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Neurosurgery Feb 2024The pipeline embolization device (PED) Flex with Shield technology is a third-generation flow diverter used for intracranial aneurysm treatment designed to decrease...
BACKGROUND AND OBJECTIVES
The pipeline embolization device (PED) Flex with Shield technology is a third-generation flow diverter used for intracranial aneurysm treatment designed to decrease thrombogenicity through a phosphorylcholine coating. Herein, we aim to compare the rate of thromboembolic events in PED with Shield technology and PED without it through propensity score matching.
METHODS
We conducted a retrospective analysis of aneurysms treated with PED first-generation/PED Flex and PED with Shield between 2013 and 2023 at a single academic institution. Patients were matched through propensity score by controlling for confounding factors including age, smoking history, diabetes, previous subarachnoid hemorrhage, modified Rankin Scale pretreatment, location, aneurysm size, previous treatment, and clopidogrel or aspirin resistance. After matching, we evaluated for periprocedural and postoperative thromboembolic events. Data analysis was performed using Stata 14.
RESULTS
A total of 543 patients with 707 aneurysms treated in 605 procedures were included in the analysis. From these, 156 aneurysms were treated with PED with Shield (22.07%) and 551 (77.93%) without Shield technology. Propensity score matching resulted in 84 matched pairs. The rate of thromboembolic events was 3.57% for PED Shield and 10.71% for PED first-generation/PED Flex (P = .07), while retreatment rates were 2.38% for PED Shield and 8.32% for PED Flex (P = .09). Complete occlusion at first (P = .41) and last imaging follow-up (P = .71), in-stent stenosis (P = .95), hemorrhagic complications (P = .31), and functional outcomes (P = .66) were comparable for both groups.
CONCLUSION
This is the first study in the literature performing a propensity scored-matched analysis comparing PED with PED with Shield technology. Our study suggests a trend toward lower thromboembolic events for PED Shield, even after controlling for aspirin and clopidogrel resistance, and a trend toward lower aneurysm retreatment rates with PED Shield, without reaching statistical significance.
PubMed: 38391195
DOI: 10.1227/neu.0000000000002883 -
Pharmaceutical Research Mar 2024Panax notoginseng saponins (PNS) are commonly used first-line drugs for treating cerebral thrombosis and stroke in China. However, the synchronized and targeted delivery...
BACKGROUND
Panax notoginseng saponins (PNS) are commonly used first-line drugs for treating cerebral thrombosis and stroke in China. However, the synchronized and targeted delivery of active ingredients in traditional Chinese medicine (TCM) poses a significant challenge for modern TCM formulations.
METHODS
Bovine serum albumin (BSA) was modified using 2-methacryloyloxyethyl phosphorylcholine (MPC), an analog of acetylcholine, and subsequently adsorbed the major PNS onto the modified albumin to produce MPC-BSA@PNS nanoparticles (NPs). This novel delivery system facilitated efficient and synchronized transport of PNS across the blood-brain barrier (BBB) through active transport mediated by nicotinic acetylcholine receptors.
RESULTS
In vitro experiments demonstrated that the transport rates of R, R, R, and R across the BBB were relatively synchronous in MPC-BSA@PNS NPs compared to those in the PNS solution. Additionally, animal experiments revealed that the brain-targeting efficiencies of R + R + R in MPC-BSA@PNS NPs were 2.02 and 7.73 times higher than those in BSA@PNS NPs and the free PNS group, respectively.
CONCLUSIONS
This study presents a simple and feasible approach for achieving the targeted delivery of complex active ingredient clusters in TCM.
Topics: Animals; Saponins; Panax notoginseng; Acetylcholine; Brain; Albumins
PubMed: 38383935
DOI: 10.1007/s11095-024-03670-w -
Cardiovascular Research Mar 2024The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an...
AIMS
The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis.
METHODS AND RESULTS
We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh.
CONCLUSION
Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.
