[A multicenter prospective study on early identification of refractory Mycoplasma pneumoniae pneumonia in children].

Objective: To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods: The prospective multicenter study was conducted in Zhejiang, China from May 1st, 2019 to January 31st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results: A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95%CI 0.593-0.771, P<0.01). Conclusion: In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

Sleeve gastrectomy links the attenuation of diabetic kidney disease to the inhibition of renal tubular ferroptosis through down-regulating TGF-ß1/Smad3 signaling pathway.

PURPOSE: To investigate how sleeve gastrectomy (SG), a typical operation of bariatric surgery, attenuated symptom, and progression of diabetic kidney disease (DKD). METHODS: DKD model was induced by high-fat diet (HFD) combined with streptozocin in Wistar rats. SG was performed, and the group subjected to sham surgery served as control. The animals were euthanized 12 weeks after surgery, followed by sample collection for the subsequent experiment. The HK-2, a renal proximal tubular epithelial cell line derived from human, was utilized to investigate the potential mechanisms. RESULTS: SG improved metabolic parameters and glucose homeostasis, and could alleviate DKD in terms of renal function indices as well as histological and morphological structures in DM rats, accompanied with a significant reduction in renal tubular injury. Compared with sham group, SG reduced the renal tubular ferroptosis. To further clarify the mechanism involved, in vitro experiments were performed. In the presence of high glucose, renal tubular TGF-ß1 secretion was significantly increased in HK-2 cell line, which led to activation of ferroptosis through TGF-ß1/Smad3 signaling pathway. Inhibition of TGF-ß1 receptor and phosphorylation of Smad3 significantly ameliorated TGF-ß1-mediated ferroptosis. In vivo experiments also found that SG improved the hyperglycemic environment, reduced renal TGF-ß1 concentrations, and down-regulated the TGF-ß1/Smad3 signaling pathway. CONCLUSIONS: With the capacity to lower the glucose, SG could attenuate the ferroptosis by inhibiting TGF-ß1/Smad3 signaling pathway in DKD rats, and eventually attenuated DKD.

Casp11 Deficiency Alters Subgingival Microbiota and Attenuates Periodontitis.

Periodontitis (PD) is the primary cause of tooth loss in adults. Porphyromonas gingivalis (P.g), a keystone pathogen, has been identified as a crucial contributor to this process. Pyroptosis activation in PD is acknowledged, with accumulating evidence underscoring the crucial role of Caspase-11 (described as Caspase-4/5 in humans)-mediated noncanonical pyroptosis. However, the mechanism behind its impact on PD remains unclear. In this study, we delved into the interplay between the Caspase-11-mediated noncanonical pyroptosis, subgingival microbiota alteration, and macrophage polarization. Clinical samples from PD patients revealed heightened expression of Caspase-4, gasdermin-D, and their active fragments, pointing to the activation of the noncanonical pyroptosis. Single-cell sequencing analysis linked Caspase-4 with gingival macrophages, emphasizing their involvement in PD. In vitro cell experiments confirmed that P.g-induced pyroptosis was activated in macrophages, with Casp11 deficiency attenuating these effects. In an experimental PD mouse model, Casp11 deficiency led to an alteration in subgingival microbiota composition and reduced alveolar bone resorption. Casp11-/- mice cohousing with wild-type mice confirmed the alteration of the subgingival microbiota and aggravated the alveolar bone resorption. Notably, Casp11 deficiency led to decreased M1-polarized macrophages, corresponding with reduced alveolar bone resorption, uncovering a connection between subgingival microbiota alteration, macrophage M1 polarization, and alveolar bone resorption. Taken together, we showed that Caspase-11 fulfilled a crucial role in the noncanonical pyroptosis in PD, potentially influencing the subgingival microbiota and linking to M1 polarization, which was associated with alveolar bone resorption. These findings underscored the pivotal role of the Caspase-11-mediated noncanonical pyroptosis in PD pathogenesis and may provide critical insights into potential therapeutic avenues for mitigating PD.

