[Mitochondrial pyruvate carrier deficiency: 3 cases report and literature review].

Objective: To analyze the clinical and genetic features of patients with mitochondrial pyruvate carrier deficiency (MPYCD). Methods: This was a case series research. The clinical data, genetic characteristics, and glutamine treatment efficacy of 3 patients diagnosed with MPYCD at the Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, Guizhou Provincial People's Hospital, from August 2019 to June 2023 were retrospectively collected. A literature search with "MPC1 gene" "MPC2 gene and" "mitochondrial pyruvate carrier deficiency" as keywords was conducted at the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI) and PubMed (up to June 2023). Clinical and genetic characteristics of patients with MPYCD were summarized. Results: Case 1 was a 3 years and 11 months old boy, while case 2 was a 4 years and 10 months old boy and case 3 was an 8 years and 9 months old girl. Case 2 and case 3 were siblings from one consanguineous family. All 3 patients presented with general developmental delay, growth failure and elevated serum lactate. Cranial magnetic resonance imaging (MRI) showed subtle bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus in case 1, but normal in case 2 and 3. Trio-WES revealed case 1 harboring compound heterozygous missense variants c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1 gene, while case 2 and 3 revealed a homozygous variant c.290G>A (p.Arg97Gln) in the same gene. All 3 cases were diagnosecl as MPYCD. Clinical symptoms including motor ability, cognition and activity endurance were improved in these 3 patients after taking glutamine for 2 years. A total of 5 articles published in English were reviewed, and no Chinese literature was found. Including these 3 cases, 15 cases were enrolled for analysis. Eleven patients carried MPC1 gene variants and 4 cases carried MPC2 gene variants. Except for 3 cases died during prenatal period, 9 of 12 enrolled born cases were onset before 6 months old. The most common clinical symptoms were mental and motor general developmental delay, microcephaly, growth failure and hypotonia. All patients had elevated blood lactate and pyruvate, but the ratio of lactate/pyruvate was normal. Seven patients performed cranial MRI, 3 exhibited non-specific changes, 2 showed bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus, and 3 were normal. A total of 5 MPC1 gene missense variants and 2 MPC2 gene variants were identified in 15 cases. Conclusions: Onset age of patients with MPYCD is usually within 6 months. The main clinical characteristics are developmental delay, microcephaly and growth failure, accompanied by increased serum lactate and pyruvate. Glutamine supplement could lead to clinical improvements.

[A pre-conception cohort study of fertility and its related factors among couples with the intention of conception].

Objective: To describe fertility and explore factors associated with it among pre-conception couples of childbearing age. Methods: Based on the pre-conceptional offspring trajectory study of the School of Public Health of Fudan University, couples of childbearing age who participated in the pre-conception physical examination in Shanghai Jiading District from 2016 to 2021 were recruited and followed up. Couples' time to pregnancy (TTP) was analyzed and Cox proportional hazards regression model was used to explore the factors associated with TTP. Kaplan-Meier was used to calculate each menstrual cycle's cumulative pregnancy rate. Results: A total of 1 095 preconception couples were included in the analysis, the M(Q1,Q3)of TTP was 4.33 (2.41, 9.78) menstrual cycles. Age of women (FR=0.90, 95%CI: 0.85-0.95, P<0.001), women who were overweight or obese before pregnancy (FR=0.36, 95%CI: 0.24-0.55, P<0.001), women who were exposed to second-hand smoking (FR=0.63, 95%CI: 0.44-0.92, P=0.016), women whose home or office had been renovated in the past 2 years and had a particular smell (FR=0.46, 95%CI: 0.26-0.81, P=0.008) were risk factors for impaired fertility. Regular menstrual cycles (FR=1.64, 95%CI: 1.16-2.31, P=0.005), females who often drank tea/coffee (FR=1.55, 95%CI: 1.11-2.17, P=0.011) and males who took folic acid before conception (FR=2.35, 95%CI: 1.38-4.23, P=0.002) were associated with better fertility. The cumulative pregnancy rate of 3, 6, and 12 menstrual cycles was 37.6%, 64.4%, and 78.4%, respectively. Conclusion: Older couples, overweight or obesity before pregnancy, irregular menstruation, exposure to secondhand smoke and decoration pollutants in females are associated with impaired fertility. Frequent tea/coffee drinking before pregnancy in females and taking folic acid before pregnancy in males are associated with shortened conception time.

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience].

