Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies

PROCESS AND MATERIAL OPTIMISATIONS FOR INTEGRATION OF CHOPPED GLASS FIBRES IN LASER SINTERED POLYMER PARTS

Additively manufactured polymer composites gain popularity in a variety of industries such as aerospace, biomedical and automotive. Laser sintering (LS) is a well-known AM process that typically uses polyamide which can serve as matrix material. Hence LS has the potential to produce reinforced polymers that can meet demanding requirements. In previous research, issues with powder flowability and poor fibre dispersion led to limited increase of mechanical properties. To overcome this, a novel fibre deposition system was recently developed and optimised at KU Leuven to successfully produce fibre reinforced LS samples with random inter- and intralayer fibre orientations. A limited but promising influence of deposited glass fibres on produced LS parts was noted after mechanical testing. In this work, the influence of different (heat) treatments on glass fibres used during LS will be discussed as well as the resulting differences in the fibre/matrix behaviour as analysed through hot stage microscopy.Mechanical Engineerin

A European study on decellularized homografts for pulmonary valve replacement: initial results from the prospective ESPOIR Trial and ESPOIR Registry data\u2020

OBJECTIVES: Decellularized pulmonary homografts (DPH) have shown excellent results for pulmonary valve replacement. However, controlled multicentre studies are lacking to date.METHODS: Prospective European multicentre trial evaluating DPH for pulmonary valve replacement. Matched comparison of DPH to bovine jugular vein (BJV) conduits and cryopreserved homografts (CH) considering patient age, type of heart defect and previous procedures.RESULTS: In total, 121 patients (59 female) were prospectively enrolled (August 2014-December 2016), age 21.3 +/- 14.4 years, DPH diameter 24.4 +/- 2.8 mm. No adverse events occurred with respect to surgical handling; there were 2 early deaths (30 + 59 years) due to myocardial failure after multi-valve procedures and no late mortality (1.7% mortality). After a mean follow-up of 2.2 +/- 0.6 years, the primary efficacy end points mean peak gradient (16.1 +/- 12.1 mmHg) and regurgitation (mean 0.25 +/- 0.48, grade 0-3) were excellent. One reoperation was required for recurrent subvalvular stenosis caused by a pericardial patch and 1 balloon dilatation was performed on a previously stented LPA. 100% follow-up for DPH patients operated before or outside the trial (n = 114) included in the ESPOIR Registry, age 16.6 +/- 10.4 years, diameter 24.1 +/- 4.2 mm, follow-up 5.1 +/- 3.0 years. The combined DPH cohort, n = 235, comprising both Trial and Registry data showed significantly better freedom from explantation (DPH 96.7 +/- 2.1%, CH 84.4 +/- 3.2%, P = 0.029 and BJV 82.7 +/- 3.2%, P = 0.012) and less structural valve degeneration at 10 years when matched to CH, n = 235 and BJV, n = 235 (DPH 61.4 +/- 6.6%, CH 39.9 +/- 4.4%, n.s., BJV 47.5 +/- 4.5%, P = 0.029).CONCLUSIONS: Initial results of the prospective multicentre ESPOIR Trial showed DPH to be safe and efficient. Current DPH results including Registry data were superior to BJV and CH.Thoracic Surger

Associations between Fatty Acid Intakes and Plasma Phospholipid Fatty Acid Concentrations in the European Prospective Investigation into Cancer and Nutrition

Background: The aim of this study is to determine the correlations between dietary fatty acid (FA) intakes and plasma phospholipid (PL) FA levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: The dietary intake of 60 individual FAs was estimated using centre-specific validated dietary questionnaires. Plasma PL FA concentrations of these FAs were measured in non-fasting venous plasma samples in nested case-control studies within the EPIC cohort (n = 4923, using only non-cases). Spearman rank correlations were calculated to determine associations between FA intakes and plasma PL FA levels. Results: Correlations between FA intakes and circulating levels were low to moderately high (-0.233 and 0.554). Moderate positive correlations were found for total long-chain n-3 poly-unsaturated FA (PUFA) (r = 0.354) with the highest (r = 0.406) for n-3 PUFA docosahexaenoic acid (DHA). Moderate positive correlations were also found for the non-endogenously synthesized trans-FA (r = 0.461 for total trans-FA C16-18; r = 0.479 for industrial trans-FA (elaidic acid)). Conclusions: Our findings indicate that dietary FA intakes might influence the plasma PL FA status to a certain extent for several specific FAs. The stronger positive correlations for health-enhancing long-chain PUFAs and the health-deteriorating trans-FA that are not endogenously produced are valuable for future cancer prevention public health interventions

An African Salmonella Typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation

Abstract: Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum β-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA