto Mares-País, Francisco José Barbosa-Camacho, Ana Olivia Cortés-Flores, Emilio Alberto Reyes-Elizalde, Bertha Georgina Guzmán-Ramírez, Paola Flores-Becerril, José Aldo Guzmán-Barba, Jonathan Matías Chejfec-Ciociano, Juan Carlos Ibarrola-Peña, Irma Valeria Brancaccio-Pérez, Alejandro González-Ojeda
Introduction: Intra-abdominal adhesions' main etiology is surgical procedures that commonly require reintervention. Oral treatments with sildenafil, zafirlukast, and pirfenidone have yielded decreased severity of fibrotic phenomena secondary to the introduction of foreign material. This study aimed to evaluate the efficacy of oral zafirlukast, sildenafil, or pirfenidone treatment on reducing or preventing intra-abdominal adhesions in an experimental rat model.
Methods: Four groups, each of 10 male Wistar rats weighing 250-300 g, were used. A midline laparotomy was used to excise an area of 1.5 × 1.5 cm and reconstructed with polypropylene mesh fixed to the abdominal wall. After 12 h, oral doses of zafirlukast (1.25 mg/kg, group B), sildenafil (15 mg/kg, group C), or pirfenidone (500 mg/kg, group D) were given every day for 8 days. The control group, A, received no treatment. At day 9, animals were reoperated. The implant was resected after ethically approved euthanasia, and specimens were fixed in 10% formaldehyde for histopathology.
Results: Control group A yielded adhesions with greater fibrovascular density and neighboring organ involvement than the other groups (p = 0.001), as well as intense inflammatory infiltrates and numerous granulomas (p = 0.04). Adhesions in group C had less fibrovascular density (p = 0.03) with decreased serosal injuries (p = 0.001) and less organ involvement. Group D had reduced adhesions without organ involvement (p < 0.01) and less inflammatory infiltrates, collagen fibers, and foreign body granulomas than group B or C (p < 0.01).
Conclusions: Oral administration of these agents did not prevent adhesions but ameliorated them. Oral pirfenidone offered the best performance and could be recommended for human use.
{"title":"Effects of Oral Zafirlukast, Sildenafil, or Pirfenidone on the Formation of Postsurgical Intra-Abdominal Adhesions in an Experimental Rat Model.","authors":"Clotilde Fuentes-Orozco, Ruben Agredano-Jiménez, Andrea Socorro Alvarez-Villaseñor, Roberto Mares-País, Francisco José Barbosa-Camacho, Ana Olivia Cortés-Flores, Emilio Alberto Reyes-Elizalde, Bertha Georgina Guzmán-Ramírez, Paola Flores-Becerril, José Aldo Guzmán-Barba, Jonathan Matías Chejfec-Ciociano, Juan Carlos Ibarrola-Peña, Irma Valeria Brancaccio-Pérez, Alejandro González-Ojeda","doi":"10.1159/000521036","DOIUrl":"https://doi.org/10.1159/000521036","url":null,"abstract":"<p><strong>Introduction: </strong>Intra-abdominal adhesions' main etiology is surgical procedures that commonly require reintervention. Oral treatments with sildenafil, zafirlukast, and pirfenidone have yielded decreased severity of fibrotic phenomena secondary to the introduction of foreign material. This study aimed to evaluate the efficacy of oral zafirlukast, sildenafil, or pirfenidone treatment on reducing or preventing intra-abdominal adhesions in an experimental rat model.</p><p><strong>Methods: </strong>Four groups, each of 10 male Wistar rats weighing 250-300 g, were used. A midline laparotomy was used to excise an area of 1.5 × 1.5 cm and reconstructed with polypropylene mesh fixed to the abdominal wall. After 12 h, oral doses of zafirlukast (1.25 mg/kg, group B), sildenafil (15 mg/kg, group C), or pirfenidone (500 mg/kg, group D) were given every day for 8 days. The control group, A, received no treatment. At day 9, animals were reoperated. The implant was resected after ethically approved euthanasia, and specimens were fixed in 10% formaldehyde for histopathology.</p><p><strong>Results: </strong>Control group A yielded adhesions with greater fibrovascular density and neighboring organ involvement than the other groups (p = 0.001), as well as intense inflammatory infiltrates and numerous granulomas (p = 0.04). Adhesions in group C had less fibrovascular density (p = 0.03) with decreased serosal injuries (p = 0.001) and less organ involvement. Group D had reduced adhesions without organ involvement (p < 0.01) and less inflammatory infiltrates, collagen fibers, and foreign body granulomas than group B or C (p < 0.01).</p><p><strong>Conclusions: </strong>Oral administration of these agents did not prevent adhesions but ameliorated them. Oral pirfenidone offered the best performance and could be recommended for human use.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39655742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: This study investigated the antiadhesive effects of Mediclore®, rosuvastatin, and a combination of Mediclore and rosuvastatin in a rat adhesion model.
