Gelsemium elegans (G. elegans) is an extremely poisonous plant that is widely distributed in southern China and southeastern Asia. G. elegans poisoning events occur frequently in southern China, and are therefore an urgent public health problem requiring multidisciplinary action. However, the toxic components and toxicological mechanisms remain unclear. Here, we describe a systematic investigation on the toxic components of G. elegans, resulting in the isolation and identification of 120 alkaloids. Based on acute toxicity screening, the structure-toxicity relationship of Gelsemium alkaloids was proposed for the first time. Moreover, gelsedine- and humantenine-type alkaloids were detected in the clinical blood sample, and were confirmed to be causative in the poisoning. The most toxic compound, gelsenicine (1), had selective inhibitory effects toward ventral respiratory group (VRG) neurons in the medulla, which is the main brain region controlling respiration in the central nervous system. Gelsenicine (1) strongly inhibited the firing of action potentials in VRG neurons through its ability to stimulate GABA_A receptors, the main receptors involved in inhibitory neurotransmission. Application of GABA_A receptor antagonists successively reversed action potential firing in gelsenicine (1)-treated VRG neurons. Importantly, the GABA_A receptor antagonists securinine and flumazenil significantly increased the survival of poisoned animals. Our findings provide insight into the components and mechanisms of G. elegans toxicity, and should assist the development of effective emergency treatments for G. elegans poisoning.

BACKGROUND:Shujin Jiannao Prescription is an empirical formula for the treatment of cerebral palsy in Dongzhimen Hospital,Beijing University of Chinese Medicine,with clear clinical efficacy,but the specific mechanism needs to be elucidated. OBJECTIVE:To explore the possible mechanism of Shujin Jiannao Prescription in treating cerebral palsy. METHODS:Sixty-four 7-day-old Sprague-Dawley rats were randomly divided into a normal group(n=12)and a model group(n=52).An animal model was established by the Rice-Vannucci method.After successful modeling,52 model rats were randomly divided into control model group(n=12),minocycline group,and the low-,medium-,and high-dose groups of the Shujin Jiannao Prescription(n=10 per group).Rats in the minocycline group were given 40 mg/kg·d minocycline by gavage;rats in the low-,medium,and high-dose groups were given 4,8,and 16 g/kg·d Shujin Jiannao Prescription granules by gavage,respectively;and rats in the normal group and control model group were given an equal dose of normal saline by gavage.Medication in each group was given once a day for 1 week.The rats in each group were evaluated behaviorally using suspension test,abnormal involuntary movement score,and Bederson score.The pathological changes of the cerebral cortex were observed by hematoxylin-eosin staining.The levels of tumor necrosis factor α,interleukin 1β,and interleukin 10 in the cerebral cortex were determined using ELISA.The positive expressions of Janus kinase 2(JAK2),phosphorylated Janus kinase 2(p-JAK2),phosphorylated signal transducer and activator of transcription 3(p-STAT3)in the cerebral cortex were detected using immunohistochemistry.The protein expression levels of JAK2,p-JAK2,and p-STAT3 were detected using western blot. RESULTS AND CONCLUSION:Compared with the normal group,the suspension test score and involuntary movement score were decreased in the control model group(P＜0.01 or P＜0.05).The pathological results showed structural disruption of nerve cells,formation of large numbers of vacuoles,cell swelling,and increased intercellular space in the control model group.In addition,the expressions of tumor necrosis factor α and interleukin 1β in the cerebral cortex were significantly increased(P＜0.01),the expression of interleukin 10 was decreased(P＜0.05),and the protein expressions of JAK2,p-JAK2,and p-STAT3 in the cerebral cortex were significantly increased(P＜0.01)in the control model group compared with the normal group.Compared with the model group,minocycline and Shujin Jiannao Prescription at each dose could improve the behavioral indexes of rats(P＜0.01 or P＜0.05)and ischemic-hypoxic pathological changes were attenuated,with only a small amount of necrotic nerve cells and a few vacuoles,and reduced intercellular space.Moreover,the expressions of tumor necrosis factor α and interleukin 1β in the cerebral cortex were decreased in each drug group compared with the control model group(P＜0.05),while the protein expressions of JAK2,p-JAK2,and p-STAT3 in the cerebral cortex were significantly decreased(P＜0.01).The most obvious improvement was observed in the high-dose Shujin Jiannao Prescription group.To conclude,Shujin Jiannao Prescription can inhibit inflammation in the cerebral cortex of rats with hypoxic-ischemic brain injury.The mechanism may be related to the regulation of the JAK2/STAT3 signaling pathway.