Objective: To explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven+AZA) in previously untreated patients unfit for standard chemotherapy and patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) in China. Methods: A retrospective study was conducted in 60 previously untreated patients unfit for standard chemotherapy and patients with R/R AML who received Ven+ AZA (venetoclax, 100 mg D1, 200 mg D2, 400 mg D3-28; azacitidine, 75 mg/m(2) D1- 7) at the Peking University Institute of Hematology from June 1, 2019 to May 31, 2021. The incidence of adverse events, complete remission (CR) /CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) , and minimal residual disease (MRD) status in patients with different risk stratification and gene subtypes were analyzed. Results: The median age of the patients was 54 (18-77) years, 33 (55.0%) were males, and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients unfit for standard chemotherapy, and 36 (60.0%) were R/R patients. The median mumber cycles of Ven+AZA in the two groups were both 1 (1-5) . According to the prognostic risk stratification of the National Comprehensive Cancer Network, it was divided into 8 cases of favorable-risk, 2 cases of intermediate risk, and 14 cases of poor-risk. In previously untreated patients unfit for standard chemotherapy, after the first cycle of Ven+AZA, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) achieved partial remission (PR) , and the ORR was 83.3%. Among them, nine patients received a second cycle chemotherapy and two received a third cycle. Among CR/CRi patients, 8/17 (47.1%) achieved MRD negativity after two cycles of therapy. In the R/R group, after the first cycle of Ven+AZA, 21/36 (58.3%) cases achieved CR/CRi (7/21 achieved MRD negativity) , 3 achieved PR, and the ORR was 66.7%. Among R/R patients, 12 were treated for more than two cycles. There were no new CR/CRi patients after the second treatment cycle, and 14 cases (66.7%) achieved MRD negativity. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 in the poor-risk group (CR to hematological recurrence<18 months, no remission after one cycle of therapy, and no remission after two or more cycles of therapy) . Eleven of 24 (45.8%) cases achieved CR/CRi after one cycle of Ven+AZA in the poor-risk R/R group, and 10 of 12 (83.3%) achieved CR/CRi in the favorable-risk R/R group, which was significantly superior to the poor-risk group (P=0.031) . After one cycle of treatment, 13 patients with IDH1/2 mutations and 4 that were TP53-positive all achieved CR/CRi. The CR/CRi rate of 18 patients with NPM1 mutations was 77.8%. Five patients with RUNX1-RUNX1T1 combined with KIT D816 mutation (two initial diagnoses and three recurrences) had no remission. Ven+ AZA was tolerable for AML patients. Conclusion: Ven+AZA has acceptable safety in previously untreated patients unfit for standard chemotherapy, patients with R/R AML can achieve a high response rate, and some patients can achieve MRD negativity. It is also effective in NPM1-, IDH1/IDH2-, and TP53-positive patients. The long-term efficacy remains to be observed.

[Preliminary study of the changes in blood system in pyrrolizidine alkaloid-related liver damage].

Objective: To preliminary explore the changes in blood system in pyrrolizidine alkaloids (PAs)-related liver damage. Methods: General situation, liver function, biochemical blood test, routine blood test, coagulation function markers, etc., of 77 cases with drug-induced liver damage admitted to the Zhongshan Hospital Affiliated to Fudan University from 2012 to 2019 were retrospectively analyzed. Patients' were divided into PA group, other traditional Chinese medicine group and Western medicine group according to their medication history. Simultaneously, the changes in liver function were observed in the established mice model of monocrotaline-induced liver damage. Liver tissues HE staining and blood routine indexes were observed. Results: 24 cases received PA, 24 cases received other traditional Chinese medicine, and 29 cases received western medicine. Alanine aminotransferase was lower in PA group than the other two groups (P < 0.05), and the total bilirubin and direct bilirubin were significantly lower than the other traditional Chinese medicine group (P < 0.05). The peripheral platelet count of the PA group was (84.11 ± 26.91) ×10(9)/L, which was significantly lower than the lower limit of normal, and had statistically significant difference with other traditional Chinese medicine and western medicine group (P < 0.01). Thrombocytocrit, mean platelet volume and platelet indices of PA group were statistically different from the other two groups (P < 0.05). The D-dimer level in patients with PA group was (2.62 ± 1.93) mg/L, which was higher than the upper limit of normal, and significantly higher than the D-dimer level of the other two groups of patients (P < 0.01). Meanwhile, prothrombin time was longer in PA group than that of the other two groups (P < 0.01), and platelets count were decreased significantly in the mouse model of monocrotaline-induced liver damage after alanine aminotransferase and aspartate aminotransferase elevation (P < 0.01). Conclusion: PA-related liver damage has lower peripheral platelet counts, and the peripheral platelet counts of these patients are lower than other types of drug-induced liver damage. In addition, increased D-dimer in patients with PA-related liver damage indicate a potential risk of thrombosis.

Changes in bacterial community and expression of genes involved in intestinal innate immunity in the jejunum of newborn lambs during the first 24 hours of life.