Methods: The adhesion models (a total of 58 adult male rats) were divided into 4 groups. The control group (group C) received no special materials except for a saline. The experimental groups were treated with 5 mL of Mediclore (group M), rosuvastatin (group R), or rosuvastatin and Mediclore (group RM), and these materials were intraperitoneally placed under the incision. At postoperative day 14, the rats underwent re-laparotomy and adhesiolysis. Three investigators blinded to group assignment scored the extent of adhesion formation, the numbers of remote adhesions, and the extent of acute/chronic inflammation, fibrosis, edema, and congestion on resected specimens via histologic examination.
Results: The macroscopic adhesion score in group RM (7.27 ± 3.51) was significantly lower than those in groups C (13.36 ± 2.24) and R (11.71 ± 1.98); group M (9.13 ± 4.09) had a significantly lower adhesion score than group C. The number of remote adhesions was significantly lower in groups R and RM than in group C. The acute inflammation score, chronic inflammation score, and fibrosis score in group RM; the acute inflammation score in group R; and the fibrosis score in group M were significantly lower than those in group C.
Conclusion: The intraperitoneal application of Mediclore and a combination of Mediclore and rosuvastatin effectively reduced postoperative adhesions.
目的:研究Mediclore®、瑞舒伐他汀及Mediclore与瑞舒伐他汀联用对大鼠黏附模型的抗黏附作用。方法:将粘连模型(58只成年雄性大鼠)分为4组。对照组(C组)除生理盐水外,不给予特殊材料。实验组分别给予5 mL Mediclore (M组)、瑞舒伐他汀(R组)或瑞舒伐他汀+ Mediclore (RM组),并在切口下腹腔放置。术后第14天,大鼠再次开腹并进行粘连松解。三名不接受分组分配的研究人员通过组织学检查对切除标本的粘连形成程度、远处粘连数量以及急性/慢性炎症、纤维化、水肿和充血程度进行评分。结果:RM组宏观粘连评分(7.27±3.51)明显低于C组(13.36±2.24)和R组(11.71±1.98);M组(9.13±4.09)的粘连评分明显低于c组,R组和RM组的远端粘连数明显低于c组。RM组的急性炎症评分、慢性炎症评分、纤维化评分;R组急性炎症评分;M组纤维化评分明显低于c组。结论:腹腔内应用Mediclore及Mediclore联合瑞舒伐他汀可有效减少术后粘连。
{"title":"Prevention of Intra-Abdominal Adhesions Using the Combination of Mediclore® and a Statin.","authors":"Jesung Park, Hyun Kang, Yoo Shin Choi, Suk-Won Suh, Soon Auck Hong, Geun Joo Choi, Woo Jung Sim","doi":"10.1159/000519708","DOIUrl":"https://doi.org/10.1159/000519708","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigated the antiadhesive effects of Mediclore®, rosuvastatin, and a combination of Mediclore and rosuvastatin in a rat adhesion model.</p><p><strong>Methods: </strong>The adhesion models (a total of 58 adult male rats) were divided into 4 groups. The control group (group C) received no special materials except for a saline. The experimental groups were treated with 5 mL of Mediclore (group M), rosuvastatin (group R), or rosuvastatin and Mediclore (group RM), and these materials were intraperitoneally placed under the incision. At postoperative day 14, the rats underwent re-laparotomy and adhesiolysis. Three investigators blinded to group assignment scored the extent of adhesion formation, the numbers of remote adhesions, and the extent of acute/chronic inflammation, fibrosis, edema, and congestion on resected specimens via histologic examination.</p><p><strong>Results: </strong>The macroscopic adhesion score in group RM (7.27 ± 3.51) was significantly lower than those in groups C (13.36 ± 2.24) and R (11.71 ± 1.98); group M (9.13 ± 4.09) had a significantly lower adhesion score than group C. The number of remote adhesions was significantly lower in groups R and RM than in group C. The acute inflammation score, chronic inflammation score, and fibrosis score in group RM; the acute inflammation score in group R; and the fibrosis score in group M were significantly lower than those in group C.</p><p><strong>Conclusion: </strong>The intraperitoneal application of Mediclore and a combination of Mediclore and rosuvastatin effectively reduced postoperative adhesions.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39960031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis.
