Ming-Shium Hsieh

Suppression of Fas ligand expression on endothelial cells by arsenite through reactive oxygen species

Chronic exposure to arsenite is associated with vascular disease, such as arteriosclerosis. However, the cellular mechanisms for vascular disease in response to arsenic are not well known. The present study has demonstrated that arsenite not arsenate decreased the Fas ligand (FasL) expression on ECV304 cells through reactive oxygen species. Incubation of ECV304 cells with arsenite decreased the FasL expression and increased the intracellular peroxide levels. In addition, hydrogen peroxide was found to suppress FasL expression in a dose-dependent manner. The antioxidant, N-acetyl-cysteine, blocked the suppression of FasL expression in response to arsenite. These data suggested that arsenite initiates endothelium dysfunction, at least partly, by suppressing the FasL expression through activating reactive oxygen species sensitive endothelial cell signaling.

Hyaluronan regulates PPARγ and inflammatory responses in IL-1β-stimulated human chondrosarcoma cells, a model for osteoarthritis

The carbohydrate polymer, hyaluronan, is a major component of the extracellular matrix in animal tissues. Exogenous hyaluronan has been used to treat osteoarthritis (OA), a degenerative joint disease involving inflammatory changes. The underlying mechanisms of hyaluronan in OA are not fully understood. Pro-inflammatory interleukin (IL)-1β downregulates peroxisome proliferator-activated receptor gamma (PPARγ), and increases expression of matrix metalloproteinases (MMPs) which are responsible for the degeneration of articular cartilage. The effects of low- and high-molecular-weight hyaluronan (oligo-HA and HMW-HA) on the inflammatory genes were determined in human SW-1353 chondrosarcoma cells. HMW-HA antagonized the effects of IL-1β by increasing PPARγ and decreasing cyclooxygenase (COX)-2, MMP-1, and MMP-13 levels. It promoted Akt, but suppressed mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NFκB) signaling, indicating anti-inflammatory effects. In contrast, the cells had overall opposite responses to oligo-HA. In conclusion, HMW-HA and oligo-HA exerted differential inflammatory responses via PPARγ in IL-1β-treated chondrosarcoma cells.

Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways.

The purpose of the present study was to elucidate the possible signal transduction pathway involved in the underlying mechanism of glucosamine (GLN)’s influence on the gene expression of matrix metalloproteinases (MMPs) in chondrocytes stimulated with IL-1β. Using chondrosarcoma cells stimulated with IL-1β, the effects of GLN on the mRNA and protein levels of MMP-3, the activation of JNK, ERK, p38, NF-κB, and AP-1, the nuclear translocation of NF-κB/Rel family members, and PI3-kinase/Akt activation were studied. GLN inhibited the expression and the synthesis of MMP-3 induced by IL-1β, and that inhibition was mediated at the level of transcription involving both the NF-κB and AP-1 transcription factors. Translocation of NF-κB was reduced by GLN as a result of the inhibition of IκB degradation. A slightly synergistic effect on the activation of AP-1 induced by IL-1β was shown in the presence of GLN. Among MAPK pathways involved in the transcriptional regulation of AP-1, phosphorylation of JNK and ERK was found to increase with the presence of GLN under IL-1β treatment, while that for p38 decreased. It was also found that GLN alone, but also synergistically with IL-1β, was able to activate the Akt pathway. The requirements of NF-κB translocation and p38 activity are indispensably involved in the induction of MMP-3 expression in chondrosarcoma cells stimulated by IL-1β. Inhibition of the p38 pathway in the presence of GLN substantially explains the chondroprotective effect of GLN on chondrocytes that regulate COX-2 expression, PGE2 synthesis, and NO expression and synthesis. The chondroprotective effect of GLN through the decrease in MMP-3 production and stimulation of proteoglycan synthesis may follow another potential signaling pathway of Akt.

Regulation of MMP-3 expression and secretion by the chemokine eotaxin-1 in human chondrocytes.