The newborn gut undergoes rapid colonization by commensal microorganisms and possible exposure to pathogens. The contribution of colostrum intake to host protection is well known; however, limited research exists on the intestinal innate immunity corresponding to colostrum intake during the passive immune transfer period in newborn ruminants. The aim of this study was to investigate the changes in bacterial community and expression of genes encoding toll-like receptors (TLR), mucins (MUC), antimicrobial peptides, and tight junctions in the jejunum of lambs that were fed colostrum during the first 24 h of life. Twenty-seven newborn lambs were used in this study, of which 18 lambs were bottle-fed pooled bovine colostrum within the first 2 h after birth to obtain an intake of approximately 8% of body weight. Lambs were slaughtered at 12 (n = 9) and 24 h (n = 9) after birth. The remaining 9 lambs without any feeding were slaughtered at 30 min after birth (0 h). Tissue and ligated segment samples from the jejunum were collected immediately after the lambs were slaughtered. The bacterial profile in the ligated jejunum segment was assessed using amplicon sequencing. The gene expression in the jejunum tissue was determined using quantitative real-time PCR. The relative abundances of Escherichia-Shigella, Lactobacillus, Lactococcus, and Streptococcus increased, whereas those of Sphingomonas, Phyllobacterium, Bradyrhizobium, and Rudaea decreased during the first 24 h of life. Expression of TLR2 and ß-defensin 109-like was upregulated at 12 h after birth, but a recovery was detected at 24 h; TLR3, TLR5, LYZ, MUC1, MUC13, MUC20, and CLDN7 showed a higher expression level in samples taken at 24 h than in those taken at 0 h. In addition, expression level of CLDN1, CLDN4, and the junctional adhesion molecule-1 tended to be higher at 24 h than at 0 h after birth. Correlation analysis indicated that TLR2 expression was negatively correlated with the relative abundance of Lactobacillus and Bradyrhizobium, whereas TLR5 expression was positively correlated with the relative abundance of Escherichia-Shigella and Pelagibacterium. These results suggest that TLR, MUC, antimicrobial peptides, and CLDN act together and play an important role in intestinal defense during the passive immune transfer period. They are potentially associated with microbial colonization. The findings from this study provide novel information to elucidate the role of colostrum components in regulating the development of the intestinal mucosal immune barrier in newborn lambs during the passive immune transfer period.

Effects of baohuoside-I on epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma.

To investigate the effect of baohuoside-I against nasopharyngeal carcinoma (NPC) and its underlying mechanism, baohuoside-I was employed to treat NPC cell lines CNE1 and CNE2 in vitro, followed by attachment and detachment assays to evalute the epithelial-mesenchymal transition (EMT) phenotype markers. Baohuoside-I was also administered to experimental mice to assess its effect on xenograft tumor growth and NPC cell metastasis. A microRNA (miRNA, miR) microarray was performed to screen for miRNA altered by baohuoside-I in NPC cells. Bioinformatic tools and luciferase activity assay was conducted to identify the downstream molecules mediating the anti-tumor property of baohuoside-I. Baohuoside-I inhibited EMT and metastasis and upregulated miR-370-3p in NPC cells, which was shown to directly recognize and inhibit expression of Hedgehog pathway component Smoothened (SMO). Baohuoside-I suppresses metastasis as well as EMT of NPC cells through targeting the Hedgehog pathway component SMO, and may serve as a potent anti-tumor agent in the clinical management of NPC.

[Terpenoids from Toona sinensis].

Eight terpenoids(1-8) were isolated from the ethyl acetate soluble fraction of 80% ethanol extract of leaf of Toona sinensis through various column chromatographies on silica gel, Sephadex LH-20, MCI and ODS. Their structures were elucidated as 8ß-hydroxypimar-15-en-19-oic acid methyl ester(1), cedrodorol B(2), 11ß-acetoxyobacunol(3), toonayunnanin D(4), toonaciliatone D(5), toonaciliatone A(6), cedrelone(7), and 11ß-hydroxygedunin(8) based on their chemical and physicochemical methods and spectroscopic data. Compound 1 was a new pimaradienediterpenoid and terpenoid 2-7 were isolated and identified from this plant for the first time. Compound 1 was tested in vitro for cytotoxic potential by employing MTT method and radical scavenging potential using DPPH test. As a result, 1 exhibited weak cytotoxic activity against three tested tumor cell lines(SMMC-7721, A549 and MCF-7) with IC_(50) values less than 40 µmol·L~(-1) and moderate radical scavenging activities with IC_(50) values of 74.3 µmol·L~(-1).

[Preliminary results of Chinese magnetic sphincter augmentation in treating gastroesophageal reflux disease].