Methods: First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients.
Results: After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine.
Conclusion: Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.
{"title":"Role of Different Doses of Ketamine in Postoperative Neurocognitive Function in Aged Mice Undergoing Partial Hepatectomy by Regulating the Bmal1/NMDA/NF-Κb Axis.","authors":"Xiaoli Niu, Simin Zheng, Siyuan Li, Hongtao Liu","doi":"10.1159/000520210","DOIUrl":"https://doi.org/10.1159/000520210","url":null,"abstract":"<p><strong>Background: </strong>The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis.</p><p><strong>Methods: </strong>First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients.</p><p><strong>Results: </strong>After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine.</p><p><strong>Conclusion: </strong>Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10622587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the mucosa of colon and rectum. Interferon regulatory factor 4 (IRF4) mediates macrophage anti-inflammatory phenotype (alternatively activated macrophages [M2]). This study aimed to investigate the mechanism of IRF4 in lipopolysaccharide (LPS)-induced colonic mucosal epithelial cell proliferation via the regulation of macrophage polarization.
Methods: Human bone marrow-derived macrophages were subjected to interleukin 4 (IL-4) induction. M2 macrophages were identified using flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). IRF4 expression in M2 macrophages was detected using Western blot and qRT-PCR. IRF4 expression was silenced in M2 macrophages. IL-10 mRNA expression and protein level were detected using qRT-PCR and Western blot. The binding relation between IRF4 and IL-10 was verified using dual-luciferase and chromatin immunoprecipitation assays. Macrophages under different treatments were cocultured with LPS-induced human colonic mucosal epithelial cells. The levels of inflammatory factors (TNF-α, IL-6, and IL-1β) were detected using enzyme-linked immunosorbent assay. The proliferation of inflammatory cells was measured using Cell Counting Kit-8 assay, and the healing of inflammatory cells was detected using wound healing assay.
Results: M2 macrophages alleviated LPS-induced inflammatory responses. IRF4 bound to IL-10 and promoted IL-10 expression. Inhibition of IRF4 reduced IL-10 expression and attenuated the alleviating effect of M2 macrophages on inflammatory responses. Inhibition of IRF4 combined with IL-10 overexpression enhanced the promoting effect of M2 macrophages on inflammatory healing.
Conclusion: IRF4 promoted colonic mucosal epithelial cell proliferation by increasing IL-10 expression and regulating macrophage polarization to M2 phenotype, which might be related to UC mucosal healing.
