AIM: To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI).

METHODS: We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed.

RESULTS: PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m2 vs 22.6 ± 2.4 kg/m2, P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia.

CONCLUSION: BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.

Self-expanding metal stent (SEMS) placement offers safe and effective palliation in patients with upper gastrointestinal obstruction due to a malignancy. Well described complications of SEMS placement include tumor growth, obstruction, and stent migration. SEMS occlusions are treated by SEMS redeployment, argon plasma coagulation application, balloon dilation, and surgical bypass. At our center, we usually place the second SEMS into the first SEMS if there is complete occlusion by the tumor. We discovered an unusual complication during SEMS redeployment. The guidewire passed through the mesh of the first SEMS and caused the second SEMS to become entangled with the first SEMS. This led to the distortion and malfunction of the second SEMS, which worsened the gastric outlet obstruction. For lowering the risk of entanglement, we studied stone extraction balloon-guided repeat SEMS placement. This is the first report of a SEMS entangled by the mesh of the first SEMS and stone extraction balloon-guided repeat SEMS placement for lowering the risk of this complication.

Background/Aims

The prevalence of colonic diverticulosis has been reported to be lower in Korea than in Western countries. This disease also shows markedly different characteristics in the Korean population. We describe herein a prospective investigation, based on colonoscopic examination, of the prevalence, clinical characteristics, and factors associated with colonic diverticulosis in Korea.

Methods

The prevalence of colonic diverticulosis has been reported to be lower in Korea than in Western countries. This disease also shows markedly different characteristics in the Korean population. We describe herein a prospective investigation, based on colonoscopic examination, of the prevalence, clinical characteristics, and factors associated with colonic diverticulosis in Korea.

Results

The overall prevalence of colonic diverticulosis was 12.1% (103 / 848). The right side of the colon was involved in 84.5% of patients (87 / 103); patients with right side diverticula were, on average, younger than those with left side diverticulosis (p = 0.014). Multiple diverticula were observed in 60.2% (62 / 103) of patients. Age greater than 60 years, a high-fat diet, and alcohol consumption were significantly associated with the presence of colonic diverticulosis (p < 0.05).

Conclusions

The prevalence of colonic diverticulosis in Korea is increasing and is most commonly located in the right side of the colon. Further, old age and diet may affect the risk of development of this disease.

Chronic diarrhea is one of the most frequent gastro-intestinal manifestations in acquired immunodeficiency syndrome (AIDS). Protozoa and nontuberculous mycobacteria (NTM) are opportunistic pathogens that can easily infect these patients. Among the NTM, Mycobacterium avium complex (MAC) is the most frequently observed pathogen in HIV-infected patients. However, NTMs other than MAC have not been reported as a gastrointestinal pathogen as yet. We present a case of chronic diarrhea in an AIDS patient in whom Mycobacterium ulcerans and cryptosporidium co-infection is evidenced from colonic tissue.

Chronic inflammatory airway diseases including asthma are characterized by immune dysfunction to inhaled allergens. Our previous studies demonstrated that T cell priming to inhaled allergens requires LPS, which is ubiquitously present in household dust allergens. In this study, we evaluated the role of vascular endothelial growth factor (VEGF) in the development of T cell priming and its polarization to Th1 or Th17 cells when exposed to LPS-contaminated allergens. An asthma mouse model was induced by airway sensitization with LPS-contaminated allergens and then challenged with allergens alone. Therapeutic intervention was performed during allergen sensitization. The present study showed that lung inflammation induced by sensitization with LPS-contaminated allergens was decreased in mice with homozygous disruption of the IL-17 gene; in addition, allergen-specific Th17 immune response was abolished in IL-6 knockout mice. Meanwhile, in vivo production of VEGF was up-regulated by airway exposure of LPS. In addition, airway sensitization of allergen plus recombinant VEGF induced both type 1 and type 17 Th cell (Th1 and Th17) responses. Th1 and Th17 responses induced by airway sensitization with LPS-contaminated allergens were blocked by treatment with a pan-VEGF receptor (VEGFR; VEGFR-1 plus VEGFR-2) inhibitor during sensitization. These effects were accompanied by inhibition of the production of Th1 and Th17 polarizing cytokines, IL-12p70 and IL-6, respectively. These findings indicate that VEGF produced by LPS plays a key role in activation of naive T cells and subsequent polarization to Th1 and Th17 cells.

Summary

The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive Oxygen Species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, ATIA (anti-TNFα-induced apoptosis), which protects cells against TNFα- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but a potentially diagnostic marker and therapeutic target in human glioblastoma.