Objective: To examine the preliminary clinical efficacy of Chinese magnetic sphincter augmentation (MSA) in the treatment of gastroesophageal reflux disease (GERD). Methods: According to the enrollment criteria for the MSA developed by ShengJieKang Co. and Shanghai Chest Hospital (SS-MSA) clinical trial, a total of 19 GERD patients were treated with SS-MSA from August 2018 to January 2020 at Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University. The majority of registered cases were male patients with age of (32.2±7.3) years (range: 22 to 50 years), height of (170.7±6.2) cm (range: 160 to 179 cm) and weight of (65.2±10.3) kg (range: 47.5 to 90.0 kg). SS-MSA was implanted via laparoscopy. The major evaluation indexs of postoperative efficacy were the total time of acid exposure within 24 hours and the total number of reflux. Secondary efficacy indicators included: (1) evaluation of the average daily dose of proton pump inhibitor medications; (2) the score of GERD health related quality of life questionnaire (GERD-Q) before and after MSA implantation. Paired design t-test was used to evaluate the efficacy of the SS-MSA. Results: A total of 19 patients underwent SS-MSA surgery successfully. The history of the GERD were 19 (54) months (M(Q(R))). The operation time was 63 (22) minutes and the in-hospital stay was 3 (2) days. No obvious surgical complications occurred. Postoperative adverse events included 14 cases with mild to moderate dysphagia exited after surgery, gradually eased within 1 to 3 months, 1 case with the removal of the device after 1 month of severe swallowing difficulties, 1 case of diarrhea. No corrosion, perforation, displacement occurred. The GERD-Q score (11.0(4.5) vs. 6(1.0), t=4.274, P=0.013), 24-hour acid exposure time (6.2(4.8)% vs. 0.1(0.9)%, t=5.814, P=0.004), and Demeester score (23.72(16.20) vs. 0.96(3.10), t=6.678, P=0.003) were significantly decreased 1 year after surgery(n=5). Proton pump inhibitor reuse rates were 6/18, 5/15, 3/10, and 1/5 in 1, 3, 6 and 12 months after the operation, respectively. Conclusions: SS-MSA implantation is feasible and safe with short hospital stay and rare perioperative complications. The preliminary results is good after 1 year follow-up. It could be expected to be an ideal substitutive for future GERD treatment.

[Berberine protects myocardial injury and cardiac dysfunction in a septic rat model].

Objectives: To investigated whether berberine could ameliorate septic cardiomyopathy in a rat model of sepsis and it's mechanisms. Methods: SD rats were divided into 3 groups: sepsis group (LPS group), rats were intraperitoneal injected of LPS (10 mg/kg); Berberine intervention group (Ber group), Ber (50 mg/kg, one time per day) was gavage fed 3 days before intraperitoneally injection of lipopolysaccharides (LPS); control group (Con group), rats were gavage fed with double distilled water (2 ml/100 g, one time per day) 3 days before intraperitoneal injection of normal saline (1 ml/100 g). LPS group and the Ber group was further divided into 3 subgroups (n=6), and the follow-up experiments were conducted at 6 h, 24 h and 48 h after LPS injection (of which 48 h subgroup rats were gavage fed with Ber/saline at 24 h). Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and the maximum rate of change of left ventricular pressure (±dp/dtmax) were monitored, the level of cardiac troponin T (cTnT), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß was detected by ELISA method, HE staining of myocardial tissues was done to observe myocardial injury; Western blotting method was used to detect the expression of toll-like receptor 4(TLR4) protein in rat myocardial tissue, the level of myocardial cell nucleus protein p65 was detected to reflects the degree of NF-κB activation. The correlation of factors was analyzed with Pearson correlation analysis. Results: Pre-treatment with berberine stabilized cardiac hemodynamics and improved the systolic function and diastolic function in the heart of LPS-induced rats, as evidenced by the partial recovery of the reduced±dp/dtmax and LVSP, as well as the decreased LVEDP. Compared with the LPS group, the Ber group showed improved myocardial injury, as demonstrated by decreased cTnT at each time point. HE staining results showed that berberine decreased inflammatory cell infiltration and LPS-induced cell swelling. These effects were observed early at 6 hours, severe at 24 hours, and become more serious at 48 hours after LPS injection. Further, TLR4 and NF-κB p65 subunits, which were the two key factors of the TLR4/NF-κB signaling, were upregulated in the LPS group and attenuated in the Ber group. Consistently, the expression levels of the downstream cytokines TNF-α and IL-1ß were lower in the Ber group than those in the LPS group (all P<0.05). Myocardial injury markers were positively correlated with the markers of TLR4/NF-κB signals and the downstream host inflammatory factors (all P<0.05). Conclusions: Berberine can improve myocardial injury and cardiac function in sepsis rats, the mechanism is considered to be related to that it can inhibit the activation of TLR4/NF-κB signaling pathway induced by LPS and further reducing the production of TNF-α and IL-1ß.

[Transnasal endoscopic surgery of choanal atresia after radiotherapy for nasopharyngeal carcinoma].

Objective: To discuss the effect of endoscopic dilatation and plasty for choanal atresia after radiotherapy for nasopharyngeal carcinoma. Methods: Nineteen patients with choanal atresia who were admitted to the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Nanchang University from Jan. 2011 to Dec. 2018 were reviewed, with 12 males and 7 females aging from 33 to 59 years old. All of the patients had a history of radiotherapy for nasopharyngeal carcinoma and were confirmed by electronic nasopharyngoscope and nasopharyngeal imaging. Among 19 patients, there were 3 cases of unilateral occlusion and 16 cases with bilateral atresia, and all of them were membranous atresia. All patients received the transnasal endoscopic surgery of resecting partial vomer bone while trying to keep normal mucosa tissues and using the septonasal mucoperiosteal flap to repair under general anesthesia. One week after operation, the patients were told to do physiological saline nasal irrigation and received regular clean and observation under endoscope. Descriptive statistical method was used to analyze the outcome. Results: The patients were followed up for 1 year postoperatively by electronic nasopharyngoscopic examination. There was no failure case in all the 19 patients including 16 patients with a wide choana and 3 patients had narrowing of the choana (<50%), with adequate and satisfactory airway. Conclusions: Transnasal endoscopic surgery was an effective treatment for choanal atresia after radiotherapy for nasopharyngeal carcinoma. Application of septonasal mucoperiosteal flap for repairing nasal and nasopharyngeal mucosa would avoid recurrence.

