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1.  ent-kaur-16-en-19-oic acid, isolated from the roots of Aralia continentalis, induces activation of Nrf2 
Journal of ethnopharmacology  2011;137(3):1442-1449.
Aim of the study
Excessive inflammation can lead to tissue damage and dysfunction of vital organs. Hence, regulating inflammatory response is a viable therapeutic approach. In Asian countries, various inflammatory diseases have often effectively been treated with herbal remedies including the root extract of Aralia continentalis Kitagawa (Araliaceae). Here, we investigated the effect of kaurenoic acid (ent-kaur-16-en-19-oic acid: KA), a diterpenoid that is extracted from Aralia continentalis Kitagawa root, on inflammation.
Results
Western blot and RT-PCR analyses show that KA induced the nuclear localization of Nrf2 as low as 1 nM in concentration and that KA treatment induced the expression of Nrf2 dependent genes such as GCLC and HO-1. On the other hand, KA did not affect the degradation of cytoplasmic IκB-α, the nuclear localization of RelA (p65), and NF-κB transcriptional activity in RAW 264.7 cells treated with endotoxin. Consistent with these data, KA treatment failed to suppress gene expression of representative pro-inflammatory mediators including COX-2, nitric oxide, IL-1β, TNF-α, and IL-12, indicating that KA did not have an important impact on NF-κB activation.
Conclusion
Together, these results show that KA was an effective activator of Nrf2, and suggest that the beneficial effects of A. continentalis Kitagawa root extract are, at least in part, mediated by activating Nrf2.
doi:10.1016/j.jep.2011.08.024
PMCID: PMC3616193  PMID: 21884778
Inflammation; Kaurenoic acid; Herbal treatment; anti-inflammation; Nrf2
2.  The Insect Peptide Coprisin Prevents Clostridium difficile-Mediated Acute Inflammation and Mucosal Damage through Selective Antimicrobial Activity▿ 
Antimicrobial Agents and Chemotherapy  2011;55(10):4850-4857.
Clostridium difficile-associated diarrhea and pseudomembranous colitis are typically treated with vancomycin or metronidazole, but recent increases in relapse incidence and the emergence of drug-resistant strains of C. difficile indicate the need for new antibiotics. We previously isolated coprisin, an antibacterial peptide from Copris tripartitus, a Korean dung beetle, and identified a nine-amino-acid peptide in the α-helical region of it (LLCIALRKK) that had antimicrobial activity (J.-S. Hwang et al., Int. J. Pept., 2009, doi:10.1155/2009/136284). Here, we examined whether treatment with a coprisin analogue (a disulfide dimer of the nine peptides) prevented inflammation and mucosal damage in a mouse model of acute gut inflammation established by administration of antibiotics followed by C. difficile infection. In this model, coprisin treatment significantly ameliorated body weight decreases, improved the survival rate, and decreased mucosal damage and proinflammatory cytokine production. In contrast, the coprisin analogue had no apparent antibiotic activity against commensal bacteria, including Lactobacillus and Bifidobacterium, which are known to inhibit the colonization of C. difficile. The exposure of C. difficile to the coprisin analogue caused a marked increase in nuclear propidium iodide (PI) staining, indicating membrane damage; the staining levels were similar to those seen with bacteria treated with a positive control for membrane disruption (EDTA). In contrast, coprisin analogue treatment did not trigger increases in the nuclear PI staining of Bifidobacterium thermophilum. This observation suggests that the antibiotic activity of the coprisin analogue may occur through specific membrane disruption of C. difficile. Thus, these results indicate that the coprisin analogue may prove useful as a therapeutic agent for C. difficile infection-associated inflammatory diarrhea and pseudomembranous colitis.
doi:10.1128/AAC.00177-11
PMCID: PMC3186999  PMID: 21807975
3.  Pharmacogenetic Warfarin Dose Refinements Remain Significantly Influenced by Genetic Factors after One Week of Therapy 
Thrombosis and Haemostasis  2011;107(2):232-240.
Summary
Introduction
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Results
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
Conclusions
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
doi:10.1160/TH11-06-0388
PMCID: PMC3292349  PMID: 22186998
warfarin; VKORC1; CYP2C9; pharmacogenetic
4.  Association Between Body Mass Index and Asthma Symptoms Among Korean Children: A Nation-Wide Study 
Journal of Korean Medical Science  2011;26(12):1541-1547.