Comparison of different dosages of propofol combined with its equivalent alfentanil in outpatient abortion: a prospective, double-blinded, randomized trial.

OBJECTIVE: This study aimed at determining the optimal dose combination of alfentanil and propofol for outpatient abortion anesthesia. PATIENTS AND METHODS: The study was separated into two parts. In the first part, patients were to determine the median effective dose (ED50) and the 95% effective dose (ED95) of alfentanil in combination with 2.5 mg·kg-1 propofol to inhibit body movements during the abortion using the Dixon up-and-down sequential allocation method. In the second part, 170 patients were randomly divided into group C (2.0 mg·kg-1 propofol with alfentanil 12.16 µg·kg-1) and group E (2.5 mg·kg-1 propofol with its ED95) to compare the anesthetic effect. The primary outcome was the sedation level during general anesthesia. The secondary outcomes were circulation, respiratory complications, and postoperative recovery quality. RESULTS: The ED50 and the ED95 values of alfentanil were 3.37 µg·kg-1 (95% CI: 2.58-3.97 µg·kg-1) and 4.68 µg·kg-1 (95% CI: 4.04-9.32 µg·kg-1). The frequency of deep sedation in group E was significantly higher than in group C (76.5% vs. 60%). Patients in group C showed more wakefulness even during the surgery (14.3% vs. 4.4%). The results of our exploratory analyses did not reveal differences in respiratory depression, circulatory depression, postoperative side effects, or recovery outcomes. CONCLUSIONS: The combination of 2.5 mg·kg-1 propofol and 4.68 µg·kg-1 alfentanil produces a better sedative effect than the combination of 2.0 mg·kg-1 propofol and 12.16 µg·kg-1 alfentanil without increasing additional risks associated with anesthesia.

Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

[Oridonin suppresses the effect of thioacetamide for promoting osteoclast differentiation of RAW264.7 cells and inhibiting osteoblast differentiation of bone mesenchymal stem cells].

OBJECTIVE: To explore the effect of oridonin (ORI) for suppressing thioacetamide (TAA)-induced osteoclast differentiation of RAW264.7 cells and antagonizing the inhibitory effect of TAA on osteogenic differentiation of bone mesenchymal stem cells (BMSCs). METHODS: The effects of TAA and ORI on the proliferation of RAW264.7 cells and SD rat BMSCs were examined using CCK-8 assay. TRAP staining and immunofluorescence staining were used to observe the effects of TAA and ORI on osteoclast differentiation in RAW264.7 cells. The expressions of osteoclast-specific proteins in the treated cells were detected using Western blotting, and p65 nuclear translocation and reactive oxygen species (ROS) production in the cells were assessed with immunofluorescence assay and flow cytometry. Alkaline phosphatase (ALP) staining and alizarin red staining were used to examine the effects of TAA and ORI on osteogenic differentiation of BMSCs, and the expressions of osteogenic and apoptosis-related proteins in the cells were detected with Western blotting. RESULTS: Compared with RAW264.7 cells treated with TAA alone, the cells with the combined treatment with TAA and ORI showed decreased osteoclast differentiation (P < 0.01) and significant inhibition of the MAPK/NF-κB pathway (P < 0.01) with reduced p65 nuclear translocation and intracellular ROS production (P < 0.01). In rat BMSCs, treatment with TAA alone significantly inhibited ALP activity and formation of calcified nodules (P < 0.01) and induced obvious cell apoptosis. Compared with TAA-treated BMSCs, the cells treated with both TAA and ORI showed upregulated expressions of the BMP-2/RUNX2 pathway with enhanced ALP activity (P < 0.01) and calcium deposition (P < 0.01) and a lowered cell apoptosis level. CONCLUSION: ORI inhibits TAA-induced osteoclast differentiation via regulating the MAPK/NF-κB pathway and antagonizes TAA-induced inhibition of bone formation by regulating the BMP-2/RUNX2 pathway.