Objective: Sialidosis type 2 has variants that are both catalytically inactive (severe), while sialidosis type 1 has at least one catalytically active (mild) variant. This study aimed to discuss the structural changes associated with these variants in a newly reported family carrying N-acetyl-α-neuraminidase-1 (NEU1) variants and explore the clinical characteristics of different combinations of variants in sialidosis type 1. Methods: First, whole-exome sequencing and detailed clinical examinations were performed on the family. Second, structural analyses, including assessments of energy, flexibility and polar contacts, were conducted for several NEU1 variants, and a sialidase activity assay was performed. Third, previous NEU1 variants were systematically reviewed, and the clinical characteristics of patients in the severe-mild and mild-mild groups with sialidosis type 1 were analyzed. Results: We report a novel family with sialidosis type 1 and the compound heterozygous variants S182G and V143E. The newly identified V143E variant was predicted to be a mild variant through structural analysis and was confirmed by a sialidase activity assay. Cherry-red spots were more prevalent in the severe-mild group, and ataxia was more common in the mild-mild group. Impaired cognition was found only in the severe-mild group. Moreover, patients with cherry-red spots and abnormal electroencephalographies and visual evoked potentials had a relatively early age of onset, whereas patients with myoclonus had a late onset. Conclusion Changes in flexibility and local polar contacts may be indicators of NEU1 pathogenicity. Sialidosis type 1 can be divided into two subgroups according to the variant combinations, and patients with these two subtypes have different clinical characteristics.

Objective Taking 41 kinds of Chinese herbal medicines commonly used in Meizhou Hakka as the research object,their inhibitory activities against α-glucosidase and α-amylase were screened and the enzyme inhibition types of the species with the strongest activities were explored.Methods The inhibitory activities of 41 commonly used Hakka herbs in Meizhou against α-glucosidase and α-amylase were evaluated by the p-Nitrophenyl a-D-mannopyranoside(pNPG)method and the 3,5-Dinitrosalicylic acid(DNS)method,using the inhibitory rate of half(IC50)as an index.The inhibitory activity of 95%ethanol extracts of 41 Chinese herbal medicines commonly used in Meizhou Hakka on α-glucosidase and α-amylase were analysed.The enzymatic kinetics method and Lineweaver-Burk curve were used to analyze the inhibitory type of the most active species.Results The results showed that 40 Chinese herbal medicines commonly used in Meizhou Hakka had α-glucosidase inhibitory activity,and 23 medicines had α-amylase inhibitory activity,among which Psychotria asiatica Wall.showed the strongest inhibitory activity with the IC50 values aganist α-glucosidase and α-amylase of 0.17±0.001 mg·mL-1 and 0.09±0.001 mg·mL-1,respectively.The inhibition types were reversible competitive inhibition and reversible non-competitive inhibition,respectively.Conclusion The Psychotria asiatica Wall.Chinese herbal medicines commonly used in Meizhou Hakka has significant inhibitory effect on the activity of glucose metabolism enzymes,which has potential value for further research and development on the prevention and treatment of diabetes mellitus.

