[Clinical analysis of adverse reactions in patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis treated with delamanid-containing regimen].

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

[Analysis of the efficacy and safety of pulsed radiofrequency for the treatment of thoracic postherpetic neuralgia in elderly patients with different pain phenotypes].

Objective: To analyze the efficacy and safety of pulsed radiofrequency (PRF) for the treatment of thoracic postherpetic neuralgia (PHN) in elderly patients with different pain phenotypes. Methods: A total of 201 elderly thoracic PHN patients, including 110 males and 91 females aged (72.2±6.9) years who received high-voltage, long-duration PRF at the dorsal root ganglion at Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine from January 2020 to December 2022, were retrospectively included. The neuropathic pain symptom inventory (NPSI) was used to evaluate the five different pain phenotypes, which included superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia, and to analyze the distribution of the five pain phenotypes. The numerical rating scale (NRS) and NPSI scores of all patients were compared before treatment and three months after treatment to evaluate the efficacy and safety of PRF for different pain phenotypes and pain phenotype combinations. Results: All patients had two or more pain phenotypes, and 50.2% (101/201) of the patients had five pain phenotypes at the same time. Compared with those before treatment, three months after treatment, the NPSI scores for superficial spontaneous pain, deep spontaneous pain, paroxysmal pain, evoked pain and paresthesia/dysesthesia decreased (all P<0.05), and the scores decreased byï¼»M（Q1，Q3）］3.0 (2.0, 4.0), 1.5 (0.5, 2.5), 3.0 (2.5, 4.0), 2.3 (1.0, 4.0), and 1.0 (0.5, 2.0) points, respectively, the differences were statistically significant (P<0.001). The decrease in the NPSI score in patients with paroxysmal pain was greater than that in patients with the other 4 pain phenotypes (all P<0.05). After treatment, the NRS score decreased by 4.0 (3.0, 5.0), 4.0 (3.0, 5.0), 4.0 (3.0, 5.0) and 5.0 (4.0, 6.0) points in patients with 2, 3, 4 and 5 pain phenotypes, respectively, and the difference was statistically significant (P<0.001). The decrease in the NRS score was greater in patients with a combination of 5 pain phenotypes than that in patients with a combination of 3 and 4 pain phenotypes (all P<0.05). No complications, such as pneumothorax, haematoma or infection, occurred in any of the patients during treatment. Conclusion: PRF has different therapeutic effects on PHN patients with different pain phenotypes, it has the best effect on paroxysmal pain, and the treatment is safe.

Adherence to guidelines and central-line-associated bloodstream infection occurrence during insertion and maintenance of intravascular catheters: evidence from 20 tertiary hospitals.

OBJECTIVE: To investigate adherence to intravascular catheter (IVC) insertion and maintenance guidelines in Chinese tertiary hospitals. METHODS: A cross-sectional questionnaire survey of adult inpatients with IVC placements was conducted from July to September 2022 in 20 tertiary hospitals in China. One clinical staff member from each department in each hospital was assigned to participate in the survey. Questionnaires were uniformly collected and reviewed after three months. RESULTS: This study included 1815 cases (62.69%) of central venous catheter, 471 cases (16.27%) of peripherally inserted central catheter, 461 cases (15.92%) of PORT, and 147 cases (5.08%) of haemodialysis catheter insertions. Statistically significant differences in compliance were observed across the four IVC types, specifically in relation to the insertion checklist, standard operating procedure, and insertion environment (P<0.05). Practice adherence during IVC maintenance differed significantly across the four IVC types in aspects such as availability of IVC maintenance verification forms, daily scrubbing of the catheterized patients, and catheter connection methods (P<0.05). A total of 386 (13.34%) patients developed fever, 1086 (37.53%) were treated with therapeutic antibiotics, 16 (0.55%) developed central-line-associated bloodstream infections, two (0.07%) developed local skin infections, and six (0.21%) developed deep vein thrombosis. CONCLUSIONS: Adherence to guidelines regarding insertion and maintenance differed across the four IVC types; there is a gap between the recommended measures and the actual operation of the guidelines. Therefore, it is necessary to further enhance training and develop checklists to prevent central-line-associated bloodstream infections.

[Preliminary studies on the role of mast cells in the phenotype and immune activation of type 2 inflammatory cytokine release of atopic dermatitis].

