[Efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis].

Objective: To explore the efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis. Methods: A cohort study. The clinical data of patients with refractory chronic gouty arthritis who were treated with rasburicase at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between January 2021 and July 2022 were retrospectively analyzed. Refractory chronic gouty arthritis was defined as serum uric acid (sUA)>360 µmol/L and urate volume>10 cm3 under dual-energy computed tomography after tolerable maximal oral urate-lowering therapy for at least 3 months. The administration of low-dose rasburicase was applied intravenously with total dosage ranging from 4.5 to 7.5 mg each dose, at 4-week intervals for a maximum of three doses. Efficacy was evaluated by the changes of sUA level, tophus and urate volume. Results: A total of 22 patients were included for analysis, with 95.4% (21/22) male, the mean age was (44±15) years, and the median duration of gout was 11 (6-15) years. The mean sUA at baseline was (667±112) µmol/L. The levels of sUA significantly decreased after each dose of rasburicase (P<0.001), and the median reduction of sUA after each dose of rasburicase was 568 (471-635), 187 (66-335) and 123 (49-207) µmol/L, respectively. At week 12, nine patients (40.9%) exhibited sUA<360 µmol/L and tophus disappeared in one patient. The urate volume significantly decreased at week 12 when compared with that before the first dose of rasburicase in all the patients [40 (16-172) cm3 vs 17 (7-134) cm3, P<0.001], with a median reduction rate of 41.6% (22.9%-58.5%). The everall safety of rasburicase was good, and no serious adverse reactions occurred. Conclusions: Low-dose rasburicase is well-tolerated and effective for decreasing the urate burden in patients with refractory chronic gouty arthritis. Further prospective randomized controlled trials are needed to validate these findings.

[Infection and distribution characteristics of HPV of middle-aged and elderly women from a certain hospital in Guangxi Zhuang Autonomous Region from 2018 to 2020].

Objectives: To analyze the type and distribution characteristics of human papillomavirus (HPV) infection along with cervical cytology in middle-aged and elderly women in Guangxi and to provide a basis for the prevention and treatment of cervical cancer in elderly women. Methods: 21 subtypes of HPV and cervical cytology of women over 45-year-old visiting the First Affiliated Hospital of Guangxi Medical University from January 2019 to December 2020 were collected. They were divided into two groups by age, 45-64 years group and over 65 years group. The HPV, HR-HPV, and multiple HPV infection prevalence were analyzed, as well as HPV genotypes, the age distribution of HPV infection rate, and cervical cytology. Results: A total of 6 657 eligible women were included. 6 238 women were in the 45-64 years group, with a HPV prevalence about 20.86% (1 301), while 419 women were in the over 65 years group, with a HPV prevalence about 32.94% (138). The age-associated HPV and HR-HPV prevalence increased with the age, peaking at the age group of 70-74 years (P<0.001). The most prevalent genotype was HPV52, and the infection rate was 5.3% (353), followed by HPV16 and HPV 58, about 4.63% (308) and 3.08% (205) respectively. The majority cytology of HPV-positive middle-aged and elderly women was normal. 8.70% (88) of them were ASC-US, 6.52% (66) for HSIL, 4.55% (46) for LSIL, and 2.96% (30) for ASC-H, and 0.10% (1) for SCC. Compared to middle-aged women, elderly women had a lower negative cytology rate, 69.79% (67) vs. 77.95% (714), but a higher HSIL rate, 13.54% (13) vs. 5.79% (53) (P<0.05). Conclusions: HPV and HR-HPV prevalence of elderly women in a medical center of Guangxi are higher than those of middle-aged women. The most prevalent genotype is HPV16 in elderly women, followed by HPV52 and HPV58.

[Expression of peroxisome proliferator-activated receptor-gamma coactivator 1ß in synovium in patients with rheumatoid arthritis and its clinical significance].

Objective: To investigate the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)1ß in synovium of patients with rheumatoid arthritis (RA) and its association with histological synovitis. Methods: This cross-sectional study recruited RA patients at the Department of Rheumatology, Sun Yat-Sen Memorial Hospital from May 2010 to October 2016. Clinical data were collected. Conventional radiographs of bilateral hands and wrists were performed and assessed according to Sharp/van der Heijde-modified Sharp score(mTSS). Synovial tissues from knee joints of all RA patients were obtained by biopsies, and then stained with HE and immunohistochemically for PGC-1ß, CD3, CD20, CD38, CD68, CD15 and CD34 to evaluate synovitis, synovial PGC-1ß expression and the densities of inflammatory cells and endothelial cells. The relationship between synovial PGC-1ß expression and histological synovitis, disease activity and joint destruction in RA was analyzed by Spearman's rank correlation and multivariate linear regression. Results: There were 83 RA patients recruited with 20 (24.1%) males and 63 (75.9%) females, aged (54±14) years. PGC-1ß expressed in the nuclei of lining synoviocytes, sublining inflammatory cells and vascular endothelial cells of RA synovium. The percentage of synovial PGC-1ß+cells was positively correlated with histological synovitis score (r=0.333) and the densities of sublining CD3+ T cells (r=0.259), CD20+ B cells (r=0.320), CD38+plasma cells (r=0.342) and CD68+ macrophages (r=0.309)(all P<0.05). It was also positively correlated with erythrocyte sedimentation rate, C reactive protein and total mTSS (r=0.219-0.301, all P<0.05). Multiple linear regression analysis further confirmed the positive correlation between the percentage of synovial PGC-1ß+cells and mTSS (ß=0.312, P=0.004). Conclusion: Synovial PGC-1ß is positively associated with local and systemic inflammation as well as joint destruction, which implies that PGC-1ß might involve in the pathogenesis of synovitis and joint destruction in RA.

