The early postnatal period is a critical window for brain maturation, during which oligodendrogenesis, myelination, and synaptogenesis are dynamically orchestrated to support cognitive development. Clinical studies have associated myelination deficits with intellectual disability (ID), but the molecular mechanisms linking myelin deficits to cognitive dysfunction remain poorly understood. Here, we generated an inducible conditional knockout (icKO) mouse model to selectively ablate 3-phosphoinositide-dependent protein kinase-1 (PDK1) in oligodendrocyte precursor cells (OPCs) during early postnatal development. Pdk1 icKO mice exhibited severe deficits in hippocampal oligodendrocyte (OL) maturation, myelination, and excitatory synaptogenesis, accompanied by impaired neuronal activation and profound memory impairments. Mechanistically, PDK1 loss led to suppression of the Akt-mTOR signaling pathway, a critical regulator of OL differentiation and myelination. Strikingly, treatment with clemastine, an FDA-approved pro-myelinating agent, effectively restored oligodendrogenesis, myelination, synaptic integrity, neuronal activity, and cognitive performance in Pdk1 icKO mice, in part by reactivating Akt-mTOR signaling. Together, these findings identify PDK1 as a pivotal regulator of postnatal myelination and cognitive maturation, establish a mechanistic link between oligodendroglial dysfunction and ID, and highlight clemastine as a promising therapeutic candidate for cognitive disorders associated with myelination deficits.

Neuropathic pain (NPP) is a critical clinical challenge with limited therapeutic options. While neuronal mechanisms have been extensively studied, the contribution of oligodendrocyte (OL) homeostasis to NPP pathogenesis is poorly understood. Here, we show that chronic constriction injury (CCI) causes demyelination and downregulation of 3-phosphoinositide-dependent kinase 1 (PDK1) in the central nervous system (CNS) in mice. Functional analysis of inducible OL lineage-specific Pdk1 conditional knockout (Pdk1 cKO) mice reveals mechanical allodynia and thermal hyperalgesia, a pattern of sensory changes that closely resembles NPP in CCI mice. RNA sequencing (RNA-seq), morphological, and molecular analyses demonstrate that PDK1 deficiency impairs myelination via the c-Myc/SOX10 axis. Notably, pharmacological enhancement of remyelination or AAV-mediated knockdown of c-Myc restores nodal integrity and alleviates NPP in Pdk1 cKO mice. Our findings establish PDK1-mediated OL homeostasis as a critical determinant of NPP pathogenesis and identify c-Myc modulation as a novel therapeutic strategy for NPP.

Purpose: The aim of this study was to investigate the effect of general anesthesia combined with transversus abdominis plane block on postoperative sleep disorders in elderly patients undergoing gastrointestinal tumor surgery. Methods: For elderly patients with gastrointestinal malignant tumors, we recruited 94 patients, aged 65-80, who were scheduled for radical laparoscopic surgery. Using the random number table method, the patients were randomly divided into two groups, the general anesthesia group (group GA) and the general anesthesia combined with transversus abdominis plane block group (group GT). The group GA received the sedation-aspiration complex general anesthesia regimen, while the group GT underwent bilateral transversus abdominis plane blocks (TAPB) after the same induction of anesthesia. Group GA was injected bilaterally with equal amounts of saline in the same way. Sleep was monitored using wearable devices on the first day before surgery (P1) and the first and third day after surgery (D1 and D3). The Pittsburgh Sleep Quality Index(PSQI) scale was used to assess sleepiness and the occurrence of postoperative sleep disorders (POSD) on P1, D1 and D3 nights, respectively. Results: Compared to the group GA, the group GT showed a significant decrease in remifentanil use during surgery (P<0.05). At D1, the group GT showed an increase in the ratio of deep sleep to rapid eye movement sleep (REM), along with a significant decrease in the number of wakefulness (P<0.05). At D3, the proportion of REM continued to increase and PSQI scores were significantly lower at both D1 and D3 (P<0.05). In addition, the incidence of POSD and the visual analog scores (VAS) at 0.5h and 6h postoperative activity in D1 showed a decreasing trend (P<0.05). However, no significant differences were observed between the two groups in general condition, intraoperative condition, remedial analgesia and number of analgesic pump presses (P>0.05). Conclusion: General anesthesia combined with transversus abdominis plane block reduces the dosage of opioids in abdominal surgery, especially gastrointestinal surgery, alleviates postoperative pain in elderly gastrointestinal oncology patients, improves sleep quality, and reduces the incidence of sleep disorders.