Topics: Humans; Mice; Animals; Immunoglobulin M; Interleukin-18; B-Lymphocytes; Atherosclerosis; Cholesterol; T-Lymphocytes, Helper-Inducer
PubMed: 38381113
DOI: 10.1093/cvr/cvae027 -
Frontiers in Bioengineering and... 2024Gram-negative bacterium sp. Tol 5 exhibits high adhesiveness to various surfaces of general materials, from hydrophobic plastics to hydrophilic glass and metals, via...
Gram-negative bacterium sp. Tol 5 exhibits high adhesiveness to various surfaces of general materials, from hydrophobic plastics to hydrophilic glass and metals, via AtaA, an trimeric autotransporter adhesin Although the adhesion of Tol 5 is nonspecific, Tol 5 cells may have prefer materials for adhesion. Here, we examined the adhesion of Tol 5 and other bacteria expressing different TAAs to various materials, including antiadhesive surfaces. The results highlighted the stickiness of Tol 5 through the action of AtaA, which enabled Tol 5 cells to adhere even to antiadhesive materials, including polytetrafluoroethylene with a low surface free energy, a hydrophilic polymer brush with steric hindrance, and mica with an ultrasmooth surface. Single-cell force spectroscopy as an atomic force microscopy technique revealed the strong cell adhesion force of Tol 5 to these antiadhesive materials. Nevertheless, Tol 5 cells showed a weak adhesion force toward a zwitterionic 2-methacryloyloxyethyl-phosphorylcholine (MPC) polymer-coated surface. Dynamic flow chamber experiments revealed that Tol 5 cells, once attached to the MPC polymer-coated surface, were exfoliated by weak shear stress. The underlying adhesive mechanism was presumed to involve exchangeable, weakly bound water molecules. Our results will contribute to the understanding and control of cell adhesion of Tol 5 for immobilized bioprocess applications and other TAA-expressing pathogenic bacteria of medical importance.
PubMed: 38375452
DOI: 10.3389/fbioe.2024.1342418 -
Parasite Immunology Feb 2024ES-62, a protein secreted by Acanthocheilonema viteae, is anti-inflammatory by virtue of covalently attached phosphorylcholine (PC) residues and thus a library of...
ES-62, a protein secreted by Acanthocheilonema viteae, is anti-inflammatory by virtue of covalently attached phosphorylcholine (PC) residues and thus a library of drug-like small molecule analogues (SMAs) based on its PC moieties has been designed for therapeutic purposes. Two members, SMAs 11a and 12b, were previously found to suppress production of pro-inflammatory cytokines by mouse bone marrow-derived macrophages (BMMs) exposed to cytosine-phosphate-guanosine oligodeoxynucleotides (CpG), agonists for Toll-like receptor 9. In order to explore the mechanism of action underlying such activities, an untargeted mass spectrometry-based metabolomics screen was undertaken. Stimulation of BMMs with CpG produced significant metabolic changes relating to glycolysis and the TCA cycle but the SMAs had little impact on this. Also, the SMAs did not promote alterations in metabolites known to be associated with macrophage M1/M2 polarization. Rather, BMMs exposed to SMAs 11a or 12b prior to CpG treatment, or even alone, revealed downregulation of metabolites of creatine, a molecule whose major role is in the transport of high energy phosphate from the mitochondria to the cytosol. These data therefore provide insight into a possible mechanism of action of molecules with significant therapeutic potential that has not previously been described for parasitic worm products.
Topics: Animals; Mice; Creatine; Macrophages; Anti-Inflammatory Agents; Helminths; Phosphates
PubMed: 38372616
DOI: 10.1111/pim.13026 -
Scientific Reports Feb 2024A single and rapid method to obtain an antigenic fraction of excretory-secretory antigens (ESAs) from Fasciola hepatica suitable for serodiagnosis of fascioliasis is...
