Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents.

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 µM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve's steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 µM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 µM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD's modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.

The effect of sugammadex versus neostigmine on postoperative nausea and vomiting: a meta-analysis of randomized controlled trials with trial sequential analysis.

INTRODUCTION: Association between sugammadex and risk of postoperative nausea and vomiting remains unclear. EVIDENCE ACQUISITION: We performed meta-analysis of randomized controlled trials with trial sequential analysis to compare sugammadex with neostigmine in adults receiving elective surgery under general anesthesia with postoperative extubation. Databases of MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to April 15, 2022. Primary outcome was risk of postoperative nausea and vomiting after patients received sugammadex or neostigmine. Secondary outcomes were incidences of sugammadex-related complications. EVIDENCE SYNTHESIS: Meta-analysis of 40 trials with 5455 patients showed an overall lower risk of postoperative nausea and vomiting in the sugammadex group than in the neostigmine group (risk ratio: 0.85, 95% CI [0.76-0.94], heterogeneity I2=4%, P=0.002). Subgroup analyses demonstrated a lower risk of postoperative nausea and vomiting associated with sugammadex than with neostigmine: 1) in the postanesthesia care unit (risk ratio: 0.77, 95% CI [0.66-0.90], I2=8%, P=0.001) but not in wards; 2) under volatile anesthetics but not total intravenous anesthesia; 3) regardless of the administration of prophylactic antiemetics; and 4) when sugammadex was administered at 2 mg/kg but not 4 mg/kg. No major complications such as cardiac arrest or refractory bradycardia were noted and every patient achieved adequate neuromuscular recovery before extubation in all of the included trials. The overall quality of evidence was moderate. CONCLUSIONS: Sugammadex was associated with a lower risk of postoperative nausea and vomiting compared with neostigmine immediately after surgery, especially for patients receiving volatile anesthetics regardless of the use of prophylactic antiemetics.

Factors influencing neutralizing antibody titers elicited by coronavirus disease 2019 vaccines.

The World Health Organization has highlighted the importance of an international standard (IS) for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) neutralizing antibody titer detection to calibrate diagnostic techniques. We applied an IS to calibrate neutralizing antibody titers (NTs) (international units/mL) in response to coronavirus disease 2019 (COVID-19) vaccination. Moreover, the association between different factors and neutralizing antibodies was analyzed. A total of 1667 serum samples were collected from participants receiving different COVID-19 vaccines. Antibody titers were determined by a microneutralization assay using live viruses in a biosafety level 3 (BSL-3) laboratory and a commercial serological MeDiPro kit. The titer determined using the MeDiPro kit was highly correlated with the NT determined using live viruses and calibrated using IS. Fever and antipyretic analgesic treatment were related to neutralizing antibody responses in ChAdOx1-S and BNT162b2 vaccinations. Individuals with diabetes showed a low NT elicited by MVC-COV1901. Individuals with hypertension receiving the BNT162b2 vaccine had lower NTs than those without hypertension. Our study provided the international unit (IU) values of NTs in vaccinated individuals for the development of vaccines and implementation of non-inferiority trials. Correlation of the influencing factors with NTs can provide an indicator for selecting COVID-19 vaccines based on personal attributes.

Prescription Opioid Use among Patients with Chronic Noncancer Pain before and after the COVID-19 Outbreak in Taiwan: A Multicenter Prospective Observational Study.

