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Emerging Infectious Diseases Mar 2024Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and...
Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and therapeutic outcomes, we studied 101 DL and 101 cutaneous leishmaniasis (CL) cases and determined cytokines and chemokines in supernatants of mononuclear cells stimulated with leishmania antigen. Patients were treated with meglumine antimoniate (20 mg/kg) for 20 days (CL) or 30 days (DL); 19 DL patients were instead treated with amphotericin B, miltefosine, or miltefosine and meglumine antimoniate. High levels of chemokine ligand 9 were associated with more severe DL. The cure rate for meglumine antimoniate was low for both DL (44%) and CL (60%), but healing time was longer in DL (p = 0.003). The lowest cure rate (22%) was found in DL patients with >100 lesions. However, meglumine antimoniate/miltefosine treatment cured all DL patients who received it; therefore, that combination should be considered as first choice therapy.
Topics: Humans; Leishmania braziliensis; Meglumine Antimoniate; Leishmaniasis, Cutaneous; Leishmania; Phosphorylcholine
PubMed: 38407142
DOI: 10.3201/eid3003.230786 -
Heliyon Feb 2024Surface modification of electrically neutral hydrophilic polymers is one of the most promising methods for preventing biofouling and biological contamination by proteins...
Surface modification of electrically neutral hydrophilic polymers is one of the most promising methods for preventing biofouling and biological contamination by proteins and bacteria. Surface modification of inorganic materials such as silica-based glass can render them more durable and thus help in achieving the sustainable development goals. This study reports a novel method for the simple and effective surface modification of glass surfaces with amphiphilic block copolymers possessing the silane coupling segment composed of 3-(methacryloyloxy)propyltris (trimethylsilyloxy) silane and 3-methacryloxypropyltrimethoxysilane. The ability of hydrophilic segments composed of either 2-methacryloyloxyethyl phosphorylcholine (MPC) or poly(ethylene glycol) methyl ether methacrylate (mOEGMA) to prevent bacterial adhesion was investigated. The target block copolymers were prepared by reversible addition-fragmentation chain transfer polymerization and the monomer units of the hydrophilic segments were controlled to be either 120 or 160. The polymers were modified on the substrate by dip-coating. Contact angle measurements indicated that the block copolymer with the PMPC hydrophilic segment formed a hydrophilic surface without pre-hydration, while those with the PmOEGMA hydrophilic segment-coated surface became hydrophilic upon immersion in water. The block copolymer-coated surfaces decreased adhesion, and a significant reduction was observed with the MPC-type block copolymer. The following surface design guidelines were thus concluded: (1) the block copolymer is superior to the random copolymer and (2) increasing the hydrophilic segment length further decreases bacterial adhesion.
PubMed: 38404882
DOI: 10.1016/j.heliyon.2024.e26347 -
Medicina (Kaunas, Lithuania) Feb 2024: Dry eye disease (DED) affects 5-50% of the global population and deeply influences everyday life activities. This study compared the efficacy, tolerability, and safety... (Randomized Controlled Trial)
Randomized Controlled Trial
: Dry eye disease (DED) affects 5-50% of the global population and deeply influences everyday life activities. This study compared the efficacy, tolerability, and safety of novel Respilac artificial tears containing lipidure and hypromellose (HPMC) with the widely used Nextal artificial tears, which are also HPMC-based, for the treatment of moderate DED in contact lenses (CL) wearers. : In a prospective, single-center, randomized investigation, 30 patients aged ≥18 years, diagnosed with moderate DED, and wearing CL were randomly assigned to the Respilac ( = 15) or Nextal group ( = 15). Patients self-administrated one drop of Respilac or Nextal in both eyes three times daily for 21 days. Changes in the endpoint (visual analogue scale (VAS) score for ocular tolerability, symptom assessment in dry eye (SANDE) score, non-invasive first break-up time (NIF-BUT) results, tear analysis value, meibography results, and CL tolerability results were assessed, comparing treatment groups and time-point evaluations. Adverse events (AEs) were also recorded and evaluated. : VAS scores decreased with time < 0.001) in both groups, showing no statistically significant difference among them ( = 0.13). Improvements were also detected from screening to end-of-treatment, which were indicated by the SANDE scores for severity and frequency ( < 0.001) and by tear analysis results ( < 0.001) with no observed difference between the Nextal and Respilac arms. NIF-BUT, meibography, and CL tolerability values were shown to be non-significantly affected by treatment and time. There were no AEs detected in this study cohort. : Respilac was confirmed to be effective, safe, and well-tolerated. Lipidure-based ophthalmic solution was shown not to be inferior to the currently used Nextal, however, showing improvements in DED symptoms. Within the existing literature, our study is one of the first to report that MPC plus HPMC-containing eye drops are an effective option for the treatment of moderate dry eye disease and desiccation damage prevention in contact lens wearers.
Topics: Humans; Adolescent; Adult; Lubricant Eye Drops; Hypromellose Derivatives; Prospective Studies; Dry Eye Syndromes; Contact Lenses; Tears
PubMed: 38399574
DOI: 10.3390/medicina60020287 -
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 -
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 -
Antiviral Research Mar 2024Coxsackievirus B3 (CVB3), one serotype of enteroviruses, can induce fatal myocarditis and hepatitis in neonates, but both treatment and vaccine are unavailable. Few...
Coxsackievirus B3 (CVB3), one serotype of enteroviruses, can induce fatal myocarditis and hepatitis in neonates, but both treatment and vaccine are unavailable. Few reports tested antivirals to reduce CVB3. Several antivirals were developed against other enterovirus serotypes, but these antivirals failed in clinical trials due to side effects and drug resistance. Repurposing of clinical drugs targeting cellular factors, which enhance viral replication, may be another option. Parasite and cancer studies showed that the cellular protein kinase B (Akt) decreases interferon (IFN), apoptosis, and interleukin (IL)-6-induced STAT3 responses, which suppress CVB3 replication. Furthermore, miltefosine, the Akt inhibitor used in the clinic for parasite infections, enhances IL-6, IFN, and apoptosis responses in treated patients, suggesting that miltefosine could be the potential antiviral for CVB3. This study was therefore designated to test the antiviral effects of miltefosine against CVB3 in vitro and especially, in mice, as few studies test miltefosine in vitro, but not in vivo. In vitro results showed that miltefosine inhibited viral replication with enhanced activation of the cellular transcription factor, STAT3, which is reported to reduce CVB3 both in vitro and in mice. Notably, STAT3 knockdown abolished the anti-CVB3 activity of miltefosine in vitro. Mouse studies demonstrated that miltefosine pretreatment reduced CVB3 lethality of mice with decreased virus loads, organ damage, and apoptosis, but enhanced STAT3 activation. Miltefosine could be prophylaxis for CVB3 by targeting Akt to enhance STAT3 activation in the mechanism, which is independent of IFN responses and hardly reported in pathogen infections.
Topics: Humans; Animals; Mice; STAT3 Transcription Factor; Proto-Oncogene Proteins c-akt; Apoptosis; Antigens, Viral; Enterovirus Infections; Interleukin-6; Antiviral Agents; Phosphorylcholine
PubMed: 38309307
DOI: 10.1016/j.antiviral.2024.105824