Objective:To investigate the pharmacokinetics of cerebrospinal fluid pemetrexed following intrathecal injection chemotherapy in patients with leptomeningeal metastasis (LM) from lung adenocarcinoma and provide a basis for clinical intrathecal injection chemotherapy.Methods:A total of 21 patients with lung adenocarcinoma LM who underwent pemetrexed intrathecal injection chemotherapy via Ommaya capsule at Nanjing Drum Tower Hospital, Aiffilitated Hospital of Nanjing University Medical School from November 2019 to November 2022 were collected, and divided into 30, 40 and 50 mg groups ( n=10, n=4, n=7) according to pemetrexed dose. Cerebrospinal fluid was collected at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy, and day 8 of each cycle for three groups. Reversed phase high performance liquid chromatography was used to determine the drug concentration in cerebrospinal fluid, to clarify the drug-related pharmacokinetic parameters, and to compare the differences in pemetrexed concentration among groups. Finally, cerebrospinal fluid pemetrexed concentration changes were observed and compared after different intrathecal injection chemotherapy cycles. Results:There were statistically significant differences in cerebrospinal fluid drug concentrations of patients in three groups at 0, 0.5, 1, 2, 4, 6, 12, 24 and 48 h after the first intrathecal injection chemotherapy (30 mg group: F=20.56, P<0.001; 40 mg group: F=27.06, P<0.001; 50 mg group: F=28.63, P<0.001), and there were statistically significant differences in the concentration of cerebrospinal fluid drugs in each dose group at 0.5, 1, 2, 4, 6 and 12 h compared to 0 h after intrathecal injection chemotherapy (all P<0.05). Compared to the 30 mg group, cerebrospinal fluid drug concentrations in the 50 mg group increased at 1, 2, 4, 6, 12 and 24 h after intrathecal injection chemotherapy, with statistically significant differences (all P<0.05). Pharmacokinetic analysis of cerebrospinal fluid pemetrexed showed that area under the concentration-time curve (AUC) 0-∞ of the 30, 40 and 50 mg groups were (5 696.12±283.32), (7 886.29±396.57), and (14 202.70±440.19) h·mg/L, respectively, with a statistically significant difference ( F=1 159.00, P<0.001) ; AUC 0-∞ increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; AUC 0-∞ increased in the 40 mg group compared to the 30 mg group ( P<0.05). The half-lives of three groups were (8.75±0.23), (11.29±0.59) and (16.42±1.23) h, respectively, with a statistically significant difference ( F=206.80, P<0.001) ; half-life was longer in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; half-life was longer in the 40 mg group compared to the 30 mg group ( P<0.05). The peak time of three groups were (1.55±0.10), (1.00±0.01), (1.43±0.11) h, respectively, with a statistically significant difference ( F=48.11, P<0.001) ; the peak time was shorter in the 40 and 50 mg groups compared to the 30 mg group (both P<0.05). Clearance of three groups were (7.02±2.46), (5.80±1.25) and (3.66±1.32) L/h, respectively, with a statistically significant difference ( F=6.02, P=0.009) ; clearance was decreased in the 50 mg group compared to the 30 mg group ( P<0.05). The peak concentration of three groups were (540.45±32.25), (820.75±46.47) and (1 014.78±64.96) mg/L, respectively, with a statistically significant difference ( F=207.70, P<0.001) ; peak concentration increased in the 50 mg group compared to the 30 and 40 mg groups (both P<0.05) ; peak concentration increased in the 40 mg group compared to the 30 mg group ( P<0.05). Cerebrospinal fluid drug concentrations were dynamically monitored after 4 cycles of intrathecal injection chemotherapy, in which cerebrospinal fluid pemetrexed concentrations in 30 mg group were (13.76±4.79), (11.41±7.08), (9.41±2.59) and (7.86±4.02) mg/L, respectively; 40 mg group were (14.45±6.59), (12.87±15.73), (11.24±2.48) and (9.09±3.38) mg/L, respectively; 50 mg group were (12.94±10.34), (9.72±7.62), (8.15±8.17) and (4.34±4.21) mg/L, respectively. There was a statistically significant difference in cerebrospinal fluid drug concentrations among different intrathecal injection chemotherapy cycles in 30 mg group ( F=4.04, P=0.016), and the cerebrospinal fluid drug concentration decreased in cycles 3 and 4 compared to cycle 1 (both P<0.05). There were no statistically significant differences in cerebrospinal fluid drug concentrations among different treatment cycles in 40 and 50 mg groups ( F=0.28, P=0.837; F=3.57, P=0.066) . Conclusion:Reversed phase high performance liquid chromatography method can effectively detect the pemetrexed concentration in cerebrospinal fluid; dynamic monitoring of cerebrospinal fluid pemetrexed concentration can provide a basis for the dosage and the treatment cycle of intrathecal injection chemotherapy in LM patients with lung adenocarcinoma.