[Efficacy analysis of anti-thymocyte globulin regimens with different timing strategies for matched sibling donor hematopoietic stem cell transplantation].

Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/µl vs 852 cells/µl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.

[The 502nd case: thrombocytopenia, splenomegaly, disseminated intravascular coagulation, and spontaneous rupture of the spleen].

A young man with a history of thrombocytopenia for seven years presented with splenomegaly and fever and rapidly evolved to disseminated intravascular coagulation (DIC) and hemorrhagic shock. Spontaneous rupture of the spleen was diagnosed. The critical patient underwent an emergency splenectomy. Pathological examination revealed splenic peliosis, an extremely rare disease with unknown etiology and pathogenesis. Despite the high mortality rate due to spontaneous splenic rupture with DIC, the patient was successfully treated and the details of the case are presented in this report.

[Normative wideband absorbance measures in children: a cross-sectional study].

Objective: This study was to investigate the main characteristics and related factors of wideband absorbance (WBA) in children with normal hearing and to obtain age-specific reference range of WBA. Methods: 384 children between 0-12 years old (615 ears) who visited the Beijing Children's Hospital, Capital Medical University from October 2019 to February 2021 were enrolled, including 230 males (376 ears) and 154 females (239 ears), with totally 306 left ears and 309 right ears. Wideband tympanometry (WBT) was performed and normative WBA data were analyzed by SPSS 24.0 statistical software. Repeated measures and multivariate analysis of variance were applied to the data from 16 points at 1/3-octave frequencies (226, 324, 408, 500, 667, 841, 1 000, 1 297, 1 682, 2 000, 2 670, 3 364, 4 000, 5 339, 6 727 and 8 000 Hz) to evaluate the effects of frequency, age, external auditory canal pressures, gender and ear on WBA. Results: According to the WBT frequency-absorbance curve, the subjects were divided into seven groups: 1-month old group, 2-month old group, 3-month old group, 4-5 month old group, 6-24 month old group,>2-6 year old group and>6-12 year old group. The WBA of normal-hearing children underwent a series of developmental changes with age at both ambient pressure and tympanometric peak pressures. WBA results for 1-month group and 2-month old group exhibited a multipeaked pattern, with the peaks occurring around 2 000 and 4 897 Hz, and a notch around 3 886 Hz. WBA results for 3-month group and 4-5 month old group exhibited a single broad-peaked pattern, with the peak occurring between 2 000-4 757 Hz. The WBA of 1-month old group to 4-5 month old group decreased gradually at low frequency (226-408 Hz) and 6 727 Hz, and increased at middle to high frequency (2 670-4 000 Hz). The WBA of 6-24 month old group were significantly lower than that of 2-month old group to 4-5 month old group at all frequencies except 3 364 and 4 000 Hz. WBA results for 6-24 month old group,>2-6 year old group and>6-12 year old group exhibited a single-peaked pattern, and the peak frequency of WBA moved to the lower frequency successively. From 6-24 month old group to>6-12 year old group, the WBA gradually increased at low to middle frequencies (667-2 670 Hz) and 8 000 Hz, and decreased at middle to high frequencies (3 364-5 339 Hz). Among the 16 frequencies of all age groups, the difference between WBA under ambient pressure and tympanometric peak pressure were -0.09-0.06, and 43.75%-81.25% frequency points had statistically significant difference, which was mainly manifested in that WBA under ambient pressure were lower than that under tympanometric peak pressure at 226-1 682 Hz. There was no significant ear effect on all of the age groups. Similarly, there was no significant gender effect except for 3-month old group and 4-5 month old group. Conclusions: The WBA of normal-hearing children measured at ambient pressure and tympanometric peak pressure varied across the frequencies with age from 1 month to 12 years old, and different frequencies followed different change patterns (increase vs. decrease) in WBA. There was also significant external auditory canal pressures effect on all of the age groups. The establishment of age-specific reference range of WBA for 0-12 years old normal-hearing children in this study would be useful for clinical practice of determining normative data regarding WBT.