Objective: To investigate the role of mast cells in atopic dermatitis (AD) phenotype and the immune activation of type 2 inflammatory cytokine release. Methods: Nine AD skin samples were obtained from the Department of Dermatology, the Second Affiliated Hospital of Xi'an Jiaotong University, and nine healthy skin control samples were obtained from the surgical excision of excess normal skin by orthopedic surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, which were subjected to toluidine blue staining and fluorescence staining to clarify the mast cell degranulation activation status of the AD skin lesions. We investigated whether MC903 could directly activate mast cells in vivo through the toe swelling and exudation assay in wild-type mice; we constructed the MC903-AD model using wild-type and KitW-sh/W-sh mast cell-deficient mice in order to investigate whether mast cells affected the phenotype, histopathology, and the level of type 2 inflammatory factors in AD mice; we extracted mouse peritoneal mast cells and the ability of MC903 to activate mast cells to release inflammatory mediators in vitro was explored by calcium imaging, tryptase and ß-aminohexokinase release assays, and MCP-1 and CXCL-2 release assays. Results: The number of degranulated mast cells in an activated state was increased in skin lesions of AD patients compared to healthy controls, with (5.40±1.14) and (2.20±0.84), respectively (P<0.001). KitW-sh/W-sh mast cell-deficient AD mice had an attenuated phenotype with ADI scores of (5.50±1.05), compared to wild-type AD mice with (10.00±0.89) (P<0.001). The release of type 2 inflammatory factors in wild-type AD mice was higher than those in KitW-sh/W-sh mast cell-deficient AD mice, with IL-4 levels of (29.50±1.87) and (15.33±1.86) pg/mg (P<0.001), IL-13 levels were (6.32±0.25) and (3.93±0.22) pg/mg (P<0.001), IL-31 levels were (9.73±0.38) and (6.89±0.27) pg/mg (P<0.001), and TSLP levels were (206.00±4.43) and (99.00±4.86) pg/mg (P<0.001), respectively. MC903 could cause mast cell activation in wild-type mice, leading to increased swelling and exudation in the toes of mice, and MC903 could activate mast cells in vitro, leading to increased degranulation and release of inflammatory factors such as MCP-1 and CXCL-2. Conclusions: The number of activated mast cells was increased in skin lesions of AD patients than in healthy controls. KitW-sh/W-sh mast cell-deficient AD mice showed significantly reduced phenotype, histopathology, and type 2 inflammatory factor levels compared with wild-type AD mice. MC903 activates mast cells in vivo and in vitro. Mast cells play a key role in AD phenotype and immune activation.

[Efficacy and safety of modified Hartel approach in the treatment of primary trigeminal neuralgia with radiofrequency thermocoagulation].

Objective: To assess the efficacy and safety of modified Hartel approach in the treatment of primary trigeminal neuralgia with radiofrequency thermocoagulation. Methods: A total of 89 patients with primary trigeminal neuralgia in Nanjing Drum Tower Clinical College of Xuzhou Medical University from July 2021 to July 2022 were prospectively included, and were divided into experimental group (n=45, modified Hartel approach: selecting 2.0 cm lateral to and 1.0 cm below angulus oris as insertion point) and control group (n=44, traditional Hartel approach: selecting 2.5 cm lateral to the angulus oris as insertion point) according to the random number table method. There were 19 males and 26 females in the experimental group, and aged (67.6±8.8) years. Meanwhile, there were 19 males and 25 females in the control group, and aged (64.8±11.7) years. All the patients were treated by CT-guided radiofrequency thermocoagulation. The success rate of one-time puncture, number of punctures, the time of puncture, operation time, numerical rating scale (NRS) scores and complications were recorded and compared between the two groups. Results: The success rate of one-time puncture in experimental group was 64.4% (29/45), which was higher than that in control group 31.8% (14/44) (P<0.05). The number of punctures [M (Q1, Q3)], the time of puncture [M (Q1, Q3)] and operation time in the experimental group were 1 (1, 2), 218 (206, 378) s, (19.9±2.7) min, which were less than those of control group [2 (1, 3), 390 (231, 598) s, (27.0±3.9) min] (all P<0.05). The NRS scores [M (Q1, Q3)] of 1 day, 1 month and 3 months after surgery in the experimental group were 1 (1, 2), 1 (0, 2) and 1(0, 1), respectively, which were lower than the baseline level [6 (6, 7)] (all P<0.05). The NRS scores [M (Q1, Q3)] of 1 day, 1 month and 3 months after surgery in the control group were 1 (1, 2), 1 (0, 2) and 1 (0, 2), respectively, which were lower than the baseline level [6 (6, 7)] (all P<0.05). There was no statistically significant difference in the incidence of nausea and vomiting, facial numbness, and decreased masticatory muscle strength between the two groups (all P>0.05) In the experimental group, two patients had puncture needles into the oral cavity, with timely detection and replacement of puncture needles, and no infection occurred. There was no cerebrospinal fluid leakage and decreased corneal reflex in both groups. Conclusion: The modified Hartel approach can significantly improve the success rate of one-time puncture via foramen ovale, reduce the operation time and the incidence of postoperative facial swelling, which is a safe and effective puncture method.