Purpose Previous reports argue that preoperative sleep conditions of patients can influence the dosage of general anaesthesia drugs. Therefore, we aimed to investigate the dose-effect relationship of preoperative sleep disorders on the induction of general anaesthesia with remimazolam tosilate and calculate the Median effective (ED50) and 95% effective (ED95) dosages. Methods Included in our study were 56 patients who underwent laparoscopic cholecystectomy at our hospital. A separate group of 27 patients with sleep disorders (SD group) and 29 patients without sleep disorders (NSD group) using the Pittsburgh Sleep Quality Index (PSQI) were also included. According to the Dixon ‘up-and-down’ design, patients received remimazolam at preselected concentrations starting at 0.2 mg/kg. After the administration of remimazolam, loss of consciousness was observed. By observing whether consciousness disappeared within a minute, we adjusted the dose of remimazolam by 0.1 mg/kg (up and down) in the following patient. The Median effective dose (ED50), 95% effective dose (ED95), and 95% confidence interval (CI) of remimazolam for effective sedation were calculated. Results The ED50 of remimazolam was 0.226 mg/kg (95%CI 0.221–0.232 mg/kg) in the SD group and 0.191 mg/kg (95%CI, 0.183–0.199 mg/kg) in the NSD group. The ED95 of remimazolam was 0.237 mg/kg (95%CI 0.231–0.262 mg/kg) in the SD group and 0.209 mg/kg (95%CI 0.200–0.254 mg/kg) in the NSD group. Conclusions In the SD group, the ED50 and ED95 of remimazolam during anaesthesia induction were 0.226 and 0.237 mg/kg, respectively. The induction dose of remimazolam in the SD group was significantly higher than that in the NSD group.

Previous reports argue that preoperative sleep conditions of patients can influence the dosage of general anaesthesia drugs. Therefore, we aimed to investigate the dose-effect relationship of preoperative sleep disorders on the induction of general anaesthesia with remimazolam tosilate and calculate the Median effective (ED50) and 95 Question: Does the preoperative variation in sleep quality of patients affect the dosage of anesthetic drugs? Findings: Compared to patients with good sleep quality, patients with sleep disorders will require increased doses of the sedative drug midazolam during anesthesia induction. Meaning: Preoperative sleep quality can affect the dosage of drugs during anesthesia induction.

The novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global public health emergency. As the number of confirmed cases increases, cardiovascular complications, such as myocardial injury and cardiac dysfunction, are evidenced. Takotsubo syndrome (TTS), which is common in the intensive care unit, is diagnosed among COVID-19 patients. There have been 68 more cases reports with over 119 patients since a COVID-19 patient with TTS was first reported on April 14, 2020. Angiotensin-converting enzyme 2 (ACE2), which is widely expressed in the lungs and heart, is the virus receptor. Nevertheless, randomized studies on COVID-19 related TTS are lacking, and the pathogenesis and pathophysiology are still unclear. Therefore, this review provides an overview of the potential pathogenesis, pathophysiology, clinical manifestations, diagnosis, and treatment strategy for TTS in the COVID-19 era based on current practices.

支撑喉镜下声带息肉摘除术是耳鼻喉科较为常见的手术,在传统气管内插管( endotracheal intubation, ETI)的麻醉方法下,手术视野与气道控制在同一狭小空间内,存在喉部视野差、工作空间狭窄等缺点.由于该类手术具有时间短、周转快,肌松要求高的特点,探索合适麻醉方式一直是临床医师关注重点.经鼻高流量氧疗( high-flow nasal cannula, HFNC)是一种新型的非插管供氧方式,通过高流量纯氧冲刷上呼吸道生理死腔,形成气道正压,持续供氧从而延长呼吸安全窒息时限[1-2].

