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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 -
Cureus Nov 2023The falciform ligament is a double peritoneal fold that separates the left and right hepatic lobes anatomically. Fatty-falciform ligament appendage torsion (F-FLAT) is...
The falciform ligament is a double peritoneal fold that separates the left and right hepatic lobes anatomically. Fatty-falciform ligament appendage torsion (F-FLAT) is defined as torsion of the extraperitoneal fat within the falciform ligament causing fat infarction, which is an uncommon surgical presentation, scarcely documented within the current literature. The objective of presenting this case report and reviewing the literature on F-FLAT is to discuss the clinical presentation, possible associated factors and management strategies in regard to this rare pathology. A 72-year-old female patient presented to the emergency department with a seven-day history of epigastric pain, reduced appetite and nausea. On admission, the patient was stable and apyrexial with abdominal examination highlighting she was tender in her right upper quadrant and epigastric region. Due to the patient's unremitting abdominal pain despite appropriate analgesia, CT of the abdomen and pelvis (CTAP) with intravenous contrast was done and a diagnosis of F-FLAT was made. The patient was treated with antibiotics and analgesia, had a negative abdominal ultrasound (US) result and due to her symptoms settling by the second day of admission, she was discharged the same afternoon. A literature review into falciform ligament infarction was conducted by two independent reviewers across four different databases: PubMed, Medline, Embase and the Cochrane Library. Search terms included "falciform ligament" OR "falciform" AND "infarction" (likewise with Medical Subject Headings, or MeSH, terms in the Cochrane Library). Eligibility criteria and our subsequent inclusion criteria were based on studies specifically discussing falciform ligament infarction and published in English. Study types were by majority case reports, but also included one literature review and a book source as well as two pictorial radiological reviews. All 13 patients presented with abdominal pain, but only 53% presented with raised infective/inflammatory markers. The majority of patients had abdominal US as a first-line investigation with 9 of 13 patients also having a CTAP with contrast, which classically showed fat stranding in the falciform ligament. Two patients had no evidence of any radiological investigation. Initially all cases were managed conservatively with non-steroidal anti-inflammatory drugs and analgesia, but in 62% of the cases (8/13), surgical intervention was needed due to unresolving abdominal pain. All eight of the excised falciform ligaments showed evidence of infarction and necrosis histologically. In conclusion, F-FLAT is a relatively rare condition making it difficult to build higher level evidence studies. The current literature has revealed some evidence of incomplete and inconsistent data, for example, in the biochemical results and management techniques presented, yet contrast-enhanced CT seems moderately sensitive for detection in the reviewed literature. Though F-FLAT is rare and unfamiliar, it is vital we exclude common acute surgical pathologies that F-FLAT mimics and monitor for unsettling symptoms that could change the management trajectory.
PubMed: 37937182
DOI: 10.7759/cureus.48361 -
Journal For Immunotherapy of Cancer Nov 2023Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by...
Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis.
BACKGROUND
Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses.
METHODS
MVA encoding scIL-12 (MVA.scIL-12) was evaluated against peritoneal carcinomatosis models based on intraperitoneal engraftment of tumor cells. CD8-mediated immune responses, elucidated antitumor efficacy, and safety were evaluated following intravenous, intratumoral, or intraperitoneal administration of the viral vector. The immune response was measured by ELISpot (enzyme-linked immunosorbent spot), RNA sequencing, flow cytometry, intravital microscopy, and depletion of lymphocyte subsets with monoclonal antibodies. Safety was assessed by body-weight follow-up and blood testing. Tissue tropism on intravenous or intraperitoneal administration was assessed by bioluminescence analysis using a reporter MVA encoding luciferase.
RESULTS
Intraperitoneal or locoregional administration, but not other routes of administration, resulted in a potent immune response characterized by increased levels of tumor-specific CD8 T lymphocytes with the ability to produce both interferon-γ and tumor necrosis factor-α. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result of intraperitoneal treatment, a single administration of MVA.scIL-12 encoding scIL-12 completely eradicated MC38 tumors implanted in the peritoneal cavity and also protected cured mice from subsequent subcutaneous rechallenges. Bioluminescence imaging using an MVA encoding luciferase revealed that intraperitoneal administration targets transgene to the omentum. The omentum is considered a key tissue in immune protection of the peritoneal cavity. The safety profile of intraperitoneal administration was also better than that following intravenous administration since no weight loss or hematological toxicity was observed when the vector was locally delivered into the peritoneal cavity.