[A multicenter randomized prospective study of concurrent chemoradiation with 60 Gy versus 50 Gy for inoperable esophageal squamous cell carcinoma].

Objective: To determine whether 60 Gy is superior to standard 50 Gy for definitive concurrent chemoradiation(CCRT) in esophageal squamous cell carcinoma (ESCC) using modern radiation technology in a phase Ⅲ prospective randomized trial. Methods: From April 2013 to May 2017, 331 patients from 22 hospitals who were pathologically confirmed with stage ⅢA-ⅣA ESCC were randomized to 60 Gy or 50 Gy with random number table. Total of 305 patients were analyzed, including 152 in 60 Gy group and 153 in 50 Gy group. The median age was 63 years, 242(79.3%) males and 63(20.7%) females. The median length of primary tumor was 5.6 cm. The clinical characteristics between two groups were comparable. All patients were delivered 2 Gy per fraction, 5 fractions per week. Concurrent weekly chemotherapy with docetaxel (25 mg/m(2)) and cisplatin (25 mg/m(2)) and 2 cycles consolidation chemotherapy with docetaxel (70 mg/m(2)) and cisplatin (25 mg/m(2), d1-3) were administrated. The primary endpoint was local/regional progression-free survival (LRPFS). The data were compared with Pearson chi-square test or Fisher's exact test. Results: At a median follow-up of 27.3 months, the disease progression rate was 37.5% (57/152), 43.8% (67/153) in the high and standard-dose group, respectively (χ(2)=1.251, P=0.263). The 1, 2, 3-year LRPFS rate was 75.4%, 56.8%, 52.1% and 74.2%, 58.4%, 50.1%, respectively (HR: 0.95, 95%CI: 0.69-1.31, P=0.761). The 1, 2, 3-year overall survival rate was 84.1%, 64.8%, 54.1% and 85.4%, 62.9%, 54.0%, respectively (HR: 0.98, 95%CI: 0.71-1.38, P=0.927). The 1, 2, 3-year progression-free survival rate was 70.8%, 54.2%, 48.5% and 65.5%, 51.9%, 45.1%, respectively (HR: 0.93, 95%CI: 0.68-1.26, P=0.621). The incidence rates in toxicities between the two groups were similar except for higher rate of severe pneumonitis in high dose group (χ(2)=11.596, P=0.021). Conclusions: The efficacy in disease control is similar between 60 Gy and 50 Gy using modern radiation technology concurrent with chemotherapy for ESCC. The 50 Gy should be recommended as the regular radiation dose with CCRT for ESCC.

[Analysis of follow-up results of chrono-chemotherapy or conventional chemotherapy combined with intensity modulated radiotherapy in locally advanced nasopharyngeal carcinoma].

Objective: To evaluate the long-term effect and safety of chrono-chemotherapy combined with intensity modulated radiotherapy (IMRT) in locally advanced nasopharyngeal carcinoma (NPC). Methods: 160 patients with locally advanced NPC were randomly divided into a chrono group and conventional group according to random number table. In the first stage, all patients underwent two cycles of induced chemotherapy, consisting of docetaxel, cisplatin and 5-Fu every 21 days. Notably, patients received chrono-moduated chemotherapy according to circadian rhythm in the chrono group, and conventional chemotherapy in the conventional group. Then, 21 days after the completion of first stage, three cycles of concurrent cisplatin chemotherapy every 21 days were given to all patients during IMRT. The median follow-up after the completion of radiotherapy was 31 months. Long-term side effects and the survival of patients were observed. Results: Patients in the chrono group had significantly lower rates of hearing loss (22.72%), dysphagia (0) and neck fibrosis (4.54%) compared with those in the conventional group (39.13%、8.69%, 15.94%, respectively, all P<0.05). Meanwhile, the 1- year overall survival rates (97.0% vs 92.8%), 3-year overall survival rates (80.3% vs 81.2%), 1-year progression free survival rates (95.5% vs 87.0%), 3-year progression free survival rates (71.2% vs 73.9%), 1-year locoregional relapse-free survival rates (97.0% vs 95.7%), 1-year locoregional relapse-free survival rates (92.4% vs 92.8%), 1-year distant metastasis-free survival rates (97.0% vs 98.6%) and 3-year distant metastasis-free survival rates (90.9% vs 91.3%) between the chrono group and the conventional group were not statistically significant (all P>0.05). Conclusions: Compared with conventional chemotherapy, chrono-chemotherapy combined with IMRT didn't affect long-term survival, but reducing the incidence of adverse events in patients with locally advanced NPC.