Sinomenine ameliorates adjuvant-induced arthritis by inhibiting the autophagy/NETosis/inflammation axis.

Studies have found that neutrophil extracellular traps (NETs) which are the specific dying form of neutrophil upon activation have fundamental role in the rheumatoid arthritis onset and progression. The purpose of this study was to explore the therapeutic effect of Sinomenine on adjuvant-induced arthritis in mice, and the neutrophil activities regulated by Sinomenine. The rheumatoid arthritis model was established by local injection of adjuvant and the Sinomenine treatment was administered orally for 30 days, during which, arthritic scores were evaluated and the joint diameter was measured to determine disease progression. The joint tissues and serum were acquired for further tests after sacrifice. Cytometric beads assay was performed to measure the concentration of cytokines. For paraffin-embedded ankle tissues, hematoxylin and erosin staining and Safranin O-fast staining were adopted to monitor the tissue changes of joint. In order to analyze the inflammation, NETs and autophagy of neutrophils in vivo, immunohistochemistry assays were applied to detect the protein expression levels in the local joints. To describe the effect brought by Sinomenine on inflammation, autophagy and NETs in vitro, the western blotting and the immunofluorescence assays were performed. The joint symptoms of the adjuvant induced arthritis were alleviated by the Sinomenine treatment significantly in terms of the ankle diameter and scores. The improvement of local histopathology changes and decrease of inflammatory cytokines in the serum also confirmed the efficacy. The expression levels of interleukin-6, P65 and p-P65 in the ankle areas of mice were remarkably reduced by Sinomenine. Compared with the model group, the decreased expression levels of lymphocyte antigen 6 complex and myeloperoxidase in the Sinomenine treating group showed the inhibitory effect of Sinomenine on the neutrophil migration. The expression of protein arginine deiminase type 4 (PAD4), ctrullinated histone H3 (CitH3) and microtubule-associated protein 1 light chain 3B (LC3B) had the similar tendency. Upon activation of lipopolysaccharide (LPS) in vitro, Sinomenine suppressed the phosphorylation of P65, extracellular signal-regulated kinase (ERK) and P38 of neutrophil. Meanwhile, Sinomenine inhibited NETs formation induced by phorbol 12-myristate 13-acetate (PMA), which were demonstrated by the decreased expression of neutrophil elastase (NE), PAD4 and CitH3. Sinomenine also inhibited PMA-induced autophagy in vitro based on the changes of Beclin-1 and LC3B. Sinomenine has good efficacy in treating adjuvant induced arthritis via regulating neutrophil activities. Apart from inhibiting activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, the mechanism includes suppression of NETs formation via autophagy inhibition.

Relationship of resting heart rate and blood pressure with all-cause and cardiovascular disease mortality.

