• Biomedical Science Letters
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• v.13 no.3
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• pp.197-206
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• 2007

P2X receptors are membrane-bound ion channels that conduct $Na^+,\;K^+$, and $Ca^{2+}$ in response to ATP and its analogs. There are seven subunits identified so far ($P2X_1-P2X_7$). $P2X_2$ receptors are known to be expressed in a wide range of organs including brains and adrenal grands. PC12 cells are originated from adrenal grand and differentiated by nerve growth factor or pituitary adenylate cyclase activating poly peptide (PACAP). Previous studies indicate that $P2X_2$ receptor activation in PC12 cells couples to $Ca^{2+}-dependent$ release of catecholamine and ATP. It is known that acidic pH potentiates ATP currents at $P2X_2$ receptors. This leads to a hypothesis that $P2X_2$ receptors may play an important role in PC12 cell differentiation, one of the characteristics of which is neurite outgrowth, induced by the hormones under lower pH. In the present study, we isolated several clones which potentiate neurite outgrowth by PACAP in acidic pH (6.8), but not in alkaline pH (7.6). RT-PCR and electrophysiology data indicate that these clones express only functional $P2X_2$ receptors in the absence or presence of PACAP for 3 days. Potentiation of neurite outgrowth resulted from PACAP (100 nM) in acidic pH is inhibited by the two P2X receptor antagonists, suramin and PPADS ($100\;{\mu}M)$ each), and exogenous exprerssion of ATP-binding mutant $P2X_2$ receptor subunit ($P2X_2[K69A]$). However, acid sensing ion channels (ASICs) are not involved in PACAP-induced neurite outgrowth potentiation in lower pH since treatments of an inhibitor of ASICs, amyloride ($10\;{\mu}M$), did not give any effects to neurite extension. The vesicular proton pump ($H^+-ATPase$) inhibitor, bafilomycin (100 nM), reduced neurite extension indicating that ATP release resulted from $P2X_2$ receptor activation in PC12 cells is needed for neurite outgrowth. These were confirmed by activation of mitogen activated protein kinases, such as ERKs and p38. These results suggest roles of ATP and $P2X_2$ receptors in hormone-induced cell differentiation or neuronal synaptogenesis in local acidic environments.

• Molecules and Cells
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• v.40 no.8
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• pp.567-576
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• 2017

The $Na^+/H^+$ exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular $Na^+$ and the extrusion of intracellular $H^+$. The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent $Na^+/H^+-exchange$ inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid-sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth-suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a $sub-G_0/G_1$ peak, and a $G_2/M$ phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with increased levels of the p-histone H2A.X, $p-ATM^{Ser1981}$, $p-ATR^{Ser428}$, $p-CHK1^{Ser345}$, and $p-CHK2^{Thr68}$, as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acidtolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic-microenvironment-associated chemotherapeutic resistance.

• The Journal of Internal Korean Medicine
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• v.37 no.1
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• pp.90-108
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• 2016

Objectives: This study aimed to learn what should be considered in the Guidelines of Clinical Trials with Herbal Medicinal Products for Gastroesophageal Reflux Disease (GERD) by analyzing the existing guidelines and clinical trials.Methods: The development committee searched the existing guidelines for herbal medicinal products or GERD. Then, clinical trials related to GERD using herbal medicine were selected. The chosen trials were analyzed in terms of their inclusion and exclusion of participants, intervention, comparators, outcome, and trial design. Then, we compared the results of the analysis according to the regulations and guidelines of the Ministry of Food and Drug Safety to suggest the issues that we will have to consider when developing the Guidelines of Clinical Trials with Herbal Medicinal Products for Gastroesophageal Reflux Disease (GERD).Results: As a result, few guidelines for GERD and clinical trials with herbal medicinal products were located in the national institution homepage. In addition, 8 articles were found using the following combination of search terms: “Gastroesophageal reflux disease”, “GERD”, “herbal medicine”, “herbal therapy”, “Korean Medicine”, “Traditional Chinese Medicine”, and “TCM”. Even though all trials had their own unique research questions, all studies were performed using a randomization method. Most trials included participants with reflux esophagitis, but two trials targeted proton pump inhibitor-refractory GERD. The type of intervention varied, such as decoction, granules, and capsules. Additionally, individualized herbal medicines were used in two studies. Comparators were diverse, such as placebo, Western medicine, and electro-acupuncture. The most frequently used outcome for efficacy was the effectiveness rate. In addition, the outcome for evaluating quality of life, esophageal mucosa and pressure, esophageal acid reflux, and recurrence rates were used. Safety was investigated by recording adverse events and carrying out laboratory tests.Conclusions: We identified some issues by reviewing the existing guidelines and comparing them with clinical trials for GERD and herbal medicinal products. These results will be utilized for developing the Guidelines of Clinical Trials with Herbal Medicinal Products for Gastroesophageal Reflux Disease (GERD).

