Experiences and perspectives related to shared decision-making among outpatients with degenerative joint disease in Taiwan: a qualitative study.

OBJECTIVES: Various treatment options are available for degenerative joint disease (DJD). During clinical visits, patients and clinicians collaboratively make decisions regarding the optimal treatment for DJD; this is the essence of shared decision-making (SDM). Here, we collated and assessed the SDM-related experiences and perspectives of outpatients with DJD in Taiwan. DESIGN: In-depth interviews and thematic analysis. SETTING: Primary care clinics of a regional teaching hospital in Taiwan, October 2021-May 2022. PARTICIPANTS: 21 outpatients with at least three visits for DJD and who were aware of SDM. RESULTS: Four main themes emerged in this study: first, equipping themselves with knowledge: outpatients obtained disease-related and treatment-related knowledge in various ways-seeking relevant information online, discussing with family and friends, learning from their own experiences or learning from professionals. Second, shared or not shared: physicians had different patterns for communicating with patients, particularly when demonstrating authority, performing mutual discussion, respecting patient preferences or responding perfunctorily. Third, seldom saying no to physician-prescribed treatment plans during clinical visits: most patients respected physicians' professionalism; however, some patients rejected physicians' recommendations indirectly, whereas some responded depending on their disease prognosis. Fourth, whose call?-participants decided to accept or reject a treatment plan independently or by discussing it with their families or by obeying their physicians' recommendations. CONCLUSIONS: In general, patients with DJD sought reliable medical information from various sources before visiting doctors; however, when having a conversation with patients, physicians dominated the discussion on treatment options. The patient-physician interaction dynamics during the SDM process determined the final medical decision, which was in accordance with either patients' original autonomy or physicians' recommendations. To alleviate medical paternalism and physician dominance, patients should be empowered to engage in medical decision-making and share their opinions or concerns with their physicians. Family members should also be included in SDM.

Attenuative effects of collagen peptide from milkfish (Chanos chanos) scales on ovariectomy-induced osteoporosis.

Osteoporosis is characterized by low bone mass, bone microarchitecture disruption, and collagen loss, leading to increased fracture risk. In the current study, collagen peptides were extracted from milkfish scales (MS) to develop potential therapeutic candidates for osteoporosis. MS was used to synthesize a crude extract of fish scales (FS), collagen liquid (COL), and hydroxyapatite powder (HA). COL samples were further categorized according to the peptide size of total COL (0.1 mg/mL), COL < 1 kDa (0.1 mg/mL), COL: 1-10 kDa (0.1 mg/mL), and COL > 10 kDa (0.1 mg/mL) to determine it. Semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and immunofluorescence labeling were used to assess the expression levels of specific mRNA and proteins in vitro. For in vivo studies, mice ovariectomy (OVX)-induced postmenopausal osteoporosis were developed, while the sham surgery (Sham) group was treated as a control. Collagen peptides (CP) from MS inhibited osteoclast differentiation in RAW264.7 cells following an insult with nuclear factor kappa-B ligand (RANKL). CP also enhanced osteoblast proliferation in MG-63 cells, possibly through downregulating NFATc1 and TRAP mRNA expression and upregulating ALP and OPG mRNA levels. Furthermore, COL1 kDa also inhibited bone density loss in osteoporotic mice. Taken together, CP may reduce RANKL-induced osteoclast activity while promoting osteoblast synthesis, and therefore may act as a potential therapeutic agent for the prevention and control of osteoporosis.

Causative microbes and antibiotic susceptibility of acute appendicitis in adults and children.