The purpose of this study was to investigate the association between body mass index (BMI) and the prevalence of wheeze using nation-wide cross-sectional study in Korean children. Total 50,200 children from 427 elementary schools were randomly selected according to residential areas (metropolitan, provincial, rural, and industrial areas) by the cluster sampling method. The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires were used to measure the prevalence of wheeze. Among 31,026 respondents, 25,322 were analyzed. BMI was classified into quartiles based on BMI-for-age percentile. In all residential areas, pets at home and visible mold or moisture were associated with an increased prevalence of wheeze in both genders. However, other living environment factors were not consistently associated among residential areas and gender. Among girls, lowest BMI was negatively associated with prevalence of wheeze and highest BMI was positively associated in all residential areas. In multilevel logistic regression analysis, environmental tobacco smoking exposure, pets at home, visible mold or moisture, and being in the lowest and highest BMI quartile were significantly associated with the prevalence of wheeze in both genders. BMI has become an important risk factor for asthma symptoms among Korean children.
doi:10.3346/jkms.2011.26.12.1541
PMCID: PMC3230012  PMID: 22147989
Asthma; Body Mass Index; Child; Residence Characteristics
5.  Hemophagocytic Lymphohistiocytosis (HLH) Associated with Plasmodium vivax Infection: Case Report and Review of the Literature 
Chonnam Medical Journal  2011;47(3):173-176.
Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and pathologic findings of hemophagocytosis in the bone marrow and other tissues. HLH may be familial or associated with different types of infections, autoimmune disorders, or malignancies. Infection-associated HLH has been reported in various viral, bacterial, fungal, and parasitic infections, and case reports of parasitic infections implicated in HLH include rare cases from Plasmodium vivax infection, which occasionally affects both military personnel and civilians in Korea. We describe an unusual case of HLH resulting from Plasmodium vivax infection and review the literature. This case suggests that clinical suspicion of HLH is important when P. vivax infection is accompanied by cytopenias. Administration of antimalarial drugs may prevent irreversible end organ damage resulting from P. vivax-associated HLH.
doi:10.4068/cmj.2011.47.3.173
PMCID: PMC3252507  PMID: 22247919
Hemophagocytic lymphohistiocytosis; Plasmodium vivax
6.  Recurring gastrointestinal stromal tumor with splenic metastasis 
Journal of the Korean Surgical Society  2011;81(Suppl 1):S25-S29.
Malignant gastrointestinal stromal tumors (GISTs) are rare non-epithelial, mesenchymal neoplasms of the gastrointestinal tract that metastasize or recur in 30% of patients who undergo surgical resection with curative intent. A 59-year-old man visited our hospital for an examination of a palpable mass in the left abdomen. Fourteen months prior to his visit, the patient underwent gastric wedge resection to remove a GIST of the gastric cardia. At the time of surgery, no evidence of metastatic disease was observed and the pathological interpretation was a high-risk GIST. A follow-up computed tomography scan of the abdomen revealed a partially necrotic solid mass (9.8 × 7.6 cm) and enhancing mass in the spleen (2.3 cm). On exploration, multiple masses were found in the liver, greater omentum, and mesentery. Here, we report a case of recurring GIST of the stomach that metastasized to the spleen. To the best of our knowledge, few reports of metastasis to the spleen exist.
doi:10.4174/jkss.2011.81.Suppl1.S25
PMCID: PMC3267060  PMID: 22319733
Gastrointestinal stromal tumors; Neoplasm metastasis; Spleen
7.  Primary leiomyosarcoma of the pancreas 
Journal of the Korean Surgical Society  2011;81(Suppl 1):S69-S73.
Primary sarcomas of the pancreas are extremely rare, accounting for 0.1% of malignant pancreatic (non-islet) neoplasms. Pancreatic leiomyosarcoma is a highly aggressive malignancy that spreads in a similar manner to gastric leiomyosarcoma, i.e., by adjacent organ invasion, hematogenous spread, and lymph node metastasis. These tumors are large at the time of diagnosis and are usually found at an advanced stage. We report a case of a 70-year-old female with intermittent right upper quadrant abdominal discomfort. Radiological, histopathological, and immunohistochemical studies revealed the tumor to be a primary leiomyosarcoma of the pancreas. Herein, we describe a patient with a primary leiomyosarcoma of the pancreas who presented with clinical and radiological findings indicative of a mass in the pancreatic head.
doi:10.4174/jkss.2011.81.Suppl1.S69
PMCID: PMC3267071  PMID: 22319744
Leiomyosarcoma; Pancreas; Primary
8.  Neuroendocrine Tumor of Unknown Primary Accompanied with Stomach Adenocarcinoma 
Journal of Gastric Cancer  2011;11(4):234-238.
