ROS-mediated PERK-CHOP pathway plays an important role in cadmium-induced HepG2 cells apoptosis.

Cadmium (Cd) is a common heavy metal that is highly toxic to the liver, however, the exact mechanism underlying this damage accompanied by apoptosis has not been thoroughly demonstrated. In this study, we found that Cd exposure significantly reduced cell viability, including the increased populations of apoptotic cells and caspase-3/-7/-12 activation in HepG2 cells. Mechanistically, Cd initiated oxidative stress via elevating reactive oxygen species (ROS) levels, leading to oxidative damage in HepG2 cells. Simultaneously, Cd exposure induced endoplasmic reticulum (ER) stress via activating the protein kinase RNA-like ER kinase (PERK)-C/EBP homologous protein (CHOP) axis in HepG2 cells, and subsequently disturbed ER function as increased Ca2+ releasing from ER lumen. Intriguingly, further study revealed that oxidative stress is closely related with ER stress, as pretreatment with ROS scavenger, N-acetyl-l-cysteine (NAC) markedly reduced ER stress as well as protected ER function in Cd treated HepG2 cell. Collectively, these findings first revealed Cd exposure induced HepG2 cells death via a ROS-mediated PERK-CHOP-related apoptotic signaling pathway, which provides a novel insight into the mechanisms of Cd-induced hepatotoxicity. Furthermore, inhibitors for oxidative stress and ER stress might be considered as a new strategy to prevent or treat this disorder.

Clinical effect and follow-up of laparoscopic radical proximal gastrectomy for upper gastric carcinoma.

Objective: To evaluate the safety and clinical effect of tubular esophagogastric anastomosis in laparoscopic radical proximal gastrectomy. Methods: A retrospective analysis was conducted involving 191 patients who underwent laparoscopic radical proximal gastrectomy in the Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University from January 2017 to October 2020. Patients were divided into tubular esophagogastric anastomosis group (TG group) and traditional esophagogastric anastomosis group (EG group) according to the digestive tract reconstruction. Their intraoperative conditions, perioperative recovery and postoperative follow-up were compared. Patients were also divided into indocyanine green group and non-indocyanine green group according to whether or not indocyanine green tracer technology was used during the operation. Their intraoperative condition and perioperative recovery were compared and analyzed after propensity score matching. Results: The operation was successfully completed in all patients. Compared with the EG group, the TG group had less volume of gastric tube drainage, shorter gastric tube drainage time and proton pump inhibitors application time, and lower reuse rate of proton pump inhibitors. However, the TG group had a higher anastomotic stenosis at three months after surgery, as measured using anastomotic width and dysphagia score. Nevertheless, the incidence of reflux esophagitis and postoperative quality of life score in the TG group were lower compared with the EG group at 1st and 2nd year after surgery. In the indocyanine green analysis, the indocyanine green group had significantly shorter total operation time and lymph node dissection time and less intraoperative blood loss compared with the non-indocyanine green group. However, compared with the non-indocyanine green group, more postoperative lymph nodes were obtained in the indocyanine green group. Conclusion: Laparoscopic radical proximal gastrectomy is safe and effective treatment option for upper gastric cancer. Tubular esophagogastric anastomosis has more advantages in restoring postoperative gastrointestinal function and reducing reflux, but it has a higher incidence of postoperative anastomotic stenosis compared with traditional esophagogastrostomy. The application of indocyanine green tracer technique in laparoscopic radical proximal gastrectomy has positive significance.

The inhibition of ORMDL3 prevents Alzheimer's disease through ferroptosis by PERK/ATF4/HSPA5 pathway.

Alzheimer's disease (AD) is a neurodegenerative disease with high incidence and widespread attention. There is currently no clear clarification of the pathogenesis. However, ORMDL3 causes ferroptosis in AD, and the potential mechanisms remain unclear. So, this study explore the function of ORMDL3 on ferroptosis in AD and its potential regulatory mechanisms. APPswe/PS1dE9 mice and C57BL/6 mice were induced into the mice model. The murine microglial BV-2 cells also were induced into the vitro model. In serum samples of AD patients, ORMDL3 mRNA expression levels were upregulated. The serum ORMDL3 levels expression was positively related to the ADL score or MoCA score in AD patients. The serum ORMDL3 expression level was positively related to MMSE score or Hcy levels in AD patients. The mRNA expression of ORMDL3 in the hippocampal tissue of the mice model of AD was upregulated at one, four and eight months. The protein expression of ORMDL3 was upregulated in the mice model of AD. ORMDL3 promoted Alzheimer's disease, and increased oxidative response and ferroptosis in a model of AD. PERK/ATF4/HSPA5 pathway is one important signal pathway for the effects of ORMDL3 in a model of AD. Collectively, these data suggested that ORMDL3 promoted oxidative response and ferroptosis in a model of AD by the PERK/ATF4/HSPA5 pathway, which might be a novel target spot mechanism of ferroptosis in AD and may serve as a regulator of AD-induced ferroptosis.