BACKGROUND: In recent years, some studies have found that acute uncomplicated appendicitis can be treated with antibiotics alone. Because of the lack of relevant research on treating acute appendicitis in Taiwan, this study investigated the microbiological characteristics of acute appendicitis to permit accurate empirical antibiotic use for uncomplicated appendicitis. METHODS: In this single-center retrospective cohort study, patients listed in the Taiwan National Health Insurance Research Database with a discharge diagnosis of acute appendicitis were identified. Data for bacterial specimens and antibiotic susceptibility tests among patients treated at Tri-Service General Hospital between January 2016 and December 2021 were analyzed. RESULTS: Among 2805 patients diagnosed with acute appendicitis, 167 (6%) were <18 years old. The culture positivity rates among children and adults were 33% and 18%, respectively. In total, 367 aerobes and 207 anaerobes were isolated. The predominant aerobic gram-positive coccus was viridans group streptococci (8.9%), the most common aerobic gram-negative bacillus was Escherichia coli (27.9%), and the most common anaerobic microorganism was Bacteroides spp. (27.7%). The results of antibiotic susceptibility testing of the predominant microorganisms revealed that 86.3% of gram-positive aerobes were susceptible to ampicillin, 76.3% of gram-negative aerobes were susceptible to gentamicin, and all anaerobic isolates were susceptible to metronidazole. CONCLUSION: Triple first-line antibiotic combination therapy, including ampicillin, gentamicin, and metronidazole, remains highly effective against the pathogens that cause acute appendicitis.

The risk factors, antimicrobial resistance patterns, and outcomes associated with extended-spectrum ß-lactamases-Producing pathogens in pediatric urinary tract infection.

BACKGROUND: Extended-spectrum ß-lactamases-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis (ESBL-producing-EKP) are an increasingly common cause of childhood urinary tract infection (UTI) worldwide. Recognizing the risk factors and antimicrobial resistance patterns may guide new management in this population. METHODS: This is a retrospective cohort study of over 5 years in Taiwan (2017-2021). Inclusion criteria are hospitalized pediatric patients with the discharge diagnosis of UTI caused by E. coli, Klebsiella pneumoniae, or Proteus mirabilis. ESBL-producing-EKP and non-ESBL-producing-EKP UTI cases were reviewed for characteristics, urinary isolate antibiotics resistance, and clinical outcomes. RESULTS: The incidence rate of ESBL-producing-EKP UTI increased over the study period (Overall incidence rate: 14.1 %, 46/327 patients). Recent antibiotic therapy in ≤6 months (X2 = 11.83, p < 0.01) and a preterm gestational history (X2 = 8.11, p < 0.05) were associated with an increased risk. The proportion of patients with these two risk factors for ESBL acquisition were 37.5 % (X2 = 9.08, p < 0.05). The co-resistance rate of ESBL-producing-EKP to other antimicrobial agents was 63.0 % for gentamicin, 56.5 % for trimethoprim-sulfamethoxazole, 52.2 % for ciprofloxacin, 4.3 % for amikacin, and 2.2 % for imipenem. The generalized linear model analysis identified a significantly longer length of stay (ß: 2.85; 95 % confidence interval [CI]: 1.14-4.56; p < 0.01) and intensive care unit duration (ß: 5.86; 95 % CI: 1.59-10.12; p < 0.01) among patients with ESBL-producing-EKP UTI. CONCLUSION: Amikacin should be considered as an alternative antimicrobial choice beyond carbapenems for ESBL-producing-EKP UTI, especially in the context of carbapenem-resistant E. coli/Klebsiella pneumoniae (CRE/CRKP) emergence.

DFATs derived from infrapatellar fat pad hold advantage on chondrogenesis and adipogenesis to evade age mediated influence.