{"title":"Interferon Regulatory Factor 4 (IRF4) Promotes Lipopolysaccharide-Induced Colonic Mucosal Epithelial Cell Proliferation by Regulating Macrophage Polarization.","authors":"Lin Hu, Song Li, Honglang Li, Bin Lai, Huabin Wen","doi":"10.1159/000525753","DOIUrl":"https://doi.org/10.1159/000525753","url":null,"abstract":"<p><strong>Introduction: </strong>Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the mucosa of colon and rectum. Interferon regulatory factor 4 (IRF4) mediates macrophage anti-inflammatory phenotype (alternatively activated macrophages [M2]). This study aimed to investigate the mechanism of IRF4 in lipopolysaccharide (LPS)-induced colonic mucosal epithelial cell proliferation via the regulation of macrophage polarization.</p><p><strong>Methods: </strong>Human bone marrow-derived macrophages were subjected to interleukin 4 (IL-4) induction. M2 macrophages were identified using flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). IRF4 expression in M2 macrophages was detected using Western blot and qRT-PCR. IRF4 expression was silenced in M2 macrophages. IL-10 mRNA expression and protein level were detected using qRT-PCR and Western blot. The binding relation between IRF4 and IL-10 was verified using dual-luciferase and chromatin immunoprecipitation assays. Macrophages under different treatments were cocultured with LPS-induced human colonic mucosal epithelial cells. The levels of inflammatory factors (TNF-α, IL-6, and IL-1β) were detected using enzyme-linked immunosorbent assay. The proliferation of inflammatory cells was measured using Cell Counting Kit-8 assay, and the healing of inflammatory cells was detected using wound healing assay.</p><p><strong>Results: </strong>M2 macrophages alleviated LPS-induced inflammatory responses. IRF4 bound to IL-10 and promoted IL-10 expression. Inhibition of IRF4 reduced IL-10 expression and attenuated the alleviating effect of M2 macrophages on inflammatory responses. Inhibition of IRF4 combined with IL-10 overexpression enhanced the promoting effect of M2 macrophages on inflammatory healing.</p><p><strong>Conclusion: </strong>IRF4 promoted colonic mucosal epithelial cell proliferation by increasing IL-10 expression and regulating macrophage polarization to M2 phenotype, which might be related to UC mucosal healing.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: High-fidelity repair of DNA damage repair (DDR) (either single-strand- [SSBs] or double-strand breaks [DSBs]) is necessary for maintaining genomic integrity and cell survival. DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway. PARP inhibitors (PARPi) exploit defects in the DNA repair pathway through synthetic lethality, DSBs being repaired only in HR-proficient cells but not in HR-deficient (HRD) cells.
Summary: A growing body of evidence supports the need for identification of germinal and somatic DDR alterations in patients with genitourinary malignancies. PARPi have already shown significant survival benefits in patients harboring HRR mutations in advanced settings, paving the way for precision medicine.
Key messages: In advanced prostate cancer (PCa), somatic mutations in HRR pathway are observed in up to 27% of metastatic resistant-to-castration PCa (mCRPC), although occurring early in PCa development, and mainly involving BRCA2, ATM, CHEK2, and BRCA1. Overall, germinal alterations are present in roughly 30-50% of cases of HRR alterations, and relative risk of PCa in germinal BRCA2 alteration carriers is 4.65-fold higher compared to noncarriers. Determination of DDR gene status is recommended in metastatic patients, a fortiori in mCRPC setting, since it could be a putative biomarker of response to first line of treatment (androgen-receptor signaling inhibitors [ARSI] vs. taxane-based chemotherapy) and allows to assess eligibility for PARPi use. Thus, olaparib (combined with androgen deprivation therapy) recently improved overall survival in mCRPC HRD patients, after new hormonal therapy (NHT) and led to its approvement for patients with an alteration in 14 of 15 prespecified HRR genes. Moreover, since preclinical data suggested synergic action between PARPi and ARSI, the use of either olaparib or niraparib has also been proposed in combination with NHT, with a radiological progression-free survival improvement when used with abiraterone. In urothelial carcinoma, a DDR gene alteration is identified in 23-54% of patients mostly in muscle-invasive bladder cancer, with a strong association between DDR gene mutation and a higher tumor mutation burden and sensitivity to cisplatin-based chemotherapy and immunotherapy. Recent phase 2 trials supported the use of HRR status to select patients for PARPi treatment in advanced urothelial carcinoma. Finally, in renal cell carcinomas (RCCs), pathogenic germline variants in DDR genes were identified in 7.3% of the cases, and deleterious somatic alterations have also been described as recurrent genomic events in patients with advanced RCC.
