Persistent isoflurane-induced hypotension causes hippocampal neuronal damage in a rat model of chronic cerebral hypoperfusion

Abstract

Background

Postoperative cognitive dysfunction (POCD) is likely to occur in elderly people, who often suffer from cerebral hypoperfusion and white matter lesions even in the absence of cerebral infarctions.

Methods

Thirty-two adult male rats were randomly assigned to one of four groups: the cerebral normoperfusion + normotension group (n = 8), cerebral normoperfusion + hypotension group (n = 8), chronic cerebral hypoperfusion (CCH) + normotension group (n = 8), and CCH + hypotension group (n = 8). A rat model of CCH was developed via the permanent ligation of the bilateral common carotid arteries, but ligation was avoided in the cerebral normoperfusion groups. Two weeks later, the rats were intubated and mechanically ventilated under isoflurane anesthesia, and their mean arterial blood pressure was maintained over 80 mmHg (normotension) or below 60 mmHg (hypotension) for 2 h. After preparing brain slices, histological cresyl violet staining, ionized calcium binding adaptor molecule 1, a marker of microglial activation, or β amyloid precursor protein, a marker of axonal damage, were performed.

Results and conclusion

CCH per se caused microglial activation and axonal damage, which was not accentuated by hypotension. CCH alone did not cause neuronal damage, but CCH combined with hypotension caused significant neuronal damage in the hippocampal CA1 region. These results suggest that persistent hypotension during general anesthesia might cause neuronal damage in patients with CCH, such as elderly people, and contribute to prevention against POCD.

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The effect of in situ simulation training on the performance of tasks related to patient safety during sedation

Abstract

In many countries, procedural sedation outside of the operating room is performed by pediatricians. We examined if in situ sedation simulation training (SST) of pediatricians improves the performance of tasks related to patient safety during sedation in the Emergency Department (ED). We performed a single-center, quasi-experimental, study evaluating the performance of sedation, before-and-after SST. Sixteen pediatricians were evaluated during sedation as part of their usual practice, using the previously validated Sedation-Performance-Score (SPS). This tool evaluates physician behaviors during sedation that are conducive to safe patient outcomes. Following the sedation, providers completed SST, followed by a structured debriefing. They were then re-evaluated with the SPS during a subsequent patient sedation in the ED. Using multivariate regression, odds ratios were calculated for each SPS component, and were compared before and after the SST. Thirty-two sedations were performed, 16 before and 16 after SST. SPS scores improved from a median of 4 (IQR 2–5) to 6 (IQR 4–7) following SST (p < 0.0009, median difference 2, 95% CI 1–3). SST was associated with improved performance in four SPS components. The findings of this pilot study suggest that sedation simulation training of pediatricians improves several tasks related to patient safety during sedation.

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NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy

Publication date: 20 February 2018
Source:Free Radical Biology and Medicine, Volume 116
Author(s): Kishore Reddy Katikireddy, Tomas L. White, Taiga Miyajima, Shivakumar Vasanth, Duna Raoof, Yuming Chen, Marianne O. Price, Francis W. Price, Ula V. Jurkunas
Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.

Graphical abstract

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An engineered cell line lacking OGG1 and MUTYH glycosylases implicates the accumulation of genomic 8-oxoguanine as the basis for paraquat mutagenicity

Publication date: 20 February 2018
Source:Free Radical Biology and Medicine, Volume 116
Author(s): Preechaya Tajai, Bogdan I. Fedeles, Tawit Suriyo, Panida Navasumrit, Jantamas Kanitwithayanun, John M. Essigmann, Jutamaad Satayavivad
Paraquat (1,1′-dimethyl, 4,4′-bipyridinium dichloride; PQ), a widely used herbicide, is toxic to mammals through ingestion, inhalation and skin contact. Epidemiological data suggest that PQ is also mutagenic and carcinogenic, especially in high doses. The toxic and mutagenic properties of PQ are attributed to the ability of the molecule to redox-cycle, which generates reactive oxygen species (ROS) and subsequent oxidative stress. ROS also cause oxidative DNA damage such as 8-oxoguanine (8OG), a mutagenic base that, when replicated, causes G to T transversion mutations. The present study employed the CHO-derived cell line AS52 to quantify the mutagenic properties of low doses of PQ. By containing a functional, chromosomally-integrated copy of the bacterial gpt gene, AS52 cells a facile system for evaluating the mutagenic properties of genotoxicants. To bolster the sensitivity of this system for detecting mutagenesis of weak mutagens like PQ, and to provide a tool for mechanistic evaluation of the mutagenic process, we constructed a new AS52-derived cell line defective for 8OG DNA repair. Specifically, we employed CRISPR-Cas9 technology to knock out 8-oxoguanine DNA glycosylase (OGG1) and MUTYH glycosylase, two key enzymes involved in the base excision repair of 8OG. The double knock-out (DKO) AS52 cells were found to be more sensitive to PQ toxicity than the parental (WT) AS52 cell line. They experienced higher levels of ROS, which translated into more DNA double-strand breaks, which explained the PQ toxicity. The increased ROS levels also led to more 8OG genomic accumulation, and a higher level of mutations in the DKO cells, suggesting that PQ mutagenesis is mediated primarily by 8OG genomic accumulation. Consistent with this view, antioxidant co-treatment lowered induced cellular ROS and PQ-induced mutagenesis. Taken together, our data demonstrate the strong protective role of OGG1 and MUTYH against PQ-induced mutagenesis. Moreover, our experiments establish the engineered OGG1^-/-MUTYH^-/- AS52 cell line and associated methods as a versatile cellular system for studying in quantitative terms the mutagenesis of other agents, environmental or endogenous, that induce oxidative stress.