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.23 no.1
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• pp.43-47
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• 2012

Background and Objectives : Laryngopharyngeal reflux disease (LPRD) originates from regurgitation of gastric contents to the laryngopharynx, and it is relatively common disease in otolaryngology. Proton-pump inhibitor (PPI) medication is frequently using treatment method in present time, but controversies exist regarding treatment for it. High-resolution manometry (HRM) system is a newly developed device that using 36 channels and pressure topography plotting program, checking the function and status of esophagus. The aim of this study was to evaluate clinical usefulness of HRM in LPRD patients who do not response to PPI medication. Materials and Method : From July 2009 to July 2010, a total of 99 patients who were suspected LPRD according to symptoms (Reflux Symptom Index >13) and laryngoscopic findings (Reflux Finding Score >7) were retrospectively enrolled in this study. Patients were consisted of 31 men and 68 women, the mean age was 51.8 years, the mean BMI was 22.46. Patients have taken PPI medication for 2 months, after medication, they performed HRM. Comparative analysis was performed with results of the difference in symptoms. Results : In 99 patients, 37 patients (37.4%) show not improvement of LPRD symptoms after PPI medication. Among them, 18 patients (48.6%) showed abnormal findings that were classified as Peristaltic dysfunction (38.9%), Diffuse esophageal spasm (11.1%), Relaxation impairment of LES (11.1%), Achalasia (5.6%), Hypotensive LES (11.1%), Relaxation impairment of UES (11.1%), Nutcracker esophagus (5.6%), Decreased resting pressure (5.6%). Other 62 patients (62.6%) show improvement of LPRD symptoms, 23 patients (37.1%) showed abnormal findings. Most common finding was Peristaltic dysfunction (43.4%) More prevalent abnormal findings of HRM were found in patients who revealed no response to PPI medication (48.6% vs. 37.1%), but it does not reach the statistical significance. Conclusion : Although statistical significances is not showed, the difference observed in the frequency of HRM abnormal finding between response and no response for PPI medication. It has been estimated that HRM may be used to determine differential diagnosis in patients with LPRD. Further studies in lager population containing normal controls will be needed to prove clinical usefulness.

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.22 no.2
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• pp.151-155
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• 2011

Background and Objectives : Laryngopharyngeal reflux disease (LPRD) originates from regurgitation of gastric contents to the laryngopharynx, and it is relatively common disease in otolaryngology. Proton-pump inhibitor (PPI) medication is frequently using treatment method in present time, but controversies exist regarding treatment for it. High-resolution manometry (HRM) system is a newly developed device that using 36 channels and pressure topography plotting program, checking the function and status of esophagus. The aim of this study was to evaluate clinical usefulness of HRM in LPRD patients who do not response to PPI medication. Subjects and Method : From July 2009 to July 2010, a total of 99 patients who were suspected LPRD according to symptoms (Reflux Symptom Index >13) and laryngoscopic findings (Reflux Finding Score >7) were retrospectively enrolled in this study. Patients were consisted of 31 men and 68 women, the mean age was 51.8 years, the mean BMI was 22.46. Patients have taken PPI medication for 2 months, after medication, they performed HRM. Comparative analysis was performed with results of the difference in symptoms. Results : In 99 patients, 37 patients (37.4%) show not improvement of LPRD symptoms after PPI medication. Among them, 18 patients (48.6%) showed abnormal findings that were classified as Peristaltic dysfunction (38.9%), Diffuse esophageal spasm (11.1%), Relaxation impairment of LES (11.1%), Achalasia (5.6%), Hypotensive LES (11.1%), Relaxation impairment of UES (11.1%), Nutcracker esophagus (5.6%), Decreased resting pressure (5.6%). Other 62 patients (62.6%) show improvement of LPRD symptoms, 23 patients (37.1%) showed abnormal findings. Most common finding was Peristaltic dysfunction (43.4%) More prevalent abnormal findings of HRM were found in patients who revealed no response to PPI medication (48.6% vs. 37.1%), but it does not reach the statistical significance. Conclusion : Although statistical significances is not showed, the difference observed in the frequency of HRM abnormal finding between response and no response for PPI medication. It has been estimated that HRM may be used to determine differential diagnosis in patients with LPRD. Further studies in lager population containing normal controls will be needed to prove clinical usefulness.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.22 no.5
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• pp.417-430
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• 2019

