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PLoS Neglected Tropical Diseases Jun 2024In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.
BACKGROUND
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
TRIAL REGISTRATION
CTRI/2017/04/008421.
Topics: Humans; Amphotericin B; Phosphorylcholine; Bangladesh; Male; Antiprotozoal Agents; Adult; Adolescent; Female; Middle Aged; Young Adult; Child; India; Leishmaniasis, Visceral; Treatment Outcome; Leishmaniasis, Cutaneous; Drug Therapy, Combination
PubMed: 38900786
DOI: 10.1371/journal.pntd.0012242 -
Biosensors Mar 2024Galactose monitoring in individuals allows the prevention of harsh health conditions related to hereditary metabolic diseases like galactosemia. Current methods of...
Galactose monitoring in individuals allows the prevention of harsh health conditions related to hereditary metabolic diseases like galactosemia. Current methods of galactose detection need development to obtain cheaper, more reliable, and more specific sensors. Enzyme-containing amperometric sensors based on galactose oxidase activity are a promising approach, which can be enhanced by means of their inclusion in a redox polymer coating. This strategy simultaneously allows the immobilization of the biocatalyst to the electroactive surface and hosts the electron shuttling units. An additional deposition of capping polymers prevents external interferences like ascorbic or uric acid as well as biofouling when measuring in physiological fuels. This work studies the protection effect of poly(2-methacryloyloxyethyl phosphorylcholine--glycidyl methacrylate (MPC) and polyvinylimidazole-polysulfostyrene (P(VI-SS)) when incorporated in the biosensor design for the detection of galactose in human plasma.
Topics: Biosensing Techniques; Humans; Galactose; Polymers; Galactose Oxidase; Methacrylates
PubMed: 38667160
DOI: 10.3390/bios14040167 -
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 -
ACS Omega Feb 2024Graphene nanosheets are highly valued in the biomedical field due to their potential applications in drug delivery, biological imaging, and biosensors. Their biological...
Graphene nanosheets are highly valued in the biomedical field due to their potential applications in drug delivery, biological imaging, and biosensors. Their biological effects on mammalian cells may be influenced by cholesterols, which are crucial components in cell membranes that take part in many vital processes. Therefore, it is particularly important to investigate the effect of cholesterols on the transport mechanism of graphene nanosheets in the cell membrane as well as the final stable configuration of graphene, which may have an impact on cytotoxicity. In this paper, the molecular details of a graphene nanosheet interacting with a 1,2-dipalmitoyl--glycero-3-phosphorylcholine (DPPC) membrane with cholesterols were studied using molecular dynamics simulations. Results showed that the structure of the graphene nanosheet transits from the cut-in state in a pure DPPC membrane to being sandwiched between two DPPC leaflets when cholesterols reach a certain concentration. The underlying mechanism showed that cholesterols are preferentially adsorbed on the graphene nanosheet, which causes a larger disturbance to the nearby DPPC tails and thus guides the graphene nanosheet into the core of lipid bilayers to form a sandwiched structure. Our results are helpful for understanding the fundamental interaction mechanism between the graphene nanosheet and cell membrane and to explore the potential applications of the graphene nanosheet in biomedical sciences.
PubMed: 38434853
DOI: 10.1021/acsomega.3c08236 -
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 -
Journal of Autism and Developmental... Jan 2024Proton magnetic resonance spectroscopy (H-MRS) has shown inconsistent alterations in brain metabolites of adults with autism spectrum disorder (ASD). We investigated...
The Lack of Alterations in Metabolites in the Medial Prefrontal Cortex and Amygdala, but Their Associations with Autistic Traits, Empathy, and Personality Traits in Adults with Autism Spectrum Disorder: A Preliminary Study.
Proton magnetic resonance spectroscopy (H-MRS) has shown inconsistent alterations in brain metabolites of adults with autism spectrum disorder (ASD). We investigated brain metabolites in the medial prefrontal cortex and amygdala of 24 drug-naive adults with ASD and no intellectual disability and 24 non-ASD control subjects, using 3 T H-MRS. Adults with ASD showed no significant differences from control in glutamate, glutamate plus glutamine, N-acetylaspartate, glycerophosphorylcholine plus phosphorylcholine, creatine plus phosphocreatine, or myo-inositol in either region. However, ASD subjects did show significant correlations of localized brain metabolites with autistic traits, empathy deficits, and personality traits using the Autism-Spectrum Quotient, Questionnaire of Cognitive and Affective Empathy, Interpersonal Reactivity Index, and NEO Personality Inventory-Revised. These findings should be taken as preliminary or exploratory.
Topics: Adult; Humans; Autism Spectrum Disorder; Autistic Disorder; Empathy; Amygdala; Glutamic Acid; Personality; Prefrontal Cortex
PubMed: 36251207
DOI: 10.1007/s10803-022-05778-7 -
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 -
Journal of Infection and Public Health May 2024In Europe, up to 70% of visceral leishmaniasis (VL) cases occurring in adults living with HIV. People living with HIV with VL co-infection often display persistent...