BACKGROUND: The COVID-19 outbreak disrupted medical access for patients receiving chronic opioid therapy. This study investigated their prescription opioid dosages before and after the 2020 outbreak in Taiwan. METHODS: A prospective questionnaire survey was conducted among registered outpatients receiving long-term opioids before July 2019 in Taiwan. The questionnaire included items from the Taiwanese Brief Pain Inventory and quality of life assessment. Follow-up surveys in outpatient departments through October 2020 were conducted to collect opioid prescription data. RESULTS: After a mean of 531 days, the questionnaire responses of 103 of the initial 117 respondents were reviewed. Daily opioid doses decreased for 31 respondents (30.1%), remained roughly equivalent (defined as ±2.5%) for 27 (26.2%), and increased for 45 (43.7%) after the first wave of the pandemic. The use of strong opioids and nonopioid medications did not significantly differ among the three groups, but less fentanyl patch use was noted in the decreased-dose group after the outbreak. More than 70% of the patients received daily high-dose opioids (≥90 morphine milligram equivalents); moreover, 60% reported constipation. No deaths due to opioid overdose occurred during the study period. CONCLUSIONS: The COVID-19 outbreak in 2020 did not interrupt access to long-term opioid prescriptions for most registered patients with chronic pain in Taiwan. Less fentanyl patch use was observed in participants whose opioid dose was tapering.

The Surface Amine Group of Ultrasmall Magnetic Iron Oxide Nanoparticles Produce Analgesia in the Spinal Cord and Decrease Long-Term Potentiation.

Our previous studies have revealed the ultrasmall superparamagnetic iron oxide in the amine group USPIO-101 has an analgesic effect on inflammatory pain. Here, we further investigated its effect on the spinal cord and brain via electrophysiological and molecular methods. We used a mouse inflammatory pain model, induced by complete Freund's adjuvant (CFA), and measured pain thresholds via von Frey methods. We also investigated the effects of USPIO-101 via an extracellular electrophysiological recording at the spinal dorsal horn synapses and hippocampal Schaffer collateral-CA1 synapses, respectively. The mRNA expression of pro-inflammatory cytokines was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Our results showed intrathecal USPIO-101 produces similar analgesic behavior in mice with chronic inflammatory pain via intrathecal or intraplantar administration. The potentiated low-frequency stimulation-induced spinal cord long-term potentiation (LTP) at the spinal cord superficial dorsal horn synapses could decrease via USPIO-101 in mice with chronic inflammatory pain. However, the mRNA expression of cyclooxygenase-2 was enhanced with lipopolysaccharide (LPS) stimulation in microglial cells, and we also found USPIO-101 at 30 µg/mL could decrease the magnitude of hippocampal LTP. These findings revealed that intrathecal USPIO-101 presented an analgesia effect at the spinal cord level, but had neurotoxicity risk at higher doses.

Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase-containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase-containing neurons but not pyramidal neurons of the hippocampus.

TGF-ß1 in plasma and cerebrospinal fluid can be used as a biological indicator of chronic pain in patients with osteoarthritis.

INTRODUCTION: Previous studies have demonstrated that cytokines, transforming growth factor (TGF-ß1), and brain-derived neurotrophic factor (BDNF) can impact the intensity of pain in rodents. However, the roles of cytokines, TGF-ß1 and BDNF in humans with chronic pain in osteoarthritis remains unclear, and no comparison between plasma and central cerebral spinal fluid (CSF) has been conducted. METHODS: Patients with osteoarthritis who were scheduled to receive spinal anesthesia were enrolled. The intensity of pain was evaluated with a visual analogue scale (VAS). In addition, patients with genitourinary system (GU) diseases and without obvious pain (VAS 0-1) were included as a comparison (control) group. The levels of TGF-ß1, BDNF, tumor necrosis factor-α (TNF-α), and interleukin (IL)-8 within the CSF and plasma were collected and evaluated before surgery. RESULTS: The plasma and CSF TGF-ß1 levels were significantly lower in the osteoarthritis patients with pain (VAS ≥ 3) than in the GU control patients. Downregulation of plasma BDNF was also found in osteoarthritis patients with pain. The Spearman correlation analysis showed that the VAS pain scores were significantly negatively correlated with the levels of TGF-ß1 in the CSF of patients with osteoarthritis. However, there was no significant correlations between the pain scores and the levels of BDNF, TNF-α, and IL-8 in either the CSF or plasma. CONCLUSIONS: TGF-ß1 but not BDNF, TNF-α, or IL-8 may be an important biological indicator in the CSF of osteoarthritis patients with chronic pain.

