Allopregnanolone Promotes Regeneration and Reduces β-Amyloid Burden in a Preclinical Model of Alzheimer's Disease

Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease

Diagnosis of Bacterial Bloodstream Infections: A 16S Metagenomics Approach

YesBackground. Bacterial bloodstream infection (bBSI) is one of the leading causes of death in critically ill patients and accurate diagnosis is therefore crucial. We here report a 16S metagenomics approach for diagnosing and understanding bBSI. Methodology/Principal Findings. The proof-of-concept was delivered in 75 children (median age 15 months) with severe febrile illness in Burkina Faso. Standard blood culture and malaria testing were conducted at the time of hospital admission. 16S metagenomics testing was done retrospectively and in duplicate on the blood of all patients. Total DNA was extracted from the blood and the V3–V4 regions of the bacterial 16S rRNA genes were amplified by PCR and deep sequenced on an Illumina MiSeq sequencer. Paired reads were curated, taxonomically labeled, and filtered. Blood culture diagnosed bBSI in 12 patients, but this number increased to 22 patients when combining blood culture and 16S metagenomics results. In addition to superior sensitivity compared to standard blood culture, 16S metagenomics revealed important novel insights into the nature of bBSI. Patients with acute malaria or recovering from malaria had a 7-fold higher risk of presenting polymicrobial bloodstream infections compared to patients with no recent malaria diagnosis (p-value = 0.046). Malaria is known to affect epithelial gut function and may thus facilitate bacterial translocation from the intestinal lumen to the blood. Importantly, patients with such polymicrobial blood infections showed a 9-fold higher risk factor for not surviving their febrile illness (p-value = 0.030). Conclusions/Significance. Our data demonstrate that 16S metagenomics is a powerful approach for the diagnosis and understanding of bBSI. This proof-of-concept study also showed that appropriate control samples are crucial to detect background signals due to environmental contamination.This work was supported by the Flemish Ministry of Sciences (EWI, SOFI project IDIS).This paper has been subject to a correction. Please see Correction file above

A multilevel approach to understanding the determinants of maternal harsh parenting: the importance of maternal age and perceived partner support

Determinants of parenting are most often considered using one child per family within a cross-sectional design. In 182 families, the current study included two siblings and sought to predict maternal harsh parenting measured prospectively when each child was age 2 years from child gender, infant temperament, maternal age, maternal educational attainment, maternal depression and anxiety and maternal perceptions of partner support. Multilevel modeling was used to examine between- and within-family variance simultaneously. Mothers reported levels of harsh parenting that were similar towards both children (intraclass correlation = 0.69). Thus, the majority of variance in maternal perceptions of their harsh parenting resided between rather than within families and was accounted for in part by maternal age and maternal perceptions of partner support. Results are discussed in relation to family-wide determinants of harsh parenting, previous literature pertaining to parenting siblings and the potential avenues for future research and practice

Technology as a disruptive agent: Intergenerational perspectives

YesThis study explores how British South Asian parents perceive their children’s technology consumption through their collectivist lenses and interdependent values. The findings for this qualitative study indicate that second and third generation South Asian parents acknowledge the benefits of children’s technology use; but largely perceive technology as a disruptive agent, whereby children are becoming isolated and increasingly independent within the household. The analysis aims to understand how parents view their children’s relationship with others as a result of technology consumption. Accordingly, this paper proposes an extension of the Construal of self conceptualisation and contributes a Techno-construal matrix that establishes a dyadic connection between technology consumption and cultural values. Overall, the study reveals that children display less inter-reliance and conformance typically associated with collectivist cultures, resulting from their technology use. Consequently, parents interpret their children’s shift from interdependence to more independence as a disruptive and unsettling phenomenon within the household