Objective Drug resistance is the main cause of chemotherapy failure in hepatocellular carcinoma (HCC), and thioredoxin reductase 1 (TXNRD1), as a major influencing factor for reactive oxygen species (ROS) metabolism, has been proven to be associated with the poor prognosis of patients with HCC. This study aims to explore the role of TXNRD1 in the mechanism of multidrug resistance in HCC. Methods BEL/FU cells in BEL-7402 cell line were selected as the multidrug-resistant cell line. The siRNA was used for the intervention of TXNRD1 expression; quantitative real-time PCR and Western blotting were used to measure the expression of TXNRD1; CCK-8 assay and flow cytometry were used to evaluate the effect of TXNRD1 on hepatocyte ROS accumulation, resistance to 5-fluorouracil (5-Fu) and doxorubicin (DOX), and apoptosis in vitro; a xenograft tumor model was established to investigate the effect of auranofin (AUR) on drug resistance in vivo. The two-independent-samples t test was used for comparison of continuous data between two groups. Results As a multidrug-resistant HCC cell line, BEL/Fu showed high mRNA and protein expression levels of TXNRD1 (both P < 0.05). Compared with 5-Fu or DOX treatment alone, the TXNRD1 inhibitor AUR combined with 5-Fu or DOX had had a significant reduction in the number of colony formation ( P < 0.01) and a significant increase in apoptosis ratio ( P < 0.001). The ROS scavenger N-acetylcysteine (NAC) significantly weakened the effect of TXNRD1 knockdown by siRNA on the drug resistance of BEL/Fu cells, and the application of NAC effectively reduced the apoptosis ratio of cells after siRNA interference ( P < 0.001). Animal experiments also confirmed that compared with the nude mice treated with 5-Fu alone, the nude mice treated with 5-Fu and AUR had a significantly lower tumor mass ( P < 0.001) and a significantly smaller tumor volume ( P < 0.001). Conclusion TXNRD1 plays an important role in the drug resistance of HCC, and inhibition of its level in cells can effectively improve drug resistance. As a TXNRD1 inhibitor, AUR has great application prospects in the multimodality therapy for HCC.

Hepatocellular carcinoma is one of the common causes of tumor-related death, and it has high morbidity and mortality rates in China. Recent studies have shown that platelets are closely associated with the development of hepatocellular carcinoma. Literature review shows that platelets not only participate in hemostasis, but also act on liver cells and tumor microenvironment, promote the formation of new blood vessels, and participate in the development and progression of hepatocellular carcinoma as a cell mediator through immune response and other pathways. In addition, platelets and their derivatives can be used as potential therapeutic targets for hepatocellular carcinoma. Therefore, antiplatelet therapy is expected to become a new adjuvant strategy for the treatment of hepatocellular carcinoma, which has important clinical significance.