[Relationship between the level of estrogen, calcium and phosphorus concentration in serum with benign paroxysmal positional vertigo].

Objective:To investigate relationship between the level of estrogen, calcium and phosphorus concentration in serum with benign paroxysmal positional vertigo(BPPV). Method:A total of 84 patients with idiopathic BPPV were enrolled in the experimental group, including 32 non-menopausal women, 24 menopausal women, and 28 males; 83 healthy people without vertigo and vestibular disease were selected as the control group consisted with 32 non-menopausal women, 24 menopausal women and 27 males. The levels of estradiol, serum calcium and serum inorganic phosphorus were measured in all participants. The difference of estrogen level, serum calcium and serum inorganic phosphorus concentration between the experimental group and the control group was analyzed by t test. Result:The total number, age distribution and gender composition of the experimental group and the control group were basically paired, and the age difference was not statistically significant (P=0.71). The overall estrogen level in the experimental group was lower than that in the control group (P<0.01). Among them, the female group's estrogen level, menopausal female estrogen level and male estrogen level in the experimental group were lower than the control group (P<0.01); there was no significant difference in serum calcium and serum inorganic phosphorus concentration between the experimental group and the control group (P=0.55, 0.11, respectively). Conclusion:The decrease of estrogen level may be a risk factor for idiopathic BPPV. The relationship between serum calcium and serum inorganic phosphorus concentration and BPPV needs further study.

[Effects of estrogen and remifemin on neuronal nitric oxide synthase and transient receptor potential vanilloid 1 in submandibular gland of ovariectomized rats].

Objective: To investigate the effects of estrogen and remifemin on the expression of neuronal nitric oxide synthase (nNOS), transient receptor potential vanilloid 1 (TRPV1), muscarinic acetylcholine receptor, member 1 and 3 (M1 and M3 receptor) and acetylcholinesterase (AChE) in the submandibular gland of rats. Methods: Forty SD female adult rats were divided into SHAM group (sham operation), OVX group (ovarian removal), OVX+E group (ovarian removal + estrogen treatment) and OVX+ICR group (ovarian removal + remifemin treatment), 10 per group. The rats were recovered for 2 weeks after operation. The SHAM group and the OVX group were treated with distilled water, the OVX+E group and the OVX+ICR group were treated with ß-estradiol and remifemin respectively. After 4 weeks, the location and expression of nNOS, TRPV1, M1 and M3 receptors in the submandibular gland were evaluated by immunohistochemistry. The changes of AChE expression in rat submandibular gland were observed by AChE staining. Results: Compared with SHAM group (0.23±0.02, 0.28±0.01, 0.25±0.03, 0.19±0.03), the expression of nNOS, TRPV1, M1 and M3 receptors in OVX group (0.16±0.01, 0.21±0.01, 0.15±0.02, 0.09±0.02) were significantly lower (P<0.05); there were no significant difference between OVX+E group (0.23±0.01, 0.28±0.02, 0.23±0.03, 0.19±0.01) and SHAM group (P>0.05). But compared with OVX group, the expression of nNOS, TRPV1 and M3 receptors in OVX+ICR group were no significantly changed (P>0.05), and only M1 receptor expression (0.22±0.03) was significantly increased (P<0.05). The expression of AChE in OVX group (0.14±0.01) was significantly higher than that in SHAM group (0.10±0.01) (P<0.05). The expression of AChE in OVX+E group (0.15±0.01) was significantly higher than that in SHAM group (P<0.05). The expression of AChE in OVX+ICR group (0.09±0.01) was not significantly different from that in SHAM group (P>0.05). Conclusions: Estrogen can significantly increase the expression of nNOS and TRPV1 in the submandibular gland of rats, suggesting that estrogen may regulate the salivary secretion function of the submandibular gland through nNOS and TRPV1. The mechanism of remifemin is different from that of estrogen, and remifemin does not play a regulatory role by nNOS and TRPV1.

Effects of arachidonic acid and its major prostaglandin derivatives on bovine myoblast proliferation, differentiation, and fusion.

