Clozapine-Induced Severe Toxicity: Exploring the Pharmacokinetic Profile of Clozapine and Its Significance in Hemodynamic Instability - A Case Report.

Hemodynamic instability in patients with clozapine intoxication can indirectly reflect the serum concentration of clozapine.We have described a case of a 32-year-old pregnant woman who developed life-threatening clozapine toxicity at 28 weeks of gestation. The levels of clozapine and norclozapine in the serum were high. We initiated hemoperfusion(HP) and other detoxification therapies to remove the drug. The patient had severely dilated peripheral blood vessels, which led to cardiac symptoms such as fatal hypotension and uncontrollable tachycardia, resulting in very high cardiac output and elevated Central venous oxygen saturation (ScvO2). Pharmacological intervention significantly improved the hemodynamics.In light of our observations in the ongoing case, we posit that evaluating hemodynamic parameters before and after blood detoxification could serve as a valuable means to gauge effectiveness and provide guidance for treatment.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

BACKGROUND: Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs. METHODS: haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model. RESULTS: The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors. CONCLUSION: haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

The vertebral Hounsfield units can quantitatively predict the risk of adjacent vertebral fractures after percutaneous kyphoplasty.

Background: Measuring the Hounsfield units (HU) of the vertebrae may yield diagnostic information for fracture risk. This study aimed to measure HU of vertebrae in percutaneous kyphoplasty (PKP) patients using computed tomography (CT) imaging to determine the HU measurements threshold for adjacent vertebral fracture and to assess the relationship between HU measurements and the risk of adjacent vertebral fracture. Methods: A retrospective study was conducted on consecutive patients who underwent PKP between January 2019 and October 2021 in the China-Japan Union Hospital of Jilin University. The HU of the vertebra was measured on the reconstructed CT images by 2 independent spine surgeons. The HU measurements of adjacent vertebrae and the ratio of HU measurements between the surgical vertebra and adjacent vertebrae were statistically analyzed to determine the best critical value and evaluate the prediction effectiveness and accuracy of the best critical value. Results: A total of 105 patients were identified with complete imaging and follow-up information. Of these, 47 patients (44.8%) had evidence of an adjacent vertebral fracture on follow-up imaging. The mean HU measurements of the fractured adjacent vertebra were significantly different from the mean HU measurements of the unfractured adjacent vertebra (50.94±20.59 vs. 81.74±18.97 HU; P<0.001). There was a significant difference in the ratio of HU measurements between the surgical vertebra and the fractured adjacent vertebra and between the surgical vertebra and the unfractured adjacent vertebra (26.34±17.52 vs. 14.53±9.40; P<0.001). Interactive scatter plots and receiver operating characteristic (ROC) curve showed that a HU measurement of 66.9 and a HU measurements ratio of 15.18 were the best thresholds for predicting the risk of fracture of adjacent vertebrae after PKP surgery, with an area under the curve (AUC) of 0.901 [95% confidence interval (CI): 0.822-0.953; P<0.001] and 0.874 (95% CI: 0.790-0.934; P<0.001), respectively. The prediction accuracy was 90.4% and 84.0%, respectively. Conclusions: A low mean HU measurements of adjacent vertebrae or a high ratio of the mean HU measurements of the operated vertebrae to the adjacent vertebrae are risk factors for the vulnerability of adjacent vertebrae to fracture. The risk of fracture in the adjacent vertebrae after PKP can be predicted by measuring HU.

Extensive spinal epidural abscess caused by Staphylococcus epidermidis: A case report and literature review.

Background: Extensive spinal epidural abscess (SEA) is an exceptional and threatening condition that requires prompt recognition and proper management to avoid potentially disastrous complications. We aimed to find key elements of early diagnosis and rational treatments for extensive SEA. Case presentation: A 70-year-old man complained of intense pain in the cervical-thoracic-lumbar spine that radiated to the lower extremity. Laboratory test results revealed a marked increase in all indicators of infection. The spinal magnetic resonance imaging (MRI) revealed a ventral SEA extending from C2 to L4. Owing to the patient's critical condition, laminectomy, drainage, and systemic antibiotic therapy were administered. And the multidrug-resistant Staphylococcus epidermidis was detected in the purulent material from this abscess. Results: Postoperative MRI revealed diminished epidural abscess, and the clinical symptoms were dramatically and gradually relieved after two rounds of surgery and systemic antibiotic therapy involving the combination of ceftriaxone, linezolid, and rifampicin. Conclusions: A comprehensive emergency assessment based on neck or back pain, neurological dysfunctions, signs of systemic infection, and MRI are important for early diagnosis of extensive SEA. Further, the combination of laminectomy, drainage, and systemic antibiotic therapy may be a rational treatment choice for patients with SEA, especially for extensive abscess or progressive neurological dysfunction.

Relationship between body composition and pulmonary function in the general population-a cross-sectional study in Ningxia.

