EETs/sEHi alleviates nociception by blocking the crosslink between endoplasmic reticulum stress and neuroinflammation in a central poststroke pain model.

BACKGROUND: Central post-stroke pain (CPSP) is a chronic and intolerable neuropathic pain syndrome following a cerebral vascular insult, which negatively impacts the quality of life of stroke survivors but currently lacks efficacious treatments. Though its underlying mechanism remains unclear, clinical features of hyperalgesia and allodynia indicate central sensitization due to excessive neuroinflammation. Recently, the crosslink between neuroinflammation and endoplasmic reticulum (ER) stress has been identified in diverse types of diseases. Nevertheless, whether this interaction contributes to pain development remains unanswered. Epoxyeicosatrienoic acids (EETs)/soluble epoxy hydrolase inhibitors (sEHi) are emerging targets that play a significant role in pain and neuroinflammatory regulation. Moreover, recent studies have revealed that EETs are effective in attenuating ER stress. In this study, we hypothesized that ER stress around the stroke site may activate glial cells and lead to further inflammatory cascades, which constitute a positive feedback loop resulting in central sensitization and CPSP. Additionally, we tested whether EETs/sEHi could attenuate CPSP by suppressing ER stress and neuroinflammation, as well as their vicious cycle, in a rat model of CPSP. METHODS: Young male SD rats were used to induce CPSP using a model of thalamic hemorrhage and were then treated with TPPU (sEHi) alone or in combination with 14,15-EET or 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, the EET antagonist), tunicamycin (Tm, ER stress inducer), or 4-PBA (ER stress inhibitor). Nociceptive behaviors, ER stress markers, JNK and p38 (two well-recognized inflammatory kinases of mitogen-activated protein kinase (MAPK) signaling) expression, and glial cell activation were assessed. In addition, some healthy rats were intrathalamically microinjected with Tm or lipopolysaccharide (LPS) to test the interaction between ER stress and neuroinflammation in central pain. RESULTS: Analysis of the perithalamic lesion tissue from the brain of CPSP rats demonstrated decreased soluble epoxy hydrolase (sEH) expression, which was accompanied by increased expression of ER stress markers, including BIP, p-IRE, p-PERK, and ATF6. In addition, inflammatory kinases (p-p38 and p-JNK) were upregulated and glial cells were activated. Intrathalamic injection of sEHi (TPPU) increased the paw withdrawal mechanical threshold (PWMT), reduced hallmarks of ER stress and MAPK signaling, and restrained the activation of microglia and astrocytes around the lesion site. However, the analgesic effect of TPPU was completely abolished by 14,15-EEZE. Moreover, microinjection of Tm into the thalamic ventral posterior lateral (VPL) nucleus of healthy rats induced mechanical allodynia and activated MAPK-mediated neuroinflammatory signaling; lipopolysaccharide (LPS) administration led to activation of ER stress along the injected site in healthy rats. CONCLUSIONS: The present study provides evidence that the interaction between ER stress and neuroinflammation is involved in the mechanism of CPSP. Combined with the previously reported EET/sEHi effects on antinociception and neuroprotection, therapy with agents that target EET signaling may serve as a multi-functional approach in central neuropathic pain by attenuating ER stress, excessive neuroinflammation, and subsequent central sensitization. The use of these agents within a proper time window could not only curtail further nerve injury but also produce an analgesic effect.

ETCO2 waveforms-assisted awake nasal fibreoptic intubation.

Awake fibreoptic intubation has always been considered the gold standard for expected difficult airway management. However, the use of fibreoptic intubation was limited because it is time-consuming, requires skillful operators and easily affected by blood or secretions in the oral or nasopharynx. We reported a modified technique of awake fibreoptic nasal intubation with the aid of End-tidal carbon dioxide (ETCO2) monitoring, aiming to improve the efficiency and safety of awake fibreoptic intubation.

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain.