Many studies have shown positive effects of prostaglandins (PGs) on various steps of skeletal muscle formation such as myoblast proliferation and myotube hypertrophy. In animals, PGs are synthesized through the action of the rate-limiting enzymes cyclooxygenase (COX) -1 and COX-2 from arachidonic acid (AA), a conditionally essential fatty acid. As a step toward exploring the possibility of using dietary supplementation of AA to improve skeletal muscle growth in cattle, which are major meat-producing animals, we determined the effects of AA and its major PG derivatives PGE2, PGF2α, and PGI2 on proliferation, differentiation, and fusion of primary bovine myoblasts in vitro. In the proliferation experiment, myoblasts were cultured in a growth medium to which was added 10 µM AA, 1 µM PGE2, 1 µM PGF2α, 1 µM PGI2, or vehicle control for 24 h, and the proliferating cells were identified by 5-ethynyl-2'-deoxyuridine (EdU) labeling. This experiment revealed that AA, PGE2, PGF2α, and PGI2 each increased the number of proliferating cells by 13%, 24%, 16%, and 16%, respectively, compared to the control (n = 7, P < 0.05). In the differentiation and fusion test, myoblasts were induced to differentiate and fuse into myotubes in the presence of the aforementioned treatments for 0, 24, 48, and 72 h. Based on quantitative reverse transcription PCR analyses of mRNAs of myoblast differentiation and fusion markers (myogenin; myosin heavy chain 3; creatine kinase, muscle; myomaker) at 0, 24, and 48 h of differentiation, AA, PGE2, and PGF2α promoted myoblast differentiation (n = 6, P < 0.05). Based on Giemsa staining and counting the number of myotubes at 72 h of differentiation, PGE2 enhanced the number of formed myotubes by 14% (P < 0.05) compared to the control. Treating the myoblasts with AA and either the COX-1 and COX-2 common inhibitor indomethacin or the COX-2-specific inhibitor NS-398 reversed the stimulatory effect of AA on myoblast proliferation (n = 4, P < 0.05). Overall, this study demonstrates that exogenous AA stimulates bovine myoblast proliferation and differentiation in culture. The results of this study suggest that AA stimulates myoblast proliferation through its metabolites PGE2, PGF2α, or PGI2, and that AA stimulates myoblast differentiation through PGE2.

[The application of holistic nursing in the rehabilitation of occupational pneumoconiosis complicated with chronic obstructive pulmonary disease].

Objective: To investigate the effect of holistic nursing on the rehabilitation of patients with occupational pneumoconiosis complicated with acute exacerbation of chronic obstructive pulmonary disease (COPD) . Methods: In October 2018, from September 2016 to September 2018, 120 pneumoconiosis patients with copd admitted to the occupational disease department of Laigang Hospital attached to Affilated to Shandong First Medical University were selected, according to random number table method is divided into experimental group (60 cases) and control group (60 cases) in the control group given conventional nursing, the experimental group to implement the holistic nursing, before and after the intervention were compared of two groups of patients with disease recognition grade self-management behavior of related parameters of blood gas analysis and lung function changes. Results: Comparison of disease recognition score between the two groups, the experimental group was higher than the control group (P<0.05) . Comparison of scores of self-management behaviors such as diseases medical management, daily life management. Emotion management and so on between the two groups showed that the experimental group was higher than the control group (P<0.05) . Comparison of blood gas analysis indicators between the two groups showed that PaO(2) in the experimental group was higher than that in the control group (P<0.05) . Comparison of pulmonary function indicators between the two groups showed that FEV(1) and FEV(1)/FVC in the experimental group were higher than that in the control group (P<0.05) . Conclusion: Holistic nursing can effectively improve the cognition of pneumoconiosis patients with copd in the acute exacerbation stage, regulate their self-management behavior, improve arterial oxygen content, improve pulmonary ventilation function. and promote the recovery of the disease.

RandomiSed clinical trial assessing Use of an anti-inflammatoRy aGent in attenUating peri-operatiVe inflAmmatioN in non-meTastatic colon cancer - the S.U.R.G.U.V.A.N.T. trial.

BACKGROUND: Peri-operative inflammation has been extensively highlighted in cancer patients as detrimental. Treatment strategies to improve survival for cancer patients through targeting peri-operative inflammation have yet to be devised. METHODS: We conducted a multi-centre, randomised controlled clinical trial using Taurolidine in non-metastatic colon cancer patients. Patients were randomly assigned to receive Taurolidine or a placebo. The primary endpoint for the study was the mean difference in day 1 IL-6 levels. Secondary clinical endpoints included rates of post-operative infections and tumor recurrence. RESULTS: A total of 293 patients were screened for trial inclusion. Sixty patients were randomised. Twenty-eight patients were randomised to placebo and 32 patients to Taurolidine. IL-6 levels were equivalent on day 1 post-operatively in both groups. However, IL-6 levels were significantly attenuated over the 7 day study period in the Taurolidine group compared to placebo (p = 0.04). In addition, IL-6 levels were significantly lower at day 7 in the Taurolidine group (p = 0.04). There were 2 recurrences in the placebo group at 2 years and 1 in the Taurolidine group. The median time to recurrence was 19 months in the Placebo group and 38 months in the Taurolidine group (p = 0.27). Surgical site infection was reduced in the Taurolidine treated group (p = 0.09). CONCLUSION: Peri-operative use of Taurolidine significantly attenuated circulating IL-6 levels in the initial 7 day post-operative period in a safe manner. Future studies are required to establish the impact of IL-6 attenuation on survival outcomes in colon cancer. TRIAL REGISTRATION: The trial was registered with EudraCT (year = 2008, registration number = 005570-12 ) and ISRCTN (year = 2008, registration number = 77,829,558 ).

