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Injury Jun 2024Nonoperative management (NOM) of blunt splenic injury (BSI) is well accepted in appropriate patients. Splenic artery embolization (SAE) in higher-grade injuries likely...
OBJECTIVES
Nonoperative management (NOM) of blunt splenic injury (BSI) is well accepted in appropriate patients. Splenic artery embolization (SAE) in higher-grade injuries likely plays an important role in increasing the success of NOM. We previously implemented a protocol requiring referral of all BSI grades III-V undergoing NOM for SAE. It is unknown the risk of complications as well as longitudinal outcomes. We aimed to examine the splenic salvage rate and safety profile of the protocol. We hypothesized the splenic salvage rate would be high and complications would be low.
METHODS
A retrospective study was performed at our Level 1 trauma center over a 9-year period. Injury characteristics and outcomes in patients sustaining BSI grades III-V were collected. Outcomes were compared for NOM on protocol (SAE) and off protocol (no angiography or angiography but no embolization). Complications for angiographies were examined.
RESULTS
Between January 2010 and February 2019, 570 patients had grade III-V BSI. NOM was attempted in 359 (63 %) with overall salvage rate of 91 % (328). Of these, 305 were on protocol while 54 were off protocol (41 no angiography and 13 angiography but no SAE). During the study period, for every grade of injury a pattern was seen of a higher salvage rate in the on-protocol group when compared to the off-protocol group (Grade III, 97 %(181/187) vs. 89 %(32/36), Grade IV, 91 %(98/108) vs. 69 %(9/13) and Grade V, 80 %(8/10 vs. 0 %(0/5). The overall salvage rate was 94 %(287) on protocol vs. 76 %(41) off protocol (p < 0.001, Cochran-Mantel-Haenszel test). Complications occurred in only 8 of the 318 who underwent angiography (2 %). These included 5 access complications and 3 abscesses.
CONCLUSION
The use of a protocol requiring routine splenic artery embolization for all high-grade spleen injuries slated for non-operative management is safe with a very low complication rate. NOM with splenic angioembolization failure rate is improved as compared to non-SAE patients' at all higher grades of injury. Thus, SAE for all hemodynamically stable patients of all high-grade types should be considered as a primary form of therapy for such injuries.
PubMed: 38942724
DOI: 10.1016/j.injury.2024.111707 -
Virus Research Jun 2024In China, a novel pathogen within the genus Circovirus has been identified as a causative agent of the 'novel acute hemorrhage syndrome' (NAHS) in aquacultured...
In China, a novel pathogen within the genus Circovirus has been identified as a causative agent of the 'novel acute hemorrhage syndrome' (NAHS) in aquacultured populations of turbot (Scophthalmus maximus L.). Histopathological examination using light microscopy revealed extensive necrosis within the cardiac, splenic, and renal tissues of the afflicted fish. Utilizing transmission electron microscopy (TEM), we detected the presence of circovirus particles within the cytoplasm of these cells, with the virions consistently exhibiting a spherical morphology of 20-40 nm in diameter. TEM inspections confirmed the predominance of these virions in the heart, spleen, and kidney. Subsequent molecular characterization through polymerase chain reaction (PCR) analysis corroborated the TEM findings, with positive signals in the aforementioned tissues, in stark contrast to the lack of detection in gill, fin, liver, and intestinal tissues. The TEM observations, supported by PCR electrophoresis data, strongly suggest that the spleen and kidney are the primary targets of the viral infection. Further characterization using biophysical, biochemical assays, and genomic sequencing confirmed the viral classification within the genus Circovirus, resulting in the nomenclature of turbot circovirus (TurCV). The current research endeavors to shed light on the pathogenesis of this pathogen, offering insights into the infection mechanisms of TurCV in this novel piscine host, thereby contributing to the broader understanding of its impact on turbot health and aquaculture.
PubMed: 38942295
DOI: 10.1016/j.virusres.2024.199428 -
Scientific Reports Jun 2024Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae...
Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae are responsible for the unequal distribution of worms in natural host populations and thus investigated a susceptible versus a resistant mouse strain. In mice, the roundworm larvae develop until the lung stage and thus early anti-Ascaris immune responses against the migrating larvae in the liver and lung can be deciphered. Our data show that susceptible C57BL/6 mice respond to Ascaris larval migration significantly stronger compared to resistant CBA mice and the anti-parasite reactivity is associated with pathology. Increased eosinophil recruitment was detected in the liver and lungs, but also in the spleen and peritoneal cavity of susceptible mice on day 8 post infection compared to resistant mice. In serum, eosinophil peroxidase levels were significantly higher only in the susceptible mice, indicating functional activity of the recruited eosinophils. This effect was associated with an increased IL-5/IL-13 production by innate lymphoid cells and CD4 T cells and a pronounced type 2 macrophage polarization in the lungs of susceptible mice. Furthermore, a comparison of wildtype BALB/c and eosinophil-deficient dblGATA-1 BALB/c mice showed that eosinophils were not essential for the early control of migrating Ascaris larvae. In conclusion, in primary infection, a strong local and systemic type 2 immune response during hepato-tracheal helminth larval migration is associated with pathology rather than protection.
Topics: Animals; Ascariasis; Larva; Mice; Th2 Cells; Mice, Inbred BALB C; Lung; Ascaris; Eosinophils; Mice, Inbred C57BL; Mice, Inbred CBA; Liver; Female
PubMed: 38942904
DOI: 10.1038/s41598-024-65281-0 -
Molecular Pharmaceutics Jun 2024Lymphocyte activation gene 3 (LAG-3) has attracted much attention as a potentially valuable immune checkpoint. Individual identification of LAG-3 expression at screening...
Lymphocyte activation gene 3 (LAG-3) has attracted much attention as a potentially valuable immune checkpoint. Individual identification of LAG-3 expression at screening and during treatment could improve the successful implementation of anti-LAG-3 therapies. HuL13 is a human IgG1 monoclonal antibody that binds to the LAG-3 receptor in T cells. Here, we used [Zr]Zr-labeled HuL13 to delineate LAG-3 T-cell infiltration into tumors via positron emission tomography (PET) imaging. A549/LAG-3 cells, which stably express LAG-3, were generated by infection with lentivirus. The uptake of [Zr]Zr-DFO-HuL13 in A549/LAG-3 cells was greater than that in the negative control (A549/NC) cells at each time point. The equilibrium dissociation constant () of [Zr]Zr-DFO-HuL13 for the LAG-3 receptor was 8.22 nM. PET imaging revealed significant uptake in the tumor areas of A549/LAG-3 tumor-bearing mice from 24 h after injection (SUVmax = 2.43 ± 0.06 at 24 h). As a proof of concept, PET imaging of the [Zr]Zr-DFO-HuL13 tracer was further investigated in an MC38 tumor-bearing humanized LAG-3 mouse model. PET imaging revealed that the [Zr]Zr-DFO-HuL13 tracer specifically targets human LAG-3 expressed on tumor-infiltrating lymphocytes (TILs). In addition to the tumors, the spleen was also noticeably visible. Tumor uptake of the [Zr]Zr-DFO-HuL13 tracer was lower than its uptake in the spleen, but high uptake in the spleen could be reduced by coinjection of unlabeled antibodies. Coinjection of unlabeled antibodies increases tracer activity in the blood pool, thereby improving tumor uptake. Dosimetry evaluation of the healthy mouse models revealed that the highest absorbed radiation dose was in the spleen, followed by the liver and heart wall. In summary, these studies demonstrate the feasibility of using the [Zr]Zr-DFO-HuL13 tracer for the detection of LAG-3 expression on TILs. Further clinical evaluation of the [Zr]Zr-DFO-HuL13 tracer may be of significant help in the stratification and management of patients suitable for anti-LAG-3 therapy.
PubMed: 38941565
DOI: 10.1021/acs.molpharmaceut.4c00343 -
Angewandte Chemie (International Ed. in... Jun 2024Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a...
A Renal Clearable Nano-Assembly with Förster Resonance Energy Transfer Amplified Superoxide Radical and Heat Generation to Overcome Hypoxia Resistance in Phototherapeutics.
Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a challenge. Herein, we present a smart molecular design strategy based on the Förster resonance energy transfer (FRET) mechanism to develop a type I photodynamic therapy (PDT) agent with an encouraging amplification effect for accurate hypoxic tumor therapy. Of note, benefiting from the FRET effect, the obtained nanostructured type I PDT agent (NanoPcSZ) with boosted light-harvesting ability not only amplifies superoxide radical (O2•-) production but also promotes heat generation upon near-infrared light irradiation. These features facilitate NanoPcSZ to realize excellent phototherapeutic response under both normal and hypoxic environments. As a result, both in vitro and in vivo experiments achieved a remarkable improvement in therapeutic efficacy via the combined effect of photothermal action and type I photoreaction. Notably, NanoPcSZ can be eliminated from organs (including the liver, lung, spleen, and kidney) apart from the tumor site and excreted through urine within 24 h of its systemic administration. In this way, the potential biotoxicity of drug accumulation can be avoided and the biosafety can be further enhanced.
PubMed: 38940633
DOI: 10.1002/anie.202411514 -
Journal of Immunology (Baltimore, Md. :... Jun 2024Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although...
Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although α2-adrenergic receptors are known to modulate the immune response in different ways, the therapeutic exploration of their utility has been limited by the lack of agonists selective for the three α2-adrenergic subtypes. We report in this study the identification of the agonist AGN-762, which activates α2B- and α2C-adrenergic subtypes, but not the α2A subtype. We show that AGN-762 reduced clinical disease in an experimental autoimmune encephalitis model of autoimmune disease via direct or indirect effects on T regulatory cells. The activity of AGN-762 was abrogated by depletion of T regulatory cells, which express the α2B-adrenergic receptor. Furthermore, a drug-induced shift to an anti-inflammatory phenotype was demonstrated in immune cells in the spleen of drug-treated experimental autoimmune encephalitis mice. AGN-762 does not display sedative and cardiovascular side effects associated with α2A subtype agonists. Immune modulation by selective α2-adrenergic agonists represents a novel, to our knowledge, approach for treating autoimmune disease.
PubMed: 38940628
DOI: 10.4049/jimmunol.2300893 -
MBio Jun 2024Transposon sequencing (Tn-seq) is a powerful genome-wide technique to assess bacterial fitness under varying growth conditions. However, screening via Tn-seq is...
UNLABELLED
Transposon sequencing (Tn-seq) is a powerful genome-wide technique to assess bacterial fitness under varying growth conditions. However, screening via Tn-seq is challenging. Dose limitations and host restrictions create bottlenecks that diminish the transposon mutant pool being screened. Here, we have developed a murine model with a disruption in that renders the resulting RECON mouse resistant to high-dose infection. We leveraged this model to perform a Tn-seq screen of the human pathogen . We identified 135 genes which were required for growth in mice including novel genes not previously identified for host survival. We identified organ-specific requirements for survival and investigated the role of the folate enzyme FolD in liver pathogenesis. A mutant lacking was impaired for growth in murine livers by 2.5-log compared to wild type and failed to spread cell-to-cell in fibroblasts. In contrast, a mutant in which encodes a transcription factor that represses an operon involved in D-allose catabolism, was attenuated in both livers and spleens of mice by 4-log and 3-log, respectively, but showed modest phenotypes in models. We confirmed that dysregulation of the D-allose catabolism operon is responsible for the growth defect, as deletion of the operon in the ∆ background rescued virulence. By undertaking an unbiased, genome-wide screen in mice, we have identified novel fitness determinants for host infection, which highlights the utility of the RECON mouse model for future screening efforts.
IMPORTANCE
is the gram-positive bacterium responsible for the food-borne disease listeriosis. Although infections with are limiting in healthy hosts, vulnerable populations, including pregnant and elderly people, can experience high rates of mortality. Thus, understanding the breadth of genetic requirements for survival will present new opportunities for treatment and prevention of listeriosis. We developed a murine model of infection using a RECON mouse that is restrictive to systemic infection. We utilized this model to screen for genes required via transposon sequencing. We identified the liver-specific gene and a repressor, , that only exhibits an growth defect. AlsR controls the expression of the D-allose operon which is a marker in diagnostic techniques to identify pathogenic . A better understanding of the role of the D-allose operon in human disease may further inform diagnostic and prevention measures.
