Pneumococcal meningitis: Clinical-pathological correlations (meningene-path)

Pneumococcal meningitis is associated with substantial mortality and morbidity. We systematically assessed brain histopathology of 31 patients who died of pneumococcal meningitis from a nationwide study (median age 67 years; 21 (67 %) were male) using a pathology score including inflammation and vascular damage. Of the 27 patients with known time from the admission to death, 14 patients died within 7 days of admission and 13 after 7 days of admission. Eleven of 25 (44 %) patients had been treated with adjunctive dexamethasone therapy. Observed pathological processes were inflammation of medium-large arteries in 30 brains (97 %), cerebral haemorrhage in 24 (77 %), cerebritis in 24 (77 %), thrombosis in 21 (68 %), infarction in 19 (61 %) and ventriculitis in 19 (of 28 cases, 68 %). Inflammation of medium-large arteries led to obstruction of the vascular lumen in 14 (of 31 cases, 45 %). Vascular inflammation was associated with infarction and thrombosis of brain parenchymal vessels. Hippocampal dentate gyrus apoptosis between patients treated with and without dexamethasone was similar (p = 0.66); however, dexamethasone treated patients had higher total pathology score than non-dexamethasone treated patients (p = 0.003). Our study shows that vascular damage is key in the process of brain damage in pneumococcal meningitis. Data and material of this study will be made open-access for translational research in pneumococcal meningitis (MeninGene-Path)

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio (‘desaturation index’) – displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = −0.80; P = 0.0001) and the Boston Naming test (r = −0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD

Induction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer’s Disease

Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer’s disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-β exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented Aβ-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD

The novel RAGE interactor PRAK is associated with autophagy signaling in Alzheimer’s disease pathogenesis

BACKGROUND: The receptor for advanced glycation end products (RAGE) has been found to interact with amyloid β (Aβ). Although RAGE does not have any kinase motifs in its cytosolic domain, the interaction between RAGE and Aβ triggers multiple cellular signaling involved in Alzheimer’s disease (AD). However, the mechanism of signal transduction by RAGE remains still unknown. Therefore, identifying binding proteins of RAGE may provide novel therapeutic targets for AD. RESULTS: In this study, we identified p38-regulated/activated protein kinase (PRAK) as a novel RAGE interacting molecule. To investigate the effect of Aβ on PRAK mediated RAGE signaling pathway, we treated SH-SY5Y cells with monomeric form of Aβ. We demonstrated that Aβ significantly increased the phosphorylation of PRAK as well as the interaction between PRAK and RAGE. We showed that knockdown of PRAK rescued mTORC1 inactivation induced by Aβ treatment and decreased the formation of Aβ-induced autophagosome. CONCLUSIONS: We provide evidence that PRAK plays a critical role in AD pathology as a key interactor of RAGE. Thus, our data suggest that PRAK might be a potential therapeutic target of AD involved in RAGE-mediated cell signaling induced by Aβ. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0068-5) contains supplementary material, which is available to authorized users

Triple Oxygen Isotopes: Fundamental Relationships and Applications

Copyright © 2016 by Annual Reviews. All rights reserved. The element oxygen has three stable isotopes: 16O, 17O, and 18O. For a defined process, a change in 18O16O scales with the corresponding change in 17O16O, or the fractionation factors 18α and 17α have a relationship of θ = ln17αln18α, in which the triple oxygen isotope exponent θ is relatively fixed but does vary with reaction path, temperature, and species involved. When the small variation is of interest, the distinction of three concepts-θ, S (a slope through data points in δ17O-δ18O space), and C (an arbitrary referencing number for the degree of 17O deviation)-becomes important. Triple oxygen isotope variations can be measured by modern instruments and thus offer an additional line of information on the underlying reaction processes and conditions. Analytical methods and Earth science applications have recently been developed for air oxygen, carbon dioxide, water, silicates, oxides, sulfates, carbonates, and phosphates

The reliability of the twelve-item general health questionnaire (GHQ-12) under realistic assumptions

Background: The twelve-item General Health Questionnaire (GHQ-12) was developed to screen for non-specific psychiatric morbidity. It has been widely validated and found to be reliable. These validation studies have assumed that the GHQ-12 is one-dimensional and free of response bias, but recent evidence suggests that neither of these assumptions may be correct, threatening its utility as a screening instrument. Further uncertainty arises because of the multiplicity of scoring methods of the GHQ-12. This study set out to establish the best fitting model for the GHQ-12 for three scoring methods (Likert, GHQ and C-GHQ) and to calculate the degree of measurement error under these more realistic assumptions.Methods: GHQ-12 data were obtained from the Health Survey for England 2004 cohort (n = 3705). Structural equation modelling was used to assess the fit of [1] the one-dimensional model [2] the current 'best fit' three-dimensional model and [3] a one-dimensional model with response bias. Three different scoring methods were assessed for each model. The best fitting model was assessed for reliability, standard error of measurement and discrimination.Results: The best fitting model was one-dimensional with response bias on the negatively phrased items, suggesting that previous GHQ-12 factor structures were artifacts of the analysis method. The reliability of this model was over-estimated by Cronbach's Alpha for all scoring methods: 0.90 (Likert method), 0.90 (GHQ method) and 0.75 (C-GHQ). More realistic estimates of reliability were 0.73, 0.87 and 0.53 (C-GHQ), respectively. Discrimination (Delta) also varied according to scoring method: 0.94 (Likert method), 0.63 (GHQ method) and 0.97 (C-GHQ method).Conclusion: Conventional psychometric assessments using factor analysis and reliability estimates have obscured substantial measurement error in the GHQ-12 due to response bias on the negative items, which limits its utility as a screening instrument for psychiatric morbidity