OBJECTIVES: This study aimed to investigate associations of resting heart rate (RHR) and blood pressure (BP) with all-cause and cardiovascular disease (CVD) mortality. STUDY DESIGN: A retrospective cohort study. METHODS: A total of 67,028 Chinese participants aged ≥60 years were included in the analysis. RHR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were evaluated according to quartiles ([41-69, 70-74, 75-79, 80-127 beats/min], [80-119, 120-129, 130-139, 140-238 mm Hg], and [40-70, 71-79, 80-84, 85-133 mm Hg]). Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and CVD mortality with RHR, SBP, and DBP. Restricted cubic splines were used to evaluate the dose-response association. RESULTS: During the 361,975 person-year follow-up, 9326 deaths were recorded, of which 5039 deaths were due to CVD. The risk of all-cause mortality was increased by 25% with the quartiles four vs quartile one of RHR (HR [95% CI]:1.25 [1.17-1.33]), and CVD mortality was increased by 32% (HR [95% CI]: 1.32 [1.22-1.44]). Similar results were observed when comparing the quartiles four vs quartile one of SBP with the risk of all-cause and CVD mortality (HRs [95% CIs]: 1.14 [1.07, 1.22] and 1.23 [1.12. 1.34]) and DBP with the risk of all-cause and CVD mortality (HRs [95% CIs]: 1.17 [1.11. 1.24] and 1.36 [1.26. 1.47]). We found linear associations of RHR, SBP, and DBP with all-cause and CVD mortality (Pnon-linearity >0.05), except for the approximately J-shaped association between DBP and all-cause mortality (Pnon-linearity = 0.008). There was a significant interaction of RHR and SBP with all-cause and CVD mortality (Pinteraction <0.05). CONCLUSIONS: RHR and BP increased the risk of all-cause and CVD mortality, especially fast RHR combined with high SBP.

The efficacy and safety of dupilumab in Chinese patients with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Dupilumab is an antibody against interleukin-4 receptor α, used in the treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult Chinese patients with moderate-to-severe AD. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator's Global Assessment score of 0-1 and a reduction from baseline of ≥ 2 points at week 16. RESULTS: Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint [difference 22·0%, 95% confidence interval (CI) 11·37-32·65; P < 0·001]. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75-55·97; P < 0·001) and had ≥ 3-point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26-55·34; P < 0·001) and ≥ 4-point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69-45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment-emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group. CONCLUSIONS: In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile.

MRI Signal Intensity and Electron Ultrastructure Classification Predict the Long-Term Outcome of Skull Base Chordomas.

BACKGROUND AND PURPOSE: MR imaging is a useful and widely used evaluation for chordomas. Prior studies have classified chordomas into cell-dense type and matrix-rich type according to the ultrastructural features. However, the relationship between the MR imaging signal intensity and ultrastructural classification is unknown. We hypothesized that MR imaging signal intensity may predict both tumor ultrastructural classification and prognosis. MATERIALS AND METHODS: Seventy-nine patients with skull base chordomas who underwent 95 operations were included in this retrospective single-center series. Preoperative tumor-to-pons MR imaging signal intensity ratios were calculated and designated as ratio on T1 FLAIR sequence (RT1), ratio on T2 sequence (RT2), and ratio on enhanced T1 FLAIR sequence (REN), respectively. We assessed the relationships among signal intensity ratios, ultrastructural classification, and survival. RESULTS: Compared with the matrix-rich type group, the cell-dense type chordomas showed lower RT2 (cell-dense type: 1.90 ± 0.38; matrix-rich type: 2.61 ± 0.60 P < .001). The model of predicting cell-dense type based on RT2 had an area under the curve of 0.83 (95% CI, 0.75-0.92). In patients without radiation therapy, both progression-free survival (P = .003) and overall survival (P = .002) were longer in the matrix-rich type group than in the cell-dense type group. REN was a risk factor for progression-free survival (hazard ratio = 10.24; 95% CI, 1.73-60.79); RT2 was a protective factor for overall survival (hazard ratio = 0.33; 95% CI, 0.12-0.87); and REN was a risk factor for overall survival (hazard ratio = 4.76; 95% CI, 1.51-15.01). CONCLUSIONS: The difference in MR imaging signal intensity in chordomas can be explained by electron microscopic features. Both signal intensity ratios and electron microscopic features may be prognostic factors.

[An interlaboratory comparison study on the detection of RUNX1-RUNX1T1 fusion transcript levels and WT1 transcript levels].