Objective:To investigate the clinical features of pregnant associated Takotsubo cardiomyopathy (PTCM).Methods:We reviewed reported PTCM cases published from January 2007 to June 2022 using the keywords "Tako-tsubo cardiomyopathy""Takotsubo cardiomyopathy" "stress cardiomyopathy" AND "parturition" "pregnancy" "cesarean delivery" "postpartum" "peripartum" "eclampsia" "abortion" in Pubmed and Web of Science databases and the corresponding Chinese words in Wanfang and Chinese Medical Journal Network. Age, obstetric history, mode of delivery, mode of anesthesia, etiological factors, clinical manifestations, treatment, and prognosis of PTCM were recorded. Descriptive statistical analysis was adopted.Results:A total of 55 articles were included, covering 60 patients with PTCM. (1) Age and time of onset: The age of onset was (32.4±6.0) years old. PTCM occurred most frequently during labor [42% (25/60)] and within one day postpartum [32% (19/60)] and during the gestational period [13%(8/60), 33.0 weeks (24.5-37.7 weeks)]. (2) Delivery-related factors: There were 38% (16/42) primiparas and 60% (25/42) multiparas. Among them, 67% (38/57) and 18% (10/57) were delivered by cesarean section and vaginal delivery, respectively. PCTM often lacks obvious triggers [40% (24/60)], with the most common inducing factor being pregnancy-related diseases [27% (16/60)]. (3) Clinical features: The initial symptoms of PTCM were dyspnea [44% (26/59)], followed by chest pain accompanied by dyspnea [17% (10/59)]. The most common subtype of PTCM was the apical type [45% (26/58)], followed by the basal type [24% (14/58)], while the biventricular type was the least common [3% (2/58)] in the PTCM classification. The left ventricular ejection fraction was (31.6±12.1) % at the onset of PTCM, which recovered to (58.2±7.6) % at discharge. PCTM was often complicated by pulmonary edema [67% (40/60)] and cardiogenic shock [55% (33/60)]. (4) Treatment and prognosis: Patients with PCTM usually require noninvasive or invasive ventilator-assisted ventilation [40% (23/58)]. One pregnant woman and five neonates died, while the remaining patients recovered well.Conclusions:PTCM should be considered in differential diagnosis of patients experiencing dyspnea and chest pain during labor and pregnancy. PTCM patients are younger and have more pulmonary edema and cardiogenic shock. Mechanical ventilation is often required, but the prognosis is favorable.

OBJECTIVE: To investigate the influence of buried thread nasal augmentation on dorsal soft tissue of nose and revision rhinoplasty. METHODS: A clinical data of 29 patients requesting revision rhinoplasty after buried thread nasal augmentation, who were admitted between July 2017 and July 2019 and met the selection criteria, was retrospectively analyzed. All patients were female with an average age of 26.8 years (range, 18-43 years). The patiens were admitted to the hospital at 3-48 months after buried thread nasal augmentation (median, 15 months). Among them, there were 18 cases of insufficient nasal tip projection, 22 cases of insufficient nasal root projection, 7 cases of threads ectasia, 5 cases of threads exposure, 3 cases of infection, and 10 cases with two or more conditions. There were 9 cases of combined short nose deformity, 1 case of spherical hypertrophy of the nasal tip, 3 cases of deviation of the nasal columella, 3 cases of excessive width of the nasal base, and 1 case of nasal hump. Three infected patients only underwent threads removal and debridement. The rest patients underwent revision rhinoplasty, and the dorsum of the nose was made with polytetrafluoroethylene expansion; the tip of the nose was reshaped by taking autologous rib cartilage and alar cartilage in 16 cases, and by taking autologous septal cartilage and alar cartilage in another 10 cases. The threads and surrounding tissue specimens removed during operation were subjected to histologic observation. Nasal length and nasal tip projection were measured after revision rhinoplasty and the ratio was calculated to evaluate the nasal morphology; patient satisfaction was evaluated using the Likert 5-grade scale. RESULTS: Patients were followed up 12-48 months (mean, 18 months). Inflammation was controlled in 3 patients with infections caused by buried thread nasal augmentation. The remaining 26 patients had satisfactory results immediately after revision rhinoplasty. Before revision rhinoplasty and at 7 days and 6 months after revision rhinoplasty, the nasal length was (4.11±0.34), (4.36±0.25), and (4.33±0.22) cm, respectively; the nasal tip projection was (2.34±0.25), (2.81±0.18), and (2.76±0.15) cm, respectively; and the nasal tip projection/nasal length ratio was 0.57±0.08, 0.65±0.05, and 0.64±0.04, respectively. There were significant differences in the nasal length and the nasal tip projection between time points ( P<0.05). There was a significant difference in the nasal tip projection/nasal length ratio between pre- and post-operation ( P<0.05), but there was no significant difference between 7 days and 6 months after operation ( P>0.05). The Likert score for satisfaction ranged from 1.5 to 5.0 (mean, 4.05). During follow-up period of 26 patients, no nasal prosthesis was exposed, and the shape of the nose was stable, and the nasal skin of 5 patients with exposed threads could be seen with different degrees of scarring; there was no infection, cartilage resorption, and no cartilage deformation, displacement, or exposure. Histological observation showed that absorbable threads were not only absorbed after implantation, but also with the prolongation of time, the inflammatory changes in the surrounding tissues caused by decomposition and absorption of the threads showed a gradual aggravation of the first, the heaviest inflammatory reaction in 6 to 12 months, and then gradually reduce the trend. CONCLUSION After implantation of the absorbable thread into the subcutaneous tissue of the nasal dorsum, the nature of the thread is different from the body's own tissue, which will affect the soft tissue compliance of the nasal dorsum. The degradation and absorption of the thread will stimulate the infiltration of inflammatory cells and the proliferation of fibroblasts in the surrounding tissue and then form scar tissue, which will affect the design and effect of revision rhinoplasty.
Humans ; Female ; Adult ; Male ; Rhinoplasty ; Retrospective Studies ; Reoperation ; Nasal Cartilages ; Nasal Septum ; Cicatrix

Objective:To summarize the clinical characteristics and therapeutic efficacy of central nervous system (CNS) aspergillosis.Methods:The clinical manifestations, laboratory examination, neuroimaging features, treatment and prognosis of 37 cases of CNS aspergillosis diagnosed and treated in the First Medical Center of People′s Liberation Army General Hospital from January 2000 to January 2021 were retrospectively analyzed. According to the correlation between intracranial lesions and paranasal sinus lesions, they were divided into two groups: rhino-cerebral aspergillosis (RA, n=21) group and cerebral aspergillosis (CA, n=16) group. Results:Only 16.2% (6/37) of CNS aspergillosis patients had a clear background of immunosuppression, but 35.1% (13/37) were complicated with diabetes. The most common clinical manifestations were headache (73.0%, 27/37), cranial nerve involvement (59.5%, 22/37) and fever (37.8%, 14/37). Cerebrospinal fluid characteristics included increased pressure (53.8%, 14/26), increased white blood cell count (46.7%, 14/30), decreased glucose (30.0%, 9/30), increased protein (70.0%, 21/30), and high positive results of the metagenomic next-generation sequencing (mNGS) of pathogenic microorganism (7/10). Cranial magnetic resonance imaging showed that commonly involved sites were sinus, orbital apex, posterior orbit, cavernous sinus (43.2%, 16/37) and cerebral lobes (27.0%, 10/37). Treatment options included antifungal drugs alone (64.9%, 24/37), combination of drugs and surgery (27.0%, 10/37) and surgery alone (8.1%, 3/37). Compared with the CA group, RA group had fewer males [47.6% (10/21) vs 14/16, χ2=6.34, P=0.012] and older age [(54.2±19.4) years vs (38.4±18.4) years, t=2.50, P=0.017], and was more prone to headache [85.7% (18/21) vs 9/16, χ2=4.00, P=0.046) and cranial nerve involvement [81.0% (17/21) vs 5/16, χ 2=9.31, P=0.006]. The misdiagnosis rate of these patients in the early stage was 73.0% (27/37). A total of 29 patients (85.3%, 29/34) were treated with voriconazole successively, and the course of treatment was 3.0 (0.5, 10.4) months. Compared with salvage therapy, the mortality of primary therapy was lower (4/17 vs 9/12, χ2=7.54, P=0.006). All patients were followed up to December 2021, and 17 patients died, with a mortality rate of 45.9% (17/37). Conclusions:CNS aspergillosis may have no definite immunosuppressive background. Some of CNS aspergillosis patients are complicated with diabetes, and the clinical manifestations of the disease lack specificity, with high misdiagnosis rate in the early stage, no inflammatory changes in cerebrospinal fluid, and high positive rate of mNGS for pathogenic microorganism. Early and long-term application of voriconazole can significantly reduce the mortality rate.

