Objective To investigate the effects of high-altitude hypoxic environment on the pharmacokinetic characteristics and brain tissue distribution of phenytoin sodium in epileptic rats.Methods A total of 70 male SPF-grade Wistar rats aged 2 months and weighing(200±20)g were used in the study.An epilepsy model was induced in the rats using the lithium chloride-pilocarpine method.The successfully modeled rats were randomly assigned to a normoxic treatment group and a high-altitude hypoxic treatment group.Phenytoin sodium was administered via intragastric gavage at a dose of 50 mg/kg in both groups.Blood samples were collected from the orbital venous plexus before treatment and 0.5,1,2,3,4,6,8,10,and 24 h post treatment.The animals were euthanized after the final blood collection,and samples of the liver and the whole brain tissue were collected.In the brain tissue distribution experiment,brain tissue samples were collected at 0.5,1,2,and 4 h after drug administration.The concentration of phenytoin sodium in rat plasma and brain tissue was determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS),and the pharmacokinetic parameters were calculated using WinNolin 8.1 software.The expression levels of CYP2C9 in liver tissue and those of P-gp in brain tissue of epileptic rats were determined by Western blot.Results Compared with those in the normoxia group,the peak concentration,peak time,and half-life of phenytoin sodium in the high-altitude hypoxia group were significantly decreased by 46.0%,42.3%,and 55.5%,respectively(all P<0.05);the clearance rate was significantly increased by 162.0%(P<0.05);and the area under the curve of plasma concentration-time curve was decreased by 45.6%(P<0.01).At 0.5,1,and 2 hours after administration,compared with that in the normoxia treatment group,the concentration of phenytoin sodium in the brain tissue of the high-altitude hypoxia treatment group was significantly decreased by 78.1%,63.5%,and 32.5%,respectively(all P<0.05).Western blot results showed that the expression levels of CYP2C9 in the liver tissue and P-gp in the brain tissue of rats in the high-altitude hypoxia group were approximately 1.78 and 1.65 times higher than those in the normoxia group,respectively(both P<0.05).Conclusion The hypoxic environment at high altitudes can promote the metabolism of phenytoin sodium,reduce its absorption efficiency,and change the characteristics its distribution in the brain,which may be related to the up-regulation of the expression of CYP2C9 in the liver and that of P-gp in the brain.

Objective:To construct a nursing norm for extracorporeal membrane oxygenation in adults, so as to provide a reference for improving the nursing care of adult extracorporeal membrane oxygenation.Methods:The first draft was developed through literature search and expert discussion. From September to October 2023, 16 experts were selected using the Delphi method to conduct two rounds of expert consultation on the first draft, and the final draft was revised with reference to the experts' comments. The expert positivity coefficient was expressed as the effective recovery rate of the questionnaire, and the degree of expert authority was evaluated with the authority coefficient, and the degree of harmonization of expert opinions was assessed with the Kendall's harmony coefficient.Results:Literature search screened a total of four guidelines and five expert consensus. In the two rounds of consultation, the effective recovery rates of the questionnaires were all 100% (16/16), and the expert authority coefficients were all 0.900, and the Kendall's harmony coefficients of the overall indicators were 0.581 and 0.666, respectively (both P<0.01). The final constructed nursing norm for extracorporeal membrane oxygenation in adults included five primary indicators, 27 secondary indicators, and 17 tertiary indicators. Conclusions:The constructed nursing norm for extracorporeal membrane oxygenation in adults is scientific, reliable and feasible, and can guide clinical nursing staff to carry out nursing care for extracorporeal membrane oxygenation.

Objective:To construct a nursing norm for extracorporeal membrane oxygenation in adults, so as to provide a reference for improving the nursing care of adult extracorporeal membrane oxygenation.Methods:The first draft was developed through literature search and expert discussion. From September to October 2023, 16 experts were selected using the Delphi method to conduct two rounds of expert consultation on the first draft, and the final draft was revised with reference to the experts' comments. The expert positivity coefficient was expressed as the effective recovery rate of the questionnaire, and the degree of expert authority was evaluated with the authority coefficient, and the degree of harmonization of expert opinions was assessed with the Kendall's harmony coefficient.Results:Literature search screened a total of four guidelines and five expert consensus. In the two rounds of consultation, the effective recovery rates of the questionnaires were all 100% (16/16), and the expert authority coefficients were all 0.900, and the Kendall's harmony coefficients of the overall indicators were 0.581 and 0.666, respectively (both P<0.01). The final constructed nursing norm for extracorporeal membrane oxygenation in adults included five primary indicators, 27 secondary indicators, and 17 tertiary indicators. Conclusions:The constructed nursing norm for extracorporeal membrane oxygenation in adults is scientific, reliable and feasible, and can guide clinical nursing staff to carry out nursing care for extracorporeal membrane oxygenation.