BACKGROUND: Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP. METHODS: We used a skin/muscle incision and retraction (SMIR) model to establish a rat CPSP model. Microglia, CXCR7, and the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways were regulated by intrathecal injections of minocycline (a non-specific microglial inhibitor), AMD3100 (a CXCR7 agonist), and LY294002 (a specific PI3K inhibitor), respectively. Mechanical allodynia was detected with von Frey filaments. The changes in microglia, A1 astrocytes, A2 astrocytes, CXCR7, and PI3K/Akt signaling pathways were examined by enzyme-linked immunosorbent assay (ELISA), western blot, and immunofluorescence. RESULTS: Microglia were found to be activated, with an increase in interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q) in the spinal cord at an early stage after SMIR. On day 14 after SMIR, spinal cord astrocytes were also activated; these were mainly of the A1 phenotype and less of the A2 phenotype. Intrathecal injection of minocycline relieved SMIR-induced mechanical allodynia and reverted the ratio of A1/A2 reactive astrocytes. The expression of CXCR7 and PI3K/Akt signaling was decreased after SMIR, while they were increased after treatment with minocycline. Furthermore, intrathecal injection of AMD3100 also relieved SMIR-induced mechanical allodynia, reverted the ratio of A1/A2 reactive astrocytes, and activated the PI3K/Akt signaling pathway, similar to the effects produced by minocycline. However, intrathecal injection of AMD3100 did not increase the analgesic effect of minocycline. Last, LY294002 inhibited the analgesic effect and A1/A2 transformation induced by minocycline and AMD3100 after SMIR. CONCLUSION: Our results indicated that microglia induce the transformation of astrocytes to the A1 phenotype in the spinal cord via downregulation of the CXCR7/PI3K/Akt signaling pathway during CPSP. Reverting A1 reactive astrocytes to A2 may represent a new strategy for preventing CPSP.

Epoxyeicosatrienoic acids: Emerging therapeutic agents for central post-stroke pain.

Central post-stroke pain (CPSP) is chronic neuropathic pain due to a lesion or dysfunction of the central nervous system following cerebrovascular insult. This syndrome is characterized by chronic somatosensory abnormalities including spontaneous pain, hyperalgesia and allodynia, which localize to body areas corresponding to the injured brain region. However, despite its potential to impair activities of daily life and cause mood disorders after stroke, it is probably the least recognized complication of stroke. All currently approved treatments for CPSP have limited efficacy but troublesome side effects. The detailed mechanism underlying CPSP is still under investigation; however, its diverse clinical features indicate excessive central neuronal excitability, which is attributed to loss of inhibition and excessive neuroinflammation. Recently, exogenous epoxyeicosatrienoic acids (EETs) have been used to attenuate the mechanical allodynia in CPSP rats and proven to provide a quicker onset and superior pain relief compared to the current first line drug gabapentin. This anti-nociceptive effect is mediated by reserving the normal thalamic inhibition state through neurosteroid-GABA signaling. Moreover, mounting evidence has revealed that EETs exert anti-inflammatory effects by inhibiting the expression of vascular adhesion molecules, activating NFκB, inflammatory cytokines secretion and COX-2 gene induction. The present review focuses on the extensive evidence supporting the potential of EETs to be a multi-functional therapeutic approach for CPSP. Additionally, the role of EETs in the crosstalk between anti-CPSP and the comorbid mood disorder is reviewed herein.

An update on reactive astrocytes in chronic pain.

Chronic pain is a critical clinical problem with an increasing prevalence. However, there are limited effective prevention measures and treatments for chronic pain. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in both physiological and pathological conditions. Over the past few decades, a growing body of evidence indicates that astrocytes are involved in the regulation of chronic pain. Recently, reactive astrocytes were further classified into A1 astrocytes and A2 astrocytes according to their functions. After nerve injury, A1 astrocytes can secrete neurotoxins that induce rapid death of neurons and oligodendrocytes, whereas A2 astrocytes promote neuronal survival and tissue repair. These findings can well explain the dual effects of reactive astrocytes in central nervous injury and diseases. In this review, we will summarise the (1) changes in the morphology and function of astrocytes after noxious stimulation and nerve injury, (2) molecular regulators and signalling mechanisms involved in the activation of astrocytes and chronic pain, (3) the role of spinal and cortical astrocyte activation in chronic pain, and (4) the roles of different subtypes of reactive astrocytes (A1 and A2 phenotypes) in nerve injury that is associated with chronic pain. This review provides updated information on the role of astrocytes in the regulation of chronic pain. In particular, we discuss recent findings about A1 and A2 subtypes of reactive astrocytes and make several suggestions for potential therapeutic targets for chronic pain.

APC-Cdh1 Regulates Neuronal Apoptosis Through Modulating Glycolysis and Pentose-Phosphate Pathway After Oxygen-Glucose Deprivation and Reperfusion.