Background: Dedifferentiated fat cells (DFATs) are highly homogeneous and multipotent compared with adipose-derived stromal cells (SCs). Infrapatellar fat pad (IFP)-SCs have advanced chondrogenic potency; however, whether IFP-DFATs could serve as better cell material remains unclear. Here, we aimed to examine the influence of age and body mass index (BMI) on the features of IFPs and IFP-derived cells (IFP-SCs and IFP-DFATs) with exploration of the clinical utilization of IFP-DFATs. Methods: We collected IFPs with isolation of paired IFP-SCs and IFP-DFATs from individuals aged 65 years and older with distinct body weights who underwent total knee replacement for osteoarthritis (OA). Flow cytometry was used to characterize the cellular immunophenotypes. Adipogenesis and chondrogenesis were performed in vitro. Real-time qPCR, western blotting, and Oil Red O or Alcian blue staining were performed to evaluate inflammation, adipogenesis, and chondrogenesis. RNA sequencing and Seahorse analyses were conducted to explore the underlying mechanisms. Results: We found that IFPs from old or normal-weight individuals with knee OA were pro-inflammatory, and that interleukin-6 (IL-6) signaling was associated with multiple immune-related molecules, whereas IFP-derived cells could escape the inflammatory properties. Aging plays an important role in diminishing the chondrogenic and adipogenic abilities of IFP-SCs; however, this effect was avoided in IFP-DFATs. Generally, IFP-DFATs presented a steady state of chondrogenesis (less influenced by age) and consistently enhanced adipogenesis compared to paired IFP-SCs in different age or BMI groups. RNA sequencing and Seahorse analysis suggested that the downregulation of eukaryotic initiation factor 2 (EIF2) signaling and enhanced mitochondrial function may contribute to the improved cellular biology of IFP-DFATs. Conclusions: Our data indicate that IFP-DFATs are superior cell material compared to IFP-SCs for cartilage differentiation and adipogenesis, particularly in advanced aging patients with knee OA. The translational potential of this article: These results provide a novel concept and supportive evidence for the use of IFP-DFATs for cell therapy or tissue engineering in patients with knee OA. Using Ingenuity Pathway Analysis (IPA) of RNA-seq data and Seahorse analysis of mitochondrial metabolic parameters, we highlighted that some molecules, signaling pathways, and mitochondrial functions are likely to be jointly coordinated to determine the enhanced biological function in IFP-DFATs.

The Value of 18F-FDG PET/MRI in Detecting Lumbar Radiculopathy for Selective Percutaneous Endoscopic Discectomy: a Case Report.

Magnetic resonance imaging (MRI) is the most popular imaging modality for investigating intervertebral disc herniation. However, it has a high chance for identifying incidental findings that are morphologically or structurally abnormal but not responsible for patients' symptoms. Although a previous study suggested that 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) may help identify neuroinflammation in lumbar radiculopathy, there is currently no direct evidence obtained from surgery. Here, we describe the case of a 32-year-old man with low back pain and right leg paresthesia for 7 months. MRI demonstrated disc herniation at the L3-L4, L4-L5 and L5-S1 levels, causing bilateral L5 and left S1 root compression. 18F-FDG PET/MRI demonstrated increased 18F-FDG uptake at the right L5 root, which was compatible with the patient's symptoms. Transforaminal percutaneous endoscopic lumbar discectomy (PELD) was performed. Intraoperative images revealed a swollen nerve root at the right L5 after removal of the herniated disc. After surgery, the patient experienced immediate pain relief and had no recurrence at the 6-month follow-up. When performing PELD in patients with multilevel radiculopathy identified on MRI, the use of 18F-FDG PET/MRI can help in accurate localization of the symptomatic roots and minimize surgical incision and soft-tissue injury.

A case-control study coupling with meta-analysis elaborates decisive association between IGF-1 rs35767 and osteoporosis in Asian postmenopausal females.

BACKGROUND: Osteoporosis (OP) is prevalent in postmenopausal women. Several studies investigated the association between IGF-1 polymorphisms and OP among postmenopausal females with conflicting outcomes. OBJECTIVE: To investigate whether the IGF-1 (rs35767, rs2288377, rs5742612) were associated with OP in postmenopausal females. METHODS: In case-control study, 95 OP cases and 222 healthy controls were recruited between March 2015 and July 2019. OP was diagnosed based on WHO criteria for diagnosis of OP as T score of bone mineral density (BMD) ≤-2.5; normal, as T score of BMD ≥-1. IGF-1 SNPs were genotyped by iPLEX Gold SNP genotyping. To be solid, related studies from PubMed, Embase, Cochrane, Web of science, and previous meta-analysis up until November 2020, along with our case-control study, were incorporated into a meta-analysis with criteria of significance using odds ratios (ORs) with corresponding 95% confidence intervals (CI) to evaluate risk factor of SNPs on OP. TSA was used to estimate the sample sizes required to achieve a conclusion. RESULTS: In dominant model of our case-control study, we found nonsignificant association of rs35767 [Adj-OR: 0.95 (95% CI: 0.56-1.60)], rs2288377 [Adj-OR: 1.15 (95% CI: 0.67-1.97)], and rs5742612 [Adj-OR: 1.07 (95% CI: 0.62-1.83)] with OP in postmenopausal females. However, integration of our case-control study and 3 published studies, rs35767 [OR: 1.24 (95% CI: 1.05-1.47)] showed a conclusively risk association with OP in postmenopausal females judged by TSA with 2267 Asians. CONCLUSIONS: This study demonstrates a crucial sample to conclude that IGF-1 rs35767 is significantly associated with OP in postmenopausal women.

