Keun-Sang Kwon

Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis

Tumor-infiltrating immune cells perform a crucial function in host immune reactions against diffuse large B-cell lymphoma (DLBCL). In this study, we have identified a subset of tumor-infiltrating FOXP3-positive regulatory T cells (Tregs) in the initial DLBCL biopsy specimens, and have evaluated their prognostic significance. Ninety six patients with DLBCL were evaluated retrospectively. The pattern of FOXP3 protein expression was evaluated using standard immunohistochemistry in paraffin-embedded tissue samples. Sixty seven of all 96 specimens were stained with antibodies for CD-10, bcl-6 and MUM1 via tissue microarray (TMA) to classify the cases into a germinal center B-cell like (GCB) group and a non-GCB group. The median overall survival (OS) was 28 months. As compared with the others, the patients with higher percentages of FOXP3-positive Tregs on initial tumor biopsy evidenced a significantly longer OS (p = 0.003). Patients classified into the GCB group evidenced a significantly longer OS as compared with the non-GCB group (p = 0.008). When the prognostic factors were evaluated via a multivariate model, the international prognostic index and the percentage of infiltrating FOXP3-positive Tregs in the initial biopsy were identified as independent predictors of OS. In conclusion, the presence of an increased percentage of FOXP3-positive Tregs in DLBCL is predictive of better prognoses.

Platelet-activating Factor–mediated NF-κB Dependency of a Late Anaphylactic Reaction

Anaphylaxis is a life-threatening systemic allergic reaction with the potential for a recurrent or biphasic pattern. Despite an incidence of biphasic reaction between 5 and 20%, the molecular mechanism for the reaction is unknown. Using a murine model of penicillin V–induced systemic anaphylaxis, we show an autoregulatory cascade of biphasic anaphylactic reactions. Induction of anaphylaxis caused a rapid increase in circulating platelet-activating factor (PAF) levels. In turn, the elevated PAF contributes to the early phase of anaphylaxis as well as the subsequent activation of the nuclear factor (NF)-κB, a crucial transcription factor regulating the expression of many proinflammatory cytokines and immunoregulatory molecules. The induction of NF-κB activity is accompanied by TNF-α production, which, in turn, promotes late phase PAF synthesis. This secondary wave of PAF production leads eventually to the late phase of anaphylactic reactions. Mast cells do not appear to be required for development of the late phase anaphylaxis. Together, this work reveals the first mechanistic basis for biphasic anaphylactic reactions and provides possible therapeutic strategies for human anaphylaxis.

Inhibition of murine allergic airway disease by Bordetella pertussis

Whole‐cell pertussis vaccines have been shown to selectively induce T helper 1 (Th1)‐type responses in human and animals. In this study, we investigated whether whole‐cell B. pertussis could inhibit allergic airway reactions in a murine model of asthma induced by ovalbumin (OVA). Systemic administration of whole‐cell B. pertussis strongly inhibited allergic airway reactions such as eosinophil recruitment into the airway, lung inflammation, and airway hyperresponsiveness to methacholine. The inhibitory effect of whole‐cell B. pertussis was mediated by chromosomal DNA and pretreatment of DNA with CpG methylase or DNase I resulted in a loss of the inhibitory effect. Treatment of animals with B. pertussis DNA significantly decreased the Th2 cytokine (interleukins IL‐4 and IL‐5) concentrations in the airways without increasing Th1 cytokines. These results suggest that B. pertussis DNA containing unmethylated CpG appears to be responsible for the inhibitory effect of whole cell B. pertussis on the allergic airway reactions through inhibition of the Th2 response.

