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Techniques in Coloproctology Dec 2023The optimal treatment of colorectal cancer is surgical resection and primary anastomosis. Anastomotic leak can affect up to 20% of patients and creates significant...
BACKGROUND
The optimal treatment of colorectal cancer is surgical resection and primary anastomosis. Anastomotic leak can affect up to 20% of patients and creates significant morbidity and mortality. Current diagnosis of a leak is based on clinical suspicion and subsequent radiology. Peritoneal biomarkers have shown diagnostic utility in other conditions and could be useful in providing earlier diagnosis. This pilot study was designed to assess the practical utility of peritoneal biomarkers after abdominal surgery utilising an automated immunoassay system in routine use for quantifying cytokines.
METHODS
Patients undergoing an anterior resection for a rectal cancer diagnosis were recruited at University Hospital of Wales, Cardiff between June 2019 and June 2021. A peritoneal drain was placed in the proximity of the anastomosis during surgery, and peritoneal fluid was collected at days 1 to 3 post-operatively, and analysed using the Siemens IMMULITE platform for interleukin (IL)-1β, IL-6, IL-10, CXCL8, tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP).
RESULTS
A total of 42 patients were recruited (22M:20F, median age 65). Anastomotic leak was detected in four patients and a further five patients had other intra-abdominal complications. The IMMULITE platform was able to provide robust and reliable results from the analysis of the peritoneal fluid. A metric based on the combination of peritoneal IL-6 and CRP levels was able to accurately diagnose three anastomotic leaks, whilst correctly classifying all negative control patients including those with other complications.
CONCLUSIONS
This pilot study demonstrates that a simple immune signature in surgical drain fluid could accurately diagnose an anastomotic leak at 48 h postoperatively using instrumentation that is already widely available in hospital clinical laboratories.
Topics: Humans; Aged; Anastomotic Leak; Interleukin-6; Pilot Projects; Biomarkers; Anastomosis, Surgical; Rectal Neoplasms; Retrospective Studies
PubMed: 37486461
DOI: 10.1007/s10151-023-02841-y -
Immunity & Ageing : I & A Jul 2023More and more evidences are proving that microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD) and the plasma Aβ levels significantly increased...
More and more evidences are proving that microglia play a crucial role in the pathogenesis of Alzheimer's disease (AD) and the plasma Aβ levels significantly increased 15 years before the onset of dominantly inherited AD. However, the effects of high plasma levels of Aβ on mononuclear macrophage, the peripheral counterparts of microglia, remain unclear. In the present study, we used APP/PS1 transgenic (Tg) mice and a parabiotic model of wild type (Wt) mice and Tg mice (Parabiotic Wt-Tg, Pa (Wt-Tg)) to investigate the effects of high plasma levels of Aβ on peripheral mononuclear macrophage. Our results showed that in the early stage of Tg mice (7 months) and Pa (Wt-Tg) mice (4 months), the proportions of pro-inflammatory macrophages in peritoneal cavity, myeloid derived suppressor cells (MDSCs) in spleen, granulocyte-monocyte progenitors (GMPs) in bone marrow, and the plasma levels of interleukin-6 (IL-6) were significantly decreased. While the proportions of pro-inflammatory macrophages, MDSCs, GMPs, and the plasma levels of IL-6 and tumor necrosis factor (TNF)-α, as well as the numbers of bone marrow-derived macrophages (BMDMs) in mice brain were increased in the late stage of Tg mice (11 months) and Pa (Wt-Tg) mice (8 months). In addition, the proportions of monocytes in spleen and the proliferation of bone marrow cells (BMCs) were enhanced consistently, and the phagocytic function of macrophages kept stably after high plasma levels of Aβ sustaining stimulation. These results demonstrated that high plasma levels of Aβ play a biphasic regulating role at different stages of the disease, namely inhibiting effects on peripheral pro-inflammatory macrophages in the early stage of AD model, while promoting effects in the late stage of AD model. The mechanism behind this may be associated with their effects on MDSCs in spleen and myeloid progenitor cells in bone marrow. Therefore, intervening the effects of plasma Aβ on pro-inflammatory macrophages might offer a new therapeutic approach to AD.