BackgroundOsteoarthritis (OA) is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins. Studies demonstrated the involvement of chemokines in this process, and some may potentially serve as diagnostic markers and therapeutic targets; however, the underlying signal transductions are not well understood.MethodsWe investigated the effects of the CC chemokine eotaxin-1 (CCL11) on the matrix metalloproteinase (MMP) expression and secretion in the human chondrocyte cell line SW1353 and primary chondrocytes.ResultsEotaxin-1 significantly induced MMP-3 mRNA expression in a dose-dependent manner. Inhibitors of extracellular signal-regulated kinase (ERK) and p38 kinase were able to repress eotaxin-1-induced MMP-3 expression. On the contrary, Rp-adenosine-3,5-cyclic monophosphorothioate (Rp-cAMPs), a competitive cAMP antagonist for cAMP receptors, and H-89, a protein kinase A (PKA) inhibitor, markedly enhanced eotaxin-1-induced MMP-3 expression. These results suggest that MMP-3 expression is specifically mediated by the G protein-coupled eotaxin-1 receptor activities. Interestingly, little amount of MMP-3 protein was detected in the cell lysates of eotaxin-1-treated SW1353 cells, and most of MMP-3 protein was in the culture media. Furthermore we found that the eotaxin-1-dependent MMP-3 protein secretion was regulated by phospholipase C (PLC)-protein kinase C (PKC) cascade and c-Jun N-terminal kinase (JNK)/mitogen-activated protein (MAP) kinase pathways. These data indicate a specific regulation of MMP-3 secretion also by eotaxin-1 receptor activities.ConclusionsEotaxin-1 not only induces MMP-3 gene expression but also promotes MMP-3 protein secretion through G protein-coupled eotaxin-1 receptor activities. Chemokines, such as eotaxin-1, could be a potential candidate in the diagnosis and treatment of arthritis.

Using 18F-FDG microPET imaging to measure the inhibitory effects of Clematis chinensis Osbeck on the pro-inflammatory and degradative mediators associated with inflammatory arthritis

AIM OF THE STUDYnThis study examined the modulating effects of Clematis chinensis Osbeck (Ranunculaeae) on pro-inflammatory and degradative mediators associated with inflammatory arthritis.nnnMATERIALS AND METHODSnPrimary human chondrocytes (PHC) were stimulated with IL-1β or lipopolysaccharide (LPS) to induce the enhanced release of prostaglandin E(2) (PGE(2)), metalloproteinase (MMP-3 and -13), and cyclooxygenase-2 (COX-2) protein expression. The (18)F-FDG microPET imaging system was used to evaluate the anti-arthritic effects of Clematis chinensisin vivo.nnnRESULTSnThe acetone extracted Clematis chinensis (CC6) contained the most total saponins compared to other solvents extracts and showed significant and dose-dependent inhibitory effects on PGE(2), MMP-3, -13, and COX-2 productions by LPS-stimulated PHC. Furthermore, CC6 also exerted inhibitory effects on 2-(18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake when assessed by positron emission tomography (PET) uptake in the joints and serum PGE(2) of rabbits with knee joints injected with LPS.nnnCONCLUSIONnThe results suggest the significant chondroprotective effects of Clematis chinensis are through its anti-inflammatory and MMPs inhibitory abilities. Meanwhile, we established a new analysis method to evaluate the Chinese herbal anti-arthritic effects.

Comparison of treatment outcomes following total knee arthroplasty among patients with rheumatoid arthritis and osteoarthritis: a nationwide population-based study

