Heart failure with preserved ejection fraction (HFPEF) is a global health problem of considerable socioeconomic burden. It is projected to worsen with the aging population worldwide. The lack of effective therapies underscores our incomplete understanding of this complex heterogeneous syndrome. A novel paradigm has recently emerged, in which central roles are ascribed to systemic inflammation and generalized endothelial dysfunction in the pathophysiology of HFPEF. In this review, we discuss the role of the endothelium in cardiovascular homeostasis and how deranged endothelial-related signaling pathways contribute to the development of HFPEF. We also review the novel therapies in various stages of research and development that target different components of this signaling pathway.

A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of f luoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed.

Eradication of Helicobacter pylori is recommended for the management of various gastric diseases, including peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Because of the increasing prevalence of antibiotic resistance, the eradication rates of antibiotic-based therapies have decreased. Therefore, alternative treatments should be considered. The antibacterial properties of fatty acids (FAs) have been investigated in various organisms, including H. pylori. Some FAs, particularly polyunsaturated FAs, have been shown to have bactericidal activity against H. pylori in vitro; however, their antibacterial effects in vivo remain controversial. Poor solubility and delivery of FAs may be important reasons for this discrepancy. Recently, a series of studies demonstrated the antibacterial effects of a liposomal formulation of linolenic acid against H. pylori, both in vitro and in vivo. Further research is needed to improve the bioavailability of FAs and apply them in clinical use.

Background/Aims: To evaluate a new monoclonal antibody for Helicobacter pylori urease in gastric tissue. Methods: A total of 107 volunteers were enrolled. All subjects underwent a $^{13}C$-urea breath test and esophagogastroduodenoscopy. Gastric aspirates were analyzed for pH and ammonia. Six biopsy specimens in the gastric antrum and body were obtained for a rapid urease test and histology. The new monoclonal antibody-based H. pylori urease test (HPU) was performed to rapidly and qualitatively detect urease in two biopsy specimens. Results: H. pylori infection was diagnosed in 73 subjects. The sensitivity and specificity of the HPU was 89% and 74%, respectively. The subjects were divided into two groups: one with true-positive and true-negative HPU results (n = 90) and the other with false-positive and false-negative HPU results (n = 17). Across all subjects, ammonia levels were $900.5{\pm}646.7$ and $604.3{\pm}594.3{\mu}mol/L$ (p > 0.05), and pH was $3.37{\pm}1.64$ and $2.82{\pm}1.51$ (p > 0.05). Sensitivity was higher in the presence of atrophic gastritis or intestinal metaplasia. Conclusions: HPU detected H. pylori in approximately 10 min. Gastric aspirate ammonia and pH levels did not affect the test results. Sensitivity was good in the presence of atrophic gastritis or intestinal metaplasia.

Background/Aims: The aim of this study was to evaluate the feasibility of ${\alpha}$-fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. Methods: We retrospectively reviewed the medical records of HCC and cirrhosis patients at three hospitals. For each HCC patient, a cirrhosis patient matched for age, sex, etiology, and Child-Pugh classification was selected by simple random sampling. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. Results: A total of 732 patients with HCC or cirrhosis were selected for each case and the control groups. The mean age was 54 years, and 72.4% of patients were male. The mean serum AFP levels in the HCC group and cirrhosis group were 3,315.6 and 117.2 ng/mL, respectively (p < 0.001). The area under the receiver operating characteristic curve for all HCC patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut-off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. Conclusions: The cut-off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, and that the appropriate value of AFP for the diagnosis of HCC may be 100 ng/mL rather than 200 ng/mL.

Background/Aims: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency that can be life threatening. This study evaluated predictive factors of 30-day mortality in patients with this condition. Methods: A prospective observational study was conducted at a single hospital between April 2010 and November 2012, and 336 patients with symptoms and signs of gastrointestinal bleeding were consecutively enrolled. Clinical characteristics and endoscopic findings were reviewed to identify potential factors associated with 30-day mortality. Results: Overall, 184 patients were included in the study (men, 79.3%; mean age, 59.81 years), and 16 patients died within 30 days (8.7%). Multivariate analyses revealed that comorbidity of diabetes mellitus (DM) or metastatic malignancy, age ${\geq}65$ years, and hypotension (systolic pressure < 90 mmHg) during hospitalization were significant predictive factors of 30-day mortality. Conclusions: Comorbidity of DM or metastatic malignancy, age ${\geq}65$ years, and hemodynamic instability during hospitalization were predictors of 30-day mortality in patients with NVUGIB. These results will help guide the management of patients with this condition.