[Structural changes of the frontal cortex in depressed mice are associated with decreased expression of brain-derived neurotrophic factor].

OBJECTIVE: To investigate the changes in gray matter volume in depressive-like mice and explore the possible mechanism. METHODS: Twenty-four 6-week-old C57 mice were randomized equally into control group and model group, and the mice in the model group were subjected to chronic unpredictable mild stimulation (CUMS) for 35 days. Magnetic resonance imaging was performed to examine structural changes of the grey matter volume in depressive-like mice. The expression of brain-derived neurotrophic factor (BDNF) in the grey matter of the mice was detected using Western blotting and immunofluorescence staining. RESULTS: Compared with the control mice, the mice with CUMS showed significantly decreased central walking distance in the open field test (P < 0.05) and increased immobile time in forced swimming test (P < 0.05). Magnetic resonance imaging showed that the volume of the frontal cortex was significantly decreased in CUMS mice (P < 0.001, when the mass level was greater than or equal to 10 756, the FDRc was corrected with P=0.05). Western blotting showed that the expression of mature BDNF in the frontal cortex was significantly decreased in CUMS mice (P < 0.05), and its expression began to decrease after the exposure to CUMS as shown by immunofluorescence staining. The volume of different clusters obtained by voxel-based morphometry (VBM) analysis was correlated with the expression level of mature BDNF detected by Western blotting (P < 0.05). CONCLUSION: The decrease of frontal cortex volume after CUMS is related with the reduction of mature BDNF expression in the frontal cortex.

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells.

Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC.

[Simultaneous detection of 7 important Rickettsiales pathogens by TaqMan-probe quantitative real-time PCR].

Objective: To establish and optimize a TaqMan-probe quantitative real-time PCR (qPCR) assay for the detection of 7 important Rickettsiales pathogens and simultaneous identification of the infection types. Methods: Based on the ompB gene of Rickettsia prowazekii, Rickettsia mooseri and spotted fever group rickettsiae, the groEL gene of Orientia tsutsugamushi, the 16S rRNA of Ehrlichia chaffeensis, the gltA gene of Anaplasma phagocytophilum and the com1 gene of Coxiella burnetii, we synthesized primers and TaqMan-probes and optimized the reaction system and reaction process to same solution. The sensitivity, specificity and reproducibility of this assay were evaluated and the assay was used for the detection of simulated and actual samples. Results: The Ct value of the standard curves of the 7 pathogens showed a good linear relationship with the number of DNA copies (all R2 >0.990 0), the minimum detection limit was 10 copies/µl, showing good specificity. In the 96 tick nucleic acid extracts, Coxiella burnetii was detected in 1 sampleand spotted fever group Rickettsiae was detected in 3 samples. In the 80 blood samples from patients with undefined febrile illness, Orientia tsutsugamushi was detected in 1 sample and spotted fever group rickettsiae was detected in 2 samples. Conclusions: In this study, based on the established TaqMan-probe qPCR assay, the reaction system and reaction condition of the 7 important pathogens of Rickettsiales were optimized to the same solution. This method overcomes the shortcomings of using different reaction systems and reaction conditions for different pathogens, which can precisely identify the species of 7 important pathogens of Rickettsiales in clinical sample detections and is important for the infection type identification and laboratory detection time reduction to facilitate precise treatment of the patients.

[Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant].

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.

Dimethyl fumarate attenuates MSU-induced gouty arthritis by inhibiting NLRP3 inflammasome activation and oxidative stress.