{"title":"DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies.","authors":"Charles Dariane, Marc-Olivier Timsit","doi":"10.1159/000526415","DOIUrl":"https://doi.org/10.1159/000526415","url":null,"abstract":"<p><strong>Background: </strong>High-fidelity repair of DNA damage repair (DDR) (either single-strand- [SSBs] or double-strand breaks [DSBs]) is necessary for maintaining genomic integrity and cell survival. DDR alterations are commonly found in genitourinary malignancies involving either DSB repair by the homologous recombination (HR) repair (HRR) system (BRCA1/2 pathway) or the SSB repair through the poly (ADP-ribose) polymerase (PARP) pathway. PARP inhibitors (PARPi) exploit defects in the DNA repair pathway through synthetic lethality, DSBs being repaired only in HR-proficient cells but not in HR-deficient (HRD) cells.</p><p><strong>Summary: </strong>A growing body of evidence supports the need for identification of germinal and somatic DDR alterations in patients with genitourinary malignancies. PARPi have already shown significant survival benefits in patients harboring HRR mutations in advanced settings, paving the way for precision medicine.</p><p><strong>Key messages: </strong>In advanced prostate cancer (PCa), somatic mutations in HRR pathway are observed in up to 27% of metastatic resistant-to-castration PCa (mCRPC), although occurring early in PCa development, and mainly involving BRCA2, ATM, CHEK2, and BRCA1. Overall, germinal alterations are present in roughly 30-50% of cases of HRR alterations, and relative risk of PCa in germinal BRCA2 alteration carriers is 4.65-fold higher compared to noncarriers. Determination of DDR gene status is recommended in metastatic patients, a fortiori in mCRPC setting, since it could be a putative biomarker of response to first line of treatment (androgen-receptor signaling inhibitors [ARSI] vs. taxane-based chemotherapy) and allows to assess eligibility for PARPi use. Thus, olaparib (combined with androgen deprivation therapy) recently improved overall survival in mCRPC HRD patients, after new hormonal therapy (NHT) and led to its approvement for patients with an alteration in 14 of 15 prespecified HRR genes. Moreover, since preclinical data suggested synergic action between PARPi and ARSI, the use of either olaparib or niraparib has also been proposed in combination with NHT, with a radiological progression-free survival improvement when used with abiraterone. In urothelial carcinoma, a DDR gene alteration is identified in 23-54% of patients mostly in muscle-invasive bladder cancer, with a strong association between DDR gene mutation and a higher tumor mutation burden and sensitivity to cisplatin-based chemotherapy and immunotherapy. Recent phase 2 trials supported the use of HRR status to select patients for PARPi treatment in advanced urothelial carcinoma. Finally, in renal cell carcinomas (RCCs), pathogenic germline variants in DDR genes were identified in 7.3% of the cases, and deleterious somatic alterations have also been described as recurrent genomic events in patients with advanced RCC.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker of the level of chronic systemic inflammation and the general condition of the patient. We aimed to investigate the impact of general anesthesia and major surgery on perioperative suPAR and C-reactive protein (CRP) levels.
Methods: This study included patients undergoing elective major noncardiac surgery with an expected duration of ≥2 h under general anesthesia. Inclusion criteria were age ≥18 years and American Society of Anesthesiologists' physical status I-IV. Blood was drawn 30 min prior to induction of anesthesia (preoperatively), as well as 30 min after emergence from anesthesia (postoperatively). Plasma suPAR levels were determined using the suPARnostic® Quick Triage lateral flow assay. CRP measurements were performed by particle-enhanced immunoturbidimetric assay.
Results: The difference in preoperative and postoperative suPAR levels was not statistically significant (7.7 [5.28-10.4] ng/mL vs. 7.15 [5.68-9.8] ng/mL, p = 0.462). CRP levels increased significantly during surgery (0.81 [0.24-2.1] mg/dL vs. 5.76 [2.2-8.75] mg/dL, p < 0.001). No correlation was observed between CRP and suPAR levels, both preoperatively (rho = 0.127; p = 0.208) and postoperatively (rho = 0.017; p = 0.87). A statistically significant increase was also observed in postoperative white blood cell count (7.576 vs. 10.711, p < 0.001).
Conclusion: General anesthesia and operative trauma did not affect perioperative suPAR levels despite the activation of systemic inflammatory response.