Synergistic effect of Hsp90 inhibitor ginkgolic acids C15 ꞉1 combined with paclitaxel on nasopharyngeal carcinoma / 中南大学学报(医学版)

OBJECTIVES@#Nasopharyngeal cracinoma is a kind of head and neck malignant tumor with high incidence and high mortality. Due to the characteristics of local recurrence, distant metastasis, and drug resistance, the survival rate of patients after treatment is not high. Paclitaxel (PTX) is used as a chemotherapy drug in treating nasopharyngeal carcinoma, but nasopharyngeal carcinoma cells are easy to develop resistance to PTX. Inhibition of heat shock protein 90 (Hsp90) can overcome common signal redundancy and resistance in many cancers. This study aims to investigate the anti-tumor effect of ginkgolic acids C15꞉1 (C15:1) combined with PTX on nasopharyngeal carcinoma CNE-2Z cells and the mechanisms.@*METHODS@#This experiment was divided into a control group (without drug), a C15:1 group (10, 30, 50, 70 μmol/L), a PTX group (5, 10, 20, 40 nmol/L), and a combination group. CNE-2Z cells were treated with the corresponding drugs in each group. The proliferation of CNE-2Z cells was evaluated by methyl thiazolyl tetrazolium (MTT). Wound-healing assay and transwell chamber assay were used to determine the migration of CNE-2Z cells. Transwell chamber was applied to the impact of CNE-2Z cell invasion. Annexin V-FITC/PI staining was used to observe the effect on apoptosis of CNE-2Z cells. The changes of proteins involved in cell invasion, migration, and apoptosis after the combination of C15꞉1 and PTX treatment were analyzed by Western blotting.@*RESULTS@#Compared with the control group, the C15꞉1 group and the PTX group could inhibit the proliferation of CNE-2Z cells (all P<0.05). The cell survival rates of the C15꞉1 50 μmol/L combined with 5, 10, 20, or 40 nmol/L PTX group were lower than those of the single PTX group (all P<0.05), the combination index (CI) value was less than 1, suggesting that the combined treatment group had a synergistic effect. Compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the combination group significantly inhibited the invasion and migration of CNE-2Z cells (all P<0.05). The results of Western blotting demonstrated that the combination group could significantly down-regulate Hsp90 client protein matrix metalloproteinase (MMP)-2 and MMP-9. The results of double staining showed that compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the apoptosis ratio of CNE-2Z cells in the combination group was higher (both P<0.05). The results of Western blotting suggested that the combination group could decrease the Hsp90 client proteins [Akt and B-cell lymphoma-2 (Bcl-2)] and increase the Bcl-2-associated X protein (Bax).@*CONCLUSIONS@#The combination of C15꞉1 and PTX has a synergistic effect which can inhibit cell proliferation, invasion, and migration, and induce cell apoptosis. This effect may be related to the inhibition of Hsp90 activity by C15꞉1.

Correlation between dyslipidemia and rheumatoid arthritis associated interstitial lung disease / 北京大学学报(医学版)

OBJECTIVE@#To study the correlation between dyslipidemia and rheumatoid arthritis associa-ted interstitial lung disease (RA-ILD) by retrospective analysis of the clinical data.@*METHODS@#The clinical data of patients with rheumatoid arthritis (RA), who were hospitalized in the Department of Rheumatism and Immunology of Peking University Shenzhen Hospital from January 2015 to July 2020 and fulfilled the criteria of the 2010 Rheumatoid Arthritis Classification Criteria established by American College of Rheumatology/European League Against Rheumatism collaborative initiative, were collected and analyzed.@*RESULTS@#There were 737 RA patients included, of whom 282(38.26%)were with interstitial lung disease (ILD). The median time from the onset of the first RA-related clinical symptoms to the onset of ILD was 13 years (95%CI 11.33-14.67). By multivariate Logistic regression analysis, we found that low-density lipoprotein cholesterol (LDL-C) was an independent risk factor for RA-ILD (OR 1.452, 95%CI 1.099-1.918, P=0.009), whereas high-density lipoprotein cholesterol (HDL-C) was a protective factor for RA-ILD (OR 0.056, 95%CI 0.025-0.125, P < 0.001). The RA patients with high LDL-C or low HDL-C had higher incidence of ILD than that of the RA patients with normal LDL-C or HDL-C(57.45% vs. 36.96%, P < 0.001; 47.33% vs. 33.81%, P < 0.001, respectively). The median time of ILD onset in the RA patients with low HDL-C was shorter than that of the RA patients with normal HDL-C [10.0(95%CI 9.33-10.67)years vs.17.0 (95%CI 14.58-19.42) years, P < 0.001]. HDL-C level was negatively correlated with disease activity. Among the RA-ILD patients, the patients with low HDL-C had higher percentage of usual interstitial pneumonia (UIP) then that of the patients with normal HDL-C (60.00% vs. 53.29%, P=0.002). The RA-ILD patients with high LDL-C had higher incidence rate of decrease in forced vital capacity (FVC) than that of the RA-ILD patients with normal LDL-C (50.00% vs. 21.52%, P=0.015). The RA-ILD patients with low HDL-C had higher incidence rate of decrease in FVC (26.92% vs. 16.18%, P=0.003) and carbon monoxide diffusion (80.76% vs. 50.00%, P=0.010) than that of RA-ILD patients with normal HDL-C.@*CONCLUSION@#LDL-C was possibly a potential independent risk factor for RA-ILD. HDL-C was possibly a potential protective factor for RA-ILD. HDL-C level was negatively correlated with disease activity of RA. The median time of ILD onset in the RA patients with low HDL-C was significantly shorter than that of the RA patients with normal HDL-C.