Anti-Inflammatory and Chondro-Protective Effects of Acidic Polysaccharide from Enteromorpha Prolifera in Experimental Models of Osteoarthritis In-Vitro and In-Vivo.

OBJECTIVE: Osteoarthritis (OA) progression has been shown to increase the expression of inflammatory cytokines in joints, leading to the destruction of cartilage matrix. Interleukin (IL)-1ß is a potent inflammatory cytokine associated with osteoarthritic synovial fluid. The protective effects of polysaccharides from Enteromorpha prolifera against acute hepatic injury was reported. DESIGN: In this study, we examined the effects of Enteromorpha polysaccharide extracts (EPEs) in the treatment of OA. The effects of the EPEs were assessed using an IL-1ß-stimulated SW1353 and SW982 cells. The expression levels of specific mRNA and proteins were evaluated using semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and western immunoblotting. An OA animal study involving C57BL/6J mice was also conducted to assess the effects on tactile sensitivity and anterior cruciate ligament transection (ACLT). RESULTS: Acidic polysaccharide extract (APE) was shown to significantly reduce cytokine and chemokine mRNA levels in IL-1ß-stimulated SW1353 and SW982 cells and attenuate the expression of proinflammatory cytokines and p38/AP-1 in SW1353 cells. APE was also shown to minimize the effect of osteolytic lesions in the knee joints of ACLT-induced osteoarthritic mice. CONCLUSIONS: APE is a potent inhibitor of joint degeneration associated with OA.

Effectiveness of question prompt lists in patients with breast cancer: A randomized controlled trial.

OBJECTIVES: To evaluate the effectiveness of a question prompt list (QPL) in decision self-efficacy, decision-making participation, patient-physician communication, decisional conflict or regret, and health status in patients with breast cancer. METHODS: A total of 240 patients with breast cancer were randomly assigned to a QPL group or control group (n = 120 each). The intervention and control groups received an additional educational QPL booklet and routine care, respectively. RESULTS: The intervention group exhibited significant improvements in decision self-efficacy, perceived patient-physician interactions, and patient-physician communication compared with the control group. Multilevel modeling analyses revealed significant group-time interaction effects on decision self-efficacy (ß = 9.99, P < 0.01), perceived patient-physician interactions (ß = 8.10, P < 0.01), patient-physician communication (ß = 5.02, P < 0.01), and anxiety status (ß = -3.78, P < 0.05). The QPL intervention exerted more favorable effects than routine care, with repeated measurements of the same patients and the data of patients under the care of the same surgeons accounted for. CONCLUSIONS: The QPL intervention exerted multidimensional effects on decision-making outcomes among patients with breast cancer. PRACTICAL IMPLICATIONS: Clinicians can integrate a QPL into routine care for patients with breast cancer.

Differential gene expression orchestrated by transcription factors in osteoporosis: bioinformatics analysis of associated polymorphism elaborating functional relationships.