Background/Aims: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. Methods: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. Results: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of $39.6{\pm}43.7$ days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The ${\leq}30-day$ group was characterized by higher peak alanine aminotransferase (ALT) level and a high proportion of patients with maintenance of first-line antituberculous drugs compared to the > 30-day group. In subgroup analysis, the ${\leq}7-day$ group was characterized by higher baseline aspartate aminotransferase and ALT, high proportion of patients with maintenance of first-line antituberculous drugs, and high proportion of patients with extrapulmonary tuberculosis compared to patients with ADIH that developed beyond 7 days. In multivariate analysis, serum ALT > 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. Conclusions: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen.

Background/Aims: The $CHADS_2$ score, used to predict the risk of ischemic stroke in atrial fibrillation (AF) patients, has been reported recently to predict ischemic stroke in patients with coronary heart disease, regardless of the presence of AF. However, little data are available regarding the relationship between the $CHADS_2$ score and cardiovascular outcomes. Methods: This was a retrospective study on 104 patients admitted for acute coronary syndrome (ACS) who underwent coronary angiography, carotid ultrasound, and transthoracic echocardiography. Results: The mean age of the subjects was $60.1{\pm}12.6years$. The $CHADS_2$ score was as follows: 0 in 46 patients (44.2%), 1 in 31 (29.8%), 2 in 18 (17.3%), and ${\geq}3$ in 9 patients (8.7%). The left atrial volume index (LAVi) showed a positive correlation with the $CHADS_2$ score ($20.8{\pm}5.9$ for 0; $23.2{\pm}6.7$ for 1; $26.6{\pm}10.8$ for 2; and $30.3{\pm}8.3mL/m^2$ for ${\geq}3$; p = 0.001). The average carotid total plaque area was significantly increased with $CHADS_2$ scores ${\geq}2$($4.97{\pm}7.17mm^2$ vs. $15.52{\pm}14.61mm^2$; p = 0.002). Eight patients experienced cardiovascular or cerebrovascular (CCV) events during a mean evaluation period of 662 days. A $CHADS_2$ score ${\geq}3$ was related to an increase in the risk of CCV events (hazard ratio, 14.31; 95% confidence interval, 3.53 to 58.06). Furthermore, LAVi and the severity of coronary artery obstructive disease were also associated with an increased risk of CCV events. Conclusions: The $CHADS_2$ score may be a useful prognostic tool for predicting CCV events in ACS patients with documented coronary artery disease.

Background/Aims: Post-extubation respiratory failure (PERF) is associated with poor clinical outcomes. High-f low nasal cannula (HFNC) oxygen therapy has been used in patients with respiratory failure, but the clinical benefit in patients with PERF remains unclear. The aim of this study was to evaluate the clinical efficacy of HFNC compared to noninvasive ventilation (NIV) in patients with PERF. Methods: A historic retrospective cohort analysis was performed in 28 beds in the medical Intensive Care Unit (ICU) at a single medical center in South Korea. In total, 73 patients with PERF were enrolled: 39 patients who underwent NIV from April 2007 to March 2009 and 34 patients who received HFNC from April 2009 to May 2011. Results: The rate of avoidance of reintubation was not different between the HFNC group (79.4%) and NIV group (66.7%, p = 0.22). All patients with HFNC tolerated the device, whereas five of those with NIV did not tolerate treatment (p = 0.057). The mean duration of ICU stay was significantly shorter in the HFNC group than in the NIV group (13.4 days vs. 20.6 days, p = 0.015). There was no difference in ICU or in-hospital mortality rate. Conclusions: HFNC is likely to be as effective as, and better tolerated than, NIV for treatment of PERF.

Background/Aims: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. Methods: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells ($NF-{\kappa}B$) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and $NF-{\kappa}B$. Conclusions: These results suggest that intranasal administration of rosiglitazone can prevent not only airway inf lammation but also airway remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and $NF-{\kappa}B$ pathways.