OBJECTIVE: Dimethyl fumarate (DMF) has shown anti-inflammatory and antioxidant activities. However, the effects of DMF on gouty arthritis remain elusive, and the underlying mechanism is not understood. In this study, we aim to investigate the role of DMF in gouty arthritis. MATERIALS AND METHODS: Mice were gavage with DMF for consecutive 7 days at two different doses (10 mg/kg/day or 30 mg/kg/day, once daily) in advance and then monosodium sodium urate (MSU) was injected into their joint to establish an acute gout mice model. The pain and swelling of the hind paw in mice were determined. The production of pro-inflammatory cytokine in the paw tissues was assessed by Elisa and the inflammatory infiltration of the joint was determined by hematoxylin and eosin (H&E) staining. The activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in the tissues were measured by commercial kits. In addition, the expression of nuclear factor kappa B (NF-κB) and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome and downstream genes were detected by PCR and Western blot. Furthermore, LPS-primed murine macrophages Raw 264.7 cells were treated with different concentrations of DMF (2 µM, 5 µM, 10 µM) for 2 h, and then challenged with MSU (200 µg/mL) for other 12 h to observe the effect of DMF on cell viability via cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) levels in the supernatant of culture medium. Immunofluorescent staining was used to detect the NLRP3 inflammasome activation and reactive oxygen species (ROS) production in vitro. Caspase-1 activity was measured by corresponding assay kits both in vivo and in vitro. RESULTS: DMF attenuated pain and swelling in MSU-induced gout mice by decreasing pro-inflammatory cytokine production and inflammatory cell infiltration, as well as improved oxidative stress. Moreover, DMF inhibited the activation of NF-κB and NLRP3 inflammasome and subsequent expression of caspase-1, interleukin-1ß (IL-1ß), and IL-18 at both mRNA and protein levels. Meanwhile, DMF suppressed NLRP3 inflammasome expression and ROS production in LPS and MSU-stimulated Raw 264.7 cells, thereby protecting the cells from inflammatory injury. CONCLUSIONS: DMF serves as a new approach for the treatment of MSU-induced gouty arthritis by suppressing NLRP3 inflammasome activation and oxidative stress.

Effect of surface gallium termination on the formation and emission energy of an InGaAs wetting layer during the growth of InGaAs quantum dots by droplet epitaxy.

Self-assembled quantum dots (QDs) based on III-V semiconductors have excellent properties for applications in quantum optics. However, the presence of a 2D wetting layer (WL) which forms during the Stranski-Krastanov growth of QDs can limit their performance. Here, we investigate WL formation during QD growth by the droplet epitaxy technique. We use a combination of photoluminescence excitation spectroscopy, lifetime measurements, and transmission electron microscopy to identify the presence of an InGaAs WL in these droplet epitaxy QDs, even in the absence of distinguishable WL luminescence. We observe that increasing the amount of Ga deposited on a GaAs (100) surface prior to the growth of InGaAs QDs leads to a significant reduction in the emission wavelength of the WL to the point where it can no longer be distinguished from the GaAs acceptor peak emission in photoluminescence measurements. However increasing the amount of Ga deposited does not suppress the formation of a WL under the growth conditions used here.

Chronotype and insomnia may affect the testosterone levels with a sexual difference: a Mendelian randomization.