Objective To evaluate the safety and mid- to long-term efficacy of surgical correction of isolated partial anomalous pulmonary venous connection (IPAPVC). Methods We retrospectively collected consecutive patients who were diagnosed with IPAPVC and underwent surgical correction at Fuwai Hospital of Chinese Academy of Medical Sciences and Fuwai Yunnan Cardiovascular Hospital from June 2009 to May 2019, summarized the basic preoperative and intraoperative data of patients, analyzed the postoperative and mid- to long-term follow-up results. Results A total of 54 patients were enrolled, including 29 males and 25 females, with an average age of 16.20±2.40 years, ranging from 1 month to 62 years. There were 28 (51.9%) patients with varying degrees of arrhythmia, 22 (40.7%) patients with cardiac insufficiency, and 39 (72.2%) patients with pulmonary hypertension. According to Bordy's typing, 14 (25.9%) patients were classified as type A, 23 (42.6%) type B, 4 (7.4%) type C, 5 (9.3%) type D and 8 (14.8%) mixed type. Transthoracic echocardiography was performed in the whole group of patients and the accuracy of staging diagnosis was 66.7% (36/54), and cardiac CT angiography (CTA) was performed in 37 patients and the accuracy of staging diagnosis was 94.6% (35/37). All surgical procedures were assisted with cardiopulmonary bypass, aortic cross-clamping time was 0-219 (67.02±5.23) min, cardiopulmonary bypass time was 40-261 (105.09±5.23) min, and there was no serious intraoperative complication. Postoperative tracheal intubation time was 0-230 (13.33±4.20) h, intensive care unit stay was 0-13 (1.89±0.28) days, postoperative hospital stay was 5-18 (7.20±0.38) days, and follow-up time was 16-140 (62.58±5.12) months. There were 2 (3.7%) all-cause postoperative deaths, including 1 in-hospital death and 1 death during the follow-up, and there was no intraoperative death. Among the survivors, there were 3 patients with surgery-related complications: 1 patient had atrial septal defect with the second surgical treatment, 1 early obstruction of the superior vena cava and 1 arrhythmia. Two patients had complications of IPAPVC (atrial fibrillation, collateral circulation) prior to surgery and underwent the second surgery with a poor prognosis, and 1 patient had preoperative cardiac insufficiency and atrial fibrillation, whose symptoms persisted for a long time during the follow-up. Conclusion IPAPVC accounts for a lower percentage of partial anomalous pulmonary venous connection, transthoracic echocardiography combined with CTA improves diagnostic accuracy, and IPAPVC should be treated with elective surgery after diagnosis. The surgical approach should be individualized with imaging features such as disease staging, number of drains and drainage location. Surgical treatment of IPAPVC is safe and effective, and regular follow-up is warranted.

OBJECTIVES: Hypoxia can alter the oral bioavailability of drugs, including various substrates (drugs) of P-glycoprotein (P-gp), suggesting that hypoxia may affect the function of P-gp in intestinal epithelial cells. Currently, Caco-2 monolayer model is the classic model for studying the function of intestinal epithelial P-gp. This study combines the Caco-2 monolayer model with hypoxia to investigate the effects of hypoxia on the expression and function of P-gp in Caco-2 cells, which helps to elucidate the mechanism of changes in drug transport on intestinal epithelial cells in high-altitude hypoxia environment. METHODS: Normally cultured Caco-2 cells were cultured in 1% oxygen concentration for 24, 48, and 72 h, respectively. After the extraction of the membrane proteins, the levels of P-gp were measured by Western blotting. The hypoxia time, with the most significant change of P-gp expression, was selected as the subsequent study condition. After culturing Caco-2 cells in transwell cells for 21 days and establishing a Caco-2 monolayer model, they were divided into a normoxic control group and a hypoxic group. The normoxic control group was continuously cultured in normal condition for 72 h, while the hypoxic group was incubated for 72 h in 1% oxygen concentration. The integrity and polarability of Caco-2 cells monolayer were evaluated by transepithelial electrical resistance (TEER), apparent permeability (Papp) of lucifer yellow, the activity of alkaline phosphatase (AKP), and microvilli morphology and tight junction structure under transmission electron microscope. Then, the Papp of rhodamine 123 (Rh123), a kind of P-gp specific substrate, was detected and the efflux rate was calculated. The Caco-2 cell monolayer, culturing at plastic flasks, was incubated for 72 h in 1% oxygen concentration, the expression level of P-gp was detected. RESULTS: P-gp was decreased in Caco-2 cells with 1% oxygen concentration, especially the duration of 72 h (P<0.01). In hypoxic group, the TEER of monolayer was more than 400 Ω·cm², the Papp of lucifer yellow was less than 5×10^-7 cm/s, and the ratio of AKP activity between apical side and basal side was greater than 3. The establishment of Caco-2 monolayer model was successful, and hypoxia treatment did not affect the integrity and polarization state of the model. Compared with the normoxic control group, the efflux rate of Rh123 was significantly reduced in Caco-2 cell monolayer of the hypoxic group (P<0.01). Hypoxia reduced the expression of P-gp in Caco-2 cell monolayer (P<0.01). CONCLUSIONS Hypoxia inhibits P-gp function in Caco-2 cells, which may be related to the decreased P-gp level.
Humans ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Caco-2 Cells ; ATP Binding Cassette Transporter, Subfamily B ; Hypoxia ; Oxygen

