Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord.

BACKGROUND: Endoplasmic reticulum stress plays a crucial role in the pathogenesis of neuroinflammation and chronic pain. This study hypothesized that PRKR-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme type 1 (IRE1) regulate lipocalin-2 (LCN2) and Nod-like receptor family pyrin domain containing 3 (NLRP3) expression in astrocytes, thereby contributing to morphine tolerance and hyperalgesia. METHODS: The study was performed in Sprague-Dawley rats and C57/Bl6 mice of both sexes. The expression of LCN2 and NLRP3 was assessed by Western blotting. The tail-flick, von Frey, and Hargreaves tests were used to evaluate nociceptive behaviors. Chromatin immunoprecipitation was conducted to analyze the binding of activating transcription factor 4 (ATF4) to the promoters of LCN2 and TXNIP. Whole-cell patch-clamp recordings were used to evaluate neuronal excitability. RESULTS: Pharmacologic inhibition of PERK and IRE1 attenuated the development of morphine tolerance and hyperalgesia in male (tail latency on day 7, 8.0 ± 1.13 s in the morphine + GSK2656157 [10 µg] group vs. 5.8 ± 0.65 s in the morphine group; P = 0.04; n = 6 rats/group) and female (tail latency on day 7, 6.0 ± 0.84 s in the morphine + GSK2656157 [10 µg] group vs. 3.1 ± 1.09 s in the morphine group; P = 0.0005; n = 6 rats/group) rats. Activation of PERK and IRE1 upregulated expression of LCN2 and NLRP3 in vivo and in vitro. Chromatin immunoprecipitation analysis showed that ATF4 directly bound to the promoters of the LCN2 and TXNIP. Lipocalin-2 induced neuronal hyperexcitability in the spinal cord and dorsal root ganglia via melanocortin-4 receptor. CONCLUSIONS: Astrocyte endoplasmic reticulum stress sensors PERK and IRE1 facilitated morphine tolerance and hyperalgesia through upregulation of LCN2 and NLRP3 in the spinal cord.

The long-term outcome of CT-guided radiofrequency ablation of the peripheral branches of the trigeminal nerve in trigeminal neuralgia.

Radiofrequency thermocoagulation (RFTC) of the peripheral branches of the trigeminal nerve has been used for trigeminal neuralgia. However, the long-term outcomes of radiofrequency thermocoagulation have not been established. To evaluate the long-term efficacy of RFTC of peripheral branches in patients with refractory trigeminal neuralgia. A retrospective cohort study was conducted in a comprehensive medical center in China. Patients who underwent radiofrequency thermocoagulation of peripheral branches for refractory trigeminal neuralgia from May 2014 to March 2021 were included for analysis. A total of 84 patients with refractory trigeminal neuralgia underwent 105 procedures. BNI I-II which represents treatment success was achieved in 76/84 (90%) patients and 93/105 (89%) procedures. During follow-up, BNI I and II were maintained in 64/76 (84%), 40/73 (55%), 20/67 (30%), 17/65 (26%), 12/61 (20%), and 8/58 (14%) of patients at 1, 2, 3, 4, 5, and 6 years, after the first procedure, respectively. For all the 105 procedures, BNI I and II were maintained in 68/93 (73%), 41/89(46%), 22/82(27%), 15/79 (19%), 8/74 (11%), and 3/72 (4%) at 1, 2, 3, 4, 5, and 6 years, respectively. There is no significant difference between the first and repeat thermocoagulation in terms of immediate (90% vs. 81%, P=0.140) and long-term efficacies (24 months vs.18 months, P=0.266). Radiofrequency thermocoagulation resulted in better long-term outcomes in patients with typical purely paroxysmal pain (24 months vs. 11 months, P=0.033). Radiofrequency ablation of the peripheral branches of the trigeminal nerve might be a safe and effective method in the treatment of refractory trigeminal neuralgia.

Suicide rates among people with serious mental illness: a systematic review and meta-analysis.