CONCLUSION
Intraperitoneal administration of MVA vectors encoding scIL-12 targets the omentum, which is the tissue where peritoneal carcinomatosis usually begins. MVA.scIL-12 induces a potent tumor-specific immune response that often leads to the eradication of experimental tumors disseminated to the peritoneal cavity.
Topics: Animals; Mice; Interleukin-12; Peritoneal Neoplasms; Omentum; Vaccinia virus; Luciferases
PubMed: 37918917
DOI: 10.1136/jitc-2023-006702 -
Cureus Sep 2023During our practice as clinical surgeons, we have encountered situations in which exploratory abdominal laparotomies have yielded unexpected outcomes, despite conducting...
During our practice as clinical surgeons, we have encountered situations in which exploratory abdominal laparotomies have yielded unexpected outcomes, despite conducting thorough and rigorous preoperative studies. A rare condition called sclerosing encapsulating peritonitis (SEP), in which a fibrocollagenous membrane encircles the intestine and other abdominal organs, surprised us in a case of an acute abdomen. Persistent descending mesocolon is another unusual condition in which the descending colon is transferred downward and to the right abdominal region because its mesocolon is unable to merge with the posterior abdominal wall. Those two different conditions are extremely rare and were never been described in a single case. We present a case of an 80-year-old male who presented in the emergency department with an acute abdomen and puzzled us.
PubMed: 37868492
DOI: 10.7759/cureus.45679 -
International Journal of Surgery Case... Nov 2023Infection with the human immunodeficiency virus (HIV) targets immune cells and exposes infected patients to several diseases. For these reasons, HIV infection should be...
INTRODUCTION AND IMPORTANCE
Infection with the human immunodeficiency virus (HIV) targets immune cells and exposes infected patients to several diseases. For these reasons, HIV infection should be suspected in each situation where post-operative sepsis occurs, to afford therapy and improve the patient's prognosis.
CASE PRESENTATION
We present a case of a pregnant woman at 39 weeks of gestation who missed her prenatal follow-up. She underwent an emergency caesarian section for severe abnormality in the fetal heart rate. The caesarian section was complicated by a post-partum hemorrhage (PPH). PPH was managed with uterine artery ligation and B-Lynch modified sutures.
CLINICAL DISCUSSION
Postoperatively, there was the succession of the following events: purulent uterine necrosis, peritonitis, and encephalitis leading to a life-saving hysterectomy. Due to the worsening of the septic condition, HIV screening was performed, after obtaining the patient's consent, and came back positive.
CONCLUSION
The aim of this case report is to push practicians to think about HIV infection when necessary because missing the diagnosis can seriously threaten patients' health.
PubMed: 37862771
DOI: 10.1016/j.ijscr.2023.108909 -
Cureus Sep 2023Gallbladder volvulus is an uncommon cause of acute cholecystitis that results from the rotation of the gallbladder about its mesentery along the axis of the cystic...
Gallbladder volvulus is an uncommon cause of acute cholecystitis that results from the rotation of the gallbladder about its mesentery along the axis of the cystic pedicle. We present the case of an 87-year-old woman with acute abdominal pain in the right upper quadrant that began two days prior with no additional symptoms. The physical examination showed a large abdominal eventration on the right side and tenderness. A CT scan showed a distended gallbladder outside its liver bed and with a twist on its cystic pedicle, suggesting a gallbladder volvulus. Abdominal ultrasonography complementary revealed the gallbladder outside its vesicular fossa with incipient changes of acute cholecystitis but without evidence of gallstones. With the diagnosis of acute abdomen secondary to gallbladder volvulus, an emergency cholecystectomy was performed. The exact etiology of the gallbladder volvulus is unknown, although anatomical variants that predispose to its appearance have been described. The clinical presentation is similar to acute cholecystitis, so preoperative diagnosis can be challenging for both surgeons and radiologists and is often misdiagnosed. This is one of the few cases diagnosed with preoperative imaging techniques. Once diagnosed, the appropriate treatment is emergency cholecystectomy. Early diagnosis and surgical treatment are important before it progresses to necrosis, perforation, biliary peritonitis, and hemodynamic instability. Gallbladder volvulus is an uncommon condition. A high index of suspicion is required because the preoperative diagnosis is unusual. Once the diagnosis is established, the treatment is fundamentally surgical.