Background::The differential diagnosis of mucoepidermoid carcinoma (MEC) from neoplasm undergoing mucinous features brings more pitfalls to pathologists. Combining specific MAML2 gene rearrangement and histological characteristics may be the solution. Methods::Twenty-five tumors with mucinous components were selected for differential diagnosis of MEC. All the cases were detected for MAML2 gene rearrangement. The cases diagnosed as MEC were classified into four variants: classic, oncocytic, Warthin-like, and nonclassified, and they were graded using the Brandwein system. The histological characteristics of non-MECs were summarized for differential diagnosis. Univariate survival analysis was performed on MECs. Results::There were 16 MECs; 62.5% were MAML2 rearranged. For the low-, intermediate-, and high-grade MECs, the rate of rearrangement was 83.3%, 100%, and 28.6%, respectively. Both the oncocytic and Warthin-like MECs were MAML2 rearranged. For the classic and nonclassified MECs without MAML2 rearrangement, non-keratinized squamoid cells and distinctive mucinous cells were essential diagnostic criteria. On survival analysis, all the disease progression occurred in high-grade MECs ( p = 0.038). Nine cases were diagnosed as non-MECs: pleomorphic adenoma with mucinous metaplasia showed no ex-capsular involvement; metaplastic Warthin tumor appeared with overt keratinization and residual oncocytic bilayered epithelium; mix squamous cell and glandular papilloma showed an endobronchial papillary growing pattern; adenosquamous carcinoma was accompanied by squamous carcinoma in situ of the overlying mucosa. All the non-MECs were negative for MAML2 rearrangement. Conclusion::The application of combining MAML2 rearrangement and histological characteristics is helpful in the differential diagnosis between MEC and other tumors with mucinous components.

Background::The differential diagnosis of mucoepidermoid carcinoma (MEC) from neoplasm undergoing mucinous features brings more pitfalls to pathologists. Combining specific MAML2 gene rearrangement and histological characteristics may be the solution. Methods::Twenty-five tumors with mucinous components were selected for differential diagnosis of MEC. All the cases were detected for MAML2 gene rearrangement. The cases diagnosed as MEC were classified into four variants: classic, oncocytic, Warthin-like, and nonclassified, and they were graded using the Brandwein system. The histological characteristics of non-MECs were summarized for differential diagnosis. Univariate survival analysis was performed on MECs. Results::There were 16 MECs; 62.5% were MAML2 rearranged. For the low-, intermediate-, and high-grade MECs, the rate of rearrangement was 83.3%, 100%, and 28.6%, respectively. Both the oncocytic and Warthin-like MECs were MAML2 rearranged. For the classic and nonclassified MECs without MAML2 rearrangement, non-keratinized squamoid cells and distinctive mucinous cells were essential diagnostic criteria. On survival analysis, all the disease progression occurred in high-grade MECs ( p = 0.038). Nine cases were diagnosed as non-MECs: pleomorphic adenoma with mucinous metaplasia showed no ex-capsular involvement; metaplastic Warthin tumor appeared with overt keratinization and residual oncocytic bilayered epithelium; mix squamous cell and glandular papilloma showed an endobronchial papillary growing pattern; adenosquamous carcinoma was accompanied by squamous carcinoma in situ of the overlying mucosa. All the non-MECs were negative for MAML2 rearrangement. Conclusion::The application of combining MAML2 rearrangement and histological characteristics is helpful in the differential diagnosis between MEC and other tumors with mucinous components.