The application of bladder stimulation technique in clean-catch urine collection of late newborns / 中国新生儿科杂志

Objective:To study the clinical value of bladder stimulation technique (BST) for clean-catch urine collection in late newborns.Methods:From November 2020 to March 2022, relatively stable late newborns hospitalized in the Department of Neonatology of our hospital were enrolled in the prospective randomized controlled trial. The newborns were assigned into BST group and control group. In BST group, urine was collected using BST (suprapubic tapping alternating with lumbosacral massage for 5 min) 20~30 min after feeding and specimen were collected using urine bag before and after BST. In the control group, urine was collected using urine bag method. The urine collection was considered successful if >1 ml of urine not contaminated by faeces were collected within 60 min. The t-test and χ 2 test were used for data analysis. Results:A total of 231 late newborns were included with 117 cases in BST group and 114 in control group. The rate of successful urine collection in BST group was higher than control group (65.8% vs. 39.4%).The time needed for successful urine collection [(30.2±8.5) min vs. (40.7±12.9) min], the incidences of faeces contamination (2.5% vs. 21.1%) and urine contamination (11.7% vs. 26.7%) in BST group were all significantly lower than control group(all P<0.05). Male and female newborns in BST group had similar success rates of urine collection (65.6% vs. 66.0%). Male newborns in BST group had similar urine contamination rate with control group (9.5% vs. 11.5%) and female newborns in BST group had significantly lower urine contamination rate than control group (14.3% vs. 47.4%, P<0.05). Urine was successfully collected in 71 newborns in BST group with median duration of BST for 81 (61,132) s. No adverse effects were observed except for transient consolable crying. Conclusions:Compared with urine bag collection method, BST improves successful urine collection rates and reduces the time needed for urine collection and urine contamination rates (especially for females).

Risk factors, diagnosis and treatment of transient hyperinsulinemic hypoglycemia in newborns / 中国新生儿科杂志

Objective:To study the risk factors, diagnosis and treatment of transient hyperinsulinemic hypoglycemia (HH) in newborns.Methods:From January 2016 to December 2020, newborns with transient HH (HH group) admitted to our hospital were enrolled in this retrospective nested case-control study. Newborns with similar gestational age (GA) (differences of GA<2 w) without HH were matched with 1∶2 ratio as the non-HH group. Clinical characteristics of the two groups were compared and the risk factors and therapeutic results of HH in newborns were analyzed using SPSS 20.0 statistical software.Results:A total of 39 cases were included in the HH group and 75 cases were matched in the non-HH group. The proportion of small for gestational age (SGA) [51.3%(20/39) vs. 32.0%(24/75)], the amount of amino acids (AA) in intravenous infusion[1.0(0.0,1.0) g/(kg·d) vs. 0.0(0.0,1.0) g/(kg·d)], the incidence of hypoglycemia [(4.3±1.9) times vs. (3.6±1.3) times] and the maximum glucose infusion rate (GIR)[(8.3±2.5) mg/(kg·min) vs. (7.4±1.1) mg/(kg·min)] in the HH group were higher than the non-HH group (all P<0.05). The platelet count in the HH group were lower than the non-HH group [(186.9±60.9)×10 9/L vs. (215.3±61.7)×10 9/L, P<0.05]. SGA ( OR=2.535, 95% CI 1.077~5.971), the amount of intravenous AA ( OR=2.180, 95% CI 1.029~4.619) and the maximum GIR ( OR=1.405, 95% CI 1.088~1.815) were independent risk factors for transient HH. In the HH group, 28/39 cases were treated with Diazoxide or Octreotide and the therapeutic effects were good with few adverse drug reactions (ADR). 37/39 cases were recovered within 28 d of birth and the other 2 cases were recovered at 2.5 m and 3.5 m, respectively. Conclusions:SGA, the amount of intravenous AA and higher GIR are risk factors for transient HH in newborns. Diazoxide or Octreotide are effective with few ADR in the treatment of transient HH. Most patients will recover from transient HH in 2 w to 3 m.

Poly-G for tumor matched samples chronicles the evolution of human colorectal cancer / 中华肿瘤杂志

Objective: To analyze poly-guanine (poly-G) genotypes and construct the phylogenetic tree of colorectal cancer (CRC) and provide an efficient and convenient method for the study of intra-tumor heterogeneity and tumor metastasis pathway. Methods: The clinicopathological information of patients with primary colorectal cancer resection with regional lymph node metastases were retrospectively collected in the Department of General Surgery, General Hospital of Tianjin Medical University from January 2017 to December 2017. The paraffin sections of the paired tumor samples were performed consecutively, and multi-region microdissection was performed after histogene staining. The phenol-chloroform extraction and ethanol precipitation scheme was used to obtain DNA, and Poly-G multiplex PCR amplification and capillary electrophoresis detection were performed. The correlation between Poly-G mutation frequency and clinicopathological parameters was analyzed. Based on the difference of Poly-G genotypes between paired samples, the distance matrix was calculated, and the phylogenetic tree was constructed to clarify the tumor metastasis pathway. Results: A total of 237 paired samples were collected from 20 patients including 134 primary lesions, 66 lymph node metastases, 37 normal tissues, and Poly-G mutation was detected in 20 patients (100%). The mutation frequency of Poly-G in low and undifferentiated patients was (74.10±23.11)%, higher than that in high and medium differentiated patients [(31.36±12.04)%, P<0.001]. In microsatellite instability patients, the mutation frequency of Poly-G was (68.19±24.80)%, which was higher than that in microsatellite stable patients [(32.40±14.90)%, P=0.003]. The Poly-G mutation frequency was not correlated with age, gender, and pathological staging (all P>0.05). Based on Poly-G genotype difference of the paired samples, the phylogenetic trees of 20 patients were constructed, showing the evolution process of the tumor, especially the subclonal origins of lymph node metastasis. Conclusion: Poly-G mutations accumulate in the occurrence and development of CRC, and can be used as genetic markers to generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.