Objective: To investigate the current status and real performance of the detection of RUNX1-RUNX1T1 fusion transcript levels and WT1 transcript levels in China through interlaboratory comparison. Methods: Peking University People's Hospital (PKUPH) prepared the samples for comparison. That is, the fresh RUNX1-RUNX1T1 positive (+) bone morrow nucleated cells were serially diluted with RUNX1-RUNX1T1 negative (-) nucleated cells from different patients. Totally 23 sets with 14 different samples per set were prepared. TRIzol reagent was added in each tube and thoroughly mixed with cells for homogenization. Each laboratory simultaneously tested RUNX1-RUNX1T1 and WT1 transcript levels of one set of samples by real-time quantitative PCR method. All transcript levels were reported as the percentage of RUNX1-RUNX1T1 or WT1 transcript copies/ABL copies. Spearman correlation coefficient between the reported transcript levels of each participated laboratory and those of PKUPH was calculated. Results: ①RUNX1-RUNX1T1 comparison: 9 samples were (+) and 5 were (-) , the false negative and positive rates of the 20 participated laboratories were 0 (0/180) and 5% (5/100) , respectively. The reported transcript levels of all 9 positive samples were different among laboratories. The median reported transcript levels of 9 positive samples were from 0.060% to 176.7%, which covered 3.5-log. The ratios of each sample's highest to the lowest reported transcript levels were from 5.5 to 12.3 (one result which obviously deviated from other laboratories' results was not included) , 85% (17/20) of the laboratories had correlation coefficient ≥0.98. ②WT1 comparison: The median reported transcript levels of all 14 samples were from 0.17% to 67.6%, which covered 2.6-log. The ratios of each sample's highest to the lowest reported transcript levels were from 5.3-13.7, 62% (13/21) of the laboratories had correlation coefficient ≥0.98. ③ The relative relationship of the reported RUNX1-RUNX1T1 transcript levels between the participants and PKUPH was not always consistent with that of WT1 transcript levels. Both RUNX1-RUNX1T1 and WT1 transcript levels from 2 and 7 laboratories were individually lower than and higher than those of PKUPH, whereas for the rest 11 laboratories, one transcript level was higher than and the other was lower than that of PKUPH. Conclusion: The reported RUNX1-RUNX1T1 and WT1 transcript levels were different among laboratories for the same sample. Most of the participated laboratories reported highly consistent result with that of PKUPH. The relationship between laboratories of the different transcript levels may not be the same.

[A new exploration and consideration of Type A fracture of distal femur based on finite element biomechanical analysis].

Objective: To investigate the changes of internal fixation stress under different angles of interior fracture line and different screw placement modes in the case of A-type distal femoral fracture. Methods: A 24-year-old healthy male volunteer was recruited to collect the right femur data. CATIA V5R21 software produced a 10 mm fracture gap at the external side of the femur 6.5 cm proximal to the joint line and different angle fracture lines were generated on the internal of the femur at the same height. Based on the actual measured dimensions, the three-dimensional (3D) model of the locking plate and screw was reconstructed using CATIA V5R21 software, ignoring the screw surface threads and then the assembly of the internal fixation of the titanium plate, screws and femur was done. All models were meshed using Hypermesh 13.0 software. The assembled 3D model was input into ABAQUS 6.14 to generate a finite element model. Preliminary finite element biomechanical analysis was performed using the four medial fracture line angles and the stress distribution of the internal fixation under the three screw placement modes, and then the analysis was continued after the optimal screw placement method was re-determined. Results: Under an axial loading of 700 N, with the increase of the angle of the fracture line, the stress of the lateral internal fixation gradually increased, and the displacement of the proximal end of the fracture gradually increased. The sequential screw placement method was superior to the leaping screw placement method. The placement of the first screw at the proximal end of the fracture was critical to the distribution of the internal fixation stress. Conclusions: The operation plan of the type A of distal femoral fracture needs to be confirmed according to the internal and external fracture's condition. When the fracture line is at a excessive positive angle or a negative angle, a simple lateral fixation may not provide a stable fracture fixation so that other fixation methods are needed.

[Changes of WT1 mRNA expression level in patients with myelodysplastic syndromes after hypomethylating agents and its prognostic significance].

Objective: To monitor the WT1 mRNA level and its dynamic changes in patients with myelodysplastic syndromes (MDS) after hypomethylating agents (HMA) , as well as to assess the significance of WT1 mRNA levels and its dynamic changes in evaluating the efficacy of HMA and distinguishing the disease status of heterogeneous patients with stable disease (SD) . Methods: Bone marrow or peripheral blood samples of 56 patients with MDS who underwent hypomethylating agents (≥4 cycles) from November 2009 to March 2018 were tested by real-time quantitative polymerase chain reaction (PCR) to detect the expression of WT1 mRNA, and to observe the correlation between the dynamic changes of WT1 mRNA expression and clinical efficacy and prognosis of patients. Results: WT1 mRNA expression levels of MDS patients decreased significantly after 3 cycles of hypomethylating agent treatment. Besides, the WT1 mRNA expression levels of patients increased significantly after diseases progression. According to the dynamic changes of WT1 mRNA expression levels during SD, 45 cases could be further divided into increased group and non-increased group. In those SD patients with increased WT1 mRNA expression level, the ratio of suffering disease progression or transformation to AML was 95.65% (22/23) , whereas the ratio turned to be 9.09% (2/22) for the non-increased group (χ(2)=33.852, P<0.001) . Compared with those SD patients reporting no increase in WT1 mRNA expression level, the overall survival[17 (95%CI 11-23) months vs not reached, P<0.001] and progression-free survival [13 (95%CI 8-18) months vs not reached, P<0.001] of those SD patients reporting increase in WT1 mRNA expression level were significantly shorter. Conclusion: WT1 mRNA expression level is a useful indicator to assess the efficacy of hypomethylating agents in MDS patients. Especially in patients with SD, detection of the changes in WT1 mRNA expression level is able to predict disease progression and help to make clinical decision.