A single and rapid method to obtain an antigenic fraction of excretory-secretory antigens (ESAs) from Fasciola hepatica suitable for serodiagnosis of fascioliasis is reported. The procedure consists in the negative selection of F. hepatica ESAs by hydroxyapatite (HA) chromatography (HAC; fraction HAC-NR) followed by antigen precipitation with 50% ammonium sulphate (AS) and subsequent recovery by means of a Millex-GV or equivalent filter (Fi-SOLE fraction). Tested in indirect ELISA, the Fi-SOLE antigens detected natural infections by F. hepatica with 100% sensitivity and 98.9% specificity in sheep, and 97.7% sensitivity and 97.7% specificity in cattle, as determined by ROC analysis. The SDS-PAGE and proteomic nano-UHPLC-Tims-QTOF MS/MS analysis of fractions showed that the relative abundance of L-cathepsins and fragments thereof was 57% in fraction HAC-NR and 93.8% in fraction Fi-SOLE. The second most abundant proteins in fraction HAC-NR were fatty-acid binding proteins (11.9%). In contrast, free heme, and heme:MF6p/FhHDM-1 complexes remained strongly bond to the HA particles during HAC. Interestingly, phosphorylcholine (PC)-bearing antigens, which are a frequent source of cross-reactivity, were detected with an anti-PC mAb (BH8) in ESAs and fraction HAC-NR but were almost absent in fraction Fi-SOLE.
Topics: Animals; Sheep; Cattle; Fasciola hepatica; Antigens, Helminth; Proteomics; Tandem Mass Spectrometry; Antibodies, Helminth; Fascioliasis; Enzyme-Linked Immunosorbent Assay; Heme; Hydroxyapatites; Sheep Diseases; Sensitivity and Specificity
PubMed: 38365880
DOI: 10.1038/s41598-024-54290-8 -
Scientific Reports Feb 2024In this work, we present the synthesis and evaluation of magnetic resonance (MR) properties of novel phosphorus/iron-containing probes for dual P and H MR imaging and...
In this work, we present the synthesis and evaluation of magnetic resonance (MR) properties of novel phosphorus/iron-containing probes for dual P and H MR imaging and spectroscopy (MRI and MRS). The presented probes are composed of biocompatible semitelechelic and multivalent phospho-polymers based on poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) coordinated with small paramagnetic Fe ions or superparamagnetic maghemite (γ-FeO) nanoparticles via deferoxamine group linked to the end or along the polymer chains. All probes provided very short H T and T relaxation times even at low iron concentrations. The presence of iron had a significant impact on the shortening of P relaxation, with the effect being more pronounced for probes based on γ-FeO and multivalent polymer. While the water-soluble probe having one Fe ion per polymer chain was satisfactorily visualized by both P-MRS and P-MRI, the probe with multiple Fe ions could only be detected by P-MRS, and the probes consisting of γ-FeO nanoparticles could not be imaged by either technique due to their ultra-short P relaxations. In this proof-of-principle study performed on phantoms at a clinically relevant magnetic fields, we demonstrated how the different forms and concentrations of iron affect both the H MR signal of the surrounding water molecules and the P MR signal of the phospho-polymer probe. Thus, this double contrast can be exploited to simultaneously visualize body anatomy and monitor probe biodistribution.
Topics: Polymers; Tissue Distribution; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Iron; Water
PubMed: 38360883
DOI: 10.1038/s41598-024-54158-x -
Revista Brasileira de Parasitologia... 2024In urban environments, domestic dogs (Canis familiaris) are a major reservoir for the parasite Leishmania infantum. Miltefosine has been used as the standard treatment...
In urban environments, domestic dogs (Canis familiaris) are a major reservoir for the parasite Leishmania infantum. Miltefosine has been used as the standard treatment for canine visceral leishmaniasis in Brazil. However, therapeutic failures have been reported. In the present study, two dogs (CG03 and CG06) with a diagnosis of infection by L. infantum underwent two cycles of treatment with miltefosine (Milteforan™ - Virbac®). Analyses showed increases in the parasite load of both CG03 and CG06, even after treatment. The clinical score of CG03 dropped from 1 to 0 (after one round of treatment), such that this dog became asymptomatic. CG06 showed clinical worsening, such that its score increased from 1 to 2. After the second therapeutic round, the parasite load in CG03 was found to have decreased, but it was still higher than before drug treatment even though this dog was physically asymptomatic. There was no decrease in the parasite load in CG06 and there was clinical worsening. The clinical response of these dogs to the treatment differed, but the parasite load remained high in both cases, which poses a risk to public health, making it essential take measures to prevent the sandfly vector from accessing the dog.