Upregulation of Glutamatergic Receptors in Hippocampus and Locomotor Hyperactivity in Aged Spontaneous Hypertensive Rat.

Epidemiologic studies have indicated that chronic hypertension may facilitate the progression of abnormal behavior, such as emotional irritability, hyperactivity, and attention impairment. However, the mechanism of how chronic hypertension affects the brain and neuronal function remains unclear. In this study, 58-week-old male spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats were used. Their locomotor activity and neuronal function were assessed by the open field test, novel object, and Y maze recognition test. Moreover brain tissues were analyzed. We found that the aged SHR exhibited significant locomotor hyperactivity when compared to the WKY rats. However, there was no significant difference in novel object and novel arm recognition between aged SHR and the WKY rats. In the analysis of synaptic membrane protein, the expression of glutamatergic receptors, such as the N-methyl-D-aspartate (NMDA) receptor receptors subunits 2B (GluN2B) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 1 (GluA1) in the hippocampus of SHR were significantly higher than those of WKY rats. In addition, in the synaptic membrane of SHR's hippocampus and medial prefrontal cortex (mPFC), a down-regulation of astrocytes was found, though the excitatory amino acid transporter 2 (EAAT2) remained constant. Moreover, a down-regulation of microglia in the hippocampus and mPFC was seen in the SHR brain. Long-term exposure to high blood pressure causes upregulation of glutamate receptors. The upregulation of glutamatergic receptors in hippocampus may contribute to the hyper-locomotor activity of aged rodents and may as a therapeutic target in hypertension-induced irritability and hyperactivity.

Population-Based Study on the All-Cause and Cause-Specific Risks of Mortality among Long-Term Opioid Analgesics Users without Cancer in Taiwan.

(1) Background: The prevalence of opioid use in Taiwan increased by 41% between 2002 and 2014. However, little is known regarding the risk of mortality among long-term opioid analgesics users who do not have cancer. This study investigated this mortality risk with an emphasis on the calendar year and patients' age and sex. (2) Methods: This retrospective cohort study included 12,990 adult individuals without cancer who were long-term users of opioid analgesics and were randomly selected from the data set of Taiwan's National Health Insurance program from 2000 to 2012. They were then followed up through 2013. Information on the underlying causes of death was retrieved from the Taiwan Death Registry. Age, sex, and calendar year-standardized mortality ratios (SMRs) of all-cause and cause-specific mortality were calculated with reference to those of the general population. (3) Results: With up to 14 years of follow-up, 558 individuals had all-cause mortality in 48,020 person-years (cumulative mortality: 4.3%, mortality rate: 11.62 per 1000 person-years). Compared with the general population, the all-cause SMR of 4.30 (95% confidence interval (95% CI): 3.95-4.66) was significantly higher: it was higher in men than in women, declined with calendar year and age, and was significantly higher for both natural (4.15, 95% CI: 3.78-4.53) and unnatural (5.04, 95% CI: 3.88-6.45) causes. (4) Conclusions: Long-term opioid analgesics use among individuals without cancer in Taiwan was associated with a significantly increased risk of mortality. The notably increased mortality in younger adults warrants attention. Strategies to reduce long-term opioid analgesics use, especially their overuse or misuse, are in an urgent need.

Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor.