BACKGROUND
In Europe, up to 70% of visceral leishmaniasis (VL) cases occurring in adults living with HIV. People living with HIV with VL co-infection often display persistent parasitemia, requiring chronic intermittent anti-Leishmania therapies. Consequently, frequent VL relapses and higher mortality rates are common in these individuals. As such, it is of paramount importance to understand the reasons for parasite persistence to improve infection management.
METHODS
To outline possible causes for treatment failure in the context of HIV-VL, we followed a person living with HIV-VL co-infection for nine years in a 12-month period. We characterized: HIV-related clinicopathological alterations (CD4 T counts and viremia) and Leishmania-specific seroreactivity, parasitemia, quantification of pro-inflammatory cytokines upon stimulation and studied a Leishmania clinical isolate recovered during this period.
RESULTS
The subject presented controlled viremia and low CD4 counts. The subject remained PCR positive for Leishmania and also seropositive. The cellular response to parasite antigens was erratic. The isolate was identified as the first Leishmania infantum case with evidence of decreased miltefosine susceptibility in Portugal.
CONCLUSION
Treatment failure is a multifactorial process driven by host and parasite determinants. Still, the real-time determination of drug susceptibility profiles in clinical isolates is an unexplored resource in the monitoring of VL.
Topics: Adult; Humans; Portugal; Coinfection; Parasitemia; Viremia; HIV Infections; Leishmaniasis, Visceral; Leishmania infantum; Phosphorylcholine
PubMed: 38522155
DOI: 10.1016/j.jiph.2024.03.008 -
Journal of Colloid and Interface Science Jul 2024Humic acids (HA) are ubiquitous in surface waters, leading to significant fouling challenges. While zwitterion-like and zwitterionic surfaces have emerged as promising...
Humic acids (HA) are ubiquitous in surface waters, leading to significant fouling challenges. While zwitterion-like and zwitterionic surfaces have emerged as promising candidates for antifouling, a quantitative understanding of molecular interaction mechanism, particularly at the nanoscale, still remains elusive. In this work, the intermolecular forces between HA and charged, zwitterion-like or zwitterionic monolayers in aqueous environments were quantified using atomic force microscope. Compared to cationic MTAC ([2-(methacryloyloxy)ethyl]trimethylammonium chloride), which exhibited an adhesion energy of ∼1.342 mJ/m with HA due to the synergistic effect of electrostatic attraction and possible cation-π interaction, anionic SPMA (3-sulfopropyl methacrylate) showed a weaker adhesion energy (∼0.258 mJ/m) attributed to the electrostatic repulsion. Zwitterion-like MTAC/SPMA mixture, driven by electrostatic attraction between opposite charges, formed a hydration layer that prevented the interaction with HA, thereby considerably reducing adhesion energy to ∼0.123 mJ/m. In contrast, zwitterionic MPC (2-methacryloyloxyethyl phosphorylcholine) and DMAPS ([2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ammonium hydroxide) displayed ultralow adhesion energy (0.06-0.07 mJ/m) with HA, arising from their strong dipole moments which could induce a tight hydration layer that effectively inhibited HA fouling. The pH-mediated electrostatic interaction resulted in the increased adhesion energy for MTAC but decreased adhesion energy for SPMA with elevated pH, while the adhesion energy for zwitterion-like and zwitterionic surfaces was independent of environmental pH. Density functional theory (DFT) simulation confirmed the strong binding capability of MPC and DMAPS with water molecules (∼-12 kcal mol). This work provides valuable insights into the molecular interaction mechanisms underlying humic-substance-fouling resistance of charged, zwitterion-like and zwitterionic materials at the nanoscale, shedding light on developing more effective strategy for HA antifouling in water treatment.
PubMed: 38603881
DOI: 10.1016/j.jcis.2024.04.038 -
Journal of Colloid and Interface Science Feb 2024A hydrated 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer brush exhibits exceptional lubricity. This lubrication mechanism has traditionally been attributed to...
HYPOTHESIS
A hydrated 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer brush exhibits exceptional lubricity. This lubrication mechanism has traditionally been attributed to either the inherent fluidity of the brush or the water film that forms owing to its hydrophilic nature. Given previous findings that the frictional properties of the MPC polymer brush film show load dependence, we hypothesize that the lubrication mechanism can be elucidated by examining the shear gap (varies owing to the load) dependence of the brush's viscoelastic response.
EXPERIMENTS
MPC polymer brush films with different thicknesses were prepared. Their viscoelastic responses were evaluated across different shear gap widths, and the frictional properties were subsequently compared across states with distinct viscoelastic behaviors.
FINDINGS
The observed shear viscoelasticity demonstrated a clear gap dependence that correlated with frictional attributes. Our data suggests that the lubrication mechanism shifts based on the shear gap. Specifically, two states exhibited low coefficients of friction: one where the osmotic pressure supports the load while allowing flexible deformation of the brush film, and the other where the brush film undergoes compression and transitions to a fully elastic state.
PubMed: 37944373
DOI: 10.1016/j.jcis.2023.11.013