Anaphase-promoting complex (APC) with its coactivator Cdh1 is required to maintain the postmitotic state of neurons via degradation of Cyclin B1, which aims to prevent aberrant cell cycle entry that causes neuronal apoptosis. Interestingly, evidence is accumulating that apart from the cell cycle, APC-Cdh1 also involves in neuronal metabolism via modulating the glycolysis promoting enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Here, we showed that under oxygen-glucose deprivation and reperfusion (OGD/R), APC-Cdh1 was decreased in primary cortical neurons. Likewise, the neurons exhibited enhanced glycolysis when oxygen supply was reestablished during reperfusion, which was termed as the "neuronal Warburg effect." In particular, the reperfused neurons showed elevated PFKFB3 expression in addition to a reduction in glucose 6-phosphate dehydrogenase (G6PD). Such changes directed neuronal glucose metabolism from pentose-phosphate pathway (PPP) to aerobic glycolysis compared to the normal neurons, resulting in increased ROS production and apoptosis during reperfusion. Pretreatment of neurons with Cdh1 expressing lentivirus before OGD could reverse this metabolic shift and attenuated ROS-induced apoptosis. However, the metabolism regulation and neuroprotection by Cdh1 under OGD/R condition could be blocked when co-transfecting neurons with Ken box-mut-PFKFB3 (which is APC-Cdh1 insensitive). Based on these data, we suggest that the Warburg effect may contribute to apoptotic mechanisms in neurons under OGD/R insult, and targeting Cdh1 may be a potential therapeutic strategy as both glucose metabolic regulator and apoptosis suppressor of neurons in brain injuries.

VivaSight™ single-lumen tube guided bronchial blocker placement for one-lung ventilation in a patient with a tracheal tumor under video-assisted transthoracic surgery: a case report.

BACKGROUND: Video-assisted transthoracic surgery (VATS) is a minimally invasive procedure that has been reported as a valid method for tracheal resection and reconstruction. However, for patients with tracheal tumors, one-lung ventilation during VATS is difficult to achieve, and utilizing a double-lumen tube is not applicable in these types of situations. When using a bronchial blocker, a fiberoptic bronchoscope is required to verify the position of bronchial blocker, though the repeated use of the fiberoptic bronchoscope increases the risk of tumor rupture and hemorrhage. CASE PRESENTATION: We report a case with a middle tracheal tumor received tracheal resection and reconstruction under VATS, in which VivaSight™ single-lumen tube guided bronchial blocker placement was used for achieving one-lung ventilation. The VivaSight™ single-lumen tube can provide real-time and continuous monitoring of the position of bronchial blocker. Moreover, it does not require the aid of fiberoptic bronchoscopy. CONCLUSIONS: VivaSight™ single-lumen tube combined with a bronchial blocker is a feasible choice for one-lung ventilation in this type of surgery.

Dexmedetomidine and sufentanil combination versus sufentanil alone for postoperative intravenous patient-controlled analgesia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have demonstrated that dexmedetomidine improves the quality of postoperative analgesia. In the present study, we performed a meta-analysis of randomized controlled trials to quantify the effect of dexmedetomidine as an adjuvant to sufentanil for postoperative patient-controlled analgesia (PCA). METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were systematically searched for randomized controlled trials in which dexmedetomidine was used as an adjuvant for PCA with sufentanil. In the retrieved studies, we quantitatively analyzed pain intensity, sufentanil consumption, and drug-related side effects. RESULTS: Nine studies with 907 patients were included in this meta-analysis. Compared with sufentanil alone, dexmedetomidine-sufentanil for postoperative intravenous PCA reduced pain intensity at 24 h (mean difference (MD) = - 0.70points; 95% confidence interval (CI): - 1.01, - 0.39; P < 0.00001) and 48 h postoperatively (MD = -0.61points; 95% CI: - 1.00, - 0.22; P = 0.002). Moreover, dexmedetomidine-sufentanil reduced sufentanil consumption during the first 24 h (MD = -13.77 µg; 95% CI: - 18.56, - 8.97; P < 0.00001) and 48 h postoperatively (MD = -20.81 µg; 95% CI: - 28.20, - 13.42; P < 0.00001). Finally, dexmedetomidine-sufentanil improved patient satisfaction without increasing the incidence of side effects. CONCLUSIONS: Dexmedetomidine as an adjuvant to sufentanil for postoperative PCA can reduce postoperative pain score and sufentanil consumption.

Downregulation of Cdh1 signalling in spinal dorsal horn contributes to the maintenance of mechanical allodynia after nerve injury in rats.