简介:可溶性尿激酶纤溶酶原激活物受体(suPAR)是慢性全身性炎症水平和患者一般状况的新兴生物标志物。我们的目的是研究全麻和大手术对围手术期suPAR和c反应蛋白(CRP)水平的影响。方法:本研究纳入全麻下接受择期非心脏大手术且预期持续时间≥2小时的患者。纳入标准为年龄≥18岁,美国麻醉医师协会身体状况I-IV级。在麻醉诱导前30分钟(术前)和麻醉苏醒后30分钟(术后)抽血。血浆suPAR水平采用suPARnostic®快速分流横向流动试验测定。采用颗粒增强免疫比浊法测定CRP。结果:术前、术后suPAR水平差异无统计学意义(7.7 [5.28-10.4]ng/mL vs. 7.15 [5.68-9.8] ng/mL, p = 0.462)。手术期间CRP水平显著升高(0.81 [0.24-2.1]mg/dL vs. 5.76 [2.2-8.75] mg/dL, p < 0.001)。术前CRP与suPAR水平无相关性(rho = 0.127;P = 0.208)和术后(rho = 0.017;P = 0.87)。术后白细胞计数也有统计学意义的增加(7.576比10.711,p < 0.001)。结论:尽管全身炎症反应被激活,但全身麻醉和手术创伤对围术期suPAR水平没有影响。
{"title":"Soluble Urokinase Receptor Levels Are Not Affected by the Systemic Inflammatory Response to Anesthesia and Operative Trauma.","authors":"Eleni Laou, Nikolaos Papagiannakis, Aikaterini Tsiaka, Stamatina Tsapournioti, Konstantinos Chatzikallinikidis, Georgios Mantzaflaras, Ioannis Karadontas, Jesper Eugen-Olsen, Athanasios Chalkias","doi":"10.1159/000524433","DOIUrl":"https://doi.org/10.1159/000524433","url":null,"abstract":"<p><strong>Introduction: </strong>Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker of the level of chronic systemic inflammation and the general condition of the patient. We aimed to investigate the impact of general anesthesia and major surgery on perioperative suPAR and C-reactive protein (CRP) levels.</p><p><strong>Methods: </strong>This study included patients undergoing elective major noncardiac surgery with an expected duration of ≥2 h under general anesthesia. Inclusion criteria were age ≥18 years and American Society of Anesthesiologists' physical status I-IV. Blood was drawn 30 min prior to induction of anesthesia (preoperatively), as well as 30 min after emergence from anesthesia (postoperatively). Plasma suPAR levels were determined using the suPARnostic® Quick Triage lateral flow assay. CRP measurements were performed by particle-enhanced immunoturbidimetric assay.</p><p><strong>Results: </strong>The difference in preoperative and postoperative suPAR levels was not statistically significant (7.7 [5.28-10.4] ng/mL vs. 7.15 [5.68-9.8] ng/mL, p = 0.462). CRP levels increased significantly during surgery (0.81 [0.24-2.1] mg/dL vs. 5.76 [2.2-8.75] mg/dL, p < 0.001). No correlation was observed between CRP and suPAR levels, both preoperatively (rho = 0.127; p = 0.208) and postoperatively (rho = 0.017; p = 0.87). A statistically significant increase was also observed in postoperative white blood cell count (7.576 vs. 10.711, p < 0.001).</p><p><strong>Conclusion: </strong>General anesthesia and operative trauma did not affect perioperative suPAR levels despite the activation of systemic inflammatory response.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10623026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jana Enderes, Shilpashree Mallesh, Kathy Stein, Melissa Wagner, Mariola Lysson, Bianca Schneiker, Joerg C Kalff, Sven Wehner
Introduction: Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model.
Methods: POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX-/-, and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry.
Results: 5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type but not in 5-LOX-/- after IM. POI was ameliorated in 5-LOX-/- as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME.
Discussion/conclusion: Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.
{"title":"Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus.","authors":"Jana Enderes, Shilpashree Mallesh, Kathy Stein, Melissa Wagner, Mariola Lysson, Bianca Schneiker, Joerg C Kalff, Sven Wehner","doi":"10.1159/000522157","DOIUrl":"https://doi.org/10.1159/000522157","url":null,"abstract":"<p><strong>Introduction: </strong>Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model.</p><p><strong>Methods: </strong>POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX-/-, and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry.</p><p><strong>Results: </strong>5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type but not in 5-LOX-/- after IM. POI was ameliorated in 5-LOX-/- as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME.</p><p><strong>Discussion/conclusion: </strong>Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9185969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-01Epub Date: 2021-09-30DOI: 10.1159/000519208
Elsaline Rijkse, Hendrikus J A N Kimenai, Frank J M F Dor, Jan N M IJzermans, Robert C Minnee
Introduction: Aorto-iliac vascular disease (AVD) is frequently found during the workup for kidney transplantation. However, recommendations on screening and management are lacking. We aimed to assess differences in screening, management, and acceptance of these patients for transplantation by performing a survey among transplant surgeons. Second, we aimed to identify center- and surgeon-related factors associated with decline or acceptance of kidney transplant candidates with AVD.