It has been shown that PP2A is critical for apoptosis in neural progenitor cells. However, it remains unknown whether PP2A is required for neuronal survival. To address this question, we generated forebrain‐specific Ppp2cα knockout (KO) mice. We show that Ppp2cα KO mice display robust neuronal apoptosis and inflammatory responses in the postnatal cortex. Previous evidence has revealed that PD98059 is a potent ERK inhibitor and may protect the brain against cell death after cardiac arrest. To study whether PD98059 may have any effects on Ppp2cα KO mice, the latter was treated with this inhibitor. We demonstrated that the total number of cleaved caspase3 positive (+) cells in the cortex was significantly reduced in Ppp2cα KO mice treated with PD98059 compared with those without PD98059 treatment. We observed that the total number of IBA1+ cells in the cortex was significantly decreased in Ppp2cα KO mice treated with PD98059. Mechanistic analysis reveals that deletion of PP2Aca causes DNA damage, which may be attenuated by PD98059. Together, this study suggests that inhibition of ERK may be an effective strategy to reduce cell death in brain diseases with abnormal neuronal apoptosis.

LncRNA five prime to Xist (FTX) has been identified to exert a protective effect in multiple diseases. However, whether and how FTX attenuates cerebral ischemia–reperfusion injury (CI/RI) is still unclear. To simulate CI/RI, an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) HT22 cell model and an in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) Sprague–Dawley rat model were respectively constructed. In CI/RI plasma samples, OGD/R-challenged HT22 cells, and brain tissues from MCAO/R rats, FTX and mouse double minute 4 (MDM4) expressions were substantially decreased while miR-186-5p abundance was evidently increased. It was also revealed that FTX obviously improved neuronal damage induced by OGD/R through increasing proliferation, reducing apoptosis, and alleviating oxidative stress in OGD/R-challenged HT22 cells. Additionally, FTX positively regulated MDM4 level in OGD/R-treated HT22 cells as a sponge of miR-186-5p. Moreover, miR-186-5p upregulation or MDM4 suppression restored the inhibitory effects of FTX upregulation on OGD/R-triggered neuronal damage in HT22 cells. Therefore, these results suggest that FTX might ameliorate CI/RI by regulating the miR-186-5p/MDM4 pathway, providing a new target for stroke impairment treatment.

BX912, an inhibitor for 3-phosphoinositide-dependent protein kinase 1 (PDK1), has been shown to produce beneficial effects in mouse models of Alzheimer’s disease (AD). To test the hypothesis that early inhibition on PDK1 may prevent neuropathology in a 5×FAD mouse model, we employed a genetic approach to generate a mutant line, termed as Pdk1 cKO/5×FAD, in which PDK1 is inactivated, specifically in the developing cortex of 5×FAD mice through Emx1-Cre-mediated gene recombination. We discovered that the Pdk1 cKO/5×FAD mice exhibited a massive reduction of plaque pathology compared with their 5×FAD littermates. We also demonstrated that gliosis was remarkably attenuated in Pdk1 cKO/5×FAD cortices and amyloid precursor protein levels were significantly lower in Pdk1 cKO/5×FAD cortices compared with 5×FAD littermates. This study suggests that early inhibition on PDK1 may effectively prevent AD-like neuropathology.

OBJECTIVE:To compare the effect of high-flow nasal cannula oxygen therapy (HFNC) from that of conventional nasal cannula oxygen therapy (CNC) on oxygenation during prostate-targeted needle biopsy under total intravenous anesthesia in high-risk patients with obstructive sleep apnea syndrome (OSAS). METHODS:We randomly assigned 64 high-risk OSAS patients to two groups of an equal number to receive HFNC and CNC, respectively, under total intravenous anesthesia. We recorded the incidence rates of SpO2<95% and the lowest SpO2 during surgery, the mean arterial pressure (MAP), heart rate (HR) and oxygen saturation (SpO2) upon entering the operation room (T0), at the beginning (T1) and the end of surgery (T2) and at 30 minutes postoperatively (T3), as well as arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2) at T0 and T2, and the incidence rates of airway intervention and adverse events, followed by comparison of the parameters between the two groups. RESULTS:Both the lowest SpO2 and PaO2 were significantly increased in the HFNC group compared with those in the CNC group (P < 0.05) while no statistically significant difference was observed in PaCO2 between the two groups (P > 0.05). The intraoperative incidence rates of hypoxia, airway intervention, choking and body movement were remarkably lower in the HFNC than in the CNC group (P < 0.05), but there were no statistically significant differences in the operation time, anesthesia duration and propofol dosage between the two groups (P > 0.05). CONCLUSION:HFNC may provide more adequate oxygenation, improve airway management, and reduce the incidence of hypoxemia in high-risk OSAS patients during prostate biopsy under total intravenous anesthesia.