BACKGROUND: Anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 are important ubiquitin-ligases in proliferating cells and terminally differentiated neurons. In recent years, APC/C-Cdh1 has been reported as an important complex contributing to synaptic development and transmission. Interestingly, cortical APC/C-Cdh1 is found to play a critical role in the maintenance of neuropathic pain, but it is not clear whether APC/C-Cdh1 in spinal dorsal cord is involved in molecular mechanisms of neuropathic pain conditions. RESULTS: Immunostaining showed that Cdh1 was mainly distributed in dorsal horn neurons of the spinal cord in rats. Its expression was downregulated in the ipsilateral dorsal horn at 14 days after spared nerve injury. Rescued expression of Cdh1 in spinal cord by intrathecal administration of recombinant lentivirus encoding Cdh1 (Lenti-Cdh1-GFP) significantly attenuated spared nerve injury-induced mechanical allodynia. Furthermore, rescued expression of spinal Cdh1 significantly reduced surface membrane expression of GluR1, but increased the expression of GluR1-related erythropoietin-producing human hepatocellular receptor A4 and its ligand EphrinA1 in dorsal horn of spared nerve injury-treated animals. CONCLUSIONS: This study indicates that a downregulation of Cdh1 expression in spinal dorsal horn is involved in molecular mechanisms underlying the maintenance of neuropathic pain. Upregulation of spinal Cdh1 may be a promising approach to treat neuropathic pain.

Alleviating neuropathic pain mechanical allodynia by increasing Cdh1 in the anterior cingulate cortex.

BACKGROUND: Plastic changes in the anterior cingulate cortex (ACC) are critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Cdh1, a co-activator subunit of anaphase-promoting complex/cyclosome (APC/C) regulates synaptic differentiation and transmission. Based on this, we hypothesised that the APC/C-Cdh1 played an important role in long-term plastic changes induced by neuropathic pain in ACC. RESULTS: We employed spared nerve injury (SNI) model in rat and found Cdh1 protein level in the ACC was down-regulated 3, 7 and 14 days after SNI surgery. We detected increase in c-Fos expression, numerical increase of organelles, swollen myelinated fibre and axon collapse of neuronal cells in the ACC of SNI rat. Additionally, AMPA receptor GluR1 subunit protein level was up-regulated on the membrane through a pathway that involves EphA4 mediated by APC/C-Cdh1, 3 and 7 days after SNI surgery. To confirm the effect of Cdh1 in neuropathic pain, Cdh1-expressing lentivirus was injected into the ACC of SNI rat. Intra-ACC treatment with Cdh1-expressing lentivirus vectors elevated Cdh1 levels, erased synaptic strengthening, as well as alleviating established mechanical allodynia in SNI rats. We also found Cdh1-expressing lentivirus normalised SNI-induced redistribution of AMPA receptor GluR1 subunit in ACC by regulating AMPA receptor trafficking. CONCLUSIONS: These results provide evidence that Cdh1 in ACC synapses may offer a novel therapeutic strategy for treating chronic neuropathic pain.

Cervical spinal cord compression after thyroidectomy under general anesthesia.

Cervical spinal cord injury is a rare but serious complication after general anesthesia. The risk factors include traumatic cervical injury, cervical spine instability, and difficult airway management. It has also occurred in the absence of cervical instability. Here we report a patient who had a history of intermittent neck pain without numbness. Preoperative radiologic examinations showed degenerative changes in the cervical spine. She developed progressive tingling and numbness in her limbs after thyroidectomy under general anesthesia. Magnetic resonance imaging showed a cervical disc protruding into the canal at C5-C6, which was considered to be induced by surgical positioning. She recovered after anterior cervical decompression and internal fixation surgery.

Recent Advances in Videolaryngoscopy for One-Lung Ventilation in Thoracic Anesthesia: A Narrative Review.

Since their advent, videolaryngoscopes have played an important role in various types of airway management. Lung isolation techniques are often required for thoracic surgery to achieve one-lung ventilation with a double-lumen tube (DLT) or bronchial blocker (BB). In the case of difficult airways, one-lung ventilation is extremely challenging. The purpose of this review is to identify the roles of videolaryngoscopes in thoracic airway management, including normal and difficult airways. Extensive literature related to videolaryngoscopy and one-lung ventilation was analyzed. We summarized videolaryngoscope-guided DLT intubation techniques and discussed the roles of videolaryngoscopy in DLT intubation in normal airways by comparison with direct laryngoscopy. The different types of videolaryngoscopes for DLT intubation are also compared. In addition, we highlighted several strategies to achieve one-lung ventilation in difficult airways using videolaryngoscopes. A non-channeled or channeled videolaryngoscope is suitable for DLT intubation. It can improve glottis exposure and increase the success rate at the first attempt, but it has no advantage in saving intubation time and increases the incidence of DLT mispositioning. Thus, it is not considered as the first choice for patients with anticipated normal airways. Current evidence did not indicate the superiority of any videolaryngoscope to another for DLT intubation. The choice of videolaryngoscope is based on individual experience, preference, and availability. For patients with difficult airways, videolaryngoscope-guided DLT intubation is a primary and effective method. In case of failure, videolaryngoscope-guided single-lumen tube (SLT) intubation can often be achieved or combined with the aid of fibreoptic bronchoscopy. Placement of a DLT over an airway exchange catheter, inserting a BB via an SLT, or capnothorax can be selected for lung isolation.