Methods: A survey was sent to transplant surgeons and urologists. The survey contained general questions (part I) and 2 patient-based cases (part II) with Trans-Atlantic Inter-Society Consensus (TASC) D and B AVD supported with videos of their CT scans.
Results: One hundred ninety-one (20.3%) participants responded; 171 were currently involved in kidney transplantation: 161 (94.2%) completed part I and 145 (84.8%) part II. Screening for AVD was often (38.5%) restricted to high-risk patients. The majority of respondents (67.7%) rated "technical problems" as the most important concern in case of AVD, followed by "increased mortality risk because of cardiovascular comorbidity" (29.8%). Pretransplant vascular interventions to facilitate transplantation were infrequently performed (71.4% mentioned <10 per year). Ninety (64.3%) respondents answered that an open vascular procedure should preferably be performed prior to kidney transplantation while 42 (30.0%) respondents preferred a simultaneous open vascular procedure. The decline rate was higher in the TASC D case compared to the TASC B case (26.9% and 9.7%, respectively). Respondents from centers with expertise in pretransplant vascular interventions were more likely to accept both patients with TASC D and B for transplantation.
Conclusion: There is no uniformity in the screening, management, and acceptance of patients with AVD for transplantation. If a center declines a patient with AVD because of technical concerns, the patient should be referred for a second opinion to a tertiary center with expertise in pretransplant vascular interventions. Multidisciplinary meetings including a vascular surgeon and a cardiologist could help optimize these patients for transplantation.
{"title":"Screening, Management, and Acceptance of Patients with Aorto-Iliac Vascular Disease for Kidney Transplantation: A Survey among 161 Transplant Surgeons.","authors":"Elsaline Rijkse, Hendrikus J A N Kimenai, Frank J M F Dor, Jan N M IJzermans, Robert C Minnee","doi":"10.1159/000519208","DOIUrl":"https://doi.org/10.1159/000519208","url":null,"abstract":"<p><strong>Introduction: </strong>Aorto-iliac vascular disease (AVD) is frequently found during the workup for kidney transplantation. However, recommendations on screening and management are lacking. We aimed to assess differences in screening, management, and acceptance of these patients for transplantation by performing a survey among transplant surgeons. Second, we aimed to identify center- and surgeon-related factors associated with decline or acceptance of kidney transplant candidates with AVD.</p><p><strong>Methods: </strong>A survey was sent to transplant surgeons and urologists. The survey contained general questions (part I) and 2 patient-based cases (part II) with Trans-Atlantic Inter-Society Consensus (TASC) D and B AVD supported with videos of their CT scans.</p><p><strong>Results: </strong>One hundred ninety-one (20.3%) participants responded; 171 were currently involved in kidney transplantation: 161 (94.2%) completed part I and 145 (84.8%) part II. Screening for AVD was often (38.5%) restricted to high-risk patients. The majority of respondents (67.7%) rated \"technical problems\" as the most important concern in case of AVD, followed by \"increased mortality risk because of cardiovascular comorbidity\" (29.8%). Pretransplant vascular interventions to facilitate transplantation were infrequently performed (71.4% mentioned <10 per year). Ninety (64.3%) respondents answered that an open vascular procedure should preferably be performed prior to kidney transplantation while 42 (30.0%) respondents preferred a simultaneous open vascular procedure. The decline rate was higher in the TASC D case compared to the TASC B case (26.9% and 9.7%, respectively). Respondents from centers with expertise in pretransplant vascular interventions were more likely to accept both patients with TASC D and B for transplantation.</p><p><strong>Conclusion: </strong>There is no uniformity in the screening, management, and acceptance of patients with AVD for transplantation. If a center declines a patient with AVD because of technical concerns, the patient should be referred for a second opinion to a tertiary center with expertise in pretransplant vascular interventions. Multidisciplinary meetings including a vascular surgeon and a cardiologist could help optimize these patients for transplantation.</p>","PeriodicalId":12222,"journal":{"name":"European Surgical Research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39474147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}