Left ventricular (LV) hypertrophy is a common finding in patients with severe aortic stenosis (AS). Cardiac magnetic resonance (CMR) is the gold-standard technique to evaluate LV remodeling. Our aim ...was to assess the prevalence and describe the patterns of LV adaptation in AS patients before and after surgical aortic valve replacement (AVR). Prospective study of 130 consecutive patients (71y IQR 68-77y, 48% men) with severe AS, referred for surgical AVR. Patterns of LV remodeling were assessed by CMR. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling. At baseline CMR study: mean LV indexed mass: 81.8 ± 26.7 g/m
; mean end-diastolic LV indexed volume: 85.7 ± 23.1 mL/m
and median geometric remodeling ratio: 0.96 g/mL IQR 0.82-1.08 g/mL. LV hypertrophy occurred in 49% of subjects (concentric 44%; eccentric 5%). Both normal LV structure and concentric remodeling had a prevalence of 25% among the cohort; one patient had an adverse remodeling pattern. Asymmetric LV wall thickening was present in 55% of the patients, with predominant septal involvement. AVR was performed in 119 patients. At 3-6 months after AVR, LV remodeling changed to: normal ventricular geometry in 60%, concentric remodeling in 27%, concentric hypertrophy in 10%, eccentric hypertrophy in 3% and adverse remodeling (one patient). Indexes of AS severity, LV systolic and diastolic function and NT-proBNP were significantly different among the distinct patterns of remodeling. Several distinct patterns of LV remodelling beyond concentric hypertrophy occur in patients with classical severe AS. Asymmetric hypertrophy is a common finding and LV response after AVR is diverse.
Water pollution by dyes is a huge environmental problem; there is a necessity to produce new decolorization methods that are effective, cost-attractive, and acceptable in industrial use. Magnetic ...cyclodextrin polymers offer the advantage of easy separation from the dye solution. In this work, the β-CD-EPI-magnetic (β-cyclodextrin-epichlorohydrin) polymer was synthesized, characterized, and tested for removal of the azo dye Direct Red 83:1 from water, and the fraction of non-adsorbed dye was degraded by an advanced oxidation process. The polymer was characterized in terms of the particle size distribution and surface morphology (FE-SEM), elemental analysis (EA), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), infrared spectrophotometry (IR), and X-ray powder diffraction (XRD). The reported results hint that 0.5 g and pH 5.0 were the best conditions to carry out both kinetic and isotherm models. A 30 min contact time was needed to reach equilibrium with a qmax of 32.0 mg/g. The results indicated that the pseudo-second-order and intraparticle diffusion models were involved in the assembly of Direct Red 83:1 onto the magnetic adsorbent. Regarding the isotherms discussed, the Freundlich model correctly reproduced the experimental data so that adsorption was confirmed to take place onto heterogeneous surfaces. The calculation of the thermodynamic parameters further demonstrates the spontaneous character of the adsorption phenomena (ΔG° = −27,556.9 J/mol) and endothermic phenomena (ΔH° = 8757.1 J/mol) at 25 °C. Furthermore, a good reusability of the polymer was evidenced after six cycles of regeneration, with a negligible decline in the adsorption extent (10%) regarding its initial capacity. Finally, the residual dye in solution after treatment with magnetic adsorbents was degraded by using an advanced oxidation process (AOP) with pulsed light and hydrogen peroxide (343 mg/L); >90% of the dye was degraded after receiving a fluence of 118 J/cm2; the discoloration followed a pseudo first-order kinetics where the degradation rate was 0.0196 cm2/J. The newly synthesized β-CD-EPI-magnetic polymer exhibited good adsorption properties and separability from water which, when complemented with a pulsed light-AOP, may offer a good alternative to remove dyes such as Direct Red 83:1 from water. It allows for the reuse of both the polymer and the dye in the dyeing process.
The capacity of the lethal
Plasmodium falciparum
parasite to develop resistance against anti-malarial drugs represents a central challenge in the global control and elimination of malaria. ...Historically, the action of drug transporters is known to play a pivotal role in the capacity of the parasite to evade drug action. MRPs (Multidrug Resistance Protein) are known in many phylogenetically diverse groups to be related to drug resistance by being able to handle a large range of substrates, including important endogenous substances as glutathione and its conjugates.
P. falciparum
MRPs are associated with in vivo and in vitro altered drug response, and might be important factors for the development of multi-drug resistance phenotypes, a latent possibility in the present, and future, combination therapy environment. Information on
P. falciparum
MRPs is scattered in the literature, with no specialized review available. We herein address this issue by reviewing the present state of knowledge.
Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin ...resistance in Southeast Asia. The
multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple
copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia.
Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target
asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the
multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a
gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of
polymorphisms.
Abstract
Since 2020, there is a new European Regulation (EU, 2020/741) on minimum requirements for water reuse, where routine and validation monitoring requirements (log reductions of indicator ...microorganisms and reference pathogens) have been established. Many reclamation facilities that are already in operation might have difficulties to comply with these performance targets. Existing disinfection systems must be expanded and upgraded. In the case of UV disinfection systems, fluence requirements must be determined to properly design with a focus on the safety and economic-environmental viability of reclaimed water. This study can be used as a reference to develop fluence-response curves for Clostridium perfringens spores, Escherichia coli, and total and F-specific coliphages, indicator microorganisms referred to in the new European Regulation. Eight UV-LED collimated beam tests were performed. Samples were obtained from filtered effluent of secondary treatment from two wastewater treatment plants (WWTPs) which ranged between 30 and 54%. Results showed UV sensitivity of 33.46 mJ/cm2 log I for C. perfringens spores and 2.86 mJ/cm2 log I for E. coli, both from environmental origin. Coliphages were inactivated below the limit of quantitation. The non-dominance of MS2 phages in environmental F-specific coliphages was observed.
Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications ...(associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With an aim to assess the pharmacokinetics of atovaquone, 10 healthy subjects were administered Malarone® alone and in combination with ketoconazole in a crossover study. The results indicated 68% ...higher Cmax, 74% higher AUC and 34% lower CL/F of atovaquone following co-administration with ketoconazole compared to administration of atovaquone alone.
Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in
malaria. It also has an effect on the gametocytes of
; however, it is unclear to what extent PQ affects
...gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with
malaria. To determine gametocyte density, we measured the levels of
transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the
mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation (
= 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in
transcripts. Based on our findings, the
variant plays a role in the persistence of gametocyte density in
malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ-PQ treatment, particularly in settings and seasons of high
human-biting rates.
Summary The prevention and management of malaria is primarily based on the use of drugs. Clinical trials have however revealed that between individuals there is large variability in the ...pharmacokinetic profiles of many antimalarial drugs. The resulting variations in concentrations of the drug within plasma might lead to either suboptimum effectiveness or drug toxicity in some patients. The evidence is increasing that polymorphically expressed drug-metabolising enzymes, predominantly various cytochrome P450 isozymes but also drug transporters, might contribute to the variability in drug response (incomplete cure, relapse, or resistance) or toxicity experienced with antimalarial drugs. For example, there is a clear association between concentrations of proguanil within plasma and certain genetic polymorphisms of CYP2C19 , and genetically established levels of CYP2C8 might have important clinical implications in the toxicity of amodiaquine. Variation in the expression of drug-metabolising enzymes and transport proteins affects the pharmacology of antimalarial drugs. Exploration of pharmacogenetics might help to optimise the use of antimalarial drugs.
Abstract Objectives Primaquine is essential for the radical cure of Plasmodium vivax malaria and must be metabolized into its bioactive metabolites. Accordingly, polymorphisms in ...primaquine-metabolizing enzymes can impact the treatment efficacy. This pioneering study explores the influence of monoamine oxidase-A (MAO-A) on primaquine metabolism and its impact on malaria relapses. Methods Samples from 205 patients with P. vivax malaria were retrospectively analysed by genotyping polymorphisms in MAO-A and cytochrome P450 2D6 (CYP2D6) genes. We measured the primaquine and carboxyprimaquine blood levels in 100 subjects for whom blood samples were available on the third day of treatment. We also examined the relationship between the enzyme variants and P. vivax malaria relapses in a group of subjects with well-documented relapses. Results The median carboxyprimaquine level was significantly reduced in individuals carrying low-expression MAO-A alleles plus impaired CYP2D6. In addition, this group experienced significantly more P. vivax relapses. The low-expression MAO-A status was not associated with malaria relapses when CYP2D6 had normal activity. This suggests that the putative carboxyprimaquine contribution is irrelevant when the CYP2D6 pathway is fully active. Conclusions We found evidence that the low-expression MAO-A variants can potentiate the negative impact of impaired CYP2D6 activity, resulting in lower levels of carboxyprimaquine metabolite and multiple relapses. The findings support the hypothesis that carboxyprimaquine may be further metabolized through CYP-mediated pathways generating bioactive metabolites that act against the parasite.
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