A 67 year old male at a regular checkup underwent esophagogastroduodenoscopy. On performing esophagogastroduodenoscopy, a lesion about 1.2 cm depressed was noted at the gastric angle. The pathology of the biopsy specimen revealed a well-differentiated adenocarcinoma. On performing an abdominal computed tomography (CT) scan & positron emission tomography-computed tomography (PET-CT) scan, no definite evidence of gastric wall thickening or mass lesion was found. However, lymph node enlargement was found in the left gastric and prepancreatic spaces. This patient underwent laparoscopic assisted distal gastrectomy and D2 lymph node dissection. On final examination, it was found out that the tumor had invaded the mucosal layer. The lymph node was a metastasized large cell neuroendocrine carcinoma with an unknown primary site. The patient refused chemotherapy. He opted to undergo a close follow-up. At the postoperative month 27, he had a focal hypermetabolic lesion in the left lobe of the liver that suggested metastasis on PET-CT scan. He refused to undergo an operation. He underwent a radiofrequency ablation.
doi:10.5230/jgc.2011.11.4.234
PMCID: PMC3273695  PMID: 22324016
Gastric cancer; Neuroendocrine tumors; Neoplasms, unknown primary
9.  Modulation of Glial and Neuronal Migration by Lipocalin-2 in Zebrafish 
Immune Network  2011;11(6):342-347.
Background
Glial cells are involved in immune and inflammatory responses in the central nervous system (CNS). Glial cells such as microglia and astrocytes also provide structural and functional support for neurons. Migration and morphological changes of CNS cells are associated with their physiological as well as pathological functions. The secreted protein lipocalin-2 (LCN2) has been previously implicated in regulation of diverse cellular processes of glia and neurons, including cell migration and morphology.
Methods
Here, we employed a zebrafish model to analyze the role of LCN2 in CNS cell migration and morphology in vivo. In the first part of this study, we examined the indirect effect of LCN2 on cell migration and morphology of microglia, astrocytes, and neurons cultured in vitro.
Results
Conditioned media collected from LCN2-treated astrocytes augmented migration of glia and neurons in the Boyden chamber assay. The conditioned media also increased the number of neuronal processes. Next, in order to further understand the role of LCN2 in the CNS in vivo, LCN2 was ectopically expressed in the zebrafish spinal cord. Expression of exogenous LCN2 modulated neuronal cell migration in the spinal cord of zebrafish embryos, supporting the role of LCN2 as a cell migration regulator in the CNS.
Conclusion
Thus, LCN2 proteins secreted under diverse conditions may play an important role in CNS immune and inflammatory responses by controlling cell migration and morphology.
doi:10.4110/in.2011.11.6.342
PMCID: PMC3275702  PMID: 22346773
LCN2; Glia; Cell migration; Neuroinflammation; Central nervous system; Spinal cord
10.  V2 Receptor Antagonist; Tolvaptan 
Hyponatremia is the most common electrolyte disorder in hospitalized patients. Many studies documented that it was related to increased morbidity and mortality in patients with congestive heart failure, liver cirrhosis, and neurologic diseases. Although knowledge of hyponatremia has been cumulated, the optimal management of hyponatremia remains incompletely established in clinical practice because of the diversity of underlying disease states, and its multiple causes with differing pathophysiologic mechanisms. Since vasopressin receptor antagonists have unique aquaretic effect to selectively increase electrolytes-free water excretion, clinicians could apply a more effective method to treat hyponatremia. Tolvaptan has significant evidence that it improves serum sodium levels in patients with euvolemic or hypervolemic hyponatremia related with heart failure, cirrhosis or syndrome of inappropriate anti-diuretic hormone. Tolvaptan has acceptable safety and tolerability for long-term usage in chronic hyponatremia, and the beneficial effects on serum Na+ occurred in patients with both mild and marked hyponatremia.
doi:10.5049/EBP.2011.9.2.50
PMCID: PMC3302906  PMID: 22438856
tolvaptan; hyponatremia; arginine vasopressin receptors
11.  Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis 
Experimental & Molecular Medicine  2011;43(10):561-570.
Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.
doi:10.3858/emm.2011.43.10.062
PMCID: PMC3222817  PMID: 21795829
antioxidants; grape seed proanthocyanidins; inflammation; interleukin-1β; osteoarthritis
12.  Impact of interleukin-21 in the pathogenesis of primary Sjogren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands 
Arthritis Research & Therapy  2011;13(5):R179.
Introduction
Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.
Methods
Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.
Results
Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.
Conclusions
Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.
doi:10.1186/ar3504
PMCID: PMC3308114  PMID: 22030011
IL-21; IL-21 receptor; Sjogren's syndrome; Immunoglobulin G1; Labial salivary gland
13.  Pigmented Basal Cell Carcinoma of the Nipple-Areola Complex in an Elderly Woman 
Annals of Dermatology  2011;23(Suppl 2):S201-S204.
Basal cell carcinoma (BCC), which frequently occurs in sun-exposed areas of the head and neck region, is the most common cutaneous malignancy. The nipple-areola complex (NAC) is an uncommon site for BCC to develop. BCCs in this region display more aggressive behavior and a greater potential to spread than when found in other anatomical sites. This paper outlines the case of 67-year-old female with a solitary asymptomatic black plaque on the right areola. The lesion was initially recognized as Paget's disease of the nipple by a general surgeon. However, the histopathological features showed a tumor mass of basaloid cells, a peripheral palisading arrangement and scattered pigment granules. Finally, the patient was diagnosed with pigmented BCC of the NAC and was referred to the department of dermatology. Positron emission tomography-computed tomography revealed the absence of distant metastasis. A wide excision was done. The lesion resolved without recurrence or metastasis during 14 months of follow-up.
doi:10.5021/ad.2011.23.S2.S201
PMCID: PMC3229065  PMID: 22148050
Areola; Basal cell carcinoma; Nipple
14.  Endobronchial Aspergilloma: Report of 10 Cases and Literature Review 
Yonsei Medical Journal  2011;52(5):787-792.
Purpose
A retrospective investigation of the clinical and radiologic features as well as the bronchoscopic appearance was carried out in patients with endobronchial aspergilloma.
Materials and Methods
Ten patients with endobronchial aspergilloma diagnosed by bronchoscopy and histological examination were identified at the Gyeongsang University Hospital of Korea, from May 2003 to May 2009.
Results
The patients included 9 men and 1 woman, and the age of the patients ranged from 36 to 76 (median, 58 years). The associated diseases or conditions were: previous pulmonary tuberculosis in 7 patients, lung cancer in 2 patients, pulmonary resection in 1 patient, and foreign body of the bronchus in 1 patient. The chest radiologic finding showed fibrotic changes as a consequence of previous tuberculosis infection in 6 patients and a mass-like lesion in 2 patients. Two patients had a co-existing fungus ball, and an endobronchial lesion was suspected in only 2 patients on the CT scan. The bronchoscopic appearance was a whitish to yellow necrotic mass causing bronchial obstruction in 7 patients, foreign body with adjacent granulation tissue and whitish necrotic tissue in 1 patient, whitish necrotic tissue at an anastomosis site in 1 patient, and a protruding mass with whitish necrotic tissue in 1 patient.
Conclusion
An endobronchial aspergilloma is a rare presentation of pulmonary aspergilosis and is usually incidentally found in immunocompetent patients with underlying lung disease. It usually appears as a necrotic mass causing bronchial obstruction on bronchoscopy and can be confirmed by biopsy.
doi:10.3349/ymj.2011.52.5.787
PMCID: PMC3159936  PMID: 21786444
Endobronchial aspergilloma
15.  Measurement of Interleukin-33 (IL-33) and IL-33 Receptors (sST2 and ST2L) in Patients with Rheumatoid Arthritis 
Journal of Korean Medical Science  2011;26(9):1132-1139.
The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1β (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.
doi:10.3346/jkms.2011.26.9.1132
PMCID: PMC3172648  PMID: 21935266
Interleukin-33; sST2, ST2L; Arthritis, Rheumatoid
16.  Early Gastric Cancer with Signet Ring Cell Histology Remained Unresected for 53 Months 
Journal of Gastric Cancer  2011;11(3):189-193.