Antinociception role of 14,15-epoxyeicosatrienoic acid in a central post-stroke pain model in rats mediated by anti-inflammation and anti-apoptosis effect.

Central post stroke pain (CPSP) is an intractable neuropathic pain syndrome that occurs after the acute focal lesion of the central nervous system (CNS) due to a cerebrovascular cause. Epoxyeicosatrienoic acids (EETs) exert many pharmacological effects in vivo and in vitro, such as anti-apoptosis, anti-inflammatory, and anti-oxidative stress. Neuroinflammation and apoptosis are the potential pathophysiological mechanisms of neuropathic pain. This study aimed to investigate whether 14,15-EET has an antinociception effect on CPSP rats through its anti-inflammation and anti-apoptosis mechanisms. Rats were treated with type IV collagenase (CPSP group) or saline (Sham group) via injection with a Hamilton syringe into the ventral posterior lateral nucleus (VPL) according to the stereotaxic coordinates. We first tested the mechanical withdrawal threshold, as well as neuroinflammation- and apoptosis-related protein expressions in the per-lesion site of CPSP and Sham rats. Sprague-Dawley rats were randomly divided into five groups, as follows: vehicle; EET at 0.025, 0.05, and 0.1 µg; and EET (0.1 µg) + EEZE (3.25 ng). EET or and vehicle were administered into VPL nuclei three consecutive days after hemorrhagic stroke. Immunostaining, ELISA, and Western blot were performed to evaluate neuroinflammation and apoptosis. Hemorrhagic stroke induced mechanical allodynia, glial activation, neuroinflammation, and apoptosis-related protein upregulation. However, early treatment with 14,15-EET inhibited glial cell activation, decreased proinflammatory cytokines and apoptosis-related protein, and alleviated the pain behavior of CPSP rats. Our results provided strong evidence that antinociception produced by 14,15-EET is partly mediated by the inhibition of neuroinflammation and apoptosis.

Bilateral ultrasound-guided transversus abdominis plane block combined with ilioinguinal-iliohypogastric nerve block for cesarean delivery anesthesia.

The ultrasound-guided transversus abdominis plane block and ilioinguinal-iliohypogastric nerve block have been shown to provide pain relief after abdominal surgery. A combination of the 2 blocks may provide acceptable surgical anesthesia for cesarean delivery. We describe 4 women who had contraindications to neuraxial anesthesia, who underwent cesarean delivery with ultrasound-guided bilateral transversus abdominis plane block combined with ilioinguinal-iliohypogastric nerve block using 40 mL 0.5% ropivacaine. Breakthrough pain during the delivery of the fetus was treated with small doses of IV ketamine and propofol. We suggest that this technique may be an alternative to local anesthesia for cesarean delivery in clinical practice.