Background/Aims: This study evaluated the relationship between thyroid nodules and metabolic syndrome (MS) and its components in apparently healthy Koreans. Methods: We reviewed the records of 3,298 subjects with no noticeable symptoms who underwent thyroid ultrasound imaging as part of a routine check-up between July 2009 and June 2010; of these, 1,308 were excluded based upon predefined criteria. Among the remaining 1,990 patients, we examined the association between MS and its components and the incidence of thyroid nodules. Results: Of the 1,990 subjects included in this study, 38.4% (n = 764) had thyroid nodules and 12.7% (n = 253) had MS. Female sex, older age, higher body mass index, larger waist circumference, higher glycated hemoglobin level, lower thyroid stimulating hormone level, and presence of MS were all closely related with the presence of thyroid nodules (all p < 0.05). Furthermore, the relevant number of MS components showed a positive linear correlation with the occurrence of thyroid nodules (p < 0.001). Evidence of MS alone was not independently associated with thyroid nodules after adjusting for sex and age in a multivariate binary logistic regression analysis; however, glycated hemoglobin for females and waist circumference for males, as well as both age and thyroid stimulating hormone for all patients, were identified as independent predictors for the existence of thyroid nodules (all p < 0.05). Conclusions: This study suggests a positive relationship between the components of MS and thyroid nodules in an ostensibly healthy Korean population. Our data support the idea that the recent increase in thyroid nodules is partly due to increases in both MS and obesity.

Background/Aims: This study analyzed the risk factors for technique survival in dialysis patients and compared technique survival rates between hemodialysis (HD) and peritoneal dialysis (PD) in a prospective cohort of Korean patients. Methods: A total of 1,042 patients undergoing dialysis from September 2008 to June 2011 were analyzed. The dialysis modality was defined as that used 90 days after commencing dialysis. Technique survival was compared between the two dialysis modalities, and the predictive risk factors were evaluated. Results: The dialysis modality was an independent risk factor predictive of technique survival. PD had a higher risk for technique failure than HD (hazard ratio [HR], 10.8; 95% confidence interval [CI], 1.9 to 62.0; p = 0.008) during a median follow-up of 11.0 months. In the PD group, a high body mass index (BMI) was an independent risk factor for technique failure (HR, 1.3; 95% CI, 1.0 to 1.8; p = 0.036). Peritonitis was the most common cause of PD technique failure. The difference in technique survival between PD and HD was more prominent in diabetic patients with a good nutritional status and in non-diabetic patients with a poor nutritional status. Conclusions: In a prospective cohort of Korean patients with end-stage renal disease, PD was associated with a higher risk of technique failure than HD. Diabetic patients with a good nutritional status and non-diabetic patients with a poor nutritional status, as well as patients with a higher BMI, had an inferior technique survival rate with PD compared to HD.

Background/Aims: We investigated whether angiotensin III (Ang III) is involved in monocyte recruitment through regulation of the chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured human proximal tubular epithelial cells (HK-2 cells). Methods: We measured MCP-1 levels in HK-2 cells that had been treated with various concentrations of Ang III and Ang II type-1 (AT1) receptor antagonists at various time points. The phosphorylation states of p38, c-Jun N-terminal kinases (JNK), and extracellular-signal-regulated kinases were measured in Ang III-treated cells to explore the mitogen-activated protein kinase (MAPK) pathway. MCP-1 levels in HK-2 cell-conditioned media were measured after pre-treatment with the transcription factor inhibitors curcumin or pyrrolidine dithiocarbamate. Results: Ang III increased MCP-1 protein production in dose- and time-dependent manners in HK-2 cells, which was inhibited by the AT1 receptor blocker losartan. p38 MAPK activity increased significantly in HK-2 cells exposed to Ang III for 30 minutes, and was sustained at higher levels after 60 minutes (p < 0.05). Total phosphorylated JNK protein levels tended to increase 20 minutes after stimulation with Ang III. Pre-treatment with a p38 inhibitor, a JNK inhibitor, or curcumin significantly inhibited Ang III-induced MCP-1 production. Conclusions: Ang III increases MCP-1 synthesis via stimulation of intracellular p38 and JNK MAPK signaling activity and subsequent activated protein-1 transcriptional activity in HK-2 cells.