PubMed: 37842445
DOI: 10.7759/cureus.45167 -
Journal of Inflammation Research 2023Intra-abdominal infection is a complex pathophysiological process involving multiple systems and organs of the body. Abdominal infections complicated by severe sepsis or...
PURPOSE
Intra-abdominal infection is a complex pathophysiological process involving multiple systems and organs of the body. Abdominal infections complicated by severe sepsis or septic shock have a high mortality rate of 30-50%. Therefore, novel strategies to treat sepsis are urgently needed.
METHODS
Andrographolide (AD), the main active ingredient of , reportedly exerts beneficial effects on mice with sepsis. However, its exact mechanism of action in attenuating inflammation due to intra-abdominal sepsis remains unclear to date. Hence, this study aimed to examine the therapeutic effects of AD on cecal ligation and puncture (CLP)-induced sepsis and elucidate the underlying mechanisms.
RESULTS
Results showed that AD therapy could significantly improve the 7-day survival rate and alleviate pathological organ injury in mice with CLP. In addition, AD treatment decreased the levels of proinflammatory factors, such as tumor necrosis factor-α and interleukin (IL)-6 in the peritoneal cavity fluid and blood and increased the level of anti-inflammatory factor IL-10 in the peritoneal cavity fluid of mice with CLP. Moreover, bacterial counts in the blood and peritoneal lavage fluid were lower in the mice treated with AD than in those untreated. Mechanistically, AD treatment increased the percentage and phagocytic activity of macrophages in the peritoneal cavity.
CONCLUSION
These data showed that AD can improve the survival of mice with intra-abdominal sepsis by enhancing bacterial clearance, as evidenced by the increased percentages and phagocytic activity of macrophages in the peritoneal cavity. This study is the first to demonstrate the protective effects of AD against intra-abdominal sepsis.
PubMed: 37822531
DOI: 10.2147/JIR.S422342 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Sep 2023To investigate the effect of Isodopharicin C (Iso C), a traditional Chinese herbal medicine extract, on NLRP3 inflammasome activation and lipopolysaccharide...
OBJECTIVE
To investigate the effect of Isodopharicin C (Iso C), a traditional Chinese herbal medicine extract, on NLRP3 inflammasome activation and lipopolysaccharide (LPS)-induced septic shock in mice.
METHODS
Murine bone marrow-derived macrophages (BMDM) and human monocytic THP-1 cells were stimulated with LPS before treatment with different NLRP3 inflammasome agonists to activate canonical NLRP3 inflammasomes. The non-canonical NLRP3 inflammasomes were activated by intracellular LPS transfection, and AIM2 inflammasomes were activated with poly A: T. The cleavage of caspase-1 induced by NLRP3 activation was measured using Western blotting. The levels of NLRP3-dependent and -independent pro-inflammatory cytokines in the cell culture supernatant were detected using ELISA, and the intracellular potassium ion concentration was measured using ICP-OES. In the animal experiment, C57BL/6J mouse models of septic shock (induced by intraperitoneal LPS injection) were treated with Iso C, and the levels of IL-1β, TNF-α and IL-6 in the serum and peritoneal lavage fluid were detected using ELISA. The survival time of the mice was observed within 48 h after LPS injection and a survival curve was plotted.
RESULTS
In BMDM cells, Iso C dose-dependently inhibited the activation of canonical NLRP3 inflammasomes and non-canonical NLRP3 inflammasomes (<0.05) without obviously affecting the secretion levels of TNF-α and IL-6 (>0.05), the activation of AIM2 inflammasomes (>0.05), or K + efflux, the upstream signaling of NLRP3 activation (>0.05). Iso C inhibited the activation of canonical NLRP3 inflammasomes in human THP-1 cells. In septic C57BL/6J mice, Iso C treatment significantly reduced IL-1β levels in the serum and peritoneal lavage fluid, and prolonged the survival time of the mice (<0.05).
CONCLUSION
Iso C specifically inhibits NLRP3 inflammasome activation and alleviates septic shock in mice, and can serve as a potential small molecule compound for treatment of inflammatory diseases.