The natural course of untreated patients with signet ring cell carcinoma of the stomach remains poorly understood while assumptions have been made to distinguish it from other types of gastric cancer. A 74-year-old Korean woman was diagnosed with early gastric cancer with signet ring cell histology and refused surgery. A satellite lesion was identified 46 months after the initial diagnosis. The patient finally agreed to undergo distal subtotal gastrectomy 53 months following the initial diagnosis. Postoperative histological examination of both lesions confirmed signet ring cell carcinoma associated with submucosal invasion. There was no evidence of lymph node metastasis.
doi:10.5230/jgc.2011.11.3.189
PMCID: PMC3204463  PMID: 22076226
Disease progression; Gastrectomy; Carcinoma, signet ring cell; Stomach neoplasms
17.  New Insights into Neuromyelitis Optica 
Neuromyelitis optica (NMO) is an idiopathic inflammatory disorder of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. In Asia, NMO has long been considered a subtype of multiple sclerosis (MS). However, recent clinical, pathological, immunological, and imaging studies have suggested that NMO is distinct from MS. This reconsideration of NMO was initially prompted by the discovery of a specific antibody for NMO (NMO-IgG) in 2004. NMO-IgG is an autoantibody that targets aquaporin-4 (AQP4), the most abundant water channel in the CNS; hence, it was named anti-AQP4 antibody. Since it demonstrated reasonable sensitivity and high specificity, anti-AQP4 antibody was incorporated into new diagnostic criteria for NMO.The spectrum of NMO is now known to be wider than was previously recognized and includes a proportion of patients with recurrent, isolated, longitudinally extensive myelitis or optic neuritis, and longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease or with brain lesions typical of NMO. In this context, a new concept of "NMO spectrum disorders" was recently introduced. Furthermore, seropositivity for NMO-IgG predicts future relapses and is recognized as a prognostic marker for NMO spectrum disorders. Humoral immune mechanisms, including the activation of B-cells and the complement pathway, are considered to play important roles in NMO pathogenesis. This notion is supported by recent studies showing the potential pathogenic role of NMO-IgG as an initiator of NMO lesions. However, a demonstration of the involvement of NMO-IgG by the development of active immunization and passive transfer in animal models is still needed. This review focuses on the new concepts of NMO based on its pathophysiology and clinical characteristics. Potential management strategies for NMO in light of its pathomechanism are also discussed.
doi:10.3988/jcn.2011.7.3.115
PMCID: PMC3212597  PMID: 22087205
neuromyelitis optica; Devic's disease; neuromyelitis optica spectrum disorder; pathogenesis; diagnosis; management
18.  Biotransformation of Ginsenoside Rb1 to Prosapogenins, Gypenoside XVII, Ginsenoside Rd, Ginsenoside F2, and Compound K by Leuconostoc mesenteroides DC102 
Journal of Ginseng Research  2011;35(3):344-351.
Ginsenoside Rb1is the main component in ginsenosides. It is a protopanaxadiol-type ginsenoside that has a dammarane-type triterpenoid as an aglycone. In this study, ginsenoside Rb1 was transformed into gypenoside XVII, ginsenoside Rd, ginsenoside F2 and compound K by glycosidase from Leuconostoc mesenteroides DC102. The optimum time for the conversion was about 72 h at a constant pH of 6.0 to 8.0 and the optimum temperature was about 30℃. Under optimal conditions, ginsenoside Rb1 was decomposed and converted into compound K by 72 h post-reaction (99%). The enzymatic reaction was analyzed by highperformance liquid chromatography, suggesting the transformation pathway: ginsenoside Rb1→ gypenoside XVII and ginsenoside Rd→ginsenoside F2→compound K.
doi:10.5142/jgr.2011.35.3.344
PMCID: PMC3659545  PMID: 23717079
Biotransformation; Gypenoside XVII; Ginsenoside Rd; Compound K; Leuconostoc mesenteroides DC102
19.  Myeloid differentiation primary response protein 88 blockade upregulates indoleamine 2,3-dioxygenase expression in rheumatoid synovial fibroblasts 
Experimental & Molecular Medicine  2011;43(8):446-454.
Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and has been implicated in tumor tolerance, autoimmune disease and asthma. IDO was detected in the joint synovial tissue in the inflammatory microenvironment of rheumatoid arthritis (RA), but IDO expression in joint synovial tissue is not sufficient to overcome the inflamed synovial environment. This study aimed to unravel the mechanisms involving the failure to activate tolerogenic IDO in the inflamed joint. We demonstrate that both poly (I:C) and lipopolysaccharide (LPS) induce expression of IDO in synovial fibroblasts. However, inflammatory cytokines such as IL-17, TNF-α, IL-12, IL-23 and IL-16 did not induce IDO expression. Poly (I:C) appeared to induce higher IDO expression than did LPS. Surprisingly, toll-like receptor (TLR)4-mediated IDO expression was upregulated after depletion of myeloid differentiation primary response protein 88 (MyD88) in synovial fibroblasts using small interfering RNA (siRNA). IDO, TLR3 and TLR4 were highly expressed in synovial tissue of RA patients compared with that of osteoarthritis patients. In addition, RA patients with severe disease activity had higher levels of expression of IDO, TLR3 and TLR4 in the synovium than patients with mild disease activity. These data suggest that upregulation of IDO expression in synovial fibroblasts involves TLR3 and TLR4 activation by microbial constituents. We showed that the mechanisms responsible for IDO regulation primarily involve MyD88 signaling in synovial fibroblasts, as demonstrated by siRNA-mediated knockdown of MyD88.
doi:10.3858/emm.2011.43.8.050
PMCID: PMC3174378  PMID: 21654189
indoleamine-pyrrole 2,3,-dioxygenase; myeloid differentiation factor 88; rheumatoid arthritis; TICAM1 protein, human; toll-like receptors
20.  Label-free shotgun proteomics and metabolite analysis reveal a significant metabolic shift during citrus fruit development 
Journal of Experimental Botany  2011;62(15):5367-5384.
Label-free LC-MS/MS-based shot-gun proteomics was used to quantify the differential protein synthesis and metabolite profiling in order to assess metabolic changes during the development of citrus fruits. Our results suggested the occurrence of a metabolic change during citrus fruit maturation, where the organic acid and amino acid accumulation seen during the early stages of development shifted into sugar synthesis during the later stage of citrus fruit development. The expression of invertases remained unchanged, while an invertase inhibitor was up-regulated towards maturation. The increased expression of sucrose-phosphate synthase and sucrose-6-phosphate phosphatase and the rapid sugar accumulation suggest that sucrose is also being synthesized in citrus juice sac cells during the later stage of fruit development.
doi:10.1093/jxb/err197
PMCID: PMC3223037  PMID: 21841177
Citrus; fruit development; juice sac cells; LC-MS/MS; proteomics
21.  Parry-Romberg Syndrome with En Coup de Sabre 
Annals of Dermatology  2011;23(3):342-347.
Parry-Romberg syndrome (PRS) is a relatively rare degenerative disorder that is poorly understood. PRS is characterized by slowly progressing atrophy affecting one side of the face, and is frequently associated with localized scleroderma, especially linear scleroderma, which is known as en coup de sabre. This is a report of the author's experiences with PRS accompanying en coup de sabre, and a review of the ongoing considerable debate associated with these two entities. Case 1 was a 37-year-old woman who had right hemifacial atrophy with unilateral en coup de sabre for seven years. Fat grafting to her atrophic lip had been conducted, and steroid injection had been performed on the indurated plaque of the forehead. Case 2 was a 29-year-old woman who had suffered from right hemifacial atrophy and bilateral en coup de sabre for 18 years. Surgical corrections such as scapular osteocutaneous flap and mandible/maxilla distraction showed unsatisfying results.
doi:10.5021/ad.2011.23.3.342
PMCID: PMC3162264  PMID: 21909205
Encoup de sabre; Hemifacial atrophy; Parry-Romberg syndrome
22.  Multiple Nevus Sebaceous Occurring on the Scalp and on the Contralateral Side of the Face 
Annals of Dermatology  2011;23(3):389-391.
