Incommensurate and multiple-q\boldsymbol{q} magnetic misfit order in the frustrated quantum spin ladder material antlerite, Cu3_3SO4_4(OH)4_4

In frustrated magnetic systems, the competition amongst interactions can introduce extremely high degeneracy and prevent the system from readily selecting a unique ground state. In such cases, the magnetic order is often exquisitely sensitive to the balance among the interactions, allowing tuning among novel magnetically ordered phases. In antlerite, Cu$_3$SO$_4$(OH)$_4$, Cu$^{2+}$ ($S=1/2$) quantum spins populate three-leg zigzag ladders in a highly frustrated quasi-one-dimensional structural motif. We demonstrate that at zero applied field, in addition to its recently reported low-temperature phase of coupled ferromagnetic and antiferromagnetic spin chains, this mineral hosts an incommensurate helical+cycloidal state, an idle-spin state, and a multiple-$q$ phase which is the magnetic analog of misfit crystal structures. The antiferromagnetic order on the central leg is reentrant. The high tunability of the magnetism in antlerite makes it a particularly promising platform for pursuing exotic magnetic order.Comment: 18.3 pages, 16 Figures, follow-up paper to arXiv:2203.1534

Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model

Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Findings: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. Conclusions/Significance: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

BACKGROUND Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT03162653

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates

BACKGROUND Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (V$_{d}$) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and V$_{d}$ relative to a formation fraction (f$_{m}$) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH

Validation of an automated system for aliquoting of HIV-1 Env-pseudotyped virus stocks

<div><p>The standardized assessments of HIV-specific immune responses are of main interest in the preclinical and clinical stage of HIV-1 vaccine development. In this regard, HIV-1 Env-pseudotyped viruses play a central role for the evaluation of neutralizing antibody profiles and are produced according to Good Clinical Laboratory Practice- (GCLP-) compliant manual and automated procedures. To further improve and complete the automated production cycle an automated system for aliquoting HIV-1 pseudovirus stocks has been implemented. The automation platform consists of a modified Tecan-based system including a robot platform for handling racks containing 48 cryovials, a Decapper, a tubing pump and a safety device consisting of ultrasound sensors for online liquid level detection of each individual cryovial. With the aim to aliquot the HIV-1 pseudoviruses in an automated manner under GCLP-compliant conditions a validation plan was developed where the acceptance criteria—accuracy, precision as well as the specificity and robustness—were defined and summarized. By passing the validation experiments described in this article the automated system for aliquoting has been successfully validated. This allows the standardized and operator independent distribution of small-scale and bulk amounts of HIV-1 pseudovirus stocks with a precise and reproducible outcome to support upcoming clinical vaccine trials.</p></div

Association between skin autofluorescence of advanced glycation end products and affective disorders in the lifelines cohort study

Background: Oxidative stress may be a mechanistic link between affective disorders (depressive and anxiety disorders) and somatic disease. Advanced glycation end products are produced under the influence of oxidative stress and in the skin (measured by skin autofluorescence [SAF]) serve as marker for cumulative oxidative stress. Aim of study was to determine whether SAF is associated with presence of affective disorders. Methods: Participants in the Lifelines cohort study who had completed the Mini-International Neuropsychiatric Interview for affective disorders and a SAF-measurement were included. Cross-sectional associations between SAF and presence of the following psychiatric disorders were investigated through logistic regression analyses adjusted for sociodemographic factors, cardiometabolic parameters, and somatic morbidities: major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia. Results: Of 81,041 included participants (41.7% male, aged 18–91 years), 6676 (8.2%) were cases with an affective disorder. SAF was associated with presence of affective disorders (OR=1.09 [95%CI 1.07–1.12], P<.001 adjusted for sociodemographic factors). Association with major depressive disorder was strongest and significant after adjustment for all confounders (OR=1.31 [95%CI 1.25–1.36], P<.001 in the crude model; OR=1.12 [95%CI 1.07–1.17], P<.001 in the fully adjusted model). For other disorders, associations lost significance after adjustment for cardiometabolic parameters and somatic morbidities. Limitations: Persons of non-Western descent and severely (mentally or physically) ill individuals were underrepresented. Conclusions: SAF was associated with presence of affective disorders, suggesting a link between these disorders and cumulative oxidative stress. For major depressive disorder, this association was strongest and independent of sociodemographic, cardiometabolic factors, and somatic morbidities

The Subjective Experience of Living with Parkinson's Disease:A Meta-Ethnography of Qualitative Literature

BACKGROUND: A better understanding of the subjective experience of living with Parkinson's disease (PD) and the factors that influence this experience can be used to improve wellbeing of people with PD (PwP). OBJECTIVE: To gain more insight in the subjective experience of PD from the PwP's perspective, and the factors that contribute to this experience. METHODS: In this qualitative review, we performed a systematic search of qualitative studies discussing the subjective experience of PD and extracted reported themes (first order themes). Using a meta-ethnographic approach, we categorized the first order themes into second order themes, and created a third order construct: a holistic model of the subjective experience of living with PD. RESULTS: We included 20 studies with a total sample of 279 PwP. Data-extraction yielded 227 first order themes, which were categorized into the second order themes: 1) Awareness, 2) Disruption, 3) Adjustment, 4) The external environment, and 5) The changing self. With these themes, we developed the "model of dialectic change" which conceptualizes life with PD as a transformative journey, wherein PwP employ strategies to stabilize their changeable relationship with their external environment, while simultaneously redefining their self-concept. CONCLUSION: Our findings indicate that not only the symptoms of PD, but also the manner in which these cause disruptions in the PwP's interaction with their personal environment and self-concept, determine the subjective experience of PD andquality of life. Some PwP experience problems with adjusting, resulting in psychological distress. This calls for a holistic, multidisciplinary and participatory approach of PD