OBJECTIVE: To evaluate the causal effects of sleep traits (i.e., chronotype, insomnia, and sleep duration) on bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), and total testosterone (TT) levels in women and men. METHODS: We performed Mendelian randomization (MR) using random-effect inverse-variance weighted (IVW) and 7 other MR analyses. Exposure data for sleep traits were obtained from the largest-to-date genome-wide association study (GWAS) from 339,926 to 1,331,010 individuals. Summary data for testosterone levels were obtained from GWAS based on the UK Biobank. RESULTS: For women, our study supported that chronotype was associated with decreased BT (IVW: ß = - 0.042, 95% CI - 0.060, - 0.023, p = 1.17E-05) and TT (IVW: - 0.053, 95% CI - 0.075, - 0.031, p = 2.30E-06). Besides, insomnia can significantly increase BT (IVW: ß = 0.025, 95% CI 0.009, 0.041, p = 0.002). These findings were significant in most sensitivity analyses. For men, statistical significance was found between chronotype and BT (ß = - 0.027, 95% CI - 0.048, - 0.005, p = 0.016), and insomnia and TT (ß = - 0.028, 95% CI - 0.049, 0.007, p = 0.009) in IVW. However, the effect estimates were not broadly consistent with other sensitivity analyses. Our study did not find support for causal effects of sleep duration on testosterone levels in both women and men. CONCLUSION: Our study reveals the sex differences in the effects of sleep traits on testosterone levels. A healthy sleep habit is vital for the maintenance of testosterone homeostasis in women. Further studies are warranted to investigate the associations between sleep traits and testosterone levels in men.

[Study on reproductive toxicity of nano-cadmium sulfide with different particle sizes on male mice].

Objective: To investigate the reproductive toxicity of cadmium sulfide nanoparticles (Nano-CdS) with different particle sizes on male mice. Methods: In January 2019, 30 SPF grade male mice were randomly divided into a control group, an experimental group[CdS Ⅰ group (particle size approximately 5 nm), and a CdS Ⅱ group (particle size approximately 50 nm) ], with 10 mice in each group. The experimental group was orally gavaged with 100 mg/kg, once a day, while the control group was gavaged with an equal volume of physiological saline for 45 consecutive days. After 45 days, levels of cadmium accumulation in testis were determined directly by AAS, deformity and testicular histopathological changes were also observed. Serum testosterone levels were measured by enzyme-linked immunosorbentassay (ELISA), expression levels of P450scc, 17ß-HSD and P450c17 mRNA were determined by real-time PCR. P450c17 protein was determinated by Western Blot. Results: The histopathological results showed that the testes of the experimental group mice showed varying degrees of damage; Ultrastructural observation showed that the ultrastructure of mouse testicular cells in each experimental group showed varying degrees of mitochondrial expansion and disappearance of cristae, as well as irregular nuclear membranes. The degree of damage in CdS Ⅰ group was milder than that in CdS Ⅱ group. Compared with the control group, the cadmium content in the testes of the CdS Ⅰ and CdS Ⅱ groups significantly increased (P=0.001, 0.001), and the CdS Ⅱ group was higher than the CdS Ⅰ group (P=0.001). Compared with the control group, the levels of testosterone in the CdS Ⅰ and CdS Ⅱ groups decreased with statistical significance (P=0.001, 0.001). Real time fluorescence quantitative PCR results showed that compared with the control group, the experimental group's P450scc, 17ß-HSD. The expression levels of 17ß-HSD and P450c17 mRNA were significantly reduced, with statistically significant differences (P=0.001, 0.001, 0.001), and CdS Ⅱ group 17ß-HSD. The expression levels of 17ß-HSD and P450c17 mRNA were significantly lower than those of CdS Ⅰ group (P=0.001, 0.036). The Western Blot assay results showed that the expression levels of P450c17 protein in the testes of CdS Ⅰ and CdS Ⅱ groups of mice were significantly reduced, with statistical significance (P=0.001, 0.001) ; And the CdS Ⅱ group was significantly lower than the CdS Ⅰ group (P=0.001). According to Spearman correlation analysis, testosterone levels are correlated with P450scc, P450c17, 17ß-HSD mRNA. There is a highly positive correlation between 17ß-HSD mRNA levels, with statistically significant differences (r(s)=0.88, 0.80, 0.70, P=0.001, 0.001, 0.004) . Conclusion: Nano cadmium sulfide may induce reproductive toxicity by reducing the expression levels of key enzyme genes and enzyme protein activity in testosterone and its synthesis in mice, and the CdS Ⅱ group has a stronger toxic effect.