BACKGROUND: Intensive phototherapy (IPT) and exchange transfusion (ET) are the main treatments for extreme hyperbilirubinemia. However, there is no reliable evidence on determining the thresholds for these treatments. This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia. METHODS: This retrospective cohort study was conducted in seven centers from January 2015 to January 2018. Patients with extreme hyperbilirubinemia that met the criteria of ET were included. Patients were divided into three subgroups (low-, medium-, and high- risk) according to gestational week and risk factors. Propensity score matching (PSM) was performed to balance the data before treatment. Study outcomes included the development of bilirubin encephalopathy, duration of hospitalization, expenses, and complications. Mortality, auditory complications, seizures, enamel dysplasia, ocular motility disorders, athetosis, motor, and language development were evaluated during follow-up at age of 3 years. RESULTS: A total of 1164 patients were included in this study. After PSM, 296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-, medium-, and high-risk subgroups with 188, 364, and 40 matched patients, respectively. No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity, complications, and sequelae. Hospitalization duration and expenses were lower in the low- and medium-risk subgroups in the IPT only group. CONCLUSIONS In this study, our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia. The indication of ET for patients with hyperbilirubinemia could be stricter. However, it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors. If IPT can be guaranteed and proved to be therapeutic, ET should be avoided as much as possible.
Child, Preschool ; Exchange Transfusion, Whole Blood/adverse effects* ; Humans ; Hyperbilirubinemia, Neonatal/therapy* ; Infant ; Infant, Newborn ; Kernicterus/therapy* ; Phototherapy/methods* ; Retrospective Studies

OBJECTIVETo investigate the clinical efficacy of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) in induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia (APL).

METHODSA retrospective analysis of 298 newly diagnosed APL patients from the department of hematology, First Affiliated Hospital of Zhejiang University since September 2004 to December 2013, including 177 cases with ATRA plus ATO and 116 ATRA plus chemotherapy (CT), was performed to investigate the clinical efficacy between the low-intermediate (WBC≤10×10⁹/L) and high (WBC>10×10⁹/L) risk APL patients, respectively.

RESULTSFor the low-intermediate risk patients, the relapse rate in ATRA plus CT and ATRA plus ATO are 22.0% and 6.1% (P=0.004), respectively; the 3 years estimated relapse-free survival (RFS) are 78.0% and 92.9% (P=0.021), respectively. For the high risk patients, the relapse rate in ATRA plus CT and ATRA plus ATO are 25.0% and 5.2% (P=0.035), respectively; the 3 years estimated RFS rate were 80.8% and 93.0% (P=0.021), respectively. But the rate of early death (ED), complete remission (CR) and overall survival (OS) between the two therapy protocols had no statistical difference (P>0.05).

CONCLUSIONATRA plus ATO in induction and maintenance therapy might prolong the RFS time of the low-intermediate risk APL patients and decrease the relapse rate of the low, intermediate and high risk APL patients.

Antineoplastic Combined Chemotherapy Protocols ; Arsenicals ; Humans ; Leukemia, Promyelocytic, Acute ; Oxides ; Recurrence ; Remission Induction ; Retrospective Studies ; Survival Rate ; Tretinoin

OBJECTIVETo investigate the expression level of SET gene in patients with acute myeloid leukemia (AML) and evaluate its significance.

METHODSThe expression level of SET gene in 141 de novo AML patients was determined by real time quantitative PCR (RQ-PCR), and its relationship with the clinical features and outcomes of these patients were analyzed.

RESULTSSET gene transcript level was detected in 141 AML patients with the median expression level of 0.86(range 0.02-15.69). AML patients with higher SET gene expression had a higher level of white blood cell (WBC ≥ 100 × 10⁹/L) count than of lower SET gene expression ones (31.0% vs 11.4%, P=0.005). In the 136 patients who received treatment after diagnosis, higher SET gene expression group had lower complete remission rate (50.0%) than of lower expression cohort (73.5%) after two cycles of chemotherapy (P=0.005). Survival analysis showed that patients with higher SET gene expression had significantly shorter overall survival(OS) (10 months vs 22 months, P=0.001) and event-free survival (EFS) (2 months vs 14 months, P=0.005) than of lower SET gene expression ones. Multivariate COX regression analysis showed SET overexpression was an independent prognostic factor for OS. In the patients with the normal karyotype, higher SET expression group also had significantly shorter OS (12 months vs 35 months, P=0.010) and EFS (4 months vs 14 months, P=0.026) than of lower SET expression ones.

CONCLUSIONHigh expression of SET gene was associated with poor prognosis and might be a prognostic molecular marker of AML.

Disease-Free Survival ; Gene Expression Regulation, Neoplastic ; Histone Chaperones ; genetics ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Prognosis ; Remission Induction ; Transcription Factors ; genetics