PubMed: 37525137
DOI: 10.1186/s12979-023-00366-4 -
Journal of Hepatology Jun 2024Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal...
BACKGROUND & AIMS
Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs).
METHODS
PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP.
RESULTS
E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1β upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP.
CONCLUSIONS
Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP.
IMPACT AND IMPLICATIONS
Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.
PubMed: 38936554
DOI: 10.1016/j.jhep.2024.06.019 -
Journal of Visualized Experiments : JoVE Mar 2024In patients with severe necrotizing pancreatitis, pancreatic necrosis and secondary infection of surrounding tissues can quickly spread to the whole retroperitoneal...
In patients with severe necrotizing pancreatitis, pancreatic necrosis and secondary infection of surrounding tissues can quickly spread to the whole retroperitoneal space. Treatment of pancreatic abscess complicating necrotizing pancreatitis is difficult and has a high mortality rate. The well-accepted treatment strategy is early debridement of necrotic tissues, drainage, and postoperative continuous retroperitoneal lavage. However, traditional open surgery has several disadvantages, such as severe trauma, interference with abdominal organs, a high rate of postoperative infection and adhesion, and hardness with repeated debridement. The retroperitoneal laparoscopic approach has the advantages of minimal invasion, a better drainage route, convenient repeated debridement, and avoidance of the spread of retroperitoneal infection to the abdominal cavity. In addition, retroperitoneal drainage leads to fewer drainage tube problems, including miscounting, displacement, or siphon. The debridement and drainage of pancreatic abscess tissue via the retroperitoneal laparoscopic approach plays an increasingly irreplaceable role in improving patient prognosis and saving healthcare resources and costs. The main procedures described here include laying the patient on the right side, raising the lumbar bridge and then arranging the trocar; establishing the pneumoperitoneum and cleaning the pararenal fat tissues; opening the lateral pyramidal fascia and the perirenal fascia outside the peritoneal reflections; opening the anterior renal fascia and entering the anterior pararenal space from the rear; clearing the necrotic tissue and accumulating fluid; and placing drainage tubes and performing postoperative continuous retroperitoneal lavage.
Topics: Humans; Retroperitoneal Space; Debridement; Abscess; Laparoscopy; Pancreatitis, Acute Necrotizing; Necrosis
PubMed: 38557558
DOI: 10.3791/66162 -
Journal of Clinical Medicine Apr 2024: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the...
: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the majority of chronic kidney disease (CKD) patients and those undergoing renal replacement therapy. The aim of the study was to assess the relation of OPG and chronic inflammation in peritoneal dialysis (PD) patients and to evaluate whether OPG concentrations in plasma and dialysate were related to plasma and dialysate levels of proinflammatory mediators (interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), interleukin 33 (IL-33) and interleukin 1 receptor-like 1IL-1RL1 (IL-1RL1, sST2)). : The study included 37 patients of the Peritoneal Dialysis Center, Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland, 4-6 weeks after the onset of peritoneal dialysis therapy. During a peritoneal equilibration test, plasma (at 2 h) and dialysate (at 4 h) OPG, IL-33, 1IL-1RL1 (sST2), IL-6 and hsCRP concentrations were determined. : Plasma concentration of OPG did not correlate with dialysate OPG level ( = 0.04, = 0.8). There was a strong positive correlation between plasma OPG concentrations and plasma IL-1RL1 (sST2) ( = 0.41; = 0.01), plasma IL-6 ( = 0.38; = 0.01) and plasma hsCRP ( = 0.35; = 0.02). Dialysate OPG concentrations were positively associated with dialysate IL-1RL1 (sST2) ( = 0.37; = 0.02) and dialysate IL-6 levels ( = 0.44; = 0.005). Multivariate analysis showed that higher IL-1RL1 (sST2) ( = +0.38, = 0.006), higher plasma hsCRP ( = +0.32, = 0.02) and older age ( = +0.35, = 0.01) were independent determinants of higher plasma OPG concentration and that higher concentrations of dialysate IL-6 ( = +0.37, = 0.02) were independent determinants of higher dialysate OPG concentration. : Both plasma and dialysate OPG levels are associated with the severity of systemic and local inflammation illustrated by the plasma and dialysate concentrations of IL-1RL1 (sST2), hsCRP and IL-6, suggesting that OPG might have a pivotal role in explaining the milieu of systemic and intraperitoneal inflammation.