A network-based analysis and experimental validation of traditional Chinese medicine Yuanhu Zhitong Formula in treating neuropathic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: The Yuanhu Zhitong Formula (YZF) consists of traditional Chinese herbs Corydalis Rhizoma (Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu; Chinese name, Yanhusuo) and Angelicae Dahuricae Radix (Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav.; Chinese name, Baizhi), which is usually administrated for painful conditions. It is well acknowledged that YZF has pharmacological effects on pain relief; nevertheless, limited data are available on its mechanism. AIM OF THE STUDY: This study aimed to explore the potential mechanism underlying YZF on nociception of rats. Also, the comprehensive mechanism of YZF was preliminarily determined based on network pharmacology on neuropathic pain. MATERIALS AND METHODS: A spared nerve injury (SNI) model was established to reveal the effects of YZF administration on nociceptive behavior in rats. Von-Frey tests were used to evaluate the paw withdrawal mechanical thresholds in rats administrated with YZF or vehicle. The "drug-ingredients" and "disease-drug-target" networks were established with a network pharmacology approach. The analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) profiles were performed based on the common targets between the herbs and neuropathic pain. Hub genes, identified with CytoHubba, were validated by Western blotting analysis. RESULTS: SNI rats developed significant nociceptive behavior as soon as 3 days after nerve injury, which was reversed by consecutive treatment with 300 mg/kg YZF for 7 days. Besides, 50 potential bioactive components in YZF with 1074 targets were identified. Then, 217 putative common genes related to YZF and neuropathic pain were identified for further study. After established a protein-protein interaction network, 12 subnetworks with CytoHubba and 10 predictive hub genes were obtained based on the maximal clique centrality model. Western blotting analysis indicated that SNI rats exhibited increased APP (Amyloid-beta precursor protein), SRC (Proto-oncogene tyrosine-protein kinase Src), and phosphorylation of JNK1 (Mitogen-activated protein kinase 8, JNK) and ERK1/2 (Mitogen-activated protein kinase 3/1). Obviously, continuous administration of YZF robustly reversed such changes. CONCLUSIONS: This study revealed that YZF modulates the nociceptive behavior in SNI rats. Moreover, the drug may be useful in the treatment of neuropathic pain through multi-components, multi-targets, and multi-pathways. Nevertheless, more attention should be paid to discriminating the potential ingredients in YZF contributing to its analgesic effects in the treatment of neuropathic pain.

Corrigendum: Neuroprotective Effects of Celastrol on Transient Global Cerebral Ischemia Rats via Regulating HMGB1/NF-κB Signaling Pathway.

[This corrects the article DOI: 10.3389/fnins.2020.00847.].

Serum amylase elevation is associated with adverse clinical outcomes in patients with coronavirus disease 2019.

OBJECTIVE: Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized. DESIGN: In this retrospective cohort study, the epidemiological, demographic, laboratory, treatment and outcome information of 1,515 COVID-19 patients with available longitudinal amylase records collected from electronic medical system were analyzed to assess the prevalence and clinical significance of hyperamylasemia in this infection. Associated variables with hyperamylasemia in COVID-19 were also analyzed. RESULTS: Of 1,515 patients, 196 (12.9%) developed hyperamylasemia, among whom 19 (1.3%) greater than 3 times upper limit of normal (ULN) and no clinical acute pancreatitis was seen. Multivariable ordered logistic regression implied older age, male, chronic kidney disease, several medications (immunoglobin, systemic corticosteroids, and antifungals), increased creatinine might be associated with hyperamylasemia during hospitalization. Restricted cubic spline analysis indicated hyperamylasemia had a J-shaped association with all-cause mortality and the estimated hazard ratio per standard deviation was 2.85 (2.03-4.00) above ULN. Based on the multivariable mixed-effect cox or logistic regression model taking hospital sites as random effects, elevated serum amylase during hospitalization was identified as an independent risk factor associated with in-hospital death and intensive complications, including sepsis, cardiac injury, acute respiratory distress syndrome, and acute kidney injury. CONCLUSIONS: Elevated serum amylase was independently associated with adverse clinical outcomes in COVID-19 patients. Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.

Upregulation of Cdh1 in the trigeminal spinal subnucleus caudalis attenuates trigeminal neuropathic pain via inhibiting GABAergic neuronal apoptosis.

Trigeminal neuropathic pain (TNP) remains a tremendous clinical challenge due to its elusive mechanisms. Previous studies showed that peripheral nerve injury facilitated a selective GABAergic neuronal apoptosis in the superficial dorsal horn and contributed to the development and maintenance of neuropathic pain. It has also demonstrated that downregulation of the anaphase-promoting complex/cyclosome(APC/C) and its coactivator Cdh1 contribute to neuronal apoptosis in diverse neurodegenerative diseases. However, whether APC/C-Cdh1 downregulation could induce GABAergic neuronal apoptosis in trigeminal caudalis nucleus (Vc), and then contribute to the development and maintenance of TNP remains unknown. In this study, we aimed to investigate the role of APC/C-Cdh1 in a TNP rat model and its underlying mechanisms. Our results showed that Cdh1 was primarily distributed in superficial laminae of Vc and significantly downregulated in Vc at day 14 post trigeminal nerve injury. Furthermore, trigerminal nerve injury leads to neuronal apoptosis, especially GABAergic interneurons in the superficial of Vc. Upregulating Cdh1 in Vc ameliorated mechanical allodynia and inhibited GABAergic neuronal apoptosis induced by chronic constriction injury of trigeminal infraorbital nerve (CCI-ION).