Chang Gung Memorial Hospital at Chia yi

Jiayi Shi, Taiwan

Chang Gung Memorial Hospital at Chia yi

Jiayi Shi, Taiwan

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Shih M.-H.,Johns Hopkins University | Shih M.-H.,Chang Gung Memorial Hospital at Chia Yi | Kao S.-C.,Johns Hopkins University | Kao S.-C.,Chang Gung Memorial Hospital | And 3 more authors.
Journal of Pain | Year: 2012

Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical for neuronal plasticity. However, how it participates in central sensitization underlying chronic pain is unclear. Here, we show that NMDA receptors are required for the functional role of spinal cord mTOR in bone cancer pain induced by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, a specific mTOR inhibitor, dose dependently attenuated the development and maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. Rapamycin alone did not affect locomotor activity and acute responses to thermal or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) was increased time dependently in L4-5 dorsal horn and transiently in L4-5 dorsal root ganglions on the ipsilateral side after PCC injection, although total expression of mTOR or p70S6K was not changed in these regions. The increases in dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn activation of the mTOR pathway participates in NMDA receptor-triggered dorsal central sensitization under cancer pain conditions. Perspective: The present study shows that inhibition of spinal mTOR blocks cancer-related pain without affecting acute pain and locomotor function. Given that mTOR inhibitors are FDA-approved drugs, mTOR in spinal cord may represent a potential new target for preventing and/or treating cancer-related pain. © 2012 by the American Pain Society.


Yu H.-P.,Chang Gung Memorial Hospital | Yu H.-P.,Chang Gung University | Hsieh P.-W.,Chang Gung University | Chang Y.-J.,Chang Gung University | And 3 more authors.
Free Radical Biology and Medicine | Year: 2011

Neutrophil activation after trauma-hemorrhagic shock (T/H) has been implicated in the development of multiple organ dysfunction (MOD). In this study, we report that a small chemical compound, 2-(2-fluorobenzamido)benzoic acid ethyl ester (EFB-1), exhibited a potent inhibitory effect on the formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-induced superoxide anion (O2 •-) release and CD11b expression by human neutrophils. Additionally, administration of EFB-1 in rats subjected to T/H caused a significant improvement in MOD. EFB-1 treatment induced an increase in cAMP formation and protein kinase (PK) A activity in FMLP-activated neutrophils, which occurred through the selective inhibition of cAMP-specific phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function or cGMP-specific PDE activity. FMLP-induced phosphorylation of protein kinase B (AKT), but not calcium mobilization, was reduced by EFB-1. The inhibitory effects of EFB-1 on O2 •- production, CD11b expression, and AKT phosphorylation were reversed by PKA inhibitors (H89 and KT5720). Significantly, administration of EFB-1 (1 mg/kg body wt) attenuated the myeloperoxidase activity of the intestines, lungs, and liver and reduced the wet/dry weight ratio of the intestines and lungs and plasma alanine aminotransferase and aspartate aminotransferase levels in Sprague-Dawley rats after T/H. Therefore, EFB-1 is a new inhibitor of cAMP-specific PDE that potently suppresses O2 •- release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats. © 2011 Elsevier Inc.


Chen M.-F.,Chang Gung Memorial Hospital at Chia Yi | Chen M.-F.,Chang Gung University | Lu M.-S.,Chang Gung Memorial Hospital at Chia Yi | Chen P.-T.,Chang Gung Memorial Hospital | And 5 more authors.
Journal of Molecular Medicine | Year: 2012