Objective:To explore the consistency of peripheral whole blood and venous serum procalcitonin (PCT) levels, and the value of peripheral whole blood PCT in evaluating pediatric bacterial infection.Methods:This multicenter cross-sectional parallel control study was conducted in 11 children′s hospital. All the 1 898 patients older than 28 days admitted to these hospitals from March 2018 to February 2019 had their peripheral whole blood and venous serum PCT detected simultaneously with unified equipment, reagent and method. According to the venous serum PCT level, the patients were stratified to subgroups. Analysis of variance and chi-square test were used to compare the demographic characteristics among groups. And the correlation between the peripheral blood and venous serum PCT level was investigated by quantitative Pearson correlation analysis.The PCT resultes were also converted into ranked data to further test the consistency between the two sampling methods by Spearman′s rank correlation test. Furthermore, the ranked data were converted into binary data to evaluate the consistency and investigate the best cut-off of peripheral blood PCT level in predicting bacterial infection.Results:A total of 1 898 valid samples were included (1 098 males, 800 females),age 27.4(12.2,56.7) months. There was a good correlation between PCT values of peripheral whole blood and venous serum ( r=0.97 , P<0.01). The linear regression equation was PCT?venous serum=0.135+0.929×PCT peripheral whole blood. However, when stratified to 5 levels, PCT results showed diverse and unsatisfied consistency between the two sampling methods ( r=0.51-0.92, all P<0.01). But after PCT was converted to ordinal categorical variables, the stratified analysis showed that the coincidence rate of the measured values by the two sampling methods in each boundary area was 84.9%-97.1%. The dichotomous variables also showed a good consistency (coincidence rate 96.8%-99.3%, Youden index 0.82-0.89). According to the severity of disease, the serum PCT value was classified into 4 intervals（<0.5、0.5-<2.0、2.0-<10.0、≥10.0 μg/L）, and the peripheral blood PCT value also showed a good predictive value (AUC value was 0.991 2-0.997 9). The optimal cut points of peripheral whole blood PCT value 0.5、1.0、2.0、10.0 μg/L corresponding to venous serum PCT values were 0.395, 0.595, 1.175 and 3.545 μg/L, respectively. Conclusions:There is a good correlation between peripheral whole blood PCT value and the venous serum PCT value, which means that the peripheral whole blood PCT could facilitate the identification of infection and clinical severity. Besides, the sampling of peripheral whole blood is simple and easy to repeat.

Objective:To explore a method of improving the nursing service ability after total hip arthroplasty (THA) among nurses in villages and towns medical health institutions under the county medical community model and to evaluate its effects.Methods:From June 1 2018 to September 30 2019, we took Department of Orthopedics, Dazhu County People's Hospital of Dazhou of Sichuan Province, as the core, and united with county medical community built by villages and towns medical health institutions with the country in organizing the nursing theoretical knowledge and specialist service ability training after THA for 140 nurses of villages and towns medical health institutions within county medical community. Before and after training, we carried out the theoretical test and practice ability test in trainers, and implemented the consistency analysis in scores of nursing assessment scales for specialist service so as to evaluate the subjective training effect. We also compared the incidence of postoperative complications, functional recovery of hip joint as well as the satisfaction among 30 THA patients before (October 2017 to September 2018) and after (October 2018 to September 2019) training so as to explore the clinical effect.Results:Before and after training, scores of theoretical achievements of nurses of villages and towns medical health institutions were 60 (56, 62) and 82 (79, 85) respectively, and scores of practice ability were 52 (47, 62) and 86 (81, 91) respectively with statistical differences ( P<0.01) . After training, the incidence of postoperative complications was lower than that before training (6.67% vs. 26.67%) ; the postoperative satisfaction, scores of Harris Hip Score (HHS) one month and three months after surgery were higher than those before training [90.00% vs. 66.67%, (73.1±6.00) vs. (57.6±6.67) , (86.6±4.49) vs. (74.5±6.20) ]among 30 THA patients with statistical differences ( P<0.05) . Conclusions:Training with the county medical community model can improve the nursing service ability of nurses in villages and towns medical health institutions among THA patients, postoperative function of hip joint of THA patients as well as patient satisfaction.