[Effect of foam sclerotherapy for the treatment of oropharyngeal venous malformation].

Objective: To evaluate the safety and efficacy of foam sclerotherapy with polidocanol for the treatment of venous malformation in the oropharynx. Methods: The clinical data of 21 children with venous malformation in the oropharynx treated by foam sclerotherapy were retrospectively analyzed. There were 10 males and 11 females, ranging in age from 1 month to 13 years, with a median age of 2.3 years. MRI was performed in all children, and the diagnosis was further confirmed by radiography. After general anesthesia, the oropharynx was exposed by opening device. Scalp acupuncture was used to pucture lesions and polidocanol foam was injected after the nidus was confirmed by digital subtraction angiography(DSA). The follow-up time ranged from 2-29 months, with a mean time of 15 months. The clinical symptoms, imaging data, therapeutic effects and postoperative complications were evaluated. Results: Total numbers of treatment were 52 times, 1-6 times/case; 13 cases were cured, 7 cases was relieved and no response in one case. Postoperative swelling in 13 cases, fever in 3 cases, local mucosal ulcer in 2 cases, difficult extubation in 2 cases. No nerve injury, swallowing function damage and cardiopulmonary accidents were found in all patients. Conclusion: Foam sclerotherapy with polidocanol in the treatment of venous malformation in the oropharynx is a safe and effective method.

A potential strategy for counteracting age-related sarcopenia: preliminary evidence of combined exercise training and leucine supplementation.

Previous research has demonstrated the positive effects of concurrent/combined aerobic and resistance exercise or leucine supplementation on skeletal muscle protein synthesis (MPS) and hypertrophy in aging organisms. However, the effects of a multimodal intervention which combines both aerobic and resistance exercise and leucine supplementation has not been fully elucidated. Eighteen month old and 2 month old C57BL/6 mice were assigned to aging control (AC, n = 8), aging and multimodal intervention (AMI, n = 8) and young control (YC, n = 8). Mice in the YC and AC groups were fed an alanine-rich diet (3.4%), and mice in the AMI group received an isonitrogenous leucine-supplemented (5%) diet in combination with combined aerobic (30 minutes swimming) and resistance exercise training (incremental jumping submersed in water with overload corresponding to 40%-50% body weight) for a total of 4 weeks. The gastrocnemius muscles were dissected for western blotting detection (signaling proteins involved in MPS) and the ex vivo determination of protein synthesis and protein content. The muscle strength of the hind limbs was measured pre-experiment and repeated once per week on Sunday for 4 weeks. Mice in the AC and AMI groups showed lower ex vivo protein synthesis, protein content, expression of signaling proteins involved in MPS, maximal grip strength but higher plasma cortisol compared with the YC group post intervention. When compared to AC mice, the multimodal treatment led to lower activity of Sestrin2, higher expression of PI3K III and the phosphorylation of mTOR, p70S6K and 4E-BP1, as well as higher plasma leucine, wet gastrocnemius muscle weight and muscle weight to body weight ratio. Furthermore, the multimodal intervention induced more pronounced anabolic response such as higher ex vivo protein synthesis rate, total protein content, and myofibrillar fractions in gastrocnemius muscle, and greater maximum grip strength. The present research shows that a multimodal intervention including combined both aerobic and resistance exercise training and 5% leucine supplementation has the potential to maintain skeletal muscle protein synthesis and attenuate losses in muscular strength during the aging process.

[A clinical analysis of 22 patients with drug-induced liver injury caused by traditional Chinese medicine Periploca forrestii Schltr].

Objective: To investigate the clinical features, diagnosis, treatment, and prognosis of patients with liver injury caused by Periploca forrestii Schltr. Methods: A retrospective analysis was performed for the general data, clinical manifestations, and laboratory examinations of 22 patients who were diagnosed with liver injury caused by Periploca forrestii Schltr. from November 2014 to December 2015, and their clinical type was determined according to the classification criteria of drug-induced liver injury recommended by the Council for International Organizations of Medical Sciences. Results: There were 12 female and 10 male patients. The mean medication time ranged from 1 week to 2 months, and as for biochemical markers, there were mainly abnormalities in alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin(TBil), alkaline phosphatase(ALP), and gamma-glutamyl transpeptidase(GGT). ALT and AST increased in all the patients, with mean levels of 676.68±481.11 U/L and 527.36±361.14 U/L, respectively; TBil increased to a mean level of 170.26±147.30 µmol/L in 19 patients; ALP increased to a mean level of 135.61±59.26 U/L in 13 patients; GGT increased to a mean level of 195.65±138.48 U/L in 20 patients. As for clinical typing, 18 patients had liver cell injury, none had cholestasis, 3 had a mixed type, and 1 had an unclassified type. One patient died and all the other patients fully recovered. Conclusion: Periploca forrestii Schltr. had complex constituents, and liver injury caused by this drug is mainly liver cell injury. The pathogenesis of liver injury caused by Periploca forrestii Schltr. is presumed to be related to patients' idiosyncratic reaction to its constituents.