At present, there are seven known types of human coronaviruses (HCoVs), which can be further divided into two categories: low pathogenic and highly pathogenic. The low pathogenic HCoVs infect the upper respiratory tract, mainly causing mild, cold-like respiratory diseases. By contrast, highly pathogenic HCoVs mainly infect the lower respiratory tract and cause fatal types of pneumonia, which include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as the recent outbreak of coronavirus disease 2019 (COVID-19). Highly pathogenic HCoV infection has a high morbidity and mortality, which is usually related to the strong immune response induced by highly proinflammatory cytokines, which is also known as "cytokine storm". Therefore, it is particularly important to explore the role of cytokine storm in the process of highly pathogenic HCoV infection. We review the epidemiological and clinical manifestations of highly pathogenic HCoV infection, and reveal the pathology of cytokine storm and its role in the process of highly pathogenic HCoV infection.

目的 探讨睡眠障碍对无痛胃肠镜检查患者丙泊酚用量及术后睡眠质量的影响.方法 选择2021年10月-2022年4月于常州市第二人民医院无痛中心接受无痛胃肠镜检查的80例患者.根据匹兹堡睡眠质量指数(PSQI)和Epworth嗜睡量表(ESS),评估患者术前睡眠质量水平和白日嗜睡严重程度.按照PSQI诊断术前有无睡眠障碍进行分组,其中,PSQI＞7分为睡眠障碍组(n=40),PSQI≤7分为睡眠正常组(n=40);2组患者诱导前静脉缓慢推注舒芬太尼0.05～0.1 μg/kg.再缓慢静脉推注丙泊酚,推注速度10 mg/s,待患者意识消失、呼唤无应答、睫毛反射消失、警觉/镇静评分(OAA/S)≤2级,停止静注丙泊酚,进行胃肠镜操作.观察并记录2组患者操作过程中丙泊酚用量、术前及术后24 h和7d等不同时间点PSQI评分、术中呼吸抑制、体动反应等不良反应发生情况及诱导时间、苏醒时间、胃肠镜操作时间、检查结束至进入恢复室的时间.使用Pearson法分析PSQI和ESS评分及丙泊酚用量和苏醒时间之间的相关性.结果 主要指标:与睡眠正常组患者比较,睡眠障碍组患者丙泊酚首次量、总用量和单位体表单位时间用量较睡眠正常组明显增多(P＜0.05),患者术后24 h和7 d 的PSQI评分较术前减小(P＜0.05);次要指标:睡眠障碍组患者苏醒时间较睡眠正常组明显延长(P＜0.05).Pearson法分析显示患者PSQI评分和ESS评分与丙泊酚用量和苏醒时间相关.2组术中呼吸抑制、体动反应、腹痛和恶心呕吐等发生情况和检查结束至进入恢复室的时间比较差异无统计学意义(P＞0.05).结论 患者术前睡眠障碍会使无痛胃肠镜检查中静脉麻醉药丙泊酚的用量增加,且会出现苏醒延迟现象,患者的白日嗜睡程度与丙泊酚用量的增加有关,静脉麻醉药的应用使患者睡眠障碍情况在短期内得到改善.

Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling. SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.