Studies considering the relationship between non-obesity-related body composition and lung function are few; therefore, this study aimed to explore these correlations and effects. This cross-sectional study conducted in rural Qingtongxia City and Pingluo County, Ningxia, China, included 776 participants aged 30-75 years. Body composition and lung function were measured using direct segmental multifrequency bioelectrical impedance analysis and a digital spirometer, respectively. Their correlation was assessed using partial correlation analysis, controlling for age and smoking status, and the body composition effect on lung function was analyzed using binomial logistic regression analysis. The body components total body water content, protein content, mineral content, muscle mass, fat-free mass (FFM), skeletal muscle mass, basal metabolic volume, and chest circumference (CC) positively correlated with pulmonary function (forced vital capacity and forced expiratory volume in one second) in both sexes. Neck circumference and hip circumference positively correlated with pulmonary function in women. Additionally, lung function declines more slowly in women (odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.44-0.98, p = 0.04); CC (OR = 0.92, 95% CI = 0.86-0.98, p = 0.01) increased as a protective factor for decreased lung function. Increased waist circumference (OR = 1.04, 95% CI = 1.00-1.09, p = 0.04) was a risk factor for reduced lung function. FFM contains body composition indicators positively correlating with lung function, excluding fat-related body composition. Abdominal obesity increases the risk of decreased lung function.

[Potential geographical distribution of Rana hanluica in China under climate change]. / 气候变化下寒露林蛙在中国的潜在地理分布.

Global warming in the last few decades had strong impacts on biodiversity and geographi-cal distribution of different animal species worldwide, especially amphibians. Rana hanluica, a frog species endemic in China, is still classified as Least Concerned in the Red List of Threatened Species because few studies have been conducted on this species. To understand the survival of Rana hanluica population, we used maximum entropy models (MaxEnt) to analyze its distribution across regions under current climatic conditions based on 47 distribution records and 20 environmental factors. We investigated the changes in distribution of this species under different climate scenarios in China (2050s and 2070s). Finally, current and future suitable habitats for R. hanluica were mode-led, and the impacts of environmental factors in shaping its distribution were evaluated. The results showed that the prediction accuracy of the MaxEnt model was high, and AUC value of the receiver operating curve was 0.993. The total suitable habitat area for R. hanluica was 36.36×104 km2, mainly located in Hunan and Guizhou provinces in China. The major environmental factors influencing the geographic distribution of R. hanluica were precipitation of dryest month and altitude. Under the future climate scenario (2050 and 2070) with two representative concentration pathways (RCPs, SSP1-2.5, SSP5-8.5), the suitable habitat of R. hanluica was reduced in different degrees, resulting in a decreasing trend of the total suitable habitat area. The center of gravity in highly suitable habitat of R. hanluica shifted to high-latitude regions, with the core distribution area in Hunan Province.

A Biofilm Microenvironment-Activated Single-Atom Iron Nanozyme with NIR-Controllable Nanocatalytic Activities for Synergetic Bacteria-Infected Wound Therapy.

Biofilm microenvironment (BME)-activated antimicrobial agents display great potential for improved biofilm-related infection therapy because of their superior specificities and sensitivities, effective eliminations, and minimal side effects. Herein, BME-activated Fe-doped polydiaminopyridine nanofusiform-mediated single-atom nanozyme (FePN SAzyme) is presented for photothermal/chemodynamic synergetic bacteria-infected wound therapy. The photothermal therapy (PTT) function of SAzyme can be specifically initiated by the high level of H2 O2 and further accelerated through mild acid within the inflammatory environment through "two-step rocket launching-like" process. Additionally, the enhanced chemodynamic therapy (CDT) for the FePN SAzyme can also be endowed by producing hydroxyl radicals through reacting with H2 O2 and consuming glutathione (GSH) of the BME, thereby contributing to more efficient synergistic therapeutic effect. Meanwhile, FePN SAzyme could catalyze biofilm-overexpressed H2 O2 decomposing into O2 and overcome the hypoxia of biofilm, which significantly enhances the susceptibility of biofilm and increases the synergistic efficacy. Most importantly, the synergistic therapy of bacterial-induced infection diseases can be switched on by the internal and external stimuli simultaneously, resulting in minimal nonspecific damage to healthy tissue. These remarkable characteristics of FePN SAzyme not only develop an innovative strategy for the BME-activated combination therapy but also open a new avenue to explore other nanozyme-involved nanoplatforms for bacterial biofilm infections.

Precision Neuromuscular Block Management for Neural Monitoring During Thyroid Surgery.