PT-2385 is currently regarded as a potent and selective inhibitor of hypoxia-inducible factor-2α (HIF-2α), with potential antineoplastic activity. However, the membrane ion channels changed by this compound are obscure, although it is reasonable to assume that the compound might act on surface membrane before entering the cell´s interior. In this study, we intended to explore whether it and related compounds make any adjustments to the plasmalemmal ionic currents of pituitary tumor (GH3) cells and human 13-06-MG glioma cells. Cell exposure to PT-2385 suppressed the peak or late amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner, with IC50 values of 8.1 or 2.2 µM, respectively, while the KD value in PT-2385-induced shortening in the slow component of IK(DR) inactivation was estimated to be 2.9 µM. The PT-2385-mediated block of IK(DR) in GH3 cells was little-affected by the further application of diazoxide, cilostazol, or sorafenib. Increasing PT-2385 concentrations shifted the steady-state inactivation curve of IK(DR) towards a more hyperpolarized potential, with no change in the gating charge of the current, and also prolonged the time-dependent recovery of the IK(DR) block. The hysteretic strength of IK(DR) elicited by upright or inverted isosceles-triangular ramp voltage was decreased during exposure to PT-2385; meanwhile, the activation energy involved in the gating of IK(DR) elicitation was noticeably raised in its presence. Alternatively, the presence of PT-2385 in human 13-06-MG glioma cells effectively decreased the amplitude of IK(DR). Considering all of the experimental results together, the effects of PT-2385 on ionic currents demonstrated herein could be non-canonical and tend to be upstream of the inhibition of HIF-2α. This action therefore probably contributes to down-streaming mechanisms through the changes that it or other structurally resemblant compounds lead to in the perturbations of the functional activities of pituitary cells or neoplastic astrocytes, in the case that in vivo observations occur.

Gender Differences in Depression and Sex Hormones among Patients Receiving Long-Term Opioid Treatment for Chronic Noncancer Pain in Taiwan-A Multicenter Cross-Sectional Study.

BACKGROUND: Long-term use of opioids for chronic noncancer pain is associated with sex hormone disturbances. The interferences with sex hormones, sexual function, and depression were investigated in patients with chronic noncancer pain. METHODS: A cross-sectional multicenter survey was conducted on 170 officially registered outpatients receiving long-term opioid treatment in nine medical centers in Taiwan between October 2018 and July 2019. Serum sex hormone levels were examined after the collection of self-administered questionnaires containing the Taiwanese version of the Brief Pain Inventory, depressive status, and sexual function interference. RESULTS: Among 117 (68.8%) questionnaire responses from 170 enrolled outpatients, 38 women and 62 men completed the sex hormone tests, among whom only 23 (23%) had previously received blood hormone tests. Low serum total testosterone levels were detected in 34 (89.5%) women (<30 ng/dL) and 31 (50%) men (<300 ng/dL). Over 60% of women and men reported reduced sexual desire and function despite a nearly 50% reduction in pain intensity and daily function interference over the previous week after opioid treatment. Women generally had higher risks of a depression diagnosis (p = 0.034) and severe depressive symptoms (p = 0.003) and nonsignificantly lower opioid treatment duration (median 81 vs. 120 months) and morphine milligram equivalent (median 134 vs. 165 mg/day) compared with men. CONCLUSIONS: This survey demonstrated the high prevalence of depression diagnosis, low sex hormone levels, and reduced sexual function among Taiwanese patients with chronic noncancer pain receiving prolonged opioid therapy. Regular hypogonadal screenings are recommended for further management.

Role of the Chaperone Protein 14-3-3ε in the Regulation of Influenza A Virus-Activated Beta Interferon.

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in retinoic acid-inducible gene I (RIG-I) translocation to mitochondrial antiviral-signaling protein (MAVS) to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-ß promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-ß expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C terminus-truncated NS1 with a T49A mutation dramatically increases IFN-ß mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-ß expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in retinoic acid-inducible gene I (RIG-I) translocation that induces type I interferon (IFN) expression, and that NS1 protein prevents RIG-I translocation to the mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-ß suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.

Cellular 5'-3' mRNA Exoribonuclease XRN1 Inhibits Interferon Beta Activation and Facilitates Influenza A Virus Replication.