Topics: Animals; Humans; Mice; Inflammasomes; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Shock, Septic; Tumor Necrosis Factor-alpha
PubMed: 37814861
DOI: 10.12122/j.issn.1673-4254.2023.09.04 -
Frontiers in Medicine 2023Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma (Xp11.2 RCC) exhibits unique biological characteristics and is associated with an increased...
BACKGROUND
Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma (Xp11.2 RCC) exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Multimodality imaging, including US, contrast-enhanced CT, multi-parametric MRI, and F-FDG PET/CT plays a crucial role in the preoperative diagnosis and differentiation of renal tumors.
CASE REPORT
A 15-year-old female presented with lumbar pain worsened, and developed persistent painless hematuria. The CT attenuation values of the scan without contrast, corticomedullary phase, nephrographic phase, and delayed phases were 35 HU, 83 HU, 82 HU, and 75 HU, respectively. The solid component of the mass displayed heterogeneous marked enhancement. Furthermore, MRU indicated that the lesion involved the cortical medulla and infringed on the renal sinus fat. The lesion appeared isosignal in T1WI, slightly low signal in T2WI, and slightly high signal in DWI. The degree of enhancement in the three phases of enhancement scan was lower than that in the renal parenchyma, and hemorrhage and necrosis were observed within the internal part of the lesion. To further clarify the staging, the patient underwent F-FDG PET/CT. PET/CT images showed multiple irregular occupancies in the right kidney with unclear borders, showing a heterogeneous increase in F-FDG uptake, with SUVmax values ranging from 2.3 to 5.2 in the routine imaging phase (60 min post-injection), compared to SUVmax values ranging from 2.8 to 6.9 in the delayed imaging phase (160 min post-injection). Additionally, multiple enlarged and fused lymph nodes were observed in the medial part of the right kidney and the retroperitoneum, exhibiting a heterogeneous increase in F-FDG uptake, with SUVmax values ranging from 4.1 to 8.7 in the routine imaging phase, compared to SUVmax values ranging from 4.4 to 9.1 in the delayed imaging phase. The postoperative pathology, immunohistochemistry, and molecular analysis of histiocytes were consistent with a diagnosis of Xp11.2 RCC. One month after surgery, enhanced-CT examination of the patient revealed lung metastasis, peritoneal metastasis, and multiple lymph node metastases throughout the body, with an overall survival of 16 months.
CONCLUSION
Xp11.2 RCC exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Long-term follow-up is essential to monitor the likelihood of recurrence and metastasis. F-FDG PET/CT examination can comprehensively visualize the lesion's location and extent, providing a basis for clinical tumor staging and aiding in treatment monitoring and follow-up. To address the limitations of FDG, the utilization of specific tracers designed for RCC or tracers that are not excreted via the urinary system would be ideal. Further advancements in molecular imaging technologies and the development of novel tracers hold great promise in advancing the diagnosis and management of RCC, ultimately contributing to better patient outcomes and overall disease management.
PubMed: 37795411
DOI: 10.3389/fmed.2023.1266630 -
Journal of Immunology Research 2023Genetic factors play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and abnormal Toll-like receptor (TLR) signaling pathways are closely...
Genetic factors play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and abnormal Toll-like receptor (TLR) signaling pathways are closely related to the onset of SLE. In previous studies, we found that the mutant somatic nuclear autoantigenic sperm protein (sNASP) gene in the mouse lupus susceptibility locus can promote the development of lupus model mice, but the mechanism is still unclear. Here, we stimulated mouse peritoneal macrophages with different concentrations of lipopolysaccharide. The results showed that sNASP gene mutations can promote the response of the TLR4-TAK1 signaling pathway but have no significant effect on the TLR4-TBK1 signaling pathway. sNASP mutations enhanced TLR4-mediated nuclear factor--gene binding and mitogen-activated protein kinase activation and IL-6, tumor necrosis factor secretion in murine peritoneal macrophages. Collectively, our study revealed the impact of sNASP gene mutation on the sensitivity of TLR4 receptors in mouse peritoneal macrophages and shed light on potential mechanisms underlying inflammation in autoimmune diseases.
Topics: Animals; Mice; Inflammation; Lupus Erythematosus, Systemic; Mutation; Toll-Like Receptor 4; Signal Transduction
PubMed: 37771504
DOI: 10.1155/2023/4877700