PubMed: 38673616
DOI: 10.3390/jcm13082345 -
Journal of Visceral Surgery Aug 2023This study aimed to investigate the incidence and degree of postoperative intra-abdominal adhesions(POAs) in secondary laparoscopic procedures and assess the power of...
AIM OF THE STUDY
This study aimed to investigate the incidence and degree of postoperative intra-abdominal adhesions(POAs) in secondary laparoscopic procedures and assess the power of the preoperative levels of tumor necrosis factor-alpha(TNF-α) and interleukin-1 beta(IL-1β) and selected peripheral inflammatory biomarkers(PIBs) in the prediction of the development and extent of POA.
PATIENTS AND METHODS
This prospective study enrolled 103 patients who had previously undergone at least one or more laparoscopic abdominal or gynecological operations. We examined TNF-α, IL-1β, and PIBs, namely C-reactive protein, white blood cell count, neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio, and systemic immune-inflammation index(SII) according to the presence, location, and score of adhesions determined during secondary laparoscopic procedures.
RESULTS
Only age, postoperative adhesion index(PAI) score, NLR, SII, TNF-α, and IL-1β resulted in a significant difference in the existence of adhesion(P<0.05). The correlation analysis of TNF-α with variables showed that the PAI score and IL 1β levels had a significantly positive correlation.
CONCLUSION
The presence and extent of POA could be predicted by examining the preoperative TNF-α level in patients who had laparoscopic abdominal surgery previously. We could overcome adverse events during secondary laparoscopic procedures by assessing high-risk patients and integrating a personalized surgical approach to managing selected patients.
Topics: Humans; Tumor Necrosis Factor-alpha; Prospective Studies; Laparoscopy; Sulfonamides; Peritoneal Diseases
PubMed: 36577610
DOI: 10.1016/j.jviscsurg.2022.12.007 -
Frontiers in Immunology 2023Persistent inflammation and associated pain significantly impact individuals' quality of life, posing substantial healthcare challenges. Proinflammatory cytokines,...
Persistent inflammation and associated pain significantly impact individuals' quality of life, posing substantial healthcare challenges. Proinflammatory cytokines, released by activated macrophages, play crucial roles in the development of chronic inflammatory conditions such as rheumatoid arthritis. To identify and evaluate potential therapeutic interventions targeting this process for mitigating inflammation and pain, we created myeloid cell-specific knockout of (vesicle-associated membrane protein 3) mice ( ) by crossing mice with newly engineered mice. Bone marrow-derived macrophages and peritoneal resident macrophages from mice exhibited a significant reduction in TNF-α and IL-6 release compared to control mice. Moreover, Vamp3 deficiency led to decreased paw edema and ankle joint swelling induced by intraplantar injection of complete Freund's adjuvant (CFA). Furthermore, Vamp3 depletion also mitigated CFA-induced mechanical allodynia and thermal hyperalgesia. Mechanistically, Vamp3 loss ameliorated the infiltration of macrophages in peripheral sites of the hind paw and resulted in reduced levels of TNF-α and IL-6 in the CFA-injected paw and serum. RT-qPCR analysis demonstrated downregulation of various inflammation-associated genes, including , , , , , , , and in the injected paw at the test day 14 following CFA administration. These findings highlight the novel role of Vamp3 in regulating inflammatory responses and suggest it as a potential therapeutic target for the development of novel Vamp-inactivating therapeutics, with potential applications in the management of inflammatory diseases.