Interleukin (IL)-1 beta has been reported to be a marker of shorter survival in gastric and colorectal adenocarcinoma. In the present study, we examined the potential role and prognostic value of IL-1 beta in esophageal squamous cell carcinoma (SCC). Human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments, in which biological changes after experimental manipulation of IL-1 beta signaling were explored, including tumor growth, invasion capacity, and the sensitivity to treatment. Moreover, 147 esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of IL-1 beta with clinical outcome. Our data revealed that IL-1 beta was significantly overexpressed both at mRNA and protein levels in cancer specimens compared to nonmalignant tissues. When IL-1 beta signaling was blocked, tumor growth, invasion ability, and treatment resistance were attenuated. Activation of NF-kappa B, increase of E2-EPF ubiquitin carrier protein and subsequent epithelial-mesenchymal transition might be the underlying mechanisms of the more aggressive tumor growth in IL-1 beta-positive esophageal cancer. The immunochemistry findings indicate that positivity staining of IL-1 beta correlated significantly with higher clinical stage, lower response rate to concurrent chemoradiotherapy (CCRT), and higher recurrence rate after curative treatment. Moreover, IL-1 beta was a significant predictor of survival in patients undergoing surgical intervention or definite CCRT. In conclusion, IL-1 beta is significantly linked to poor prognosis for patients with esophageal cancer and may be a promising molecular target for therapeutic intervention for esophageal SCC. © Springer-Verlag 2011.


Hwang T.-L.,Chang Gung University | Wang C.-C.,Chang Gung University | Kuo Y.-H.,National Research Institute of Chinese Medicine | Huang H.-C.,China Medical University at Taichung | And 3 more authors.
Biochemical Pharmacology | Year: 2010

The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O2 -) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-α-l-arabinopyranoside)-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O2 - generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47phox expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O2 - generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases. © 2010 Elsevier Inc.


Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung University | Chen C.-F.,National Tsing Hua University | Chen C.-F.,Industrial Technology Research Institute of Taiwan | And 8 more authors.
Biomaterials | Year: 2010

Osteomyelitis characterized by an inflammatory response often leads to bone loss and the spread of bacterial infection to surrounding soft tissues. To overcome the side effects induced by the systemic antibiotic treatment for osteomyelitis, recent investigations have explored the use of antibiotic-loaded undegradable or biodegradable delivery implants at the infected bone. Here, we show a novel biodegradable thermosensitive implant composed of poly(ethylene glycol) monomethyl ether (mPEG) and poly(lactic-co-glycolic acid) (PLGA) copolymer as a sol-gel drug delivery system for treating bone infection. The physical properties of a series of mPEG-PLGA nanocomposites, including the critical micelle concentration (CMC), particle size, polyindex (PI), sol-gel transition, viscosity and degradation rate, have been characterized in vitro. This sol-to-gel drug delivery system could provide several advantages in treating osteomyelitis, including easy preparation, 100% encapsulated rate, near-linear sustained release of drugs, injectable design and in situ gelling at the target tissue. Similar to the undegradable teicoplanin-impregnated polymethylmethacylate (PMMA) bone cements, we showed that implantation of the mPEG-PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The use of the mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for other infected diseases. © 2010 Elsevier Ltd.


Tsai Y.-H.,Chang Gung Memorial Hospital at Chia Yi | Tsai Y.-H.,Chang Gung University | Hsu R.W.-W.,Chang Gung Memorial Hospital at Chia Yi | Hsu R.W.-W.,Chang Gung University | And 5 more authors.
Clinical Orthopaedics and Related Research | Year: 2010

Background: Vibrio necrotizing fasciitis is a rare and life-threatening soft tissue infection, with fulminant clinical courses and high mortality rates. However, the lack of specific disease characteristics and diagnostic tools during the initial examination may delay diagnosis. Questions/purposes: We (1) asked whether the clinical indicators could predict laboratory findings during the initial stage of Vibrio necrotizing fasciitis and (2) determined the relationships between the laboratory risk indicator for necrotizing fasciitis (LRINEC) score and the diagnosis of Vibrio infection. Methods: We retrospectively reviewed 70 patients with 71 episodes of Vibrio necrotizing fasciitis and sepsis. Of the 70 patients, 68 had a history of contact with seawater or raw seafood; 66 had underlying chronic diseases. Results: Eighteen patients (25.7%) died a mean 18.7 days after admission, and 52 patients survived. A systolic blood pressure of 90 mm Hg or less at the time of admission to the emergency room was associated with mortality. Patients who died had lower leukocyte counts, segmented leukocyte counts, platelet counts, and serum albumin levels compared with the patients who survived and higher counts of band forms of leukocytes. Only eight patients (11%) who survived had a LRINEC score of 6 or greater. Conclusions: The LRINEC scoring system is not applicable when treating such a highly lethal disease. We propose that severe hypoalbuminemia, severe thrombocytopenia, and increased banded forms of leukocytes are laboratory risk indicators of necrotizing fasciitis that aid in pointing toward initiation of early surgery and predict a higher risk of death. Level of Evidence: Level III Prognostic study. See the Guidelines for Authors for complete descriptions of levels of evidence. © 2010 The Association of Bone and Joint Surgeons®.