Objective To explore the functional properties of the brain's resting state networks in neonates with hypoxic ischemic encephalopathy.Methods Use the methods of functional MRI probabilistic tractography and graph theory to compare the global and local functional properties of the brain's resting state network between 12 cases of children with mild HIE and 14 cases of children with moderate/severe HIE.Results In terms of global topological properties,both the mild and moderate/severe group showed small-world properties.The γ and λ in the mild group were 2.450± 1.642 and 1.542±0.564 and in the moderate/severe group were 2.331± 1.554 and 1.353±0.672,respectively,which were in line with the characteristics of small-world properties (γ＞ 1 and λ ≈ 1).As far as local topological properties were concerned,the distribution of hub regions in the functional networks had smaller number of nodes in the moderate/severe group (8 nodes) than the mild group (14 nodes).The comparison of nodal efficiencies showed that the moderate/severe group had significantly reduced nodal efficiency in the left insula opercula,left supramarginal gyrus,left and right temporal pole and right middle temporal gyrus(the nodal efficiencies of the moderate/severe group:0.4089±0.0865,0.3377±0.1223,0.3842±0.0898,0.3508±0.1295,0.3564±0.0843;the nodal efficiencies of the mild group:0.4801±0.0762,0.4465±0.0898,0.4655 ±0.0812,0.4640±0.0690,0.4271±0.0636,all P＜0.05).Conclusion The topological structure of resting state functional network in children with moderate and severe hypoxic-ischemic encephalopathy is obviously backward than that in children with mild hypoxic-ischemic encephalopathy,which may be related to abnormal language,movement and cognitive function in the late stage.

Objective To compare and analyze the event related potential ( ERP ) and behavioral characteristics of sleep disordered breathing ( SDB ) and normal children by the persistent operating test ( CPT-AX) task,and to explore the characteristics and neural mechanism of the cognitive deficits in the left and right brain of school age SDB children. Methods SDB children( n=20) and normal children( n=20) aged 6-8 were selected. All subjects were tested by CPT-AX ( Go/Nogo task) . The ERP behavior of SDB and normal children was recorded,and the N2,P3 amplitude and latency of F3,Fz,F4 lead were compared. Re-sults ( 1) There was no significant difference between SDB group and normal group in behavioral correct number (36. 45±4. 69 vs 35. 00±3. 46),the reaction time ((516. 84±54. 14)ms vs (496. 94±78. 89)ms) and false alarm number( 1. 0 ( 0. 25,3. 75) vs 0. 5 ( 0. 00,3. 00) ) ( all P>0. 05) . ( 2) Comparison of F3,Fz and F4 lead:(1) SDB group:there was no significant difference in Go-N2 amplitude (-7. 75(-12. 03,-1. 09)μV vs (-8. 69±5. 72) μV vs ( -7. 12±4,68)μV) and Nogo-N2 amplitude((-10. 72±4. 49)μV vs (-12. 16±4. 60) μV vs (-11. 78±4. 44) μV) in the left,middle,and right of frontal regions. (2) Control group:there was no statistical difference between F3 and Fz ((-7. 26±3. 18)μV vs (-9. 09±3. 11)μV)(P>0. 05) in N2 amplitude and there was no statistical difference between F3 and F4((-7. 26±3. 18) μV vs (-6. 10±3. 36)μV) in N2 amplitude (P>0. 05). The N2 amplitude difference of Fz and F4 ((-9. 09± 3. 11) μV vs (-6. 10±3. 36)μV ) was statistically significant (P<0. 05). The Nogo-N2 amplitude differ-ence between F3 and Fz((-14. 05±3. 31) μV vs (-15. 50±3. 52) μV) was no statistically significant (P>0. 05) . The left frontal lobe Nogo-N2 amplitude was significantly higher than that of the right frontal lobe ((-14. 05±3. 31) μV vs-11. 75(-12. 68,-10. 43) μV) (P<0. 05),and the center of the frontal lobe No-go-N2 was significantly higher than that in the right frontal lobe((-15. 50±3. 52) μV vs -11. 75(-12. 68,-10. 43) ) ,and the difference was statistically significant (P<0. 05) . ( 3) There was no significant difference in N2 latency,P3 amplitude and latency between F3,Fz and F4 leads (P>0. 05). Conclusion Compared with normal children,SDB children showed no left dominant brain region while dealing with the same conflict monitoring tasks. It is suggested that left hemisphere activation is poor and function is incompatible. Left fron-tal lobe injury in SDB is more obvious than that in the right side.