Topics: Animals; Mice; Cytokines; Freund's Adjuvant; Hyperalgesia; Inflammation; Interleukin-6; Macrophages, Peritoneal; Pain; Quality of Life; Tumor Necrosis Factor-alpha; Vesicle-Associated Membrane Protein 3
PubMed: 37965323
DOI: 10.3389/fimmu.2023.1239592 -
Photochemical & Photobiological... Nov 2023This study assessed the therapeutic efficacy of intraperitoneal photodynamic therapy (PDT) using photosensitizer activation at two different wavelengths, 405 and...
BACKGROUND
This study assessed the therapeutic efficacy of intraperitoneal photodynamic therapy (PDT) using photosensitizer activation at two different wavelengths, 405 and 664 nm, in a mouse model of peritoneal carcinomatosis.
METHODS
The dark and light cytotoxicity of chlorin e6-polyvinylpyrrolidone (Phonozen) were measured in vitro under 402 ± 14 and 670 ± 18 nm LED activation in bioluminescent human gastric cancer cells, MKN45-luc. Cell viability was measured at 6 h after irradiation using the PrestoBlue assay. Corresponding in vivo studies were performed in athymic nude mice by intraperitoneal injection of 1 × 10 MKN45-luc cells. PDT was performed 10 d after tumor induction and comprised intraperitoneal injection of Phonozen followed by light irradiation at 3 h, delivered by a diffusing-tip optical fiber placed in the peritoneal cavity and coupled to a 405 or 664 nm diode laser to deliver a total energy of 50 J (20 mice per cohort). Whole-body bioluminescence imaging was used to track the tumor burden after PDT out to 130 days, and 5 mice in each cohort were sacrificed at 4 h post treatment to measure the acute tumor necrosis.
RESULTS
Photosensitizer dose-dependent photocytotoxicity was higher in vitro at 405 than 664 nm. In vivo, PDT reduced the tumor growth rate at both wavelengths, with no statistically significant difference. There was substantial necrosis, and median survival was significantly prolonged at both wavelengths compared with controls (46 and 46 vs. 34 days).
CONCLUSIONS
Phonozen-mediated PDT results in significant cytotoxicity in vitro as well as tumor necrosis and prolonged survival in vivo following intraperitoneal light irradiation. Blue light was more photocytotoxic than red in vitro and had marginally higher efficacy in vivo.
Topics: Humans; Mice; Animals; Photosensitizing Agents; Photochemotherapy; Peritoneal Neoplasms; Mice, Nude; Disease Models, Animal; Necrosis; Cell Line, Tumor
PubMed: 37632684
DOI: 10.1007/s43630-023-00470-w -
International Immunopharmacology Nov 2023Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly...
BACKGROUND
Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture. It exerts its toxic effects mainly as a result of its redox cycle via the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The aim of this study was to estimate the beneficial protective role of nilotinib (NIL) on PQ-induced hepatic and pulmonary toxicity in rats.
METHODS
Male wistar rats were randomly divided into four groups, namely control, PQ (15 mg/kg), PQ plus NIL (5 mg/kg) and PQ plus NIL (10 mg/kg). NIL (5 and 10 mg/kg/day) was taken by oral syringe for five days followed by a single intra-peritoneal administration of PQ (15 mg/kg) on sixth day.