Clinical significance of hypoalbuminemia in outcome of patients with scrub typhus

BackgroundThis study was designed to investigate the clinical significance of hypoalbuminemia as a marker of severity and mortality in patients with Scrub typhus.MethodsThe patients with scrub typhus were divided into two groups based on the serum albumin levels; Group I (serum albumin <3.0 g/dL) and Group II (serum albumin ≥3.0 g/dL). The outcome of patients with hypoalbuminemia was compared with that of normoalbuminemia.ResultsOf the total 246 patients who underwent the study, 84 patients (34.1%) were categorized as Group I and 162 patients were (65.9%) as Group II. Group I showed significantly higher incidence of confusion (24.6% vs. 5.3%, p < 0.001), pulmonary edema (15.8% vs. 3.2%, p = 0.002), pleural effusion (22.8% vs. 11.1%, p = 0.03), arrhythmia (12.3% vs. 2.6%, p = 0.008) and non-oliguric acute renal failure (40.4% vs. 11.1%, p < 0.001) compared to group II. Hypoalbuminemic group had a higher APACHE II score (11.37 ± 5.0 vs. 6.94 ± 4.2, p < 0.001), longer hospital stay (19.9 ± 42.1 days vs 7.5 ± 13.8 days, p = 0.012), and higher hospital cost compared to Group II.ConclusionsThis study showed hypoalbuminemia in scrub typhus was closely related to the frequency of various complication, longer hospital stay, consequently the higher medical cost, necessitating more efficient management of patients, including medical resources.

Sulfuretin attenuates allergic airway inflammation in mice

Sulfuretin is one of the main flavonoids produced by Rhus verniciflua, which is reported to inhibit the inflammatory response by suppressing the NF-κB pathway. Because NF-κB activation plays a pivotal role in the pathogenesis of allergic airway inflammation, we here examined the effect of sulfuretin on an ovalbumin-induced airway inflammation model in mice. We isolated sulfuretin from R. verniciflua. Sulfuretin was delivered intraperitoneally after the last ovalbumin challenge. Airway hyper-responsiveness, cytokines, mucin, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. A single administration of sulfuretin reduced airway inflammatory cell recruitment and peribronchiolar inflammation and suppressed the production of various cytokines in bronchoalveolar fluid. In addition, sulfuretin suppressed mucin production and prevented the development of airway hyper-responsiveness. The protective effect of sulfuretin was mediated by the inhibition of the NF-κB signaling pathway. Our results suggest that sulfuretin may have therapeutic potential for the treatment of allergic airway inflammation.

Screening strategies for the diagnosis of coronary artery stenosis in patients with cerebral infarction using dual-source spiral CT

This study was to evaluate the benefit of the screening of coronary artery stenosis (CAS) using dual-source CT (DSCT) in patients with cerebral infarction caused by a Large Artery Atherosclerosis (LAA). From November 2007 to February 2008, 34 patients (25 males and 9 females; mean age, 62.4 +/- 9.5 years) were enrolled. All of them had ischemic strokes of LAA type but with no cardiac symptoms. All patients underwent coronary CT angiography (CCTA) using DSCT. A significant coronary artery stenosis was defined as the one having more than 50% of luminal narrowing. We evaluated diagnostic accuracy for CAS in stroke patients of LAA with a receiver operating characteristics curve analysis. Of the 34 ischemic stroke patients, 18 (52.9%) had normal coronary arteries, 5 (14.7%) had insignificant CAS, and 11 (32.4%) had a significant CAS. The Agatston scores were more than 400 in 54.5% of the patients with a significant CAS, but less than 40 in 86.9% of the patients without it (p for trend = 0.001). For age, the optimal cut-off point for a diagnosis of CAS was 63, which had a sensitivity of 90.9%, a specificity of 69.6%, a positive predictive value of 58.8%, and a negative predictive value of 94.1%, respectively. For the Agatston score, the optimal cut-off was 40, which had 81.8%, 91.3%, 81.8%, and 91.3%, respectively. CCTA using DSCT appears to be a promising screening technique for CAS in patients with an ischemic stroke of LAA.

Enhanced M2 macrophage polarization in high n-3 polyunsaturated fatty acid transgenic mice fed a high-fat diet.