Definition of community-onset, hospital-acquired Clostridium difficile infection (CO-HA-CDI) is difficult in patients presenting with diarrhea at hospitals or outpatient clinics, especially 4 to 12 weeks after the last discharge. We performed C. difficile stool culture for 272 diarrheic patients visiting the emergency room (ER) between January 2006 and June 2010. C. difficile was isolated from 36 cases (13.2%), and isolation rates increased year by year, from 10.1% in 2008 to 12.4% in 2009 and 16.7% in 2010. Among 32 toxin-positive isolates, 13 (40.6%) and 19 (59.4%) were associated with CO-HA-CDI and community-acquired CDI (CA-CDI), respectively, if cases with CDI diagnosed within 12 weeks after discharge were considered hospital associated. The majority (70%) of CO-HA-CDI cases occurred within 2 weeks after hospital discharge, although the interval from discharge to onset of symptoms was as long as 10 weeks. We found via tcdA and tcdB and repetitive sequence PCR analysis, that toxin A-positive/toxin B-positive isolates were the most prevalent in both CO-HA-CDI (53.8%) and CA-CDI (94.7%) cases. Toxin A-negative/toxin B-positive isolates were also still highly associated with HA-CDI cases but were also observed in CA-CDI cases. Younger age, fewer underlying diseases, lack of prior antibiotic use, and genetic diversity of isolates in repetitive sequence PCR were the main characteristics in CA-CDI cases visiting the ER.

Background/Aims

Heat shock proteins (HSPs) protect rats from cerulein-induced acute pancreatitis (AP) by preventing the subcellular redistribution of cathepsin B and the activation of trypsinogen. Autophagy plays a critical role in the secretion of digestive enzymes and triggering of cerulein-induced AP via the colocalization of trypsinogen and lysosomes. Therefore, using a rat cerulein-induced AP model, we investigated whether HSPs prevent AP by regulating autophagy.

Methods

Twelve hours after fed standard laboratory chow and water, the experimental groups (cerulein, water-immersion [WI]-cerulein and heat-shock [HS]-cerulein) and the control groups (control, WI, and HS) received one intraperitoneal injection of cerulein (50 µg/kg) or saline, respectively. All of the rats were sacrificed at 6 hours after injection. The severity of the AP was assessed based on the serum amylase level and the histological and electron microscopy findings. Western blotting was also performed for HSP60/70 and LC3B-II.

Results

WI and HS induced HSP60 and HSP70, respectively. The induced HSP60/70 effectively prevented the development of cerulein-induced AP. Autophagy developed in the rats with cerulein-induced AP and was documented by the expression of LC3-II and electron microscopy findings. The WI-stressed rats and HS-treated rats did not develop cerulein-induced autophagy.

Conclusions

HSPs exert protective effects against cerulein-induced AP in rats by inhibiting autophagy.

Background/Aims

Microscopic colitis (MC) encompasses collagenous and lymphocytic colitis and is characterized by chronic diarrhea. In cases of MC, colonic mucosae are macroscopically normal, and diagnostic histopathological features are observed only upon microscopic examination. We designed a prospective multicenter study to determine the clinical features, pathological distribution in the colon and prevalence of MC in Korea.

Methods

We prospectively enrolled patients having watery diarrhea no more than 3 times a day between March 2008 and February 2009. We obtained patient histories and performed colonoscopies with random biopsies at each colon segment.

Results

A total of 100 patients with chronic diarrhea were enrolled for a normal colonoscopy and stool exam. MC was observed in 22 patients (22%) (M:F 1.2:1; mean age, 47.5 years). Of those 22 patients, 18 had lymphocytic colitis and 4 had collagenous colitis. The entire colon was affected in only 3 cases (13.6%), the ascending colon in 6 cases (27.2%), the transverse colon in 3 cases (13.6%), and the left colon in 3 cases (13.6%). More than 2 segments were affected in 7 cases (31.8%). Nonsteroidal anti-inflammatory drug-associated MCs were observed in 4 cases (18.2%), 3 of which showed improved diarrhea symptoms following discontinuation of the medication. Frequently associated symptoms were abdominal pain and weight loss. Autoimmune diseases were observed in 4 cases (18.2%). Half of the 22 patients with MC improved with conservative care by loperamide or probiotics.

Conclusions

In a prospective multicenter study of Korean patients with chronic diarrhea, the frequency of MC was found to be approximately 20%, similar to the percentage observed in Western countries. Therefore, the identification of MC is important for the adequate management of Korean patients with chronic diarrhea.

MicroRNAs are key regulators in many biological processes including cell differentiation. Here we show that during human monocyte-macrophage differentiation, the expression of the microRNAs miR-223, miR-15a, and miR-16 is dramatically decreased, leading to increased expression of the serine-threonine kinase IKKα in macrophages. In macrophages, higher IKKα expression in conjunction with stabilization of the kinase NIK induces elevated p52. Due to low RelB transcription factor expression in untreated macrophages, high p52 expression represses the basal level of both canonical and noncanonical NF-κB target genes. However, proinflammatory stimuli in macrophages result in greater induction of noncanonical NF-κB target genes. Thus a decrease in certain microRNAs likely prevents macrophage hyperaction yet primes the macrophage for certain responses to proinflammatory stimuli.