Comparison of treatment outcomes following total knee arthroplasty among patients with rheumatoid arthritis and osteoarthritis: a nationwide population-based study SIR, Total knee arthroplasty (TKA) is one of the most commonly performed surgeries for treating end-stage OA and RA to alleviate pain and recondition knee function [1]. There have long been concerns about post-operative treatment outcomes for OA and RA patients. However, most studies have focused on the long-term survival rate [2, 3] or standardized mortality ratios [4, 5] following TKA on patients with OA and/or RA. Very few studies have attempted to compare the short-term treatment outcomes following TKA for OA and RA patients. The aim of this study is to compare the risk of treatment outcomes (90-day re-admission and 90-day mortality) between OA and RA patients, using a 3-year nationwide populationbased database in Taiwan. This study used the National Health Insurance Research Database. In Taiwan, 29 266 patients who underwent primary TKA from 2002 to 2004 were identified based on procedure code 81.54 (total knee replacement). We excluded patients under 18 years of age in order to limit the study sample to the adult population. We also excluded patients who had diagnoses of metastatic or bone cancer, fracture or infection at admission. A total of 29 198 patients, including 768 suffering from RA and 28 430 from OA, were left. Since patients with RA were more likely to be female and younger than patients with OA, we then randomly extracted 3840 patients with OA (five for every patient with RA) matched with the RA patients in terms of age (<60, 60–69 and >69 years) and gender. Ultimately, our study cohort included 4608 patients who underwent TKA. The primary study outcomes were binary variables, including ‘90-day mortality’ and ‘90-day re-admission’. The ‘90-day re-admission’ was defined as patients re-hospitalized for local infection (including post-operative infection, infected post-operative seroma, infection and inflammation due to internal prosthetic device, implant and graft, acute osteomyelitis, chronic osteomyelitis and other cellulitis and abscess), cerebrovascular accident, thrombo-embolic events (including pulmonary embolism, fat embolism and deep venous thrombosis), cardiovascular/coronary heart disease (including myocardial infarction, angina, cardiac arrhythmias and congestive heart failure) and pneumonia within 90 days of the index TKA. Conditional logistic regression analyses which were conditioned on patient’s age and gender were performed. Table 1 shows that patients with RA have a higher rate of 90-day re-admission than patients with OA (14.2 vs 11.3%). After adjusting for the patient’s age, gender, Charlson Comorbidity Index, surgical procedure (unilateral vs bilateral), hospital accreditation level, teaching status and geographical location and surgeon’s age, conditional logistic regression revealed that the odds ratio (OR) of 90-day re-admission was 1.37 (95% CI 1.09, 1.74; P1⁄4 0.002) for patients with RA, compared with those with OA. No significant difference in 90-day mortality between patients with RA and OA was observed. We further analysed the causes and ORs for 90-day re-admission between the two groups of patients. Most re-hospitalizations within 90 days of the index TKA were due to local infection and pneumonia. After adjusting for other factors, patients with RA were more likely to be re-hospitalized within 90 days of the index TKA due to local infection (OR1⁄4 1.59; 95% CI 1.05, 2.39) and pneumonia (OR1⁄4 2.39; 95% CI 1.63, 3.48) compared with patients with OA. To our knowledge, this is the first population-based study to explore the risks for short-term re-admission and mortality among RA and OA patients receiving primary TKA in a Chinese population. Our results indicate that there was no significant difference in 90-day mortality between RA and OA patients. Nevertheless, the 90-day re-admission rate after TKA was significantly higher among the patients with RA compared with those with OA. We found infection was the predominant cause of 90-day re-admission following TKA. In addition, we also found that increased risks for re-admission, due to both pneumonia and local wound infection, were significantly higher among RA patients compared with those with OA. The mechanisms contributing to infection following TKA are multi-factorial, including biological (immunological, nutritional, etc.) and procedural factors [6]. Relatively compromised immune status that puts them at risk of infection has been recognized in RA patients [7]. In addition, some medications used for RA patients could alter immunological responses and wound healing processes, which further increase the risk for systemic and local infection [8, 9]. Our study has several limitations. First, some confounding variables such as obesity, social support and patients’ motivation and emotional status, which can potentially affect surgical outcomes, could not be assessed in our study. Secondly, we did not analyse medication use that could be associated with potential side effects. For example, NSAID use can lead to gastrointestinal bleeding and immunosuppressants can be associated with developing infection. In summary, the risk of 90-day re-admission after TKA is significantly higher among patients with RA compared with those with OA. In particular, increased risks of re-admission for pneumonia and local infection were

Correlation Between Scoliosis and Breast Asymmetries in Women Undergoing Augmentation Mammaplasty

BackgroundBreast asymmetries and scoliosis influence the results of augmentation mammaplasty. Although a variety of methods have been proposed to resolve breast asymmetries, to date, no simple preoperative algorithm has been proposed for predicting the breast volume and decreasing breast asymmetries in the place of subjective or expensive evaluation. The relationship between the scoliosis and breast volume asymmetry was further analyzed statistically in this study.MethodsThe study enrolled 60 scoliotic patients from 780 patients undergoing augmentation mammaplasty between January 2000 and March 2008. The average follow-up period was 2xa0years. The inclusion criteria required hypoplastic breasts, a difference in bilateral breast volumes greater than 20xa0ml, and scoliosis with a Cobb angle greater than 10°. The authors’ surgical algorithm demonstrated an anthropomorphic equation for predicting breast volume and selecting the correct implant size.ResultsPearson regression analysis showed that the breast volume asymmetry difference was significantly correlated with the severity of scoliosis (Cobb angle) (correlation coefficient, 0.901). No correlation between the difference in pre- and postoperative nipple and inframammary levels and the severity of scoliosis was noted. Augmentation mammaplasty significantly decreased the breast asymmetry differences (volume and nipple level) (pxa0<xa00.001). The average preoperative estimated breast volume was 45.3xa0ml for the smaller breast and 88.4xa0ml for the larger breast.ConclusionThis study found that the severity of scoliosis showed significant correlation with the breast volume asymmetry differences. Augmentation mammaplasty for breast asymmetries decreased not only the volume difference but also the difference in nipple levels.