ObjectiveTo explore the mechanism of Tangbikang granules （TBK） against diabetic peripheral neuropathy （DPN） based on network pharmacology and in-vivo experiment. MethodThe active components in medicinals of TBK and their target genes were searched from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. The active components of the medicinals which are not included in TCMSP were searched from previous research. After the analysis of drug-likeness by SwissADME， the target genes of them were predicted with SwissTargetPrediction. DPN-related target genes were retrieved from GeneCards. The common targets of the disease and the prescription were the hub genes of TBK against DPN， which were uploaded to Metascape for Gene Ontology （GO） term enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. High-sugar and high-fat diet and low-dose streptozotocin （STZ， ip） were employed to induce diabetes in rats， and then the model rats were respectively treated with low-dose （0.625 g·kg^-1）， medium-dose （1.25 g·kg^-1）， and high-dose （2.5 g·kg^-1） TBK for 12 weeks. Sensory nerve conduction velocity （SNCV） was evaluated. After hematoxylin and eosin （HE） staining， the sciatic nerve was observed under light microscope to examine the nerve damage. Real-time PCR was performed to detect the gene expression of adenosine monophosphate-activated protein kinase （AMPK） pathway-related targets in rat sciatic nerve， and Western blot to measure the protein expression of AMPK and phosphorylated （p）-AMPK in rat sciatic nerve. ResultThe main active components of TBK， such as quercetin， kaempferol， β-sitosterol， leech pteridine A， stigmasterol， and baicalein were screened out， mainly acting on interleukin-6 （IL-6）， tumor necrosis factor （TNF）， protein kinase B （Akt）， JUN， and HSP90AA1 and signaling pathways such as AMPK， nuclear factor-κB （NF-κB）， and Janus kinase/signal transducer and activator of transcription （JAK/STAT）. Molecular docking results showed that β-sitosterol and stigmasterol had high binding affinity with IL-6， TNF， JUN， and HSP90AA1. As for the animal experiment， compared with the normal group， model group had low SNCV of sciatic nerve （P<0.01）， disordered and loose myelinated nerve fibers with axonotmesis and demyelinization， low mRNA expression of AMPKα， AMPKβ， peroxisome proliferator-activated receptor γ coactivator-1α （PGC-1α）， Sirtuin 3 （SirT3）， mitochondrial transcription factor A （TFAM）， and low p-AMPK/AMPK ratio in sciatic nerve （P<0.05， P<0.01）. Compared with the model group， TBK of the three doses raised the SNCV （P<0.01）， restored nerve morphology and nerve compactness， and increased the mRNA expression of AMPKα， AMPKβ， PGC-1α， SirT3， and TFAM （P<0.05， P<0.01）. The ratio of p-AMPK/AMPK in the high-dose and medium-dose TBK groups was higher than that in the model group （P<0.01）， while the protein expression in the low-dose TBK group was insignificantly different from that in the model group. ConclusionTBK exerts therapeutic effect on DPN through multiple pathways and targets. The mechanism is that it activates and regulates AMPK/PGC-1α/SirT3 signaling， which lays a basis for further study of TBK in the treatment of DPN.

