The effect of remimazolam-based total intravenous anesthesia versus sevoflurane-based inhalation anesthesia on emergence delirium in children undergoing tonsillectomy and adenoidectomy: study protocol for a prospective randomized controlled trial.

Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.

GMMAD: a comprehensive database of human gut microbial metabolite associations with diseases.

BACKGROUND: The natural products, metabolites, of gut microbes are crucial effect factors on diseases. Comprehensive identification and annotation of relationships among disease, metabolites, and microbes can provide efficient and targeted solutions towards understanding the mechanism of complex disease and development of new markers and drugs. RESULTS: We developed Gut Microbial Metabolite Association with Disease (GMMAD), a manually curated database of associations among human diseases, gut microbes, and metabolites of gut microbes. Here, this initial release (i) contains 3,836 disease-microbe associations and 879,263 microbe-metabolite associations, which were extracted from literatures and available resources and then experienced our manual curation; (ii) defines an association strength score and a confidence score. With these two scores, GMMAD predicted 220,690 disease-metabolite associations, where the metabolites all belong to the gut microbes. We think that the positive effective (with both scores higher than suggested thresholds) associations will help identify disease marker and understand the pathogenic mechanism from the sense of gut microbes. The negative effective associations would be taken as biomarkers and have the potential as drug candidates. Literature proofs supported our proposal with experimental consistence; (iii) provides a user-friendly web interface that allows users to browse, search, and download information on associations among diseases, metabolites, and microbes. The resource is freely available at http://guolab.whu.edu.cn/GMMAD . CONCLUSIONS: As the online-available unique resource for gut microbial metabolite-disease associations, GMMAD is helpful for researchers to explore mechanisms of disease- metabolite-microbe and screen the drug and marker candidates for different diseases.

Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel.

Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V1/2 values were changed from -39.54 ± 2.77 mV to -65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 µM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development.

Mass-like extragonadal endometriosis associated malignant transformation in the pelvis: A rare case report.

BACKGROUND: Endometriosis affects approximately 10% of reproductive-age women, however, endometriosis associated malignant transformation is rare and is often report as a rare case. CASE SUMMARY: Herein, we report of a 49-year-old female patient who suffered from severe left lower abdominal pain and imaging examination revealed an irregular mass in the left iliac fossa. Histopathological examination revealed main undifferentiated adenocarcinoma with a few typical endometrial epithelial and stromal tissues in the adjacent area. Combined with the immunohistochemical staining and the negative intra- or postoperative results from exploratory laparotomy, gastroscopy, enteroscopy and positron emission tomography, the tumor was considered to be derived from endometriosis. The patient underwent hysterectomy, bilateral salpingectomy, bilateral ovariectomy, and multipoint biopsy of the pelvic peritoneum. Subsequent radiotherapy and chemotherapy were performed. The patient recovered well post-operation and there was no evidence of recurrence after 10 mo of follow-up via computed tomography and magnetic resonance imaging. CONCLUSION: This case highlights a rare presentation of mass-like extragonadal endometriosis associated malignant transformation in the pelvis. Endometriosis associated malignant transformation is rare and difficult to diagnose in clinical settings, with diagnoses depending on pathological results and the exclusion of metastasis from other organs. Fortunately, patients are often diagnosed at younger ages, as well as at early stages; thus they generally have relatively favorable prognoses.

Discovery of Drug Candidates for Specific Human Disease Based on Natural Products of Gut Microbes.

The beneficial metabolites of the microbiome could be used as a tool for screening drugs that have the potential for the therapy of various human diseases. Narrowing down the range of beneficial metabolite candidates in specific diseases was primarily a key step for further validation in model organisms. Herein, we proposed a reasonable hypothesis that the metabolites existing commonly in multiple beneficial (or negatively associated) bacteria might have a high probability of being effective drug candidates for specific diseases. According to this hypothesis, we screened metabolites associated with seven human diseases. For type I diabetes, 45 out of 88 screened metabolites had been reported as potential drugs in the literature. Meanwhile, 18 of these metabolites were specific to type I diabetes. Additionally, metabolite correlation could reflect disease relationships in some sense. Our results have demonstrated the potential of bioinformatics mining gut microbes' metabolites as drug candidates based on reported numerous microbe-disease associations and the Virtual Metabolic Human database. More subtle methods would be developed to ensure more accurate predictions.

Epidemiology of Birth Defects in Eastern China and the Associated Risk Factors.