Background

Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3 deficient mice are more susceptible to endotoxic shock. This study addresses the role of ATF3 in the Kdo2-Lipid A-induced Toll-like receptor 4 (TLR4) signaling pathway in mouse embryonic fibroblasts (MEF). Kdo2-Lipid A upregulates ATF3 expression in wild type MEF cells and induces both nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation via the TLR4 signaling pathway, while neither of these pathways is activated in ATF3-/- MEF cells. Interestingly, in contrast to Kdo2-Lipid A, the activation of both NF-κB and JNK by TNF-α was normal in ATF3-/- MEF cells.

Methodology/Principal Findings

We found that several genes were dramatically upregulated in ATF3+/+ MEF cells in response to Kdo2-Lipid A treatment, while little difference was observed in the ATF3-/- MEF cells. However, we also found that the signal intensities of IκBζ in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated IκBζ expression was detected in the cytosol fraction.

Conclusions/Significance

Our findings indicate that ATF3 deficiency affects Kdo2-Lipid A-induced TLR4 signaling pathways in MEF cells, that it may upregulate IκBζ expression and that the high levels of IκBζ expression in ATF3-/- cells disrupts Kdo2-Lipid A-mediated signaling pathways.

Asthma is characterized by airway inflammation induced by immune dysfunction to inhaled antigens. Although respiratory viral infections are the most common cause of asthma exacerbation, immunologic mechanisms underlying virus-associated asthma exacerbation are controversial. Clinical evidence indicates that nitric oxide (NO) levels in exhaled air are increased in exacerbated asthma patients compared to stable patients. Here, we evaluated the immunologic mechanisms and the role of NO synthases (NOSs) in the development of virus-associated asthma exacerbation. A murine model of virus-associated asthma exacerbation was established using intranasal challenge with ovalbumin (OVA) plus dsRNA for 4 weeks in mice sensitized with OVA plus dsRNA. Lung infiltration of inflammatory cells, especially neutrophils, was increased by repeated challenge with OVA plus dsRNA, as compared to OVA alone. The neutrophilic inflammation enhanced by dsRNA was partly abolished in the absence of IFN-gamma or IL-17 gene expression, whereas unaffected in the absence of IL-13. In terms of the roles of NOSs, dsRNA-enhanced neutrophilic inflammation was significantly decreased in inducible NOS (iNOS)-deficient mice compared to wild type controls; in addition, this phenotype was inhibited by treatment with a non-specific NOS inhibitor (L-NAME) or an specific inhibitor (1400 W), but not with a specific endothelial NOS inhibitor (AP-CAV peptide). Taken together, these findings suggest that iNOS pathway is important in the development of virus-associated exacerbation of neutrophilic inflammation, which is dependent on both Th1 and Th17 cell responses.

The serine-threonine kinase RIP1 was originally identified through its ability to bind to the death domain of Fas (CD95). RIP1 has been shown to be recruited to the Fas Death-Inducing Signaling Complex (DISC) and is required for the induction of necrotic cell death. Here we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane-bound Fas Ligand (memFasL), but not with agonistic antibodies or crosslinked soluble Fas Ligand. RIP1 participates in the FADD-mediated recruitment of caspase-8 to the Fas receptor complex in a manner that promotes caspase-8 activation. Crosslinking antibodies, such as CH11, bypass the requirement for RIP1 in caspase activation by initiating larger, though less efficient, DISC complexes, while memFasL initiates a smaller but more efficient DISC that functions, in part, by effectively incorporating more RIP1 into the complex. Consequently, RIP1 is likely a more integral part of physiological signaling through the Fas/CD95 receptor complex than previously recognized; at least when the signal is mediated by full-length membrane bound Fas Ligand. Crosslinked Soluble FasL, which also occurs physiologically, behaves similarly to the CH11 antibody, and may therefore be more likely to initiate non-apoptotic Fas signaling due to less RIP1 in the receptor complex. Thus, agonists that bind the same Fas receptor initiate mechanistically distinct pathways resulting in differential cytotoxicity.

Background/Aims

Ciprofloxacin has been widely prescribed for acute infectious diarrhea. However, the resistance to this drug is increasing. Rifaximin is a novel but poorly absorbed rifamycin derivative. This study evaluated and compared the efficacies of rifaximin and ciprofloxacin for the treatment of acute infectious diarrhea.