Progress in preparation and application of sodium alginate microspheres / 生物医学工程学杂志

Sodium alginate (SA) is a kind of natural polymer material extracted from kelp, which has excellent biocompatibility, non-toxicity, biodegradability and abundant storage capacity. The formation condition of sodium alginate gel is mild, effectively avoiding the inactivation of active substances. After a variety of preparation methods, sodium alginate microspheres are widely used in the fields of biomaterials and tissue engineering. This paper reviewed the common methods of preparing alginate microspheres, including extrusion, emulsification, electrostatic spraying, spray drying and coaxial airflow, and discussed their applications in biomedical fields such as bone repair, hemostasis and drug delivery.

Light-initiated chemiluminescent assay of 17ß-estradiol metrological traceability system established by manufacturer according to ISO17511:2020 and basic performance evaluation performed by clinical end-users.

BACKGROUND: In order to ensure the accuracy of the product, we established 1st model of metrological traceability hierarchy for light-initiated chemiluminescent assay (LICA) of 17ß-estradiol (E2 ) at the manufacturer, based on International Organization for Standardization (ISO) 17511:2020. Moreover, we verified/validated the basic performance (such as matrix effect and long-term stability of end-user IVD MD calibrator, precision, linearity interval, accuracy/ trueness, and detection capability) at the clinical end-user. METHODS: Human serum samples were used in this study. E2 was detected by mass spectrometry (MS) and LICA. The metrological traceability of LICA for E2 was established according to ISO 17511: 2020 standards, and pools of human samples were used as the m.3. secondary calibrator. Precision was validated according to Clinical and Laboratory Standards Institute (CLSI) EP05-A3. The linear interval was verified according to CLSI EP06-ED2. Comparison of accuracy and trueness of E2 with MS and Roche according to CLSI EP09-A3. The detection capability was validated according to EP17-A2. Matrix effect and long-term stability evaluation of end-user IVD MD calibrator were carried out according to CLSI EP14-A2, EP25-A. Statistical software was used for data analyses. RESULTS: The use of pools of human samples and fine adjusting calibrators ensured the accuracy of end-user test results. The metrological traceability of LICA for E2 was established. It showed excellent precision, meeting the requirements of allowable imprecision (7.5%). The allowable deviation from linearity (ADL) of 5% was allowed to show a good linear interval (12.52-4167.25 pg/ml). The accuracy/ trueness was verified, and relative deviation in the medical decision level met the performance specification of 10.03% compared with MS or Roche. The validated limit of blank, limit of detection, and limit of quantitation of E2 were 4.95 pg/ml, 8.93 pg/ml, and 9.88 pg/ml, respectively (the allowed imprecision is 20.00%). The interference rate of E2 ranged from -5.5% to 6.6%. CONCLUSION: LICA showed high sensitivity, high specificity, excellent precision, wide linearity interval, IVD MD calibrator has long-term stability, and no matrix effect. The metrological traceability of E2 established by using pools of human samples as M.3. can deliver accuracy to the end-user IVD MD and show good consistency with MS and Roche.

A novel prognostic signature for lung adenocarcinoma based on cuproptosis-related lncRNAs: A Review.

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease with complex pathogenesis, high mortality, and poor prognosis. Cuproptosis is a new type of programmed cell death triggered by copper accumulation that may play an important role in cancer. LncRNAs are becoming valuable prognostic factors in cancer patients. The effect of cuproptosis-related lncRNAs (CRlncRNAs) on LUAD has not been clarified. Based on the Cancer Genome Atlas database, CRlncRNAs were screened by co-expression analysis of cuproptosis- related genes and lncRNAs. Using CRlncRNAs, Cox and LASSO regression analyses constructed a risk prognostic model. The predictive efficacy of the model was assessed and validated using survival analysis, receiver operating characteristic curve, univariate and multifactor Cox regression analysis, and principal component analysis. A nomogram was constructed and calibration curves were applied to enhance the predictive efficacy of the model. Tumor Mutational Burden analysis and chemotherapeutic drug sensitivity prediction were performed to assess the clinical feasibility of the risk model. The novel prognostic signature consisted of 5 potentially high-risk CRlncRNAs, MAP3K20-AS1, CRIM1-DT, AC006213.3, AC008035.1, and NR2F2-AS1, and 5 potentially protective CRlncRNAs, AC090948.1, AL356481.1, AC011477.2, AL031600.2, and AC026355.2, which had accurate and robust predictive power for LUAD patients. Collectively, the novel prognostic signature constructed based on CRlncRNAs can effectively assess and predict the prognosis of patients and provide a new perspective for the diagnosis and treatment of LUAD.