Cellular 5'-3' exoribonuclease 1 (XRN1) is best known for its role as a decay factor, which by degrading 5' monophosphate RNA after the decapping of DCP2 in P-bodies (PBs) in Drosophila, yeast, and mammals. XRN1 has been shown to degrade host antiviral mRNAs following the influenza A virus (IAV) PA-X-mediated exonucleolytic cleavage processes. However, the mechanistic details of how XRN1 facilitates influenza A virus replication remain unclear. In this study, we discovered that XRN1 and nonstructural protein 1 (NS1) of IAV are directly associated and colocalize in the PBs. Moreover, XRN1 downregulation impaired viral replication while the viral titers were significantly increased in cells overexpressing XRN1, which suggest that XRN1 is a positive regulator in IAV life cycle. We further demonstrated that the IAV growth curve could be suppressed by adenosine 3',5'-bisphosphate (pAp) treatment, an inhibitor of XRN1. In virus-infected XRN1 knockout cells, the phosphorylated interferon regulatory factor 3 (p-IRF3) protein, interferon beta (IFN-ß) mRNA, and interferon-stimulated genes (ISGs) were significantly increased, resulting in the enhancement of the host innate immune response and suppression of viral protein production. Our data suggest a novel mechanism by which the IAV hijacks the cellular XRN1 to suppress the host innate immune response and to facilitate viral replication. IMPORTANCE A novel mechanistic discovery reveals that the host decay factor XRN1 contributes to influenza A virus replication, which exploits XRN1 activity to inhibit RIG-I-mediated innate immune response. Here, we identified a novel interaction between viral NS1 and host XRN1. Knockdown and knockout of XRN1 expression in human cell lines significantly decreased virus replication while boosting RIG-I-mediated interferon immune response, suggesting that XRN1 facilitates influenza A virus replication. The pAp effect as XRN1 inhibitor was evaluated; we found that pAp was capable of suppressing viral growth. To our knowledge, this study shows for the first time that a negative-strand and nucleus-replicating RNA virus, as influenza A virus, can hijack cellular XRN1 to suppress the host RIG-I-dependent innate immune response. These findings provide new insights suggesting that host XRN1 plays a positive role in influenza A virus replication and that the inhibitor pAp may be used in novel antiviral drug development.

Erector Spinae Plane Block Similar to Paravertebral Block for Perioperative Pain Control in Breast Surgery: A Meta-Analysis Study.

BACKGROUND: Erector spinae plane block could be a potential alternative to paravertebral block or other analgesic techniques for breast surgery, but the current evidence on erector spinae plane block in breast surgery is conflicting. OBJECTIVE: To compare the analgesic effectiveness between erector spinae plane block, systemic analgesic, and paravertebral block for breast surgery. STUDY DESIGN: Meta-analysis. SETTING: The literature search was performed from 2016 to August 2020 using the MEDLINE, EMBASE, Cochrane library, and ClinicalTrials.gov databases. METHODS: Clinical trials comparing erector spinae plane block to systemic analgesic and paravertebral block were included from the aforementioned databases. Primary outcomes were 24-hour postoperative opioid administration and postoperative pain score. Secondary outcomes were patient satisfaction levels, post-anesthesia care unit and hospital stay, block-related side effects, and opioid-related side effects. Systematic search, critical appraisal, and pooled analysis were performed according to the PRISMA statement. RESULTS: We analyzed 495 cases in 8 randomized controlled trials. Compared with a systemic analgesic, the use of erector spinae plane block resulted in a reduced 24-hour postoperative intravenous morphine equivalent dose by a mean difference of 7.59 mg (P < 0.00001). Compared with paravertebral block, no statistical difference was found in opioid administration. No differences were observed in pain score, opioid-related side effects, or analgesic technique-related complications. Between the trials, heterogeneity existed and could not be evaluated using meta-regression owing to inadequate reported data. LIMITATIONS: Moderate heterogeneity among the included trials could not be assessed by potential covariates owing to the limited reported data in each trial. CONCLUSION: Erector spinae plane block is superior to systemic analgesic within 24 hours after breast surgery and can serve as an alternative to paravertebral block with similar analgesic effects.

Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea.

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

Morphine produces better thermal analgesia in young Huntington mice and are associated with less neuroinflammation in spinal cord.