Objective To explore the characteristics of functional connectivity based on cerebellum at resting state and the brain functions related to cognitive function on attention deficit hyperactivity disorder (ADHD).Methods Thirty ADHD children (ADHD group) were diagnosed at ADHD Specialist Clinic of Changzhou Children's Hospital,Nantong University from June 2015 to July 2017,and 33 healthy children (healthy control group) were selected from a normal school in Changzhou.Then,they received the functional and structural magnetic resonance imaging (MRI)scans.Finally,the differences of the characteristics of functional connectivity were compared between the 2 groups based on cerebellum which had been found with dysfunction on the previous study of amplitude of low-frequency fluctuation.Results It all showed positive activated brain regions when comparing ADHD group and healthy control group based on left cerebellum (-49.5,-58.5,-18.5) as ADHD children's functional connectivity scores were higher in left middle frontal gyrus [volume =835 mm3,coordinate (-27,-21,51)],right middle frontal gyrus [volume =755 mm3,coordinate(45,-3,6)],right superior temporal gyrus [volume =256 mm3,coordinate (45,-24,-6)],left limbic lobe[volume =513 mm3,coordinate (-15,-3,-18)],and there were statistically significant differences between the 2 groups (t =4.10,4.38,3.97,3.32,all P ＜ 0.05).Conclusions There exist abnormal functional connectivity between cerebellum and left middle frontal gyrus,right middle frontal gyrus,right superior temporal gyrus and left limbic lobe.It may be one of the brain mechanisms of the main clinical manifestations of the decreasing of attention,hyperactivity and impulsiveness and the dysfunction of cognitive function.

Objective To investigate the characteristics of cognitive development of children with attention deficit hyperactivity disorder (ADHD) by using resting-state functional magnetic resonance imaging (fMRI) degree centrality (DC) from the view of neuro-imaging.Methods Forty-five ADHD children were diagnosed at specialist clinic of Changzhou Children's Hospital,Nantong University from June 2015 to December 2016,and they were divided into 3 groups according to their ages (children aged 7-8 years old,9-10 years old and 11-12 years old,15 children in each group) and received the resting-state fMRI scans.DC value was used to analyze fMRI data.Comparative analysis was done pairwise between the three groups.Results Compared with 7-8 years old group,9-10 years old group showed lower DC value in cerebellum posterior lobe (t =-4.36) and higher DC in inferior parietal lobe (t =-5.86),and the differences were statistically significant (all P ＜ 0.05,after correction).Compared with 7-8 years old group,11-12 years old group showed lower DC value in cerebellum posterior lobe (t =-4.99) and higher DC in left superior temporal gyrus (t =5.18) and superior frontal gyrus (t =4.58),and the differences were statistically significant (all P ＜ 0.05,after correction).Compared with 9-10 years old group,11-12 years old group showed lower DC value in inferior parietal lobe (t =-5.71) and higher DC value in left superior temporal gyrus (t =5.05) and superior frontal gyrus (t =4.36),and all the differences were statistically significant (all P ＜ 0.05,after correction).Conclusion Children with ADHD at different ages had different characteristics of brain regions of fMRI.It can offer objective evidence for early cognitive intervention of children with ADHD at different ages.