Role of platelets aggregation in the process of ductus arteriosus closure of newborn pups / 中华危重病急救医学

Objective:To investigate the role of platelets aggregation in the developing process of ductus arteriosus closure of newborn pups, and the effect of platelet membrane glycoprotein Ⅱb-Ⅲa (GPⅡb-Ⅲa) receptor antagonist (tirofiban).Methods:Four 24-month-old Beagle bitches were selected and numbered 1, 2, 3, and 4 respectively, and their pups were removed by cesarean section in two batches 1-2 days before the expected date of delivery. Bitches 1 and 2 were the first batch. Eighteen newborn pups were removed after cesarean section as the control group. They were divided into three subgroups: 1-hour subgroup, 4-hour subgroup, and 12-hour subgroup according to postnatal time point, with 6 pups in each subgroup. The newborn pups were injected with normal saline 10 mL/kg via jugular vein immediately after birth. Bitches 3 and 4 were the second batch. Nineteen newborn pups were removed by cesarean section as tirofiban group. They were also divided into three subgroups: 1-hour subgroup ( n = 6), 4-hour subgroup ( n = 6), and 12-hour subgroup ( n = 7) according to the postnatal time point. The newborn pups were injected with tirofiban hydrochloride injection 10 mL/kg (10 mL injection including 2.5 mg of tirofiban) via jugular vein immediately after birth. The diameter of ductus arteriosus was measured by echocardiography. Ductus arteriosus was removed by surgical dissection and divided into two parts. Western blotting and immunohistochemistry were used to detect the expression of platelet membrane GPⅡb-Ⅲa, respectively. Results:In the control group, 1 newborn pup died at 0.5 hour after birth in the 1-hour subgroup. The experiment was completed by 19 in the tirofiban group. Ductus arteriosus of all pups were not closed in 1-hour subgroups of the two groups, and there was no significant difference in the diameter of ductus arteriosus between the control group and the tirofiban group (mm: 1.72±0.08 vs. 1.70±0.11, P > 0.05). Ductus arteriosus of 1 newborn pup in 4-hour subgroup of the control group was closed, but the ductus arteriosus of all the newborn pups in 4-hour subgroup of the tirofiban group were not closed. The diameter of ductus arteriosus of the tirofiban group was significantly larger than that of the control group (mm: 1.52±0.15 vs. 0.95±0.48, P < 0.05). Ductus arteriosus of all pups were closed in 12-hour subgroup of the control group, but the ductus arteriosus of 2 pups of the tirofiban group were still not closed, with the diameter of ductus arteriosus of 1.0 mm and 1.1 mm, respectively. Western blotting showed that at 1-hour, 4-hour and 12-hour after birth, the expression of platelet membrane GPⅡb-Ⅲa was gradually increased in ductus arteriosus of newborn pups of the two groups. The expression of GPⅡb-Ⅲa in 1-hour subgroup of the tirofiban group was significantly lower than that in the control group (GPⅡb-Ⅲa/β-actin: 0.67±0.07 vs. 0.84±0.16, P < 0.05). The expression of GPⅡb-Ⅲa in 4-hour and 12-hour subgroups of the tirofiban group were slightly lower than those in the control group (GPⅡb-Ⅲa/β-action: 0.85±0.12 vs. 0.95±0.11 in 4-hour subgroup, 1.04±0.16 vs. 1.09±0.17 in 12-hour subgroup, both P > 0.05). Immunohistochemistry showed that the change trend of platelet membrane GPⅡb-Ⅲa in ductus arteriosus of newborn pups in both groups was similar to the results of Western blotting. Conclusions:The ductus arteriosus of newborn pups begin to close 1-4 hours after birth, and all closed at 12 hours after birth. The expression of platelet membrane GPⅡb-Ⅲa in ductus arteriosus increase gradually after birth, and the platelet aggregation may participate in and promote ductus arteriosus closure to some extent. Tirofiban, a platelet membrane GPⅡb-Ⅲa receptor antagonist, may delay ductus arteriosus closure of newborn pups to some extent by inhibiting platelet aggregation.

Effects of non-invasive positive pressure ventilation on plasma B-type natriuretic peptide level and Tei index of right ventricle in preterm infants / 中华全科医师杂志