Background/Aims: It has been suggested that chronic kidney disease (CKD) is a risk factor for Clostridium difficile infection (CDI) and is associated with increased mortality among patients infected with C. difficile. However, recent studies of the clinical impact of CKD on CDI in Asians are still insufficient. We sought to determine the relationship between CKD and CDI in a Korean population. Methods: This was a single-center, retrospective case-control study. In total, 171 patients with CDI were included as cases and 342 age- and gender-matched patients without CDI were used as controls. We compared the prevalence of CKD in the study sample and identified independent risk factors that could predict the development or prognosis of CDI. Results: Independent risk factors for CDI included stage IV to V CKD not requiring dialysis (odds ratio [OR], 2.90) and end-stage renal disease requiring dialysis (OR, 3.34). Patients with more advanced CKD (estimated glomerular filtration rate < 30) and CDI showed higher in-hospital mortality and poorer responses to the initial metronidazole therapy. Conclusions: More advanced CKD is an independent risk factor for CDI and is associated with higher in-hospital mortality and poor treatment responses in CDI patients. Thus, in CKD patients, careful attention should be paid to the occurrence of CDI and its management to improve the outcome of CDI.

Background/Aims: The objective of this study was to assess the prognostic roles of treatment response and tissue necrosis after chemoradiotherapy (CRT) in locally advanced rectal cancer. Methods: A total of 243 patients with locally advanced rectal cancer who underwent neoadjuvant CRT were included. Three treatment response groups were classified by their pathological stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified based on tissue pathological results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR). Results: Overall survival (OS) and recurrence-free survival (RFS) rate at three years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR groups were 83.7%, 75.9%, and 69.7%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p < 0.001). The 3-year OS rates of the CNR, INR, and PNR groups were 83.7%, 80.6%, and 61.8%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p < 0.001). When compared to CTR/CNR, PTR/PNR was strongly related to an increased risk of recurrence (hazard ratio [HR], 5.53; 95% confidence interval [CI], 2.01 to 15.23 vs. HR, 6.37; 95% CI, 2.29 to 17.74, respectively) in univariate Cox regression. Both PTR and PNR were strongly associated with shorter RFS and OS when compared with CTR and CNR in the multivariate Cox regression. Conclusions: Tissue necrosis is an equally important prognostic marker as treatment response for oncologic outcomes in locally advanced rectal cancer.

Background/Aims: Efforts to decrease the use of extended-spectrum cephalosporins are required to prevent the selection and transmission of multi-drug resistant pathogens, such as extended-spectrum ${\beta}$-lactamase (ESBL)-producing Enterobacteriaceae. The objectives of this study were to assess the clinical efficacy of intravenous cefuroxime as an empirical antibiotic for the treatment of hospitalized women with acute pyelonephritis (APN) caused by Escherichia coli. Methods: We analyzed the clinical and microbiologic database of 328 hospitalized women with community-onset APN. Results: Of 328 women with APN, 22 patients had cefuroxime-resistant E. coli APN, and 306 patients had cefuroxime-susceptible E. coli APN. The early clinical success rates were significantly higher (p = 0.001) in the cefuroxime-susceptible group (90.8%, 278/306) than in the cefuroxime-resistant group (68.2%, 15/22) at 72 hours. The clinical cure rates at 4 to 14 days after completing antimicrobial therapy were not significantly different in the cefuroxime-resistant or -susceptible groups, with 88.2% (15/17) and 97.8% (223/228; p = 0.078), respectively. The microbiological cure rates were not significantly different and were 90.9% (10/11) and 93.4% (128/137), respectively (p =0.550). The median duration of hospitalization in the cefuroxime-resistant and -susceptible groups was 10 days (interquartile range [IQR], 8 to 13) and 10 days (IQR, 8 to 14), respectively (p=0.319). Conclusions: Cefuroxime, a second-generation cephalosporin, can be used for the initial empirical therapy of community-onset APN if tailored according to uropathogen identification and susceptibility results, especially in areas where the prevalence rate of ESBL-producing uropathogens is low.