BACKGROUND: Identification of candidate SNPs from transcription factors (TFs) is a novel concept, while systematic large-scale studies on these SNPs are scarce. PURPOSE: This study aimed to identify the SNPs of six TF binding sites (TFBSs) and examine the association between candidate SNPs and osteoporosis. METHODS: We used the Taiwan BioBank database; University of California, Santa Cruz, reference genome; and a chromatin immunoprecipitation sequencing database to detect 14 SNPs at the potential binding sites of six TFs. Moreover, we performed a case-control study and genotyped 109 patients with osteoporosis (T-score ≤ -2.5 evaluated by dual-energy X-ray absorptiometry) and 262 healthy individuals (T-score ≥ -1) at Tri-Service General Hospital from 2015 to 2019. Furthermore, we used the expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression database to identify downstream gene expression as a criterion for the function of candidate SNPs. RESULTS: Bioinformatic analysis identified 14 SNPs of TFBSs influencing osteoporosis. Of these SNPs, the rs130347 CC + TC genotype had 0.57 times higher risk than the TT genotype (OR = 0.57, p = 0.031). Validation of eQTL analysis revealed that rs130347 T allele influences mRNA expression of downstream A4GALT in whole blood (p = 0.0041) and skeletal tissues (p = 0.011). CONCLUSIONS: We successfully identified the unique osteoporosis locus rs130347 in the Taiwanese and functionally validated this finding. In the future, this strategy can be expanded to other diseases to identify susceptible loci and achieve personalized precision medicine.

Decisive gene strategy on osteoporosis: a comprehensive whole-literature-based approach for conclusive candidate gene targets.

PURPOSE: Previous meta-analyses only examined the association between single gene polymorphisms and osteoporosis; there is no compilation of all gene loci that correlate with osteoporosis in the literature. In this study, we develop a new literature-based approach, a decisive gene strategy (DGS), to examine the sufficiency of the cumulative sample size for each gene locus and to assess whether a definite conclusion of the association between the gene locus and osteoporosis can be drawn. METHODS: The DGS was used to search PubMed, Embase, and Cochrane databases for all meta-analyses that correlated gene polymorphisms with osteoporosis. Trial sequential analysis was employed to examine the sufficiency of the cumulative sample size. Finally, we assessed the importance of gene loci in osteoporosis based on whether there were enough sample sizes and the heterogeneity of the literature with the I2 value. RESULTS: After excluding 169 irrelevant publications, 39 meta-analysis papers were obtained. Among Caucasians, in 17 gene loci, there were eight gene loci (e.g., vitamin D Receptor ApaI rs7975232) with sufficient cumulative sample size to confirm that they were unrelated to the disease. Among Asians, in 15 gene loci, four gene loci that had sufficient sample sizes were risk factors: VDR FokI rs2228570 (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.22-1.70), TGF ß1 rs1800470 (OR = 1.35, 95% CI = 1.10-1.65), IGF1 rs2288377 (OR = 1.44, 95% CI = 1.28-1.62), and IGF1 rs35767 (OR = 1.20, 95% CI = 1.06-1.36), respectively, whereas one gene locus, ESR2 RsaI rs1256049 (OR = 0.69, 95% CI = 0.59-0.81), was a protective factor. CONCLUSIONS: The DGS successfully identified five gene loci in osteoporosis that will apply to other diseases to find causal genes, which may contribute to further genetic therapy.

Positive Association Between Fluoroquinolone Exposure and Tendon Disorders: A Nationwide Population-Based Cohort Study in Taiwan.

Introduction: Fluoroquinolone exposure is reportedly associated with a higher risk of tendon disorders, tendonitis, or tendon rupture. However, studies in East Asian populations have not confirmed these risks in patients with comorbidities or concomitant medication use. This cohort study was designed to investigate the associations among fluoroquinolone exposure, comorbidities, medication use, and tendon disorders in Taiwan. Materials and Methods: This population-based, nationwide, observational, cohort study used data from the National Health Insurance Research database in Taiwan, a nationwide claims database that covers more than 99% of the Taiwanese population. The study period was from January 2000 to December 2015, and the median follow-up time was 11.05 ± 10.91 years. Patients who were exposed to fluoroquinolones for more than three consecutive days were enrolled, and patients without fluoroquinolone exposure who were matched by age, sex, and index year were enrolled as controls. The associations of comorbidities and concomitant medication use with tendon disorder occurrence were analyzed using Cox regression models. Results: The incidence of tendon disorders were 6.61 and 3.34 per 105 person-years in patients with and without fluoroquinolone exposure, respectively (adjusted hazard ratio, 1.423; 95% confidence interval [1.02,1.87]; p = 0.021). Sensitivity analyses yielded similar results. Patients under 18 and over 60 years with fluoroquinolone exposure; those with chronic kidney disease, diabetes, rheumatologic disease, cardiac disease, lipid disorder, or obesity; and those who concomitantly used statins, aromatase inhibitors, or glucocorticoids, had a significantly higher risk of tendon disorders. Conclusion: The long-term risk of tendon disorders was higher in patients with fluoroquinolone exposure than in those without fluoroquinolone exposure. Clinicians should assess the benefits and risks of fluoroquinolone use in patients at high risk of tendon disorders who require fluoroquinolone administration.