Lin S.-J.,Chang Gung Memorial Hospital at Chia Yi | Chen C.-L.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Hsu W.-H.,Chang Gung Memorial Hospital at Chia Yi | Hsu W.-H.,Chang Gung University
Injury | Year: 2014

Objective Our study aimed to determine whether the displacement and morphology of a fragment in femur fracture with Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association/32-B/32-C (AO/OTA/32-B/32-C) classification affect the outcomes following closed reduction and internal fixation with an interlocking nail. Design This was a retrospective study. Setting The study was conducted at a Level III trauma centre. Patients A total of 50 consecutive patients presenting femoral shaft fracture with AO/OTA-type 32-B/32-C were included in the present study. Interventions Patients were divided into two groups according to the displacement of the fragments. In the large displacement group, patients were further subgrouped according to whether a reversed morphology of the fragment was present. Outcomes measurement The radiographic union score of femur (RUSF), the mean union time and the re-operation rate were assessed. Results The union rate of small- and large-gap groups at 12 months postoperatively was 75.9% and 21.1%, respectively (p = 0.000). The mean union time of those union cases in these two groups was 7.8 and 13.0 months, respectively (p = 0.000). The union rate of the non-reversed and reversed groups at 12 months postoperatively was 30% and 11.1%, respectively (p = 0.179). The mean RUSF at 12 months in the non-reversed and reversed groups was 8.8 and 8.3, respectively (p = 0.590). However, we found that patients presenting a reversed fragment had an increased risk of more than one re-operation (p = 0.030). Conclusions A fragmentary displacement of >1 cm in AO/OTA-type 32-B/32-C femoral shaft fracture after nailing affected bone healing. Among the large-gap group patients, an unreduced reverse fragment presented a negative prognostic factor for re-operation. Level of evidence Prognostic level III. © 2013 Elsevier Ltd.


Huang T.-W.,Chang Gung Memorial Hospital at Chia Yi | Hsu W.-H.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Hsu R.W.-W.,Chang Gung Memorial Hospital at Chia Yi | And 2 more authors.
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: The value of computer-assisted surgery in total knee arthroplasty for arthritic knees continues to be debated. We hypothesized that the usefulness of computer assistance is related to the magnitude of the deviation from the preoperative mechanical axis and that computer-assisted surgery may be beneficial under certain circumstances. Methods: Patients with bilateral knee osteoarthritis and genu varus deformity who were to have staged bilateral total knee arthroplasty were enrolled. The patients randomly underwent computer-assisted total knee arthroplasty in one knee and conventional total knee arthroplasty in the contralateral knee. The two methods were compared for accuracy of placement of the components and lower extremity alignment after total knee arthroplasty as determined by six radiographic parameters. Results: One hundred and thirteen patients (226 knees) met the inclusion criteria. For patients with a preoperative mechanical axis deviation of <10° and those with a deviation of 10° to 14.9° in both knees, the postoperative radiographic parameters did not differ significantly between the two techniques. In patients with a preoperative mechanical axis deviation of >20°, the reconstructed mechanical axes were significantly closer to normal in the computer-assisted total knee arthroplasty group. Significant results were also noted in the anatomical axes, femoral valgus angle, and femoral flexion angle. Furthermore, a higher percentage of knees in which computer-assisted surgery was used had restoration of the mechanical axis within 3° of neutral. Conclusions: Computer-assisted surgery was a valuable adjunct for obtaining proper alignment during total knee arthroplasty in patients with knee osteoarthritis with severe varus deformity. Conventional total knee arthroplasty was as effective as computer-assisted total knee arthroplasty for obtaining proper alignment in patients with a minor to moderate deformity. Level of Evidence: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.