Background/Aims: The number of urinary tract infections (UTIs) caused by extended-spectrum ${\beta}$-lactamase-producing Escherichia coli (ESBL-EC) is increasing. In an outpatient setting, there are limited therapeutic options to treat ESBL-producing pathogens. We evaluated the outcomes of amikacin outpatient parenteral antibiotic therapy (OPAT) for UTIs caused by ESBL-EC in patients not pre-treated with carbapenem. Methods: We retrospectively evaluated the outcomes of amikacin OPAT for UTIs caused by ESBL-EC. Results: From November 2011 to October 2012, eight females, who could not be hospitalized for carbapenem treatment, were treated with amikacin OPAT for nine episodes of non-bacteremic ESBL-EC UTIs. Seven of the eight patients had one or more comorbidities. Of the nine UTI cases, three had symptomatic lower UTIs and six had non-bacteremic upper UTIs. In all of the cases, symptomatic and laboratory improvements were observed following amikacin OPAT. One patient showed a delayed relapse with bilateral microabscesses 3 weeks after treatment cessation; however, a clinical and microbiological cure was eventually reached. All of the patients were able to tolerate amikacin OPAT without any significant nephrotoxicity or ototoxicity. Conclusions: Amikacin OPAT represents a feasible therapeutic option for non-bacteremic UTIs caused by ESBL-EC in settings with limited resources.

Background/Aims: Surgical site infection (SSI) is a major complication after radical neck dissection (RND) in patients with head and neck cancer (HNC). We investigated the incidence, risk factors, and etiology of SSI among patients who underwent RND. Methods: A retrospective cohort study was performed on HNC patients, excluding those with thyroid cancer, who underwent first RND at a teaching hospital between January 2006 and June 2010. Medical records were collected and analyzed to evaluate the risk factors and microbiological etiologies. Results: A total of 370 patients underwent first RND. The overall incidence of SSI was 19.7% (73/370). Multivariate analysis showed that male sex (odds ratio [OR], 4.281; p = 0.004), cardiovascular diseases (OR, 1.941; p = 0.020), large amount of blood loss during surgery (OR, 4.213; p = 0.001), and surgery lasting longer than 6 hours (OR, 4.213; p = 0.002) were significantly associated with SSI. The most common causative pathogen was Staphylococcus aureus (32.6%), and 93.2% of S. aureus isolates were methicillin-resistant. Klebsiella pneumoniae (13/92, 14.1%), Pseudomonas aeruginosa (11/92, 12.0%), and Enterococcus species (11/92, 12.0%) were also frequently detected. Conclusions: Based on our results, we predict that certain groups of patients are at high risk for SSIs after major HNC surgery. Preventive measures or close monitoring in these patients may be required to reduce the likelihood of postoperative SSIs. Furthermore, even though additional research is required, we would consider changing the prophylactic antibiotic regimens according to the causative organisms.

Background/Aims: We prepared a cross-cultural adaptation of the Behcet's Syndrome Activity Scale (BSAS) and evaluated its reliability and validity in Korea. Methods: Fifty patients with Behcet's disease (BD) who attended the Rheumatology Clinic of Gachon University Gil Medical Center were included in this study. The first BSAS questionnaire was administered at each clinic visit, and the second questionnaire was completed at home within 24 hours of the visit. A Behcet's Disease Current Activity Form (BDCAF) and a Behcet's Disease Quality of Life (BDQOL) form were also given to patients. The test-retest reliability was analyzed by intraclass correlation coefficients (ICC). To assess the validity, the total BSAS score was compared with the BDCAF score, the patient/physician global assessment, and the BDQOL by Spearman rank correlation. Results: Twelve males and 38 females were enrolled. The mean age was 48.5 years and the mean disease duration was 6.7 years. Thirty-eight patients (76.0%) returned the questionnaire by mail. For the test-retest reliability, the two assessments were significantly correlated on all 10 items of the BSAS questionnaire (p < 0.05) and the total BSAS score (ICC, 0.925; p < 0.001). The total BSAS score was statistically correlated with the BDQOL, BDCAF, and patient/physician global assessment (p < 0.01). Conclusions: The Korean version of BSAS is a reliable and valid instrument to measure BD activity.