Injectable hyaluronic-acid-doxycycline hydrogel therapy in experimental rabbit osteoarthritis

BackgroundOsteoarthritis (OA) is a common joint disease that causes disabilities in elderly adults. However, few long-lasting pharmacotherapeutic agents with low side effects have been developed to treat OA. We evaluated the therapeutic effects of intra-articular injections of hydrogels containing hyaluronic acid (HA) and doxycycline (DOX) in a rabbit OA model.ResultsThirteen week old New Zealand White rabbits undergone a partial meniscectomy and unilateral fibular ligament transection were administered with either normal saline (NT), HA, DOX or HA-DOX hydrogels on day 0, 3, 6, 9 and 12; animals were also examined the pain assessment in every three days. The joint samples were taken at day 14 post-surgery for further histopathological evaluation. The degree of pain was significantly attenuated after day 7 post-treatment with both HA and HA-DOX hydrogels. In macroscopic appearance, HA-DOX hydrogel group showed a smoother cartilage surface, no or minimal signs of ulceration, smaller osteophytes, and less fissure formation in compare to HA or DOX treatment alone. In the areas with slight OA changes, HA-DOX hydrogel group exhibited normal distribution of chondrocytes, indicating the existence of cartilage regeneration. In addition, HA-DOX hydrogels also ameliorated the progression of OA by protecting the injury of articular cartilage layer and restoring the elastoviscosity.ConclusionOverall, from both macroscopic and microscopic data of this study indicate the injectable HA-DOX hydrogels presented as a long-lasting pharmacotherapeutic agent to apply for OA therapy.

Students’ view upon graduation: a survey of medical education in Taiwan

BackgroundImproving the quality of medical education is a key goal of government policy in Taiwan. The aim of this study was to reflect the responses of medical education from the perspective of graduating medical students in Taiwan. This is the first survey study of medical education in Taiwan.MethodsUsing the Medical School Graduation Questionnaire from the Association of American Medical Colleges (AAMC), we distributed 406 questionnaires to medical students of four medical schools in their last semester, and received 270 back (response rate, 66.5%). There were 11 medical schools in Taiwan. Most questions were assessed on a 5-point Likert scale.ResultsStudents identified genetics, biochemistry, and ethics as the three most important premedical subjects preparing them for medical education and gross anatomy, physiology, and pharmacology as the three most helpful basic science subjects preparing them for clinical clerkships and electives. Most Taiwanese students were satisfied with their learning experience in internal medicine. Only 55.9% of students were confident that they had acquired the clinical skills required to become a resident, and 70.7% were satisfied with the quality of their medical education.ConclusionThe study offers preliminary results on the views of graduating students on the medical education system in Taiwan. In particular, our government and medical educators need to continuously put more effort into building students’ confidence in their clinical skills.

Serum Level of Interleukin-21 is Elevated in Chronic Rhinosinusitis:

Background Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinuses and mucosa with unclear pathogenesis. Interleukin (IL)-21 is mainly expressed in activated cluster of differentiation (CD)4+ T cells and has potent regulatory effects on the immune system. Objective This study is to determine whether IL-21 in the blood is correlated with CRS. Methods The blood samples from CRS patients and normal controls were analyzed in correlation with clinical features. The eosinophil percentage was counted, and serum levels of total immunoglobulin E (IgE) and IL-21 were analyzed by enzyme-linked immunosorbent assay (ELISA). In addition, IL-21 and interferon (IFN)-γ secreted from stimulated peripheral blood mononuclear cells (PBMCs) were measured by ELISA, and their mRNA expression levels were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Disease severity was scored based on computed tomography (CT) scan, nasal endoscopy, and global osteitis scoring scale (GOSS). Results A total of 55 CRS and 37 healthy subjects were recruited. The average levels of serum total IgE were 20 kU/L in normal group, 290 kU/L in CRS with nasal polys (CRSwNP), and 187 kU/L in CRS without nasal polys (CRSsNP). IL-21 levels were 28 pg/mL in normal group, 54 pg/mL in CRSwNP, and 71 pg/mL in CRSsNP. Both IgE and IL-21 were significantly elevated in both CRS patient subgroups. However, no significant difference was found between these two patient subgroups. The serum IL-21 levels correlated well with the disease severity in the patients. In addition, the secreted IL-21 was enhanced significantly in the patients PBMCs stimulated by phytohemagglutin (PHA). Conclusion IL-21 could be a target for diagnosis and treatment of CRS.