BACKGROUND: People with serious mental illness are at great risk of suicide, but little is known about the suicide rates among this population. We aimed to quantify the suicide rates among people with serious mental illness (bipolar disorder, major depression, or schizophrenia). METHODS: PubMed and Web of Science were searched to identify studies published from 1 January 1975 to 10 December 2020. We assessed English-language studies for the suicide rates among people with serious mental illness. Random-effects meta-analysis was used. Changes in follow-up time and the suicide rates were presented by a locally weighted scatter-plot smoothing (LOESS) curve. Suicide rate ratio was estimated for assessments of difference in suicide rate by sex. RESULTS: Of 5014 identified studies, 41 were included in this analysis. The pooled suicide rate was 312.8 per 100 000 person-years (95% CI 230.3-406.8). Europe was reported to have the highest pooled suicide rate of 335.2 per 100 000 person-years (95% CI 261.5-417.6). Major depression had the highest suicide rate of 534.3 per 100 000 person-years (95% CI 30.4-1448.7). There is a downward trend in suicide rate estimates over follow-up time. Excess risk of suicide in males was found [1.90 (95% CI 1.60-2.25)]. The most common suicide method was poisoning [21.9 per 100 000 person-years (95% CI 3.7-50.4)]. CONCLUSIONS: The suicide rates among people with serious mental illness were high, highlighting the requirements for increasing psychological assessment and monitoring. Further study should focus on region and age differences in suicide among this population.

Medrysone promotes corneal injury repair by promoting M2-like polarization of macrophages.

BACKGROUND: Accumulated evidence suggests that M2-like polarized macrophages plays an important role in reducing inflammation, promoting and accelerating wound healing process and tissue repair. Thus, M2-like TAMs (Tumour-associated macrophages) was an appealing target for therapy intervention. METHOD: Flow cytometry and RT-PCR assay were used to detect the polarization of macrophages induced by Medrysone, and the rat corneal mechanical injury model was established to evaluate the efficacy of Medrysone in cornel repair. RESULTS: Here we found that Medrysone enhanced IL-4 induced M2 polarization of macrophages, as illustrated by increased expression of CD206, up-regulation of M2 marker mRNAs. Medrysone promoted VEGF and CCL2 secretion in IL-4 induced M2-like polarization. IL-4 triggered STAT6 activation was further enhanced by Medrysone and silencing of STAT6 partially abrogated the stimulatory effect of Medrysone. Medrysone improved migration-promoting feature of M2-like macrophages, as indicated by increased migration of endothelial cells. Further, Medrysone promoted corneal injury repair by inducing M2 polarization of macrophages in vivo. CONCLUSION: Our study suggest that Medrysone promotes corneal injury repair by inducing the M2 polarization of macrophages, providing a theoretical basis for the application of Medrysone in the treatment of corneal injury.

Effectiveness of percutaneous balloon compression (PBC) in improving physical function and quality of life in trigeminal neuralgia: a retrospective study.

OBJECTIVE: To evaluate the effectiveness of percutaneous balloon compression (PBC) in treating trigeminal neuralgia (TN) and determine improvements in quality of life (QoL) and daily functional status. METHODS: Data from primary TN (pTN) patients treated with PBC from December 2018 to April 2021 were retrospectively analyzed. Short-Form 36 (SF-36) Health Survey and Functional Independence Measure (FIM) assessments were used to evaluate patients' QoL and physical function every 6 months after surgery, and facial pain was evaluated every 3 to 6 months post-surgery. RESULTS: A total of 80 pTN patients were enrolled for analysis. The Barrow Neurological Institute (BNI) scores of I-II were achieved in 67 (83.8%) patients immediately after the surgery. The estimated rates of BNI I-II pain relief at one, two, and three years were 94.2%, 87.6%, and 83.2%, respectively. All aspects of the SF-36 questionnaire were significantly improved after the PBC, especially in terms of role physical (RP), bodily pain (BP), and social functioning (SF). Patients' functional outcomes measured by FIM at the 6-month follow-up examination were 108.6 ± 9.9, which was significantly improved compared with the pretreatment scores (90.8 ± 12.7). There was no difference between the severity of facial numbness in FIM and any item of the SF-36 except RP (P = 0.004) at 6 months after surgery. There was also no difference in SF-36 and FIM between patients with or without facial hyperalgesia. CONCLUSIONS: PBC can produce long-term and stable pain relief and significantly improve the patient's QoL and physical function. However, further well-designed, high-level, evidence-based studies are needed to precisely assess the efficacy of PBC for pTN patients.