Nevus sebaceous (NS) is a benign neoplasm occurring mainly on the face and scalp. It commonly occurs as a solitary, well-demarcated lesion. This paper presents a case of multiple nevus sebaceous, which presented as multiple lesions occurring on the temporal scalp and on the contralateral side of the chin. Multiple NS have only rarely been reported.
doi:10.5021/ad.2011.23.3.389
PMCID: PMC3162275  PMID: 21909216
Multiple; Nevus sebaceus
23.  Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells 
Undifferentiated carcinoma with osteoclast-like giant cells is a rare neoplasm of the exocrine pancreas. Some similar cases have been reported, but the histogenesis of these tumors varies and is controversial. We report here on a case of undifferentiated carcinoma of the pancreas with osteoclast-like giant cells. A 77-year old woman presented with abdominal pain and anorexia. Abdominal computed tomography and magnetic resonance imaging showed an approximately 10 × 5 cm highly attenuated mass arising from the tail of the pancreas and invading the spleen and adjacent bowel loop. The initial impression was a malignant endocrine tumor or solid-pseudopapillary tumor of the pancreas. The patient underwent a distal pancreatectomy with splenectomy and left hemicolectomy. The histopathology and immunohistochemistry helped make the diagnosis that of an undifferentiated carcinoma with osteoclast-like giant cells of the pancreas.
doi:10.4174/jkss.2011.81.2.146
PMCID: PMC3204565  PMID: 22066115
Osteoclast-like giant cells; Undifferentiated carcinoma; Pancreas
24.  A phase II study of mitomycin-C and S-1 as third-line chemotherapy in patients with advanced colorectal cancer 
Oncology Letters  2011;2(6):1253-1256.
This study was conducted to evaluate the efficacy and safety of the combination of mitomycin-C (MMC) and S-1 as third-line chemotherapy for patients with advanced colorectal cancer (CRC) showing resistance to irinotecan- and oxaliplatin-containing regimens. Patients were recruited into the study from January 2009 and 10 patients were enrolled for 10 months. However, since no patients had shown a response by 10 months, the study was terminated early according to the protocol. MMC 7 mg/m2 was administered intravenously on day 1 every 6 weeks in the first 4 cycles. S-1 was administered twice daily at 35 mg/m2, within 1 h of meals on days 1–14. Following a rest for 7 days, S-1 was administered again on days 22–35, followed by a 7-day rest. A total of 14 cycles were delivered for 10 patients. All 10 patients were assessable for response. A total of 3 patients (30%) had stable disease and the remaining 7 showed disease progression. With a median follow-up of 7 months, the median overall survival was 10.5 months. Grade 3–4 myelotoxicities included neutropenia in two patients, anemia in two and thrombocytopenia in one. Grade 1–2 nausea and vomiting developed in 5 patients. One patient experienced grade 3 diarrhea. Grade 1–2 hand-foot syndrome occurred in 4 patients. In conclusion, the combination of MMC and S-1 as third-line chemotherapy in patients with advanced CRC appears to be well tolerated but has poor activity.
doi:10.3892/ol.2011.367
PMCID: PMC3406541  PMID: 22848297
colorectal cancer; mitomycin-C; S-1
25.  Health Risks Assessment in Children for Phthalate Exposure Associated with Childcare Facilities and Indoor Playgrounds 
Objectives
This study assessed the health risks for children exposed to phthalate through several pathways including house dust, surface wipes and hand wipes in child facilities and indoor playgrounds.
Methods
The indoor samples were collected from various children's facilities (40 playrooms, 42 daycare centers, 44 kindergartens, and 42 indoor-playgrounds) in both summer (Jul-Sep, 2007) and winter (Jan-Feb, 2008). Hazard index (HI) was estimated for the non-carcinogens and the examined phthalates were diethylhexyl phthalate (DEHP), diethyl phthalate (DEP), dibutyl-n-butyl phthalate (DnBP), and butylbenzyl phthalate (BBzP). The present study examined these four kinds of samples, i.e., indoor dust, surface wipes of product and hand wipes.
Results
Among the phthalates, the detection rates of DEHP were 98% in dust samples, 100% in surface wipe samples, and 95% in hand wipe samples. In this study, phthalate levels obtained from floor dust, product surface and children's hand wipe samples were similar to or slightly less compared to previous studies. The 50th and 95th percentile value of child-sensitive materials did not exceed 1 (HI) for all subjects in all facilities.
Conclusions
For DEHP, DnBP and BBzP their detection rates through multi-routes were high and their risk based on health risk assessment was also observed to be acceptable. This study suggested that ingestion and dermal exposure could be the most important pathway of phthalates besides digestion through food.
doi:10.5620/eht.2011.26.e2011008
PMCID: PMC3214980  PMID: 22125769
Phthalate; Childcare facilities; Health risk assessment; Multi-route exposure

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