Preoperative cerebrospinal fluid β-Amyloid/Tau ratio and postoperative delirium

Objective: The neuropathogenesis of postoperative delirium remains unknown. Low cerebrospinal fluid (CSF) β-amyloid protein (Aβ) and high CSF Tau levels are associated with Alzheimer's disease. We, therefore, assessed whether lower preoperative CSF Aβ/Tau ratio was associated with higher incidence and greater severity of postoperative delirium. Methods: One hundred and fifty-three participants (71 ± 5 years, 53% men) who had total hip/knee replacement under spinal anesthesia were enrolled. CSF was obtained during initiation of spinal anesthesia. The incidence and severity of postoperative delirium were determined by Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS) on postoperative day 1 and 2. Aβ40, Aβ42, and Tau levels in the CSF were measured by enzyme-linked immunosorbent assay. The relationships among these variables were determined, adjusting for age and gender. Results: Participants in the lowest quartile of preoperative CSF Aβ40/Tau and Aβ42/Tau ratio had higher incidence (32% vs. 17%, P = 0.0482) and greater symptom severity of postoperative delirium (Aβ40/Tau ratio: 4 vs. 3, P = 0.034; Aβ42/Tau ratio: 4 vs. 3, P = 0.062, the median of the highest MDAS score) as compared to the combination of the rest of the quartiles. The preoperative CSF Aβ40/Tau or Aβ42/Tau ratio was inversely associated with MDAS score (Aβ40/Tau ratio: −0.12 ± 0.05, P = 0.014, adj. −0.12 ± 0.05, P = 0.018; Aβ42/Tau ratio: −0.65 ± 0.26, P = 0.013, adj. −0.62 ± 0.27, P = 0.022). Interpretation Lower CSF Aβ/Tau ratio could be associated with postoperative delirium, pending confirmation of our preliminary results in further studies. These findings suggest potential roles of Aβ and/or Tau in postoperative delirium neuropathogenesis

A Higher Correlation of HCV Core Antigen with CD4+ T Cell Counts Compared with HCV RNA in HCV/HIV-1 Coinfected Patients

Development of HCV infection is typically followed by chronic hepatitis C (CHC) in most patients, while spontaneous HCV viral clearance (SVC) occurs in only a minority of subjects. Compared with the widespread application of HCV RNA testing by quantitative RT-PCR technique, HCV core antigen detection may be an alternative indicator in the diagnosis of hepatitis C virus infections and in monitoring the status of infectious individuals. However, the correlation and differences between these two indicators in HCV infection need more investigation, especially in patients coinfected by HIV-1. In this study, a total of 354 anti-HCV and/or anti-HIV serum positive residents from a village of central China were enrolled. Besides HCV-related hepatopathic variables including clinical status, ALT, AST, anti-HCV Abs, as well as the altered CD4+/CD8+ T cell counts, HCV core antigen and HCV viral load were also measured. The concentration of serum HCV core antigen was highly correlated with level of HCV RNA in CHC patients with or without HIV-1 coinfection. Of note, HCV core antigen concentration was negatively correlated with CD4+ T cell count, while no correlation was found between HCV RNA level and CD4+ T cell count. Our findings suggested that quantitative detection of plasma HCV core antigen may be an alternative indicator of HCV RNA qPCR assay when evaluating the association between HCV replication and host immune status in HCV/HIV-1 coinfected patients

Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice

Objective and designCystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.Materials and methodsCFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-κB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.ResultsPharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.ConclusionsLack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury

Nonlinear Modeling of Cortical Responses to Mechanical Wrist Perturbations Using the NARMAX Method

Objective: Nonlinear modeling of cortical responses (EEG) to wrist perturbations allows for the quantification of cortical sensorimotor function in healthy and neurologically impaired individuals. A common model structure reflecting key characteristics shared across healthy individuals may provide a reference for future clinical studies investigating abnormal cortical responses associated with sensorimotor impairments. Thus, the goal of our study is to identify this common model structure and therefore to build a nonlinear dynamic model of cortical responses, using nonlinear autoregressive-moving-Average model with exogenous inputs (NARMAX). Methods: EEG was recorded from ten participants when receiving continuous wrist perturbations. A common model structure detection method was developed for identifying a common NARMAX model structure across all participants, with individualized parameter values. The results were compared to conventional subject-specific models. Results: The proposed method achieved 93.91% variance accounted for (VAF) when implementing a one-step-Ahead prediction and around 50% VAF for a k-step ahead prediction (k = 3), without a substantial drop of VAF as compare to subject-specific models. The estimated common structure suggests that the measured cortical response is a mixed outcome of the nonlinear transformation of external inputs and local neuronal interactions or inherent neuronal dynamics at the cortex. Conclusion: The proposed method well determined the common characteristics across subjects in the cortical responses to wrist perturbations. Significance: It provides new insights into the human sensorimotor nervous system in response to somatosensory inputs and paves the way for future translational studies on assessments of sensorimotor impairments using our modeling approach

Deficiency in the catalytic subunit of DNA-Dependent protein kinase causes down-regulation of ATM

Previous reports have suggested a connection between reduced levels of the catalytic subunit of DNA-dependent protein kinases (DNA-PKcs), a component of the nonhomologeus DNA double-strand break end-joining system, and a reduction in ATM. We studied this possible connection in other DNA-PKcs-deficient cell types, and following knockdown of DNA-PKcs with small interfering RNA, Chinese hamster ovary V3 cells, lacking DNA-PKcs, had reduced levels of ATM and hSMG-1, but both were restored after transfection with PRKDC. Atm levels were also reduced in murine scid cells. Reduction of ATM in a human glioma cell line lacking DNA-PKcs was accompanied by defective signaling through downstream substrates, post-irradiation. A large reduction of DNA-PKcs was achieved in normal human fibroblasts after transfection with two DNA-PKcs small interfering RNA sequences. This was accompanied by a reduction in ATM. These data were confirmed using immunocytochemical detection of the proteins. Within hours after transfection, a decline in PRKDC mRNA was seen, followed by a more gradual decline in DNA-PKcs protein beginning 1 day after transfection. No change in ATM mRNA was observed for 2 days post-transfection. Only after the DNA-PKcs reduction occurred was a reduction in ATM mRNA observed, beginning 2 days post-transfection. The amount of ATM began to decline, starting about 3 days post-treatment, then it declined to levels comparable to DNA-PKcs. Both proteins returned to normal levels at later times. These data illustrate a potentially important cross-regulation between the nonhomologous end-joining system for rejoining of DNA double-strand breaks and the ATM-dependent damage response network of pathways, both of which operate to maintain the integrity of the genome