Senile plaques consisting of amyloid-beta (Aβ) peptides are a major pathological hallmark of Alzheimer’s disease (AD). Aβ peptides are heterogeneous regarding the exact length of their amino- and carboxy-termini. Aβ1-40 and Aβ1-42 are often considered to represent canonical “full-length” Aβ species. Using immunohistochemistry, we analyzed the distribution of Aβ1-x, Aβx-42 and Aβ4-x species in amyloid deposits in the subiculum, hippocampus and cortex in 5XFAD mice during aging. Overall plaque load increased in all three brain regions, with the subiculum being the area with the strongest relative plaque coverage. In the subiculum, but not in the other brain regions, the Aβ1-x load peaked at an age of five months and decreased thereafter. In contrast, the density of plaques positive for N-terminally truncated Aβ4-x species increased continuously over time. We hypothesize that ongoing plaque remodeling takes place, leading to a conversion of deposited Aβ1-x peptides into Aβ4-x peptides in brain regions with a high Aβ plaque burden.

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNɣ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/ɣ-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.

Significance: Psychosocial stress is associated with alterations in serum glucocorticoids and cytokines, such as interleukin-6 (IL-6) and IL-1β, which functionally interact. However, the molecular mechanisms and physiological relationship between the two systems within the context of stress exposure are not well characterized. Recent Advances: Extracellular IL-6, which stimulates the release of cortisol from the zona fasciculata of the adrenal cortex, mediates its intracellular effects by tyrosine phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3). Mitochondrial electron transfer reactions are involved in both STAT3-driven ATP production in oxidative respiration and adrenocortical steroid biosynthesis. Critical Issues: The role of STAT3 in oxidative respiration and steroidogenesis suggests that it integrates both nuclear and mitochondrial actions, thereby preserving main steps of glucocorticoid biosynthesis in the adrenal gland under psychosocial stress. This review discusses the notion that these two pathways are together simultaneously involved in protection against chronic stressors. Future Directions: Linking the function of cytokines and main components of the hypothalamic–pituitary–adrenal (HPA) axis to molecular mechanisms of mitochondrial redox signaling will be essential for a better understanding of the relevant stress-responsive systems engaged in stress vulnerability. Antioxid. Redox Signal. 00, 000–000.

Background In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion. Aims To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times. Methods A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included. Results There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1–2 hours, 2–6 hours and 6–24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C<60 min) had the highest survival benefit from timely reperfusion with PCI within 90 min (OR 0.27, 95% CI 0.23 to 0.31, p<0.0001) as compared with the three groups with longer S2C intervals of 1 hour<S2C≤2 hours (OR 0.44, 95% CI 0.33 to 0.59, p<0.0001), 2 hours<S2C≤6 hours (OR 0.49, 95% CI 0.38 to 0.64, p<0.0001) and 6 hours<S2C≤24 hours (OR 0.42, 95% CI 0.30 to 0.58, p<0.0001). Conclusions Timely reperfusion with a contact-to-balloon time of less than 90 min is most effective in patients presenting with short S2C intervals of less than 1 hour, but has also beneficial effects in patients with S2C intervals of up to 24 hours. Trial registration number NCT00794001.

Physical activity (PA) may have positive effects on mental health in children and adolescents. This post hoc study aimed to further investigate the relationship between different frequency levels of PA and general mental health as well as specific hyperactivity/inattention symptoms in children and adolescents. Methods: The analyses were based on data drawn from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study, a regularly conducted large-scale, epidemiological investigation of somatic and mental health of children and adolescents in Germany. Parents were asked about their children’s attention deficit hyperactivity disorder (ADHD) records and answered questionnaires concerning any mental health problem behavior of the children and adolescents using the Strengths and Difficulties Questionnaire (SDQ). The overall problem score as well as the hyperactivity/inattention symptoms subscale (SDQ-H/I) were entered as outcomes in a regression model controlling for parental socio-economic status and participants’ sex, age, and body mass index (BMI). Cross-sectional analyses were conducted at three time points of the KiGGS study (baseline, wave 1, and wave 2) using general linear models (GLM). This was performed for different age groups (4–5, 6–9, 10–17 years). Results: Significant negative relationships were found between PA and general mental health problems. For the relationship between PA and SDQ-H/I, different patterns emerged at the three time points. There was no interaction between PA frequency levels and diagnosis of ADHD (ADHD vs. non-ADHD controls) regarding the SDQ total score. Conclusion: This study underlines the importance of a high frequency level of PA for a good mental health status among children and adolescents, irrespective of the diagnosis of ADHD.