Topics: Animals; Dogs; Leishmania infantum; Dog Diseases; Leishmaniasis, Visceral; Phosphorylcholine
PubMed: 38359300
DOI: 10.1590/S1984-29612024012 -
International Journal of Molecular... Jan 2024Phosphorus-containing metabolites occupy a prominent position in cell pathways. The phosphorometabolomic approach in human sperm samples will deliver valuable...
Phosphorus-containing metabolites occupy a prominent position in cell pathways. The phosphorometabolomic approach in human sperm samples will deliver valuable information as new male fertility biomarkers could emerge. This study analyzed, by P-NMR, seminal plasma and whole semen from asthenozoospermic and normozoospermic samples (71% vs. 27% and 45% vs. 17%, total and progressive sperm motility, respectively), and also ejaculates from healthy donors. At least 16 phosphorus-containing metabolites involved in central energy metabolism and phospholipid, nucleotide, and nicotinamide metabolic pathways were assigned and different abundances between the samples with distinct sperm quality was detected. Specifically, higher levels of phosphocholine, glucose-1-phosphate, and to a lesser degree, acetyl phosphate were found in the asthenozoospermic seminal plasma. Notably, the phosphorometabolites implicated in lipid metabolism were highlighted in the seminal plasma, while those associated with carbohydrate metabolism were more abundant in the spermatozoa. Higher levels of phosphocholine, glucose-1-phosphate, and acetyl phosphate in the seminal plasma with poor quality suggest their crucial role in supporting sperm motility through energy metabolic pathways. In the seminal plasma, phosphorometabolites related to lipid metabolism were prominent; however, spermatozoa metabolism is more dependent on carbohydrate-related energy pathways. Understanding the presence and function of sperm phosphorylated metabolites will enhance our knowledge of the metabolic profile of healthy human sperm, improving assessment and differential diagnosis.
Topics: Humans; Male; Semen; Phosphorylcholine; Sperm Motility; Spermatozoa; Asthenozoospermia; Phosphorus; Semen Analysis; Organophosphates
PubMed: 38338962
DOI: 10.3390/ijms25031682 -
International Immunopharmacology Mar 2024Residing obligatorily as amastigotes within the mammalian macrophages, the parasite Leishmania donovani inflicts the potentially fatal, globally re-emerging disease...
Residing obligatorily as amastigotes within the mammalian macrophages, the parasite Leishmania donovani inflicts the potentially fatal, globally re-emerging disease visceral leishmaniasis (VL) by altering intracellular signaling through kinases and phosphatases. Because the phosphatases that modulate the VL outcome in humans remained unknown, we screened a human phosphatase siRNA-library for anti-leishmanial functions in THP-1, a human macrophage-like cell line. Of the 251 phosphatases, the screen identified the Ca-activated K-channel-associated phosphatase myotubularin-related protein-6 (MTMR6) as the only phosphatase whose silencing reduced parasite load and IL-10 production in human macrophages. Virulent, but not avirulent, L. donovani infection increased MTMR6 expression in macrophages. As virulent L. donovani parasites expressed higher lipophosphoglycan, a TLR2-ligand, we tested the effect of TLR2 stimulation or blockade on MTMR6 expression. TLR1/TLR2-ligand Pam3CSK4 enhanced, but TLR2 blockade reduced, MTMR6 expression. L. donovani infection of macrophages ex vivo increased, but miltefosine treatment reduced, MTMR6 expression. Corroboratively, compared to endemic controls, untreated VL patients had higher, but miltefosine-treated VL patients had reduced, MTMR6 expression. The phosphatase siRNA-library screening thus identified MTMR6 as the first TLR2-modulated ion channel-associated phosphatase with significant implications in VL patients and anti-leishmanial functions.
Topics: Animals; Humans; Ion Channels; Leishmania donovani; Leishmaniasis, Visceral; Ligands; Mammals; Phosphorylcholine; Protein Tyrosine Phosphatases, Non-Receptor; RNA, Small Interfering; Toll-Like Receptor 2
PubMed: 38330797
DOI: 10.1016/j.intimp.2024.111644