BACKGROUND This study aimed to survey the overall situation of birth defects (BDs) among citizens of Hangzhou, China, and the risk factors of different BD types. MATERIAL AND METHODS We collected the data of 4349 perinatal infants with BDs in Hangzhou. The potentially associated risk factors of BDs were recorded and logistic regression analysis was used to predict the high incidence of BDs. RESULTS Among all perinatal infants with BDs, there were 4105 (94.3%) single births, 225 (5.2%) twin births, and 10 (0.2%) multiple births. In clinical outcomes, there were 2477 (57.0%) live births, 1806 (41.5%) dead fetuses, and 11 (0.3%) stillbirths. Down syndrome ranked first, accounting for 30.7% of the total births, followed by cleft lip and polydactyly. Low family income, nulliparity, high parity, high education level, and taking contraceptives in early pregnancy were found to be risk factors of Down syndrome. Low parity, low education level, and pesticide exposure were found to be risk factors of cleft lip. For polydactyly, young age of the mother and a parity above 0 were identified as risk factors. CONCLUSIONS Different risks factors can influence BD development and potentially help to predict specific BD types, such as demographic features and harmful exposure in early pregnancy.

[Effect of icariin on bone destruction and serum RANKL/OPG levels in type II collagen-induced arthritis rats].

OBJECTIVE: To observe the effect of Icariin (ICA) on serum receptor activator of NFkappaB-ligand (RANKL)/osteoprotegerin (OPG) production and bone destruction in type II collagen-induced arthritis (CIA) rats. METHODS: The CIA rat model was established in all rats, except those in the normal group (n = 8) using bovine type II collagen and complete Freund's adjuvant. Totally 24 CIA rats with arthritis index (AI) > or = 6 were selected and divided into the model group, the methotrexate (MTX) group, and the ICA group according to the AI score, 8 in each group. Normal saline was given to rats in the normal group and the model group by gastrogavage. MTX at the weekly dose of 5 mg/kg was given to rats in the MTX group. ICA at the daily dose of 20 mg/kg was given to rats in the ICA group. All medication lasted for 4 weeks. The AI scores were recorded once a week. Histomorphologic changes of the ankle joint were observed by HE staining. The bone destruction and the osteoporosis of the foot phalanx were detected by X-ray. Serum levels of RANKL and OPG were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: After 4-week intervention, when compared with the model group, AI score and Larsen score were significantly lower, the serum RANKL concentration and the RANKL/OPG ratio obviously decreased, while the serum OPG concentration obviously increased in the CIA group (P < 0.05, P < 0.01). In the MTX group, the aforesaid indices decreased, but without statistical difference (P > 0.05). Results of HE staining indicated that hyperplasia of joint synovium, infiltration of inflammatory cells, and the degree of articular cartilage destruction were obviously alleviated in the ICA group. CONCLUSION: ICA could alleviate or lessen the degree of articular cartilage destruction in CIA rats, and its mechanism might be associated with reducing serum levels of RANKL and elevating levels of OPG, thus further decreasing the ratio of RANKL/OPG.

TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway.

TIEG1 can induce apoptosis of cancer cells, but its role in inhibiting invasion and metastasis has not been reported and is unclear. In this study, we find that decreased TIEG1 expression is associated with increased human epidermal growth factor receptor (EGFR) expression in breast cancer tissues and cell lines. TIEG1 plays an important role in suppressing transcription of EGFR by directly binding to the EGFR promoter. While overexpression of TIEG1 attenuates EGFR expression, knockdown of TIEG1 stimulates EGFR expression. Furthermore, TIEG1 and HDAC1 form a complex, which binds to Sp1 sites on the EGFR promoter and inhibits its transcription by suppressing histone acetylation. TIEG1 significantly inhibits breast cancer cell invasion, suppresses mammary tumorigenesis in xenografts in mice, and decreases lung metastasis by inhibition of EGFR gene transcription and the EGFR signaling pathway. Therefore, TIEG1 is an antimetastasis gene product; regulation of EGFR expression by TIEG1 may be part of an integral signaling pathway that determines and explains breast cancer invasion and metastasis.

Arginine/serine repeats are sufficient to constitute a splicing activation domain.

SR proteins are essential pre-mRNA splicing factors that have been shown to bind a number of exonic splicing enhancers where they function to stimulate the splicing of adjacent introns. Members of the SR protein family contain one or two N-terminal RNA binding domains, as well as a C-terminal arginine-serine (RS) rich domain. The RS domains mediate protein-protein interactions with other RS domain containing proteins and are essential for many, but not all, SR protein functions. Hybrid proteins containing an RS domain fused to the bacteriophage MS2 coat protein are sufficient to activate enhancer-dependent splicing in HeLa cell nuclear extract when bound to the pre-mRNA. Here we report progress towards determining the protein sequence requirements for RS domain function. We show that the RS domains from non-SR proteins can also function as splicing activation domains when tethered to the pre-mRNA. Truncation experiments with the RS domain of the human SR protein 9G8 identified a 29 amino acid segment, containing 26 arginine or serine residues, that is sufficient to activate splicing when fused to MS2. We also show that synthetic domains composed solely of RS dipeptides are capable of activating splicing, although their potency is proportional to their size.