Methods

We performed a randomized controlled multicenter study in Korea. Patients with acute diarrhea were enrolled and randomized to receive rifaximin or ciprofloxacin for 3 days. The primary efficacy endpoint was the time to last unformed stool (TLUS). Secondary endpoints were enteric wellness (reduction of at least 50% in the number of unformed stools during 24-hour postenrollment intervals), general wellness (subjective feeling of improvement), and proportion of patients with treatment failure.

Results

Intent-to-treat analysis (n=143) showed no significant difference between the rifaximin and ciprofloxacin groups in the mean TLUS (36.1 hours vs 43.6 hours, p=0.163), enteric wellness (49% vs 57%, p=0.428), general wellness (67% vs 78%, p=0.189), or treatment failure rate (9% vs 12%, p=0.841). The adverse events did not differ significantly between the two groups.

Conclusions

These results suggest that rifaximin is as safe and effective as ciprofloxacin in the treatment of acute infectious diarrhea.

IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-γ-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-γ over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-γ-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-γ expression were impaired in allergen-challenged IL-12Rβ2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Rα-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-γ. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-γ axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.

Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-α and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection.

Theophylline is commonly used to treat severe asthma and chronic obstructive pulmonary disease (COPD) characterized by non-eosinophilic inflammation. Acetyl salicylic acid (ASA) is one of the most widely used medications worldwide, but up to 20% of patients with asthma experience aggravated respiratory symptoms after taking ASA. Here we evaluated the adverse effect of ASA on the therapeutic effect of theophylline in mice with non-eosinophilic asthma. A non-eosinophilic asthma mouse model was induced by airway sensitization with lipopolysaccharide-containing allergen and then challenged with allergen alone. Therapeutic intervention was performed during allergen challenge. Theophylline inhibited lung inflammation partly induced by Th1 immune response. ASA attenuated the beneficial effects of theophylline. However, co-administration of the ASA metabolite salicylic acid (SA) showed no attenuating effect on theophylline treatment. The therapeutic effect of theophylline was associated with increase in cAMP levels, which was blocked by co-treatment of theophylline and ASA. ASA co-treatment also attenuated the anti-inflammatory effects of a specific phosphodiesterase 4 inhibitor. These results demonstrate that ASA reverses anti-inflammatory effects of theophylline, and that ASA exerts its adverse effects through the inhibition of cAMP production. Our data suggest that ASA reverses lung inflammation in patients taking theophylline, although clinical evidence will be needed.

Trichuris trichiura, commonly referred to as a whipworm, has a worldwide distribution, particularly among countries with warm, humid climates. In Korea, trichuriasis was a highly prevalent soil-transmitted helminthiasis until the 1970s. However, the nationwide prevalence decreased to 0.02% in 2004 as a result of national control activities and improvement in the socioeconomic status of Koreans. Most infected individuals have no distinct symptoms, if lightly infected. The diagnosis is typically confirmed by detection of T. trichiura eggs on examination of a stool sample; few reports have described detection of the parasite during colonoscopy. Recently, we managed 4 patients with trichuriasis who were diagnosed by detection of the parasite on colonoscopy, and we reviewed the literature on the colonoscopic diagnosis of T. trichiura in Korea. We suggest that colonoscopy might be a useful diagnostic tool, especially when infected by only a few male worms with no eggs in the stool.

The physiological role of the TRADD adaptor protein remains unclear due to the unavailability of a TRADD-deficient animal model. By generating TRADD-deficient mice, we demonstrated that TRADD plays a significant role in tumor necrosis factor receptor-1 (TNFR1) signaling by orchestrating the formation of TNFR1 signaling complexes. TRADD was essential for TNFR1 signaling in mouse embryonic fibroblasts (MEFs) but partially dispensable in macrophages; abundant expression of the adaptor RIP in macrophages may allow some transmission of TNFR1 signals in the absence of TRADD. Although morphologically normal, TRADD-deficient mice were resistant to TNF-, lipopolysaccharide- and poly(I:C)-induced toxicity. TRADD was also required for TRIF-dependent Toll-like receptor signaling in MEFs but not macrophages. These findings definitively establish the biological role of TRADD in TNF signaling.

LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin β receptor (LTβR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTβR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTβR-mediated activation of both the transcription factor NF-κB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-κB and JNK activation, which can be blocked by the dominant negative mutant of TRAF2. In these cells, LIGHT causes the recruitment of TRAF2, TRAF3, and IκB kinase into the LTβR complex. Importantly, while both NF-κB and JNK are activated by LIGHT in wild-type mouse embryonic fibroblasts, no activation of either of these two pathways is observed in TRAF2 null fibroblasts. However, LIGHT-induced NF-κB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF2−/− cells. Interestingly, in contrast to TNF signaling, the activation of both NF-κB and JNK by LIGHT was normal in RIP−/− and TRAF5−/− cells. Taken together, our data demonstrate that TRAF2, an important effector molecule of TNF signaling, plays a critical, nonredundant role in LIGHT-LTβR signaling.