RESULTS
Pretreatment with NIL relieved the histological damage in liver and lung tissues and improved hepatic biochemical markers. It significantly (p < 0.05) reduced serum levels of ALT, AST, ALP, Y-GT and total bilirubin while increased that of albumin. Meanwhile, NIL significantly (p < 0.05) reduced oxidative stress markers via reduction of malondialdhyde (MDA) and elevation of glutathione (GSH) contents in liver and lung tissues. In addition, it significantly (p < 0.05) decreased the inflammation by reducing hepatic and pulmonary tumor necrosis factor alpha (TNF-α) and nuclear transcription factor kappa B (NF-KB/p65) contents. Nilotinib also down-regulated apoptosis by reducing cysteinyl aspartate-specific proteinase-3 (caspase-3). Furthermore, it upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) in liver and lung tissues.
SIGNIFICANCE
NIL suppressed PQ-induced inflammation, oxidative stress and apoptosis in liver and lung tissues by modulating Nrf2/Nf-kB axis.
PubMed: 37678030
DOI: 10.1016/j.intimp.2023.110886 -
Military Medicine Nov 2023Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been...
INTRODUCTION
Noncompressible torso hemorrhage is the leading cause of exsanguination on the battlefield. A self-expanding, intraperitoneal deployed, thermoreversible foam has been developed that can be easily administered by a medic in austere settings to temporarily tamponade noncompressible torso hemorrhage. The purpose of this study was to assess the long-term safety and physical characteristics of using Fast Onset Abdominal Management (FOAM; Critical Innovations LLC) in swine.
MATERIALS AND METHODS
Yorkshire swine (40-60 kg) were sedated, intubated, and placed on ventilatory support. An external jugular catheter was placed for sampling of blood. Continuous heart rate, temperature, saturation of peripheral oxygen, end-tidal carbon dioxide, and peak airway pressures were monitored for a 4-hour period after intervention (i.e., FOAM agent injection or a sham introducer without agent delivery). The FOAM agent was injected to obtain an intra-abdominal pressure of 60 mmHg for at least 10 minutes. After 4 hours, the animals were removed from ventilatory support and returned to their housing for a period of 7-14 days. Group size analysis was not performed, as this was a descriptive safety study. Blood samples were obtained at baseline and at 1-hour post-intervention and then on days 1, 3, 7, and 14. Euthanasia, necropsy, and harvesting of samples for histologic analysis (from kidneys, terminal ilium, liver, pancreas, stomach, spleen, and lungs) were performed upon expiration. Histologic scoring for evidence of ischemia, necrosis, and abdominal compartment sequela was blinded and reported by semi-quantitative scale (range 0-4; 0 = no change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked). Oregon Health & Science University's Institutional Animal Care and Use Committee, as well as the U.S. Army Animal Care and Use Review Office, approved this protocol before the initiation of experiments (respectively, protocol numbers IP00003591 and MT180006.e002).
RESULTS
Five animals met a priori inclusion criteria, and all of these survived to their scheduled endpoints. Two animals received sham injections of the FOAM agent (one euthanized on day 7 and one on day 14), and three animals received FOAM agent injections (one euthanized on day 7 and two on day 14). A transitory increase in creatinine and lactate was detected during the first day in the FOAM injected swine but resolved by day 3. No FOAM agent was observed in the peritoneal cavity upon necropsy at day 7 or 14. Histologic data revealed no clinically relevant differences in any organ system between intervention and control animals upon sacrifice at day 7 or 14.
CONCLUSIONS
This study describes the characteristics, survival, and histological analysis of using FOAM in a porcine model. In our study, FOAM reached the desired intra-abdominal pressure endpoint while not significantly altering basic hematologic parameters, except for transient elevations of creatinine and lactate on day 1. Furthermore, there was no clinical or histological relevant evidence of ischemia, necrosis, or intra-abdominal compartment syndrome. These results provide strong support for the safety of the FOAM device and will support the design of further regulatory studies in swine and humans.
Topics: Humans; Swine; Animals; Creatinine; Abdominal Injuries; Hemorrhage; Torso; Necrosis; Lactates; Ischemia
PubMed: 35820028
DOI: 10.1093/milmed/usac206