SCOPE Diet-induced obesity and consequent insulin resistance are caused, in part, by macrophage polarization and accumulation in peripheral tissues. Here, we examined the effects of endogenously synthesized n-3 PUFAs on macrophage chemotaxis and polarization. METHODS AND RESULTS Fat-1 mice and wild-type (WT) littermates were fed a 60% calorie high-fat diet (HFD) for 10 weeks. Bone marrow macrophages (BMMs) from fat-1 and WT mice were used in in vitro chemotaxis assays and macrophage polarization studies. WT mice fed a HFD exhibited glucose intolerance, insulin resistance, and lipid accumulation and macrophage infiltration in liver and adipose tissue. However, these metabolic and inflammatory phenotypes were not observed in HFD-fed fat-1 mice. In flow cytometric analysis, M1 macrophage infiltration into adipose tissue was markedly attenuated in fat-1 mice. Consistently, results from in vitro experiments indicated that n-3 PUFAs prevented adipocyte conditioned medium-mediated macrophage chemotaxis, stimulated M2 polarization, and suppressed M1 polarization. The inhibition of macrophage migration by n-3 PUFAs was associated with suppression of multiple kinases, such as IκB kinase, AKT, and focal adhesion kinase. CONCLUSION Our results indicate that n-3 PUFAs play a crucial role in macrophage polarization and chemotaxis, and thus regulate the development of HFD-induced tissue inflammation and metabolic derangements.

Role of leptin in legg–calvé–perthes disease

Obesity is considered a clinical risk sign for Legg–Calvé–Perthes disease (LCPD). Leptin is primarily secreted by adipocytes, and it regulates adipose tissue mass and body weight. Furthermore, obesity is clearly associated with increased leptin levels. We investigated the roles of leptin and the soluble leptin receptor (sOB‐R) in LCPD. This matched case–control study included 38 male and 3 female patients with LCPD, and an equal number of age—(range was 4–12) and sex‐matched control patients with healthy fractures. Serum leptin and sOB‐R levels were quantified with ELISA. The free leptin index (FLI) was defined as the ratio of leptin to sOB‐R levels. Serum leptin levels, sOB‐R, and FLI were compared between groups. The relationship between leptin, disease severity, and treatment outcomes were analyzed in the LCPD group. There were no significant differences between groups in terms of age, sex, and body mass index (BMI) percentile. Mean leptin levels (p = 0.042), sOB‐R levels (p = 0.003), and FLI (p = 0.013) differed significantly between groups. In the LCPD group, the serum leptin levels, sOB‐R levels, and FLI differed significantly between the lateral pillar and Stulberg classification groups (p < 0.05). Also, the leptin levels and FLI increased significantly according to the lateral pillar and Stulberg classifications even after adjusting for age and BMI percentile (p < 0.05). Circulating leptin and FLI were significantly higher in the LCPD group. Furthermore, leptin, disease severity, and treatment outcomes were associated. This correlation suggests that leptin might play an important role in LCPD pathogenesis.

Needs Assessment for the Beneficiaries of Home-Based Cancer Patients Management Project

Objectives: This study was performed to investigate the service needs of the beneficiaries who had enrolled in home-based management programs for cancer patients. Methods: From March to May 2009, 676 cancer patients who were registered in home-based cancer patient management programs were selected as subjects for this study. The data were collected using a questionnaire along with a face-to-face interview performed by officers in charge of the home-based care programs of 47 regional health centers. Fifteen patients were excluded due to incomplete data, leaving 661 subjects who were ultimately enrolled in the study. Results: The mean age of subjects was 64.0 ± 12.5 years, and males comprised 45.1% (298/661) of the sample. The results of factor analysis for service needs showed that there were five main categories and Cronbachs alpha ranged from 0.593 to 0.890 for each factor. The service needs categories in order of importance were social support, information and education, psychological problems, physical symptoms and household chores. The service needs scores were significantly different when subjects were stratified by age, habitation, religion and disease classification. When we divided the subjects into complete remission, under treatment and terminally ill groups, the needs scores of the terminally ill patient group were significantly higher than those of the other groups (p<0.001). Conclusions: Service provision based on patient and beneficiary needs could be an effective intervention to reduce the economic burden of cancer management and to improve the quality of life of cancer patients receiving home-based care. Therefore, it is recommended that individual cancer patient care programs be developed and administered according to patient age, habitation and disease severity.

Facial wrinkles as a predictor of decreased renal function.

Aims:  Oxidative stress generated either by exogenous or endogenous sources can lead to progressive organ damage and skin ageing over a long period of time. Moreover, some dermatological signs are independent of chronological ageing, and may reflect the long‐term redox state of internal organs. Therefore, we hypothesized that there might be an association between facial wrinkles and decreased renal function, an oxidative stress‐related disease.