[Quick community survey on the impact of COVID-19 outbreak for the healthcare of people living with HIV].

Objective: To collect the current status and healthcare needs of people living with HIV (PLHIV) in China during the COVID-19 outbreak to inform quick response from government and communities. Methods: During February 5(th) to 10(th), 2020, a national anonymous survey was conducted using an online questionnaire among PLHIV at least 18 years of age and had started antiretroviral treatment (ART) to collect the information on COVID-19 prevention, HIV-related health services and the needs on psychosocial support. Current status and needs of people living with HIV were analyzed in Hubei and other regions. Results: A total of 1 014 valid questionnaires were collected, with PLHIV respondents cross the country. The survey revealed that 93.79% of the respondents could obtain information regarding the prevention of COVID-19 from their communities or villages. Respondents were concerned with HIV-specific protective measures and personal protective equipment shortage. 32.64% of all respondents were not carrying sufficient antiretroviral medicines (ARVs) to meet the needs under traffic and travel restrictions, and some could face stock-outs in the coming month. In Hubei province where 53 respondents needed ARV refill, 64.15% reported difficulty accessing ARV due to the "blockage" . 28.93% respondents were in need of sociopsychological support, and 85.31% anticipated further improvement of the out-of-town ARV refill process from the government. Conclusion: PLHIV wants to know HIV-specific protective measures against COVID-19 outbreak. PLHIV who returned to their home-towns and affected by the lock-downs reported challenges with refills. We should undertake a more systematic study on impacts of the COVID-19 on PLHIV to develop preparedness capacity for future public health emergency.

[Potential mechanism of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta on promoting osteoclastogenesis].

Objective: To investigate the role of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1ß) on osteoclastogenesis and related regulatory mechanism in the mouse monocyte-macrophage cell line (RAW264.7). Methods: PGC-1ß expression and location in RAW264.7 cells was detected by immunofluorescence, flow cytometry and western blot analysis with nuclear protein extraction. RAW264.7 cells were transfected with lentivirus for gene silencing or over-expression of PGC-1ß and cultured with macrophage colony-stimulating factor and receptor activator for nuclear factor-κB ligand. Cell viability was detected by cell counting kit-8. Cell apoptosis and cell cycle were detected by flow cytometry. Mature osteoclasts and their bone resorption activity were determined by tartrate-resistant acid phosphatase (TRAP) expression and toluidine blue staining. Western blot analysis was performed for detecting dendritic cell-specific transmembrane protein (DC-STAMP), cathepsin K, TRAP and matrix metalloproteinase (MMP)-9 expression, as well as cytoplasmic NF-κB-inducing kinase (NIK) and nuclear RelB. Results: PGC-1ß expression was observed in the nuclei of RAW264.7 cells. Down-regulation or overexpression of PGC-1ß in RAW264.7 cells did not affect cell viability, apoptosis or cell cycle. Down-regulation of PGC-1ß decreased the count of mature osteoclasts (49±21 cells vs. 147±42 cells, P=0.004) and the pit area of bone resorption lacunae (42.11µm(2)±11.30 µm(2) vs. 204.80µm(2)±31.09 µm(2), P<0.001), as well as the expression of cathepsin K, TRAP and MMP-9, but not DC-STAMP. Overexpression of PGC-1ß promoted osteoclast differentiation and bone resorption activity, as well as the expression of cathepsin K, TRAP and MMP-9. Down-regulation of PGC-1ß suppressed the protein expression of cytoplasmic NIK and nuclear RelB in RAW264.7 cells. Conclusion: PGC-1ß can promote the differentiation of RAW264.7 into osteoclasts and improve the bone resorption ability of the cells via activation of NIK/RelB pathway, which might be a promising therapeutic target for osteoporosis.

[Clinical characteristics and renal uric acid excretion in early-onset gout patients].