PubMed: 38940553
DOI: 10.1128/mbio.01332-24 -
Bioanalysis Jun 2024Increased knowledge of biodistribution and pharmacokinetics of lipid nanoparticle (LNP)-encapsulated mRNA drug components may aid efficacy and safety evaluation. Mice...
Increased knowledge of biodistribution and pharmacokinetics of lipid nanoparticle (LNP)-encapsulated mRNA drug components may aid efficacy and safety evaluation. Mice were subcutaneously administrated LNP encapsulated enhanced green fluorescent protein mRNA and sampled up to 72 h after dosing. LNP, mRNA and translated protein were quantified by LC-MS, branched DNA and ELISA. Highest levels of LNP and mRNA were detected in skin, followed by spleen, but also rapidly distributed to circulation. Translated protein showed high concentration in skin and spleen, but also in liver and kidney across 24 h where the LNP was cleared at 4 h. Subcutaneously dosing LNP encapsulated mRNA in mice resulted in a nonlinear relationship of LNP, mRNA and protein concentration across multiple tissues.
PubMed: 38940441
DOI: 10.1080/17576180.2024.2360361 -
Cureus May 2024Steatotic liver grafts are associated with increased post-transplant complications and graft failure. The field of transplantation faces a challenge in the absence of a...
Steatotic liver grafts are associated with increased post-transplant complications and graft failure. The field of transplantation faces a challenge in the absence of a reliable pre-donation protocol for quantitatively assessing steatosis in cadaveric liver grafts. Current pre-donation evaluation protocols often involve non-contrast computed tomography (CT) scans of the chest and/or abdomen as an initial step in organ donation assessment. These routine scans have the potential to identify and quantify hepatic fat content when more than 20% of the liver parenchyma is affected. By incorporating both abdominal and thoracic CT scans during the donor workup, an assessment of the quality of the liver and spleen can be achieved. Our study is based on the hypothesis that a precise pre-donation evaluation utilizing Hounsfield units (HU) derived from CT images of the liver and spleen can provide transplant programs with crucial data regarding the extent of steatosis. This approach is envisioned as a significant advancement that could potentially eliminate the need for preoperative liver biopsies by offering essential information to streamline the evaluation process.
PubMed: 38939256
DOI: 10.7759/cureus.61196 -
Biochemistry and Biophysics Reports Sep 2024Prostacyclin or prostaglandin I (PGI), a metabolite of arachidonic cyclooxygenase pathway, has been demonstrated as an effector of adipocyte differentiation. However,...
Prostacyclin or prostaglandin I (PGI), a metabolite of arachidonic cyclooxygenase pathway, has been demonstrated as an effector of adipocyte differentiation. However, due to its instability in biological fluid, it is difficult to evaluate the role of PGI in regulating adipocyte differentiation in different stages in culture. Therefore, this study aimed to establish a simple and rapid method for the production of monoclonal antibody against 6-Keto PGFα, a stable PGI metabolite, and its quantification to determine the role of PGI in culture medium. Eight-week-old female BALB/c mice were immunized with the hapten of 6-Keto PGFα and BSA for several weeks until a higher antibody titer (absorbance value > 0.9 at 1000-times dilution) against 6-Keto PGFα was found. Then, fusion of antibody-producing spleen lymphocytes with SP-2 myeloma cells and thymocytes was performed and cultured in HAT-medium supplemented with hypoxanthine, aminopterin, and thymine. Specific antibody-producing cells (M2-A4-B8-D10) against 6-Keto PGFα were identified and separated. A standard ELISA calibration curve was developed with 100% reactivity for 6-Keto-PGF 1 α ranging from 0.26 pg to 6.44 ng corresponding to 90% and 10% of the maximum binding capacity for the immobilized antigen respectively. This method can easily be applied to monitor PGI regulation in different stages of cultured adipocytes to reveal the regulatory roles of PGI in maintaining homeostasis and adipocyte differentiation.
PubMed: 38939124
DOI: 10.1016/j.bbrep.2024.101748