Utility of magnetic resonance spectroscopy and diffusion-weighted imaging for detecting changes in the femoral head in divers with hip pain at risk for dysbaric osteonecrosis.

BACKGROUND: Ischemia before the development of dysbaric osteonecrosis (DON) in femoral heads has never been investigated. We assessed whether quantitative magnetic resonance spectroscopy (MRS) and diffusion weighted imaging (DWI) could detect dysbaric changes in divers with hip pain. METHODS: This IRB-approved exploratory study recruited 17 divers [9 with hip pain (Group 1); 8 asymptomatic (Group 2)] with normal findings on radiographs and conventional magnetic resonance imaging scans were age-, gender- and body-mass-index matched to 17 non-divers as controls (Group 1C, 2C). Apparent diffusion coefficients (ADCs) and MRS spectra were obtained from regions/voxels of interest on the femoral heads of all subjects. LCModel was used to determine water content, lipid composition, and the unsaturation index in bone marrow. Mann-Whitney non-parametric test was used to compare results of quantitative MRS and ADCs of ipsilateral femoral heads between divers and controls. RESULTS: MRS of the ipsilateral femoral heads revealed higher water (peak: 4.7 ppm) content, lower total lipid fraction (TLF), and higher unsaturation index (UI) of lipids in Group 1 than in Group 2 (water: P=0.040; UI: P=0.022) and Group 1C (water: P=0.027; TLF: P=0.039; UI: P=0.009). In contrast, femoral head ADCs were comparable between divers and controls. Five out of nine symptomatic divers were contacted for follow-up MRS and DWI studies, and the mean difference in water content in the femoral heads of patients with osteonecrosis was also higher than that in patients with symptom relief (osteonecrosis: 0.077±0.130 vs. symptom relief: 0.003±0.010). CONCLUSIONS: Dysbaric change in the femoral heads of divers with hip pain can be detected using quantitative MRS, which reveals increases in water content and UI of lipids, and a decrease in TLF.

Generation of human induced pluripotent stem cells from cystic fibrosis patient carrying nonsense mutation (p.S308X) in CFTR gene.

Cystic fibrosis (CF) is a genetic disease affects CFTR channel synthesis. While 90 percent of the CF patients now benefit from small molecule target therapies, this treatment has yet to extend to those bearing nonsense mutations. Studies of these rare mutations using cell lines with native pathological signatures of the disease may lead to breakthroughs in therapeutic development. Here, we report the generation of CF patient-derived induced pluripotent stem cells (iPSCs) carrying a nonsense mutation at position 308 (S308X). The pluripotency and genomic profile of the iPSC line was validated as a resource that can enable future research for CF.

Implantation of monocusp valve prolongs the duration of chest tube drainage in children with tetralogy of fallot after corrective surgery.