Objective: To investigate clinical characteristics and renal uric acid excretion in early-onset gout patients. Methods: Consecutive inpatients with primary gout were recruited between 2013 and 2017. The patients with gout onset younger than 30 were defined as early-onset group while the others were enrolled as control group. Clinical characteristics and uric acid (UA) indicators were compared between two groups. Results: Among 202 recruited patients, the early-onset group included 36 patients (17.8%). Compared with control group, the early-onset group presented more patients with obesity [13 patients (36.1%) vs. 22 patients (13.3%), P<0.05], significantly higher serum UA level [(634±124)µmol/L vs.(527±169)µmol/L] and glomerular load of UA[(7.2±2.8)mg·min(-1)·1.73m(-2) vs. (4.4±2.2)mg·min(-1)·1.73m(-2)] and estimated glomerular filtration rate (GFR) [(83±21)ml·min(-1)·1.73m(-2) vs. (67±21)ml·min(-1)·1.73m(-2)] (all P<0.05), lower fractional excretion of UA [4.4% (3.4%,6.1%) vs. 7.2% (5.2%,9.6%),P<0.05], whereas 24h urinary UA excretion was comparable [(2 788±882)µmol/1.73m(2) vs. (2 645±1 140)µmol/1.73m(2), P=0.274]. Subgroup analysis of patients without chronic kidney disease showed significantly lower fractional excretion of UA in the early-onset group [4.5%(3.3%,6.1%) vs. 6.7% (5.1%,8.7%),P<0.05]. Logistic regression analysis showed that obesity (OR=3.25) and fractional excretion of UA less than 7% (OR=9.01, all P<0.05) were risk factors of gout early onset. Conclusion: The gout patients with early-onset younger than 30 present high serum and glomerular load of uric acid which might be due to obesity and relative under-excretion of renal uric acid.

MicrobPad MD: microbial pathogen diagnostic methods database.

Medical pathogens induce infections, illnesses and sometimes serious medical conditions in the infected hosts. Diagnosis of these pathogens is important for proper treatment and investigation of pathogenesis processes. Molecular techniques have been developed for facilitating accurate, sensitive and low-cost diagnosis of these pathogens. Based on these techniques, diagnostic devices have been developed for a number of pathogens. More devices are needed for comprehensive coverage of medical pathogens. To facilitate the development of these devices, a database with integrated information about diagnostic methods, targets, and primers/probes for the known bacterial, fungal and viral pathogens is needed. We developed the microbial pathogen diagnostic methods database MicrobPad MD (http://bidd.nus.edu.sg/group/MicrobPad/MicrobPad.asp or http://pha-bidd.nus.edu.sg/group/MicrobPad/MicrobPad.asp) to provide comprehensive information about the molecular diagnostic techniques, targets, primers/probes, detection procedures and conditions, and tested diagnostic accuracies and limit of diagnosis for 314 bacterial, fungal and viral species from 61 genera. While available, additional information such as pathogen strains and hosts, tissue distribution or habitats, cultivation methods, biochemical characteristics, virulence factors, morphology, diseases, symptoms, treatment and prevention methods are provided. Our Database covers 242 gene targets, 700 primers/probes, 340 virulence factors, and 261 diseases. Cross-links to the NCBI genome and SwissProt/UniProt databases are provided.

An integrated mathematical model of thrombin-, histamine-and VEGF-mediated signalling in endothelial permeability.

BACKGROUND: Endothelial permeability is involved in injury, inflammation, diabetes and cancer. It is partly regulated by the thrombin-, histamine-, and VEGF-mediated myosin-light-chain (MLC) activation pathways. While these pathways have been investigated, questions such as temporal effects and the dynamics of multi-mediator regulation remain to be fully studied. Mathematical modeling of these pathways facilitates such studies. Based on the published ordinary differential equation models of the pathway components, we developed an integrated model of thrombin-, histamine-, and VEGF-mediated MLC activation pathways. RESULTS: Our model was validated against experimental data for calcium release and thrombin-, histamine-, and VEGF-mediated MLC activation. The simulated effects of PAR-1, Rho GTPase, ROCK, VEGF and VEGFR2 over-expression on MLC activation, and the collective modulation by thrombin and histamine are consistent with experimental findings. Our model was used to predict enhanced MLC activation by CPI-17 over-expression and by synergistic action of thrombin and VEGF at low mediator levels. These may have impact in endothelial permeability and metastasis in cancer patients with blood coagulation. CONCLUSION: Our model was validated against a number of experimental findings and the observed synergistic effects of low concentrations of thrombin and histamine in mediating the activation of MLC. It can be used to predict the effects of altered pathway components, collective actions of multiple mediators and the potential impact to various diseases. Similar to the published models of other pathways, our model can potentially be used to identify important disease genes through sensitivity analysis of signalling components.

Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach.

Histone deacetylase inhibitors (HDACi) have been successfully used for the treatment of cancers and other diseases. Search for novel type ZBGs and development of non-hydroxamate HDACi has become a focus in current research. To complement this, it is desirable to explore a virtual screening (VS) tool capable of identifying different types of potential inhibitors from large compound libraries with high yields and low false-hit rates similar to HTS. This work explored the use of support vector machines (SVM) combined with our newly developed putative non-inhibitor generation method as such a tool. SVM trained by 702 pre-2008 hydroxamate HDACi and 64334 putative non-HDACi showed good yields and low false-hit rates in cross-validation test and independent test using 220 diverse types of HDACi reported since 2008. The SVM hit rates in scanning 13.56 M PubChem and 168K MDDR compounds are comparable to HTS rates. Further structural analysis of SVM virtual hits suggests its potential for identification of non-hydroxamate HDACi. From this analysis, a series of novel ZBG and cap groups were proposed for HDACi design.