BACKGROUND: Huntington's disease (HD) is an inherited disease characterized by both mental and motor dysfunctions. Our previous studies showed that HD mice demonstrate a diminished pain response. However, few studies have focused on the relationship between HD and morphine analgesia. The purpose of this study is to investigate and compare the analgesic effects of morphine in HD and wild-type (WT) mice. METHODS: We used clinically similar transgenic HD mice (7-10 weeks of age with motor dysfunction at 8-9 mo of age) carrying a mutant Huntington CAG trinucleotide repeats to evaluate morphine analgesia. The morphine (10 mg/kg subcutaneously) analgesia was evaluated with a tail-flick in hot water (52°C). Mice spinal cords were harvested at the end of the analgesia studies. An immunofluorescence assay and western blotting were used to identify changes in the cells and cytokines. RESULTS: Our data demonstrate that preonset young HD mice exhibited a better analgesic response to morphine than the WT mice. Western blotting and an immunohistological examination of the lumbar spinal cord tissue indicated less activation of glial cells and astrocytes in the HD mice compared with the WT mice. The production levels of tumor necrosis factor α and interleukine-1ß were also lower in the young HD mice. CONCLUSION: Our data demonstrate better morphine analgesic and less pain-related cytokine responses at the spinal cord level for HD mice. Further studies are needed to determine the morphine analgesia mechanism in HD.

Optimize General Anesthesia for a Dystrophic Epidermolysis Bullosa Patient That Cannot Be Intubated.

Dystrophic epidermolysis bullosa (DEB) is a rare genetic skin disease characterized by blisters and ulcers on the skin and mucosa after minor friction. The risk of invasive squamous cell carcinoma on the unhealed ulcers increases with age. Tracheal intubation during general anesthesia may induce tracheal stricture due to blister formation and/or scarring in DEB patients and cause severe airway obstruction. There is no consensus for handling DEB patients' fragile mucosa and skin during general anesthesia. We report an adult DEB patient who received two operations under different general anesthesia methods. The experience from this particular patient and her response to anesthesia may provide a satisfactory guide to avoid complications and improve the outcome for DEB patients receiving general anesthesia.

Mortality Risks for Dialysis Patients: A Nationwide Population-Based Study.

OBJECTIVE: Several studies have demonstrated increased postoperative mortality rates in patients on chronic hemodialysis compared with non-dialyzed patients. However, limited studies have examined factors that may contribute to postoperative mortality. METHODS: In this retrospective cohort study, data were collected from 9,140 dialysis and 45,725 non-dialysis patients undergoing surgery between 2007 to 2009 from Taiwan's National Health Insurance Registry Database. Patient demographics, comorbidities, and anesthesia duration were used to compare 30-day postoperative mortality differences in dialysis patients. RESULTS: Dialysis patients undergoing first-time surgery were significantly older, more likely male, and possessed more comorbidities. Overall, dialysis patients had significantly higher all-cause postoperative mortality (odds ratio, 15.005; 95% confidence interval, 11.917-18.893). Gender (hazard ratio [HR], 0.762), age (HR, 1.012), longer duration of inhalation general anesthesia (HR, 1.113), and comorbidities of hypertension (HR, 0.759), diabetes (HR, 1.339), congestive heart failure (HR, 1.232), coronary artery disease (HR, 1.326), cerebral vascular accident (HR, 1.312), intracranial hemorrhage (HR, 6.765), gastrointestinal bleeding (HR, 1.396), and liver cirrhosis (HR, 2.027), independently increased postoperative mortality risk in dialysis patients. Of the comorbidities, intracranial hemorrhage posed the greatest risk. CONCLUSION: Patient demographics, anesthesia factors, and comorbidities help dialysis patients understand their postoperative mortality. These potential risk factors also inform anesthesiologists and surgeons weight perioperative conditions in dialysis patients before surgery.

SARS-CoV-2 genomic surveillance in Taiwan revealed novel ORF8-deletion mutant and clade possibly associated with infections in Middle East.

Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.