BACKGROUND: Right ventricular outflow tract obstruction relief is one of the major procedures during the total correction of tetralogy of Fallot (TOF). Pulmonary insufficiency (PI) is usually inevitable after a transannular incision with a patch repair is performed. Therefore, some surgeons advocate to place a monocusp valve within the transannular patch (TAP) in order to decrease the severity of the PI. However, the monocusp valve seemed not be very effective in some patients who underwent the complete TOF repair. METHODS: Patients who had the classic form of TOF between January 2009 and January 2017 and underwent the corrective surgery with a TAP by the same cardiovascular surgeon were identified for further analysis. Clinical information including demographics at operation, perioperative data, and postoperative outcome were collected retrospectively and compared between the group with and without a monocusp valve. RESULTS: A total of 24 TOF cases were included in the final analysis, and 16 (66.7%) patients received a monocusp valve placement. The patients' characteristics before and during the surgery were similar between the two groups. The median duration of chest tube drainage after the total correction in the monocusp group was longer than those without the valve (p = 0.04). There was no difference in the immediate postoperative data, including the inflammation/infection status, the duration of mechanical ventilation, and the length of ICU and hospital stay. CONCLUSION: Implantation of a monocusp valve during the total TOF correction using a TAP did not bring benefit to improve the immediate postoperative outcomes, especially the duration of the pleural drainage. Further study with a prospective design and a larger number of cases is needed.

Genetic association between TNF-α G-308A and osteoarthritis in Asians: A case-control study and meta-analysis.

BACKGROUND: Osteoarthritis (OA) is an important health issue in elderly people. Many studies have suggested that genetic factors are important risk factors for OA, of which tumor necrosis factor-α (TNF-α) is one of the most examined genes. Moreover, several studies have investigated the relationship between TNF-α G-308A polymorphisms and OA risk, but consistent results have not been obtained. OBJECTIVE: This study examines the association between TNF-α G-308A polymorphisms and knee OA. Moreover, meta-analysis and trial sequential analysis (TSA) was used to determine whether this is a susceptibility gene for knee OA. METHODS: Between 2015 and 2019, 591 knee OA cases and 536 healthy controls were recruited. The Kellgren-Lawrence grading system was used to identify the knee OA cases. A meta-analysis was conducted including related studies published until 2020 from PubMed, Embase, and previous meta-analysis to improve the evidence level of the current study. The results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) to evaluate the effect of this polymorphism on knee OA risk. The TSA was used to estimate the sample sizes required in this issue. RESULTS: A nonsignificant association was found between the AA genotype and knee OA [adjusted OR, 0.84; 95% CI, 0.62-1.15) in the recessive model] in the present case-control study, and analysis of other genetic models showed a similar trend. After adding the critical case-control samples for Asians, the TNF-α G-308A, AA genotype exhibited 2.57 times more risk of developing arthritis when compared with the GG + GA genotype (95% CI, 1.56-4.23), and the cumulative samples for TSA (n = 2182) were sufficient to obtain a definite conclusion. CONCLUSIONS: The results of this meta-analysis revealed that the TNF-α G-308A, AA genotype is a susceptible genotype for OA in the Asian population. This study integrated all current evidence to arrive at this conclusion, suggesting that future studies on Asians are not required.

High-Molecular-Weight Hyaluronic Acid Inhibits IL-1ß-Induced Synovial Inflammation and Macrophage Polarization through the GRP78-NF-κB Signaling Pathway.

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1ß to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1ß increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1ß-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1ß culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

Attenuative Effects of Platelet-Rich Plasma on 30 kDa Fibronectin Fragment-Induced MMP-13 Expression Associated with TLR2 Signaling in Osteoarthritic Chondrocytes and Synovial Fibroblasts.

Proteolytic fragments of fibronectin can have catabolic effects on cartilage, menisci, and synovium. Previous studies have reported that Toll-like receptor (TLR) signaling pathways might be associated with joint inflammation and joint destruction. Platelet-rich plasma (PRP) is increasingly being used to treat a range of joint conditions; however, it has yet to be determined whether PRP influences fibronectin fragment (FN-f) procatabolic activity and TLRs. In this study, human primary culture cells were treated with 30 kDa FN-f with/without PRP co-incubation, and then analyzed using real-time PCR to determine gene expression levels in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts. Protein levels were evaluated by Western immunoblotting. This study observed an increase in the protein expression of matrix metalloproteinases (MMPs), Toll-like receptor 2 (TLR2), nitric oxide synthase 2 (NOS2), prostaglandin-endoperoxide synthase (PTGS2), and cyclooxygenase 2 (COX2) in articular chondrocytes, meniscal fibrochondrocytes, and synovial fibroblasts following insult with 30 kDa FN-f. Upregulation of these genes was significantly attenuated by PRP treatment. TLR2 and matrix metalloproteinase 13 (MMP-13) were also significantly attenuated by cotreatment with 30 kDa FN-f + PRP + TLR2 inhibitor. PRP treatment was shown to attenuate the 30 kDa FN-f-induced MMP-13 expression associated with the decreased expression of TLR2 in osteoarthritic chondrocytes and synovial fibroblasts. PRP treatment was also shown to attenuate procatabolic activity associated with MMP-13 expression via the TLR2 signaling pathway.