Graphical abstract

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Editorial Board

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115





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Targeting the 15-keto-PGE2-PTGR2 axis modulates systemic inflammation and survival in experimental sepsis

Publication date: 1 February 2018
Source:Free Radical Biology and Medicine, Volume 115
Author(s): Ing-Jung Chen, Siow-Wey Hee, Chun-Hsing Liao, Shih-Yao Lin, Lynn Su, Chia-Tung Shun, Lee-Ming Chuang
Sepsis is a systemic inflammation accompanied by multi-organ dysfunction due to microbial infection. Prostaglandins and their metabolites have long been studied for their importance in regulating the innate immune response. 15-keto-PGE2 (15k-PGE2) is a prostaglandin E2 (PGE2) metabolite, whose further processing is catalyzed by prostaglandin reductase 2 (PTGR2). We showed disruption of the Ptgr2 gene in mice improves the survival rate under both LPS- and cecum ligation/puncture (CLP)-induced experimental sepsis. Knockdown of PTGR2 showed significant accumulation of intracellular 15k-PGE2 in activated macrophages. Both PTGR2 knockdown and exogenous treatment with 15k-PGE2 resulted in reduced pro-inflammatory cytokines production in LPS-stimulated RAW264.7 cells or bone marrow-derived macrophages (BMDM). The same treatment in RAW264.7 and BMDM also led to increased levels of the anti-oxidative transcription factor, Nuclear factor (erythroid-2) related factor-2 (NRF2), augmented anti-oxidant response element (ARE)-mediated reporter activity and upregulated expression of the corresponding anti-oxidant genes. 15k-PGE2 further demonstrated modification to Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, at cysteine 288 (Cys288) site post-translationally. Finally, 15k-PGE2-treated mice were found to be more resistant to experimental sepsis. Taken together, our study affirms the significance of PTGR2 and 15k-PGE2 in mitigating inflammatory responses and suggests a novel anti-oxidative and anti-inflammatory therapy for sepsis through targeting PTGR2 and administering15k-PGE2.

Graphical abstract

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Distance between mandibular canal and third molar root among 20-year-old subjects

Abstract

Objectives

The aim of the study was to evaluate the proximity of the mandibular third molar (M3) and the inferior alveolar canal (IAC) in a panoramic radiograph of 20-year-old subjects. The specific aim was to assess differences in this proximity over time.

Materials and methods

Two similar samples of panoramic radiographs taken in a routine oral health examination with 20-year time interval were examined retrospectively and images with both mandibular M3s were included. The material consisted of 300 subjects (25% men, mean age 20.5 ± 0.6 years). The radiographic relationship between the mandibular M3 root and the IAC was assessed as follows: the M3 root was either apart from, tangential to, superimposed with, or inferior to the IAC. Differences between frequencies were tested using the chi-squared test.

Results

In the combined samples, only 16% of the M3s located apart from the IAC, 15% located tangential to, 61% superimposed with, and 8% inferior to the IAC. The proportion of the intimate locations had increased during the 20-year time interval from 79 to 88% (P < 0.01) and especially in females (P < 0.05).

Conclusion

The vast majority of the mandibular M3s situated very close to the mandibular canal.

Clinical relevance

Our results suggest that in the cohort of 20-year-old non-extraction subjects, most of the M3s are possibly at risk for inferior alveolar nerve injury at removal, as judged from the panoramic radiograph, and also the number of such teeth has increased over the 20-year period.

http://ift.tt/2rzVgYW