Lee C.-Y.,Chang Gung Memorial Hospital at Chia Yi | Kuo L.-T.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung Memorial Hospital at Chia Yi | Peng K.-T.,Chang Gung University | And 4 more authors.
BMC Infectious Diseases | Year: 2011

Background: Monomicrobial necrotizing fasciitis is rapidly progressive and life-threatening. This study was undertaken to ascertain whether the clinical presentation and outcome for patients with this disease differ for those infected with a gram-positive as compared to gram-negative pathogen.Methods: Forty-six patients with monomicrobial necrotizing fasciitis were examined retrospectively from November 2002 to January 2008. All patients received adequate broad-spectrum antibiotic therapy, aggressive resuscitation, prompt radical debridement and adjuvant hyperbaric oxygen therapy. Eleven patients were infected with a gram-positive pathogen (Group 1) and 35 patients with a gram-negative pathogen (Group 2).Results: Group 2 was characterized by a higher incidence of hemorrhagic bullae and septic shock, higher APACHE II scores at 24 h post-admission, a higher rate of thrombocytopenia, and a higher prevalence of chronic liver dysfunction. Gouty arthritis was more prevalent in Group 1. For non-survivors, the incidences of chronic liver dysfunction, chronic renal failure and thrombocytopenia were higher in comparison with those for survivors. Lower level of serum albumin was also demonstrated in the non-survivors as compared to those in survivors.Conclusions: Pre-existing chronic liver dysfunction, chronic renal failure, thrombocytopenia and hypoalbuminemia, and post-operative dependence on mechanical ventilation represent poor prognostic factors in monomicrobial necrotizing fasciitis. Patients with gram-negative monobacterial necrotizing fasciitis present with more fulminant sepsis. © 2011 Lee et al; licensee BioMed Central Ltd.


Tsai Y.-H.,Chang Gung Memorial Hospital at Chia Yi | Hsu R.W.-W.,Chang Gung Memorial Hospital at Chia Yi | Huang K.-C.,Chang Gung Memorial Hospital at Chia Yi | Huang T.-J.,Chang Gung Memorial Hospital at Chia Yi
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: Vibrio vulnificus can cause a rapidly progressive fatal soft-tissue infection. Staphylococcus aureus is the most common cause of skin and soft-tissue infections reported worldwide, and, in particular, methicillin-resistant Staphylococcus aureus has emerged as the most common isolate in emergency departments. The purposes of the present study were to compare the specific characteristics of Vibrio vulnificus and Staphylococcus aureus infections and to compare the clinical outcomes of Vibrio vulnificus, methicillin-resistant Staphylococcus aureus, and methicillin-sensitive Staphylococcus aureus necrotizing infections. Methods: One hundred and fifteen patients with necrotizing fasciitis caused by Vibrio vulnificus (sixty patients) or Staphylococcus aureus (fifty-five patients) were retrospectively reviewed over a six-year period. Differences in mortality, patient characteristics, clinical presentations, laboratory data, and hospital course were compared between the Vibrio vulnificus and Staphylococcus aureus groups. Results: Nineteen patients (including eleven in the Vibrio vulnificus group and eight in the Staphylococcus aureus group) died, resulting in a mortality rate of 16.5%. We found significant differences between the two groups with regard to hypotension, fever, the interval between contact and admission, the interval between the diagnosis of necrotizing fasciitis and the first operation, and admission to the intensive care unit. The patients in the Vibrio vulnificus group had significantly lower total white blood-cell counts, higher banded white blood-cell counts, and lower platelet counts as compared with those in the Staphylococcus aureus group. The proportion of patients who were hypotensive (as indicated by a systolic blood pressure of ≤90 mm Hg) was significantly greater in the methicillin-resistant Staphylococcus aureus subgroup than in the methicillin-sensitive Staphylococcus aureus subgroup. Patients with hepatic dysfunction were significantly more likely to have Vibrio vulnificus infection, and those with diabetes mellitus were significantly more likely to have Staphylococcus aureus infection. Conclusions: Necrotizing fasciitis caused by Vibrio vulnificus and Staphylococcus aureus is a surgical emergency. Vibrio vulnificus infection progresses more rapidly and the clinical characteristics are more fulminant than either methicillin-resistant Staphylococcus aureus or methicillin-sensitive Staphylococcus aureus infection. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

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