Ameliorative Effects of Cardamonin on Monosodium Urate-Induced Gouty Arthritis through Inhibiting NLRP3 Inflammasome Mediation.

Background and Objectives: Gouty arthritis is an acute inflammatory response caused by the precipitation of monosodium urate (MSU) crystals in joints. The triggering of MSU leads to increased production of inflammatory cytokines, such as interleukin-1ß, which in turn lead to the formation of macromolecular complexes, referred to as inflammasomes. Thorough characterization of the NLRP3 inflammasome can be used as an indicator of an immune response against harmful stimuli. Cardamonin is a chalcone, mainly found in the seeds of Alpinia katsumadai, and exhibits anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines in vitro. However, the mechanism by which cardamonin treatment alleviates gouty arthritis has yet to be fully elucidated. Materials and Methods: In vitro or in vivo models were used to study whether cardamonimn inhibited NLRP3 inflammasome activation or suppressed gouty inflammation. Results: In the current study, we determined that most NLRP3 was released passively after MSU stimulation, and this release of NLRP3 promoted caspase-1 activation and IL-1ß secretion. Cardamonin was shown to decrease both the activity of caspase-1 and secretion of IL-1ß in J774A.1 macrophage cells subjected to MSU stimulation. Cardamonin was also shown to attenuate the production of COX-2 in MSU-stimulated J774A.1 macrophage cells. Finally, cardamonin reduced the thickness of the synovial lining and the infiltration of gouty arthritis in a rat model. Conclusions: Overall, cardamonin significantly attenuated IL-1ß secretion, caspase-1 activity, and COX-2 production stimulated by MSU. These findings provide new insights into the molecular mechanisms underlying the effects of cardamonin treatment for gouty arthritis.

Interleukin-26 Has Synergistic Catabolic Effects with Palmitate in Human Articular Chondrocytes via the TLR4-ERK1/2-c-Jun Signaling Pathway.

The inflammatory cytokine interleukin-26 (IL-26) is highly expressed in the serum and synovial fluid of patients with inflammatory arthritis. The effect of IL-26 on human articular chondrocytes (HACs) remains unclear. Obesity is associated with disability of patients with rheumatoid arthritis and disease activity in those with ankylosing spondylitis. The saturated free fatty acid palmitate with IL-1ß can synergistically induce catabolic effects in HACs. The aim of this study was to evaluate the effects of IL-26 and palmitate in HACs. In this study, palmitate markedly synergizes the IL-26-induced proinflammatory effects and matrix protease, including COX-2, IL-6, and MMP-1, in HACs via the toll-like receptor 4 (TLR4)-ERK1/2-c-Jun signal transduction pathway. The synergistic catabolic effects of palmitate and IL-26 were attenuated by inhibitors of TLR4 (TAK242), ERK1/2 (U0126), or c-Jun (SP600125) in HACs and cartilage matrix. In addition, metformin, a potential inhibitor of TLR4, also decreased expression of COX-2 and IL-6 induced by co-incubation with IL-26 and palmitate. IL-26 and palmitate synergistically induced expression of inflammatory and catabolic mediators, resulting in articular cartilage matrix breakdown. The present study also revealed a possible mechanism and therapeutic targets against articular cartilage degradation by increased saturated fatty acids in patients with inflammatory arthritis.