Decompression versus decompression plus fusion for treating degenerative lumbar spinal stenosis: A systematic review and meta-analysis.

BACKGROUND: Degenerative lumbar spinal stenosis (DLSS) is a complex clinical syndrome that leads to spinal compression. Decompression with fusion has been the most commonly used surgical procedure for treating DLSS symptoms for many years. However, the exact role of fusion and its effectiveness in DLSS therapy has recently been debated. OBJECTIVE: The main purpose of this study was to compare the efficacy and safety of decompression alone and decompression plus fusion in the treatment of DLSS with or without spondylolisthesis. STUDY DESIGN: A systematic review and meta-analysis of the therapeutic effects of decompression for DLSS with or without the combination of fusion. METHODS: A literature search in five relevant databases, including Web of Science, PubMed, Embase, Medline, and Cochrane Library was performed from the inception of the database to March 2022. Only randomized controlled trials (RCTs) assessing the comparison between decompression and decompression plus fusion for DLSS were included. RESULTS: A total of seven studies, 894 patients were analyzed in this meta-analysis. Among these, 443 patients were included in the decompression plus fusion group while 451 patients were included in the decompression alone group. Pooled analysis showed that the combination of decompression with fusion had no superior benefits to decompression alone in terms of Oswestry Disability Index (ODI) score in the first 2 years and long-term follow-up after surgery, also no significant difference in the improvement of back and leg pain was found between two groups. Adding fusion to decompression was associated with a longer operation time, higher complication rate, more blood loss, and extended hospital stay. Furthermore, there was no difference in reoperation rates and patients' satisfaction between the two groups at the last follow-up. CONCLUSION: Decompression plus fusion may not be associated with a better clinical outcome in ODI scores and back or leg pain improvement but with a longer duration of operation time, extended hospital stay, and more blood loss.

Assessment of the Exposure to NNN in the Plasma of Smokeless Tobacco Users.

N-Nitrosonornicotine (NNN) is a human carcinogen present in cigarette smoke and smokeless tobacco. Urinary NNN is usually measured in order to assess the exposure to this toxicant for tobacco users. NNN excretion in urine can be highly biased due to the formation of NNN by nitrosation of nornicotine under acidic conditions, both endogenously and exogenously. Hence, urinary NNN levels may not necessarily correctly reflect the product-specific exposure. Measurement of plasma NNN may be less prone to endogenous formation due to the stable pH (7.4) of blood. We developed an LC-MS/MS method for the quantification of NNN using 1 mL of human plasma. Validation according to FDA guidelines proved that the method is selective and highly sensitive with an LLOQ of 0.3 pg/mL. Accuracy and precision averaged to 98.7 and 7.5% (CV), respectively. The assay was applied to plasma samples collected from 10 experienced moist smokeless tobacco users during and after a single use of 2 g of the product for 40 min under controlled use conditions. Blood was drawn at 15 time points over a 6 h time course. The maximum NNN concentration (Cmax) ranged from 3.5 to 10 pg/mL (mean: 7.1 pg/mL) at a tmax of 32 min. Plasma NNN and nicotine were found to have similar time courses. In conclusion, the determination of NNN in plasma may be fit-for-purpose to evaluate the product-use-specific exposure to this carcinogen.

Influence of Nitrite on Formation of Tobacco-Specific Nitrosamines in Electronic Cigarette Liquids and Aerosols.