Parathyroid hormone independently predicts fracture, vascular events, and death in patients with stage 3 and 4 chronic kidney disease.

Doctors do not know whether treatment of high parathyroid hormone levels is linked to better outcomes in their patients with kidney disease. In this study, lower parathyroid hormone levels at baseline were linked to lower risk of fracture, vascular events, and death in people with kidney disease. PURPOSE: Chronic kidney disease (CKD) affects ~ 20% of older adults, and secondary hyperparathyroidism (HPT) is a common condition in these patients. To what degree HPT predicts fractures, vascular events, and mortality in pre-dialysis CKD patients is debated. In stage 3 and 4 CKD patients, we assessed relationships between baseline serum PTH levels and subsequent 10-year probabilities of clinical fractures, vascular events, and death. METHODS: We used Marshfield Clinic Health System electronic health records to analyze data from adult CKD patients receiving care between 1985 and 2013, and whose PTH was measured using a second-generation assay. Covariates included PTH, age, gender, tobacco use, vascular disease, diabetes, hypertension, hyperlipidemia, obesity, GFR, and use of osteoporosis medications. RESULTS: Five thousand one hundred eight subjects had a mean age of 68 ± 17 years, 48% were men, and mean follow-up was 23 ± 10 years. Fractures, vascular events, and death occurred in 18%, 71%, and 56% of the cohort, respectively. In univariate and multivariate models, PTH was an independent predictor of fracture, vascular events, and death. The hazards of fracture, vascular events and death were minimized at a baseline PTH of 0, 69, and 58 pg/mL, respectively. CONCLUSIONS: We found that among individuals with stage 3 and 4 CKD, PTH was an independent predictor of fractures, vascular events, and death. Additional epidemiologic studies are needed to confirm these findings. If a target PTH range can be confirmed, then randomized placebo-controlled trials will be needed to confirm that treating HPT reduces the risk of fracture, vascular events, and death.

[Artesunate attenuate chronic graft-versus-host disease by regulating Th17/Treg balance].

Objective: To investigate the effects of artesunate treatment on chronic graft-versus-host disease (cGVHD). Methods: Recipient BALB/c mice received 8 × 10(6) bone marrow cells with 8×10(6) spleen cells from B10D2 mice. Artesunate solubilized in acetone was injected intraperitoneally every day at the dose of 1 mg/kg at Day 28 after BMT. The clinical scores, survival and histopathological damage were analyzed. The frequency of Th17 and Tregs in PB and spleens from the mice were evaluated by flow cytometry. In addition, CD4(+) T cells from the spleens of mice were cultured in vitro, then stimulated with artesunate, the frequency of Th17 and Tregs in these splenocytes were evaluated by flow cytometry. Results: Artesunate administration diminished clinical and histopathological damage, and improved the survival of cGVHD mice[(46.57±7.83)% vs (55.71±6.99)%, χ(2)=5.457, P=0.020]; Artesunate contributed to Tregs development [(4.45±0.04)% vs (8.40±0.23)%, t=15.679, P<0.001; (6.62±0.24)% vs (10.48±0.48)%, t=6.587, P=0.003] while decreased Th17 cells [(1.51±0.18)% vs (0.58±0.19)%, t=7.233, P<0.001; (1.48±0.38)% vs (0.71±0.18)%, t=3.653, P=0.011] expressions in both PB and spleens, and decreased the Th17/Treg ratio (0.34±0.05 vs 0.09±0.03, t=7.621, P=0.002; 0.19±0.03 vs 0.06±0.02, t=6.993, P=0.002). Moreover, artesunate suppressed the Th17 cells expressions [(0.82±0.37) % vs (3.39±1.22) %, t=4.044, P=0.007] and contributed to Tregs development [(34.63±1.29) % vs (14.28±1.69) %, t=19.119, P<0.001], and also decreased the Th17/Treg ratio (0.24±0.09 vs 0.02±0.01, t=4.780, P=0.003) in vitro. Conclusions: Artesunate suppressed the Th17 cells expressions and contributed to Tregs development, which provided new sights into the development of a novel drug for cGVHD, e.g., artemisinin.