To investigate the γ pass rate limit of plan verification equipment for volumetric modulated arc therapy (VMAT) plan verification and its sensitivity on the opening and closing errors of multi-leaf collimator (MLC), 50 cases of nasopharyngeal carcinoma VMAT plan with clockwise and counterclockwise full arcs were randomly selected. Eight kinds of MLC opening and closing errors were introduced in 10 cases of them, and 80 plans with errors were generated. Firstly, the plan verification was conducted in the form of field-by-field measurement and true composite measurement. The γ analysis with the criteria of 3% dose difference, distance to agreement of 2 mm, 10% dose threshold, and absolute dose global normalized conditions were performed for these fields. Then gradient analysis was used to investigate the sensitivity of field-by-field measurement and true composite measurement on MLC opening and closing errors, and the receiver operating characteristic curve (ROC) was used to investigate the optimal threshold of γ pass rate for identifying errors. Tolerance limits and action limits for γ pass rates were calculated using statistical process control (SPC) method for another 40 cases. The error identification ability using the tolerance limit calculated by SPC method and the universal tolerance limit (95%) were compared with using the optimal threshold of ROC. The results show that for the true composite measurement, the clockwise arc and the counterclockwise arc, the descent gradients of the γ passing rate with per millimeter MLC opening error are 10.61%, 7.62% and 6.66%, respectively, and the descent gradients with per millimeter MLC closing error are 9.75%, 7.36% and 6.37%, respectively. The optimal thresholds obtained by the ROC method are 99.35%, 97.95% and 98.25%, respectively, and the tolerance limits obtained by the SPC method are 98.98%, 97.74% and 98.62%, respectively. The tolerance limit calculated by SPC method is close to the optimal threshold of ROC, both of which could identify all errors of ±2 mm, while the universal tolerance limit can only partially identify them, indicating that the universal tolerance limit is not sensitive on some large errors. Therefore, considering the factors such as ease of use and accuracy, it is suggested to use the true composite measurement in clinical practice, and to formulate tolerance limits and action limits suitable for the actual process of the institution based on the SPC method. In conclusion, it is expected that the results of this study can provide some references for institutions to optimize the radiotherapy plan verification process, set appropriate pass rate limit, and promote the standardization of plan verification.
Humans ; Radiotherapy, Intensity-Modulated ; Immune Tolerance ; Nasopharyngeal Carcinoma ; ROC Curve ; Nasopharyngeal Neoplasms/radiotherapy*

Objective:To explore the morbidity, clinical features and mortality of unilateral pulmonary edema (PE) in the intensive care unit (ICU).Methods:Clinical data of PE patients in ICU between January 2018 and January 2021 were retrospectively collected. All patients were divided into the bilateral PE and unilateral PE groups according to imaging manifestations. Etilogy, clinical performance, cardiac ultrasound parameters, complications, treatment and prognosis were compared between the two groups. Binary logistic regression analysis was used to screen out the risk factors of death.Results:Of the 314 PE patients, 14 (4.5%) were unilateral PE patients , and 11 (78.5%) were right-sided unilateral PE. There were no differences in age, gender, heart rate, respiratory rate and left ventricular eject fraction between the unilateral and bilateral PE groups. Compared with the bilateral PE group, systolic and diastolic blood pressure were significantly lower in the unilateral PE group [128 (102.7-138) mmHg vs. 135 (116-166) mmHg, 72 (54-88.2) mmHg vs. 82 (69-97.7)mmHg, respectively]. The incidence of cardiac arrest and hospital mortality were higher in the unilateral PE group [28.6% vs. 8.0%, 42.9% vs. 10%, all P<0.05]. Binary logistic regression analysis showed that age, unilateral PE, and use of vasoactive agent were associated with poor prognosis. Odds ratio of unilateral PE and use of vasoactive agent were 17.78 and 11.67, respectively. Conclusions:Unilateral PE is not rare, which is an independent risk factors for mortality and should be promptly recognized to avoid delays in treatment.