Objective:To investigate the effects of non-invasive positive pressure ventilation (NPPV) on plasma B-type natriuretic peptide (BNP) level and Tei index of right ventricle in preterm infants.Methods:Premature infants of gestational age<34 weeks with respiratory distress syndrome who were admitted in Neonatal Intensive Care Unit of Xuzhou Central Hospital and requiring for NPPV from December 2018 to October 2020, were enrolled in the study. Patients were randomly divided into two groups 46 patients received nasal continuous positive airway pressure ventilation (NCPAP group) and 49 patients received bi-level positive airway pressure ventilation (BiPAP group); 42 preterm infants of gestational age<34 weeks and without NPPV were selected as the control group. The plasma BNP, Tei index of right ventricle, mean airway pressure and oxygen index at 0-12 h and 48-60 h after NPPV were monitored in NCPAP group and BiPAP group. The plasma BNP and Tei index of right ventricle at 0-12 h and 48-60 h after admission were monitored in the control group. SPSS 20.0 statistical software was used for data analysis.Results:(1)The plasma BNP and Tei index of right ventricle at 48-60 h after NPPV were significantly higher than those at 0-12 h after NPPV in NCPAP group and BiPAP group [NCPAP group: (287.5±155.5) vs. (179.9±102.3) ng/L, (0.43±0.08) vs. (0.38±0.06); BiPAP group: (303.1±135.4) vs. (186.5±95.6) ng/L, (0.45±0.08) vs. (0.39±0.06); t=6.00, 3.34, 7.47, 4.48; all P<0.05]. There were no significant differences in the plasma BNP and Tei index of right ventricle at 48-60 h and 0-12 h after admission in the control group [(181.9±86.8) vs. (169.5±78.9) ng/L, (0.34±0.05) vs. (0.36±0.05); t=0.83, -1.59; all P>0.05].(2) There were no significant differences in the plasma BNP and Tei index of right ventricle at 48-60 h after NPPV between NCPAP group-and BiPAP group (all P>0.05), but they were significantly higher than those in control group at 48-60 h after admission(all P<0.05). (3)The mean airway pressure and oxygen index at 48-60 h after NPPV in NCPAP group and BiPAP group showed a decrease trend compared to those at 0-12 h after NPPV, but the differences were not significant [NCPAP group: (6.8±1.2) vs. (7.0±1.3) cmH 2O(1 cmH 2O=0.098 kPa), (5.7±2.1) vs. (6.1±2.3); BiPAP group: (7.0±1.3) vs. (7.2±1.2) cmH 2O, (5.5±2.0) vs. (5.8±2.1); t=-1.05, -0.80, -1.88, -0.67; all P>0.05]; while there were no significant differences between the two groups (all P>0.05). (4)There was a positive correlation between the plasma BNP and mean airway pressure ( r=0.48, P<0.001), but no correlation between Tei index of right ventricle and mean airway pressure ( r=0.17, P=0.119) at 48-60 h after NPPV. Conclusion:The cardiac function indexes such as plasma BNP and Tei index of right ventricle in preterm infants are increased at 48-60 h after NPPV. When mean airway pressure is the same, the effects of NCPAP and BiPAP on plasma BNP and Tei index of right ventricle in preterm infants are similar.

Clinical research of the LISA technique combined with caffeine in the treatment of respiratory distress syndrome in preterm infants / 中华急诊医学杂志

Objective:To evaluate the efficacy and safety of less invasive surfactant administration (LISA) combined with caffeine citrate in the treatment of respiratory distress syndrome (RDS) in preterm infants receiving continuous positive airway pressure (NCPAP) ventilation.Methods:From August 2019 to April 2021, a total of 112 preterm infants with RDS (26 weeks≤gestational age ≤32 weeks) who were hospitalized in the Neonatal Intensive Care Unit of Xuzhou Central Hospital, were chosen as research subjects. The patients were randomly divided into the LISA combined treatment group ( n=58) and the INSURE group ( n=54). In the LISA combined treatment group, a LISA tube was inserted through the vocal cords under direct vision with a direct laryngoscope and then infused with pulmonary surfactant (PS) into the lung when NCPAP ventilation was applied, and caffeine citrate was given intravenously. In the INSURE group, the patients were endotracheally intubated and infused with PS into the lung through an endotracheal tube, and then extubated and put on NCPAP again. The following indicators were examined: the general clinical data, results of blood gas analysis at 1 h and 6 h after infusion of PS into the lung, clinical efficacy and related complications. Results:①No significant differences were found between the two groups in the general clinical data (all P>0.05).Intra-group comparison within LISA combined treatment group or INSURE group showed that partial pressure of arterial carbon dioxide (PaCO 2), partial pressure of arterial oxygen (PaO 2) of blood gas analysis and PaO 2/fraction of inspired oxygen (P/F) at 1 h and 6 h after infused PS into the lung were all improved compared to those of before treatment, and the differences were statistically significant (all P<0.05). The PaO 2 and P/F in the LISA combined treatment group at 1 h and 6 h after breath support therapy were higher than those in the INSURE group, while PaCO 2 was lower than that in the INSURE group, and the differences were statistically significant (all P<0.05). The duration of noninvasive ventilation, total oxygen inhalation, re-administration of PS, failure rate of machine withdrawal, the rate of tracheal intubation within 72 h and the times of apnea in the LISA combined treatment group were significantly shorter, or lower, or less than those in the INSURE group [3.0 (1.0, 18.0) d vs. 7.5 (2.0, 22.0) d, 5.5 (3.0, 21.0) d vs. 10.5 (4.0, 28.0) d, 9 (15.5%) vs. 17 (31.5%), 6 (10.3%) vs. 14 (25.9%), 5 (8.6%) vs. 12 (22.2%), 5.0 (3.0, 21.0) times vs. 15.0 (4.0, 28.0) times], and the differences were all statistically significant (all P<0.05). The incidence of bronchopulmonary dysplasia in the LISA combined treatment group was less than that in the INSURE group [(5 (8.6%) vs. 13 (24.1%)], and the difference was statistically significant ( P<0.05). There was no significant difference between the two groups in other complications( P>0.05). Conclusions:Compared with INSURE, the LISA technique combined with caffeine citrate can effectively improve oxygenation, reduce the mechanical ventilation rate, shorten the duration of noninvasive mechanical ventilation, and reduce the incidence of BPD in the treatment of premature infants with RDS at the gestational age of 26-32 weeks.