Context: Since December 2019, more than 80,000 patients have been diagnosed with coronavirus disease 2019 (COVID-19) in China. Social support status of COVID-19 patients, especially the impact of social support on their psychological status and quality of life, needs to be addressed with increasing concern. Objectives: In this study, we used social support rating scale (SSRS) to investigate the social support in COVID-19 patients and nurses. Methods: The present study included 186 COVID-19 patients at a Wuhan mobile cabin hospital and 234 nurses at a Wuhan COVID-19 control center. Responses to a mobile phone app-based questionnaire about social support, anxiety, depression, and quality of life were recorded and evaluated. Results: COVID-19 patients scored significantly lower than nurses did on the Social Support Rating Scale (SSRS). Among these patients, 33.9% had anxiety symptoms, while 23.7% had depression symptoms. Overall SSRS, subjective social support scores and objective support scores of patients with anxiety were lower than those of patients without anxiety. This result was also found in depression. In addition, all dimensions of social support were positively correlated with quality of life. Interestingly, in all dimensions of social support, subjective support was found to be an independent predictive factor for anxiety, depression, and quality of life, whereas objective support was a predictive factor for quality of life, but not for anxiety and depression via regression analysis. Conclusion: Medical staffs should pay attention to the subjective feelings of patients and make COVID-19 patients feel respected, supported, and understood from the perspective of subjective support, which may greatly benefit patients, alleviate their anxiety and depression, and improve their quality of life.

股骨颈骨折是老年病人常见的骨折类型[1] ,髋关节置换术是治疗股骨颈骨折的常用手术方式,术中出血是此类手术术中最常见的并发症之一,可导致术中视野差,血流动力学不稳定,增加机体多器官负担[2].因此,临床上亟需寻找一种操作简单、安全可靠的方法来减少髋关节置换术术中出血.

Clinical evidence shows that chronic pain and depression often accompany each other, but the underlying pathogenesis of comorbid chronic pain and depression remains mostly undetermined. Biotechnology is gradually revealing the phenotype and function of microglia, with great progress regarding microglia's role in neurodegeneration, depression, chronic pain, and other conditions. This article summarizes the role of microglia in chronic pain, depression, and comorbidities, which is conducive to finding new targets to treat chronic pain and depression.

内镜下逆行性胰胆管造影术(ERCP)是诊断和治疗胰胆管相关疾病的重要方法.ERCP在实施时常需适度镇静、镇痛来减轻病人焦虑、不适和疼痛感,从而提高病人对手术的耐受性,便于内镜手术操作[1].盐酸羟考酮注射液是近期上市的羟考酮制剂,是μ、κ受体激动剂,对内脏痛有更好的镇痛作用[2].本研究通过观察羟考酮复合右美托咪定用于老年行ERCP病人的安全性和有效性,为临床用药提供更好的选择.

Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation.SIGNIFICANCE STATEMENT Dysfunction of Akt is associated with white matter diseases including the agenesis of the corpus callosum. However, it remains unknown whether Akt plays an important role in oligodendrocyte differentiation. To address this question, we generated oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional knock-out mice. Akt mutants exhibit deficient white matter development, loss of mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell death in the CNS. We demonstrate that deletion of Akt three isoforms leads to downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical for Sox10 expression. Together, these findings reveal a novel mechanism to regulate Sox10 expression. This study may provide insights into molecular mechanisms for neurodevelopmental diseases caused by dysfunction of protein kinases.

良性前列腺增生是临床进展性疾病,且患病率随着年龄增长而增加,80岁以上老年人发病率可达80％[1].腰硬联合阻滞麻醉由于起效快、镇痛作用强且无需气道操作,对全身器官影响小,术后可留置硬膜外导管进行硬膜外镇痛,成为目前经尿道前列腺电切术( TURP )常用的麻醉方式.老年病人特有的生理改变(骨质增生、椎间隙变窄、硬膜外腔静脉丛血管硬化充血)会增加硬膜外穿刺及置管操作的难度.有文献报道,硬膜外导管置管成功率与导管的物理特性有关,钢丝加强型硬膜外导管能有效提高产科椎管内麻醉操作中硬膜外置管成功率[ 2-3].我们先前的研究发现,钢丝加强型硬膜外导管可降低产妇腰硬联合麻醉下硬膜外出血[4].然而,有关钢丝加强型硬膜外导管在老年病人硬膜外置管中的成功率鲜见报道.本研究拟探讨国产钢丝加强型硬膜外导管对行TURP 术的老年病人硬膜外置管成功率的影响,为临床麻醉的合理应用提供参考.