Species-specific aggregation pheromones contribute to coexistence in two closely related thrips species.

Pheromones play an important role in mediating interspecific interactions in insects. In an insect community, pheromones can reveal information about the senders, which could be used by other members of the food web (competitor, natural enemies, etc.) to their own advantage. The aggregation pheromones of two closely related thrips species, Frankliniella occidentalis and Frankliniella intonsa, have been identified with the same major compounds, (R)-lavandulyl acetate and neryl (S)-2-methylbutanoate, but in different ratios. However, the roles of the aggregation pheromones in the interspecific interactions between these two closely related species are unknown. Here, we investigated the roles of major aggregation pheromone compounds in interspecific interactions between F. occidentalis and F. intonsa for both long and short ranges. The results showed that, at tested doses, neither aggregation pheromone-induced long range cross-attraction nor short range cross-mating was detected between F. occidentalis and F. intonsa. Field-trapping trials showed that the species-specificity in aggregation pheromones was regulated by the ratio of two major compounds. However, species-specific blends of the two major compounds had no effect on short-range interactions between these two species. Our data from the thrips species provide support for the 'aggregation model of coexistence', explaining the species-specific pheromone-mediated coexistence of closely related species. Thus, species-specific pheromones could be one of the factors affecting population dynamics and community structure in closely related insects with similar niches.

Study on the relationship between changes of immune cells and TNF-α in peripheral blood of patients with multidrug-resistant and extensively drug-resistant tuberculosis.

OBJECTIVE: To investigate the relationship between changes in CD4- and CD8-positive immune cells and TNF-α in the peripheral blood of patients affected by multidrug-resistant and extensively drug-resistant tuberculosis. PATIENTS AND METHODS: 179 patients suffering from tuberculosis treated in the Chest Hospital of Hebei from April 2010 to December 2015 were selected for the study. There were 47 cases affected by drug-resistant tuberculosis and 132 cases affected by non-drug-resistant tuberculosis. The control group included 183 healthy subjects examined during the same period. ELISA was used to compare and analyze serum levels of TNF-α, CD4- and CD8-positive cell levels, and CD4/CD8 ratio in the two groups. RESULTS: CD4- and CD8-positive cell count, CD4/CD8 ratio, and serum TNF-a were significantly higher in patients with drug-resistant tuberculosis compared with healthy controls and the non-drug-resistant tuberculosis patients (p < 0.05). There was a positive correlation between TNF-α level and CD4/CD8 ratio (r=0.892, p < 0.05). Before treatment, the differences in the levels of TNF-a in the different groups of drug-resistant patients were insignificant (p >0.05). After treatment, the levels of TNF-a in the different groups of drug-resistant patients were decreased, except for patients with extensively drug-resistant tuberculosis, whose levels were significantly decreased compared with before treatment (t = 0.648, p>0.05). The differences in the levels of TNF-α in the other groups of patients before and after treatment were statistically significant (t = 8.497, 6.258, 5.346, p < 0.05, fully sensitive tuberculosis single drug-resistant tuberculosis, multidrug-resistant tuberculosis, respectively). CONCLUSIONS: The level of TNF-α plays a critical role in the evaluation of the severity of patients with drug-resistant tuberculosis and it has a clinical value.

3,5-Dicaffeoylquinic Acid Disperses Aspergillus Fumigatus Biofilm and Enhances Fungicidal Efficacy of Voriconazole and Amphotericin B.