Efficacy and safety of initial treatment with ibuprofen or paracetamol and rescue treatment with high-dose ibuprofen in preterm infants with patent ductus arteriosus / 中华全科医师杂志

Objective:To investigate the efficacy and safety of initial treatment with ibuprofen or paracetamol and rescue treatment with high-dose ibuprofen in preterm infants with haemodynamically significant patent ductus arteriosus (hsPDA).Methods:The preterm infants (gestational age ≤ 32 weeks) with hsPDA who were admitted to neonatal intensive care unit (NICU) of Xuzhou Central Hospital from October 2016 to November 2019 were enrolled in the study. A total of 110 eligible cases were included and randomly divided into three groups for initial treatment: 38 cases received oral ibuprofen 10 mg/kg, and 5 mg/kg after 24 h and 48 h (ibuprofen group), 37 cases received oral paracetamol 15 mg/kg, q.8.h for 3 d (paracetamol group) and 35 cases received oral injection water 1 ml/kg, and 0.5 ml/kg after 24 h and 48 h (conservative management group). The preterm infants who failed in the initial treatment were given high-dose ibuprofen for rescue treatment (oral ibuprofen 20mg/kg, and 10 mg/kg after 24 h and 48 h). Serum creatinine, cystatin C, glutamic-pyruvic transaminase (GPT), total bilirubin, fecal occult blood and urinary prostaglandin E 2 were measured; echocardiography and brain color Doppler ultrasonography examinations were performed before and after treatment. Urine output and complications were recorded. The data were analyzed by ANOVA, t-test, non-parametric test, chi-square test and Pearson correlation coefficient with SPSS 20.0 statistical software. Results:During initial treatment, the success rates of ibuprofen group and paracetamol group were higher than that of conservative management group [71.1% (27/38) and 70.3%(26/37) vs. 40.0% (14/35), P=0.008 and 0.010]. Thirty one patients, who failed in initial treatment, received rescue treatment (8, 7, 16 cases from ibuprofen, paracetamol and conservative groups, respectively). The success rate of rescue treatment with high-dose ibuprofen was 58.1% (18/31). During initial treatment, there were no significant differences in the incidence of oliguria, upper gastrointestinal bleeding, positive fecal occult blood tests, Ⅲ-Ⅳ grade intraventricular hemorrhage, and ≥Ⅱ stage necrotizing enterocolitis among the three groups (all P>0.05). There were no significant differences in the incidence of above complications between rescue treatment and initial treatment [6.5% (2/31) vs. 6.4%(7/110), 3.2%(1/31) vs. 4.5%(5/110), 12.9%(4/31) vs. 6.4%(7/110), 0 vs. 4.5%(5/110), 3.2%(1/31) vs. 1.8%(2/110), all P>0.05]. The changes of serum creatinine and GPT before and after treatment were not significant in all groups ( P>0.05). Serum cystatin C were increased in both ibuprofen group[(0.44±0.17)μmol/L] and paracetamol group [(0.18±0.09)μmol/L] after treatment ( t=-15.70, -14.64; P<0.001), and the increase in ibuprofen group was greater than that in paracetamol group ( P<0.001). Urinary prostaglandin E 2 were decreased in both ibuprofen group [(-11.63±3.70)ng/L] and paracetamol group[(-4.89±1.91)ng/L] after treatment ( t=15.57, 7.03; P<0.001), and the decrease in ibuprofen group was greater than that in paracetamol group ( P<0.001). Serum cystatin C was not significantly increased after high dose ibuprofen rescue treatment [(1.67±0.17)mg/L vs.(1.71±0.21)mg/L; t=-1.12, P=0.273]. Conclusion:Both initial treatment with ibuprofen or paracetamol and rescue treatment with high-dose ibuprofen can effectively promote hsPDA closure in preterm infants without increase of complications. However, renal function indexes such as urine output and serum cystatin C should be monitored. The high-dose ibuprofen is relatively safe, and can be used as one of rescue treatment.

Application and experience of laparoscopy for gastric cancer after transformation therapy (report of 7 cases) / 中国医师杂志

Objective:To investigate the application value of laparoscopy for stage Ⅳ gastric cancer after transformation therapy.Methods:The clinical data of 7 patients with advanced gastric cancer who underwent laparoscopic surgery after transformation therapy in the First Affiliated Hospital of Hebei North University from January 2016 to December 2020 were retrospectively analyzed. Seven patients were diagnosed as stage Ⅳ gastric cancer by computed tomography (CT), positron emission tomography (PET-CT) and laparoscopy, and underwent paclitaxel based conversion therapy. After evaluating the curative effect, they underwent surgical resection. The intraoperative and postoperative conditions and survival rate of the patients were analyzed.Results:After transformation therapy, 6 patients (85.7%) had partial remission, 1 patient (14.3%) had stable disease, and the overall effective rate was 6/7. Laparoscopic-assisted surgery was performed in 3 patients, and 4 patients were converted to laparotomy. The operation time was (297.9±35.6)min, the intraoperative blood loss was (257.0±106.0)ml, the number of dissected lymph nodes was (38.4±9.1), the gastric tube indwelling time was (72.4±9.6)h, the jejunal feeding tube indwelling time was (15.4±5.6)d, and the liquid diet time was (8.6±3.4)d, the length of hospital stay was (17.1±5.5)d. The postoperative complication rate was 3/7, and there were no unplanned secondary operations and deaths. R0 resection was performed in 6 cases, and R1 resection in 1 case. Tumor regression grade (TRG) classification: 5 cases were grade 2 and 2 cases were grade 3. The median progression free survival of the 7 patients was 15.3 months, the median overall survival was 21.6 months, and the 1-year survival rate was 6/7.Conclusions:Laparoscopy has irreplaceable value in the staging and efficacy judgment of transformation therapy for gastric cancer. However, after transformation therapy, the tissue edema increases, the tumor boundary becomes more unclear, and the surgical operation becomes more difficult. Therefore, it is not necessary to force the laparoscopic operation, and switch to laparotomy according to the situation.