INTRODUCTION: Titration of neuromuscular block (NMB) plays a key role in intraoperative recurrent laryngeal nerve monitoring during thyroid surgery. The combination of neuromuscular blocking agent and timely partial reversal of NMB was investigated in both animal experiments and clinical neuro-monitored thyroidectomy. METHODS: In animal experiments, 8 piglets received sugammadex to assess the laryngeal EMG recovery after rocuronium-induced NMB. In clinical monitored thyroidectomy, 40 patients each were allocated to conventional group and sugammadex group. Conventional group received rocuronium 0.3 mg/kg at anesthesia induction, while sugammadex group received partial NMB recovery protocol- 0.6 mg/kg of rocuronium at anesthesia induction and 0.5 mg/kg of sugammadex. Main outcome was assessed by first (V1) and final (V2) EMG signal induced by vagal stimulation. RESULTS: In the porcine model, 50% recovery of laryngeal EMG amplitude was achieved at 16.8 ± 1.9 and 6 ± 2.7 minutes respectively after 0.5 and 1 mg/kg of sugammadex (p < 0.01). In monitored thyroidectomy, EMG amplitudes at V1 in group S and group C were 1214 ± 623 and 915 ± 476 µV, respectively (p = 0.02). Positive and adequately high EMG amplitudes were observed at the early surgical stage for all patients. Sugammadex groups were superior to conventional group in EMG tube placement (p < 0.001). CONCLUSION: Both porcine model and clinical application showed that precise NMB management by low-dose sugammadex was effective for intraoperative neural monitoring (IONM). The regimen ensured optimal conditions for tracheal intubation and timely neuromuscular function restoration for high-quality EMG signal.

Bacteria responsive polyoxometalates nanocluster strategy to regulate biofilm microenvironments for enhanced synergetic antibiofilm activity and wound healing.

Backgroud: Nowadays, biofilms that are generated as a result of antibiotic abuse cause serious threats to global public health. Such films are the primary factor that contributes to the failure of antimicrobial treatment. This is due to the fact that the films prevent antibiotic infiltration, escape from innate immune attacks by phagocytes and consequently generate bacterial resistance. Therefore, exploiting novel antibacterial agents or strategies is extremely urgent. Methods: Herein, we report a rational construction of a novel biofilm microenvironment (BME)-responsive antibacterial platform that is based on tungsten (W)-polyoxometalate clusters (POMs) to achieve efficient bactericidal effects. Results: On one hand, the acidity and reducibility of a BME could lead to the self-assembly of POMs to produce large aggregates, which favor biofilm accumulation and enhance photothermal conversion under near-infrared (NIR) light irradiation. On the other hand, reduced POM aggregates with BME-induced photothermal-enhanced efficiency also exhibit surprisingly high peroxidase-like activity in the catalysis of bacterial endogenous hydrogen peroxide (H2O2) to produce abundant reactive oxygen species (ROS). This enhances biofilm elimination and favors antibacterial effects. Most importantly, reduced POMs exhibit the optimal peroxidase-like activity in an acidic BME. Conclusion: Therefore, in addition to providing a prospective antibacterial agent, intelligent acid/reductive dual-responsive POMs will establish a new representative paradigm for the areas of healthcare with minimal side effects.

Tibetan medicine Kuan-Jin-Teng exerts anti-arthritic effects on collagen-induced arthritis rats via inhibition the production of pro-inflammatory cytokines and down-regulation of MAPK signaling pathway.

BACKGROUND: The stems of Tinospora sinensis (Lour.) Merr commonly named "Kuan-Jin-Teng" in Chinese, have been used to treat rheumatoid arthritis as a Tibetan medicine. PURPOSE: The effects of the EtOAc fraction of ethanolic extract from the stems of T. sinensis (KJT) on the pro-inflammatory cytokines and MAPK pathway were studied in collagen-induced arthritis (CIA) model. STUDY DESIGN: Anti-arthritic activity of KJT was investigated in CIA model. METHODS: The chemical constituents of KJT were analyzed by LC-MS and HPLC. The CIA model was established with injecting the bovine CII emulsified in Freund's adjuvant in Wistar rats. Several doses of KJT (50.0, 100.0 and 200.0 mg/kg) were administrated via oral gavage to CIA rats daily for 4 weeks. The anti-arthritic activity of KJT was investigated by clinical arthritis scoring, paw swelling inspection and hyperalgesia measurement, as well as radiological and histological analysis in CIA rats. The impacts of KJT on the activation of MAPK pathway, production of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-17) in ankle joints, serum, and spleen in CIA rats were examined by western blot, immunohistochemical staining, ELISA, and quantitative real-time PCR respectively. Lastly, the effects of KJT on production of the nitric oxide (NO) and pro-inflammatory cytokines as well as the regulation of the phosphorylation of p38 and Erk were detected in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. RESULTS: KJT significantly alleviated the paw swelling, hyperalgesia and arthritic severity, and reduced the synovial tissue proliferation and inflammatory cell infiltration in the CIA rats. Moreover, KJT suppressed the production of TNF-α, IL-1ß, and IL-17 in ankle joints, serum, and spleen and reversed the up-regulation of the phosphorylation of p38 and Erk in CIA rats. KJT was also demonstrated to inhibit the production of NO and pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), and phosphorylation of p38 and Erk in LPS-stimulated RAW264.7 cells. CONCLUSION: These results suggest the mechanisms of KJT performing its anti-arthritis effect may be attributed to inhibiting the production of pro-inflammatory cytokines and down-regulating the MAPK signaling pathway.