Tobacco-specific nitrosamine (TSNA) formation occurred during aerosol generation from select commercial cig-a-like e-cigarette products. To understand the drivers behind the potential formation of TSNAs in electronic cigarette (e-cigarette) aerosols and e-liquids, model e-liquid systems were generated in the lab to demonstrate that nitrite can react with nicotine and minor alkaloids to form TSNAs in e-liquids. In the presence of nitrite and nicotine, TSNA levels in e-liquids increased over time and the process was accelerated by elevated temperature. Additionally, TSNAs formed during aerosol generation when nitrite was present in the corresponding e-liquids. The commercial e-cigarette products that showed higher levels and formation of TSNAs were observed to contain nitrite and minor alkaloid impurities in the corresponding e-liquids. This study provides valuable information about drivers for TSNA formation in e-liquids and e-cigarette aerosols that may be applied to the evaluation and quality assurance of e-cigarette products.

COVID-19 in patients with systemic lupus erythematosus: A systematic review.

The objectives of the study were to review the articles to identify (a) the epidemiology of systemic lupus erythematosus (SLE) and coronavirus disease 2019 (COVID-19); (b) the clinical characteristics of SLE patients with COVID-19; (c) the treatment of COVID-19 in SLE patients; and (d) the impact of COVID-19 pandemic on SLE patients. PubMed was systematically reviewed for literature published from December 2019 to June 2021. Our search was limited to human studies, with language restriction of English. Studies were included if they reported COVID-19 in SLE patients. Our systematic review included 52 studies. The prevalence of COVID-19 infection ranged from 0.0% to 18.1% in SLE patients, and the hospitalisation rates ranged from 0.24% to 10.6%. COVID-19 infection is likely to mimic SLE flare. Hydroxychloroquine (HCQ) was ineffective in prevention of COVID-19, and SLE patients with COVID-19 faced difficulty in healthcare access, had financial constraints and suffered from psychological distress during the pandemic. The pandemic had a significant effect on mental and physical health. Adequate healthcare access, along with containment policies, social distancing measures and psychological nursing was required.

PMN Apoptosis Induced by SNHG11 through the Inhibition of Endotoxin-induced Acute Lung Injury NF-κB Pathway.

This study aimed to investigate the impacts of small nucleolar RNA host gene 11 (SNHG11) on nuclear factor kappa-B (NF-κB) pathway polymorphonuclear neutrophils (PMN) apoptosis in rats with endotoxin-induced acute lung injury (ALI). Forty rats were the experimental subjects. They were randomly grouped as a control group (Group C), an endotoxin group (Group E), an inhibitor group (Group I), and an activator group (Group A), with 10 rats in each group. The endotoxin-educed ALI rat model was built. Arterial Blood Gas Test (ABGT) was performed, and the Wet/Dry (W/D) ratio of lung weight was determined. The pathological variations in rat pulmonary tissues were scrutinized and scored. PMN in peripheral blood was isolated; its apoptosis was assessed, and its total NF-κB p65 and p-NF-κB p65 expressions were assessed. The expression of SNHG11 mRNA in pulmonary tissues was assessed. Results: Compared to Group C, the W/D ratios and pathological scores of Group E, Group I, and Group A boosted notably (P <0.05), while their ABGT indicators and PMN apoptosis rates dropped (P <0.05). Compared to Group E and Group I, the W/D ratio and pathological score of Group A dropped notably (P <0.05), while its ABGT indicators and PMN apoptosis rate boosted (P <0.05). Compared to Group C, the p-NF-κB p65 and SNHG11 expressions boosted in Group E, Group I, and Group A (P <0.05); compared to Group E and Group I, the p-NF-κB p65 and SNHG11 expressions in Group A dropped (P <0.05). SNHG11 could relieve endotoxin-induced ALI, which might be associated with the acceleration of PMN apoptosis and the inhibition of the NF-κB pathway.