BACKGROUND The aim of this study was to evaluate the dispersal effects of 3,5-dicaffeoylquinic acid (3,5-DCQA) against the preformed biofilm of Aspergillus fumigatus and to investigate its potential mechanism. MATERIAL AND METHODS Aspergillus fumigatus biofilms of laboratory strain AF293 and clinical strain GXMU04 were generated in 24- or 96-well polystyrene microtiter plates in vitro. Crystal violet assay and XTT reduction assay were performed to evaluate the effects of 3,5-DCQA on biofilm biomass, extracellular matrix, and metabolic activity alteration of cells in biofilms. Real-time PCR was performed to quantify the expression of hydrophobin genes. The cytotoxicity of 3,5-DCQA on human erythrocytes was evaluated by a hemolytic assay. RESULTS The results indicated that 3,5-DCQA in subminimum inhibitory concentrations (256 to 1024 mg/L) elicited optimal A. fumigatus biofilm dispersion activity and improved the efficacy of VRC and AMB in minimal fungicidal concentrations (MFCs) to combat fungal cells embedded in biofilms. The results of scanning electron microscope (SEM) and confocal laser scanning microscopy (CLSM) revealed 3,5-DCQA facilitated the entry of antifungal agents into the A. fumigatus biofilm through eliminating the hydrophobic extracellular matrix (ECM) without affecting fungal growth. Real-time PCR indicated that 3,5-DCQA down-regulated the expression of hydrophobin genes. Hemolytic assay confirmed that 3,5-DCQA exhibited a low cytotoxicity against human erythrocytes. CONCLUSIONS Subminimum inhibitory concentrations of 3,5-DCQA can disperse A. fumigatus biofilm and enhance fungicidal efficacy of VRC and AMB through down-regulating expression of the hydrophobin genes. The study indicated the anti-biofilm potential of 3,5-DCQA for the management of A. fumigatus biofilm-associated infection.

[Effects of simvastatin on the proliferation, invasion and radiosensitivity in Lewis lung cancer cell line].

Objective: To investigate the effects of simvastatin on proliferation, invasion and radiosensitivity of mouse Lewis lung cancer cell line in vitro. Methods: The inhibitory effects of simvastatin on proliferation of Lewis lung cancer cells were detected by MTT assay. Matrigel invasion and migration assay was used to determine the invasion and motility ability of the Lewis cells. P38 activity was measured by p38 activity detection kit, and the expressions of p-p38, MKP-1, RhoA and MMP-2 were analyzed by Western blot. Lung cancer xenograft model was established in C57BL/6 mice. The mice were randomly divided into control group, simvastatin group, radiotherapy alone group and combined treatment group. The mice were killed 27 days after inoculation. The tumor mass, volume and lung metastatic nodules in the mice were compared. Results: The cell proliferation rates of 0 µmol/L, 10 µmol/L, 20 µmol/L and 30 µmol/L simvastatin groups were 100%, (87.0±9.0)%, (76.5±8.1)% and (67.0±7.3)%, respectively (P<0.05). Invasive cell numbers of the above groups were 298±30, 251±26, 207±20 and 132±19 per field, respectively (P<0.05). The intracellular p38 activities were 100%, (83.1±8.8)%, (70.2±8.2)% and (59.0±6.4)%, respectively. The relative expressions of p-p38 were 100%, (76.2±6.7)%, (56.4±5.4)% and (36.5±3.2)%, respectively. The expressions of RhoA were 100%, (80.1±5.3)%, (55.3±6.2)% and (38.6±4.8)%, respectively. The expressions of MMP-2 were 100%, (89.6±8.6)%, (51.9±4.7)% and (42.7±3.1)%, respectively, while the expressions of MKP-1 were 100%, (136.5±12.2)%, (168.8±15.3)% and (187.7±13.4)%, respectively (all P<0.05). Lung metastatic nodules and mass in the control, simvastatin, radiotherapy group and combined treatment groups were 6.24±1.09, 3.07±0.71 g, 5.09±1.16, 2.43±0.53 g, 3.12±0.68, 1.96±0.62 g and 2.65±0.38, 1.12±0.43 g, respectively (all P<0.05). The tumor inhibition rates were 39.0%, 48.1% and 26.5%, respectively, in the radiotherapy alone, combined treatment and simvastatin groups (all P<0.05). Conclusions: Simvastatin inhibits the proliferation of Lewis cell line by inhibiting the activity of p38 and expression of p-p38. Meanwhile, simvastatin reduces the invasion and motility of Lewis cell line through down-regulating the expression of RhoA and MMP-2. When combined with radiotherapy, simvastatin can inhibit tumor growth and metastasis, and improve the treatment efficacy of radiotherapy synergistically.