The effects of hyperbilirubinemia on the myocardium of newborn rats / 中国新生儿科杂志

Objective:To study the influences of different levels of hyperbilirubinemia on the myocardium of newborn rats.Methods:Ninety-six 7-day-old newborn SD rats were selected and randomly assigned into control group (n=32, intraperitoneal injection of normal saline 0.5 ml), test group 1 (n=32, intraperitoneal injection of bilirubin solution 100 mg/kg) and test group 2 (n=32, intraperitoneal injection of bilirubin solution 200 mg/kg). Four time points were set at 0 h, 8 h, 24 h and 48 h. The general conditions of 8 rats from every group at each time point were recorded. The total serum bilirubin (TSB), cardiac troponin I (cTnI),heart fatty acid-binding protein (H-FABP) and B-type natriuretic peptide (BNP) were examined. The heart was removed and the pathological changes of the myocardium were observed under microscope. The caspase-3, B-cell lymphoma-2 protein (bcl-2) and bcl-2-associated X protein (bax) were tested. Using SPSS 20.0 statistical software, two-way ANOVA analysis of variance was conducted.Results:The TSB in test group 1 and 2 at 8~48 h were 2.5~4.4 times and 3.5~7.4 times higher than at 0 h [(20.8±3.0~36.5±10.4) μmol/L and (31.9±12.3~67.4±19.0) μmol/L vs. (8.4±2.1) μmol/L and (9.1±2.9) μmol/L]. No significant changes existed in cardiac histopathology at each time point among the three groups. At 48 h, as TSB level increased, the expression of apoptosis-related proteins caspase-3 and bax increased and the expression of bcl-2 decreased. Significant differences existed in the protein levels between any two groups (all P<0.05), except that bcl-2 in test group 1 was similar to control group ( P=0.255). With the prolonged duration of hyperbilirubinemia in test group 2, the expression of caspase-3 and bax increased, while the expression of bcl-2 decreased. Statistically significant differences existed in the protein levels between any two time points (all P<0.05), except that bax in 8 h subgroup was similar to 12 h subgroup ( P=0.820), and bcl-2 in 8 h subgroup was similar to 0 h subgroup ( P=0.064). The cTnI at 8 h, 24 h and 48 h in test group 1 and 2 were all significantly higher than the control group (all P<0.05),however, no significant differences existed between test group 1 and 2 (all P>0.05). H-FABP and BNP showed no significant differences among the three groups at any time point (all P>0.05). Conclusions:Hyperbilirubinemia can induce apoptosis of myocardial cells in newborn rats in a concentration- and time-dependent manner. Hyperbilirubinemia shows no significant effects on cardiac tissue pathology. Hyperbilirubinemia may cause mild injury to myocardium of newborn rats. The injury shows no correlation with TSB level and BNP level was not influenced.

Single Cell Traction Force Measured by Foldable Microplates / 医用生物力学

Objective To fabricate a foldable microplate for single cell culture and establish finite element model of the folding microplate, so as to calculate traction force of single cells during contraction in three-dimensional (3D) state.Methods The folding angle of the microplate casued by cell traction force was calculated. Then the relation between bending moment and folding angle as well as the relation between traction force and bending moment were derived by using finite element simulation, so as to realize the characterization of traction force for singel cell in 3D state.Results The folding angles of the microplate with HSF and MC3T3-E1 cells in 3D state were 73°-173° and 49°-138°, respectively. The single cell traction forces of HSF and MC3T3-E1 cells were 55-210 nN and 52-161 nN, respectively.Conclusions The proposed method for measuring traction force of single cells in 3D state by fabricating the foldable microplate for single cell culture will provide some references for further development of calculating traction forces in 3D cell adhesion, spreading and migration.

PFKL, a novel regulatory node for NOX2-dependent oxidative burst and NETosis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Neutrophils are predominant leukocytes in the circulation, which are essential for killing invading pathogens via the activation of effector responses and the production of reactive oxygen species (ROS), also named as "oxidative burst." When infected, activated neutrophils fight bacteria, fungi, and viruses through oxidative burst, phagocytosis, degranulation, and the production of neutrophil extracellular traps (NETs) in a neutrophil death process named as "NETosis" (Mutua and Gershwin, 2021). NETs, consisting of DNA fibers decorated with modified histones and numerous antimicrobial proteins from cytoplasmic granules and the nucleus, can either be beneficial or detrimental (Mutua and Gershwin, 2021). Several pathways can lead to this death process. In response to various stimuli, NETosis traps and clears pathogens, facilitating phagocytosis by other neutrophils and phagocytes. However, excessive NETosis often results in disease due to increasing the pro-inflammatory response and perpetuating the inflammatory condition (Hellebrekers et al., 2018; Hidalgo et al., 2019; Klopf et al., 2021). Accordingly, inhibiting aberrant NETosis may alleviate the severity of various autoimmune and inflammatory diseases.