The policies developed for the treatment of Helicobacter pylori infection in adults may not be the most suitable ones to treat children and adolescents. Methods used to treat children and adolescents in Europe and North America may not be appropriate for treating children and adolescents in Korea due to differences in epidemiological characteristics of H. pylori between regions. Moreover, the agreed standard guidelines for the treatment of H. pylori infection in children and adolescents in Korea have not been established yet. In this study, the optimal treatment strategy for H. pylori infection control in children and adolescents in Korea is discussed based on these guidelines, and recent progress on the use and misuse of antimicrobial agents is elaborated. Non-invasive as well as invasive diagnostic test and treatment strategy for H. pylori infection are not recommendable in children aged less than ten years or children with body weight under 35 kg, except in cases of clinically suspected or endoscopically identified peptic ulcers. The uncertainty, whether enough antimicrobial concentrations to eradicate H. pylori can be maintained when administered according to body weight-based dosing, and the costs and adverse effects outweighing the anticipated benefits of treatment make it difficult to decide to eradicate H. pylori in a positive noninvasive diagnostic test in this age group. However, adolescents over ten years of age or with a bodyweight of more than 35 kg can be managed aggressively as adults, because they can tolerate the adult doses of anti-H. pylori therapy. In adolescents, the prevention of future peptic ulcers and gastric cancers is expected after the eradication of H. pylori. Bismuth-based quadruple therapy (bismuth-proton pump inhibitor-amoxicillin/tetracycline-metronidazole) with maximal tolerable doses and optimal dose intervals of 14 days is recommended, because in Korea, the antibiotic susceptibility test for H. pylori is not performed at the initial diagnostic evaluation. If the first-line treatment fails, concomitant therapy plus bismuth can be attempted for 14 days as an empirical rescue therapy. Finally, the salvage therapy, if needed, must be administered after the H. pylori antibiotic susceptibility test.

• Tuberculosis and Respiratory Diseases
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• v.79 no.1
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• pp.14-21
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• 2016

Cough is one of the most common symptom of many respiratory diseases. The Korean Academy of Tuberculosis and Respiratory Diseases organized cough guideline committee and cough guideline was developed by this committee. The purpose of this guideline is to help clinicians to diagnose correctly and treat efficiently patients with cough. In this article, we have stated recommendation and summary of Korean cough guideline. We also provided algorithm for acute, subacute, and chronic cough. For chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered. If UACS is suspicious, first generation anti-histamine and nasal decongestant can be used empirically. In CVA, inhaled corticosteroid is recommended in order to improve cough. In GERD, proton pump inhibitor is recommended in order to improve cough. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, angiotensin converting enzyme inhibitor, habit, psychogenic cough, interstitial lung disease, environmental and occupational factor, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and idiopathic cough can be also considered as cause of chronic cough. Level of evidence for treatment is mostly low. Thus, in this guideline, many recommendations are based on expert opinion. Further study regarding treatment for cough is mandatory.

• Tuberculosis and Respiratory Diseases
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• v.84 no.4
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• pp.263-273
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• 2021

Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient's quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

• Journal of Gastric Cancer
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• v.1 no.1
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• pp.55-59
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• 2001

Purpose: Several studies of an endoscopic mucosal resection(EMR) have been reported, but reports about benign protruding lesions that arise at the scar of EMR for early gastric cancer (EGC) or a gastric adenoma are rare. The purpose of this study was to elucidate endoscopic and histological characteristics of benign protruding lesions which arise at the scar of an EMR for EGC and a gastric flat adenoma. Materials and Methods: In 101 lesions (73 gastric flat adenomas and 28 EGCs) from 96 patients, 16 lesions developed new protruding lesions that arose at the scar of the EMR. We retrospectively analyzed the endoscopic findings of initial and protruding lesions, and several other clinical factors (H. pylori infection, eradication therapy, and proton pump inhibitor (PPI) or H2-blocker use). Results: 1. The mean duration until detection of the protruding lesion was 8.9 months ($1.5\∼27$). Protruding lesions arose at the scar of the EMR in 1 of 28 EGCs ($3.6\%$) and from 15 of 73 gastric flat adenomas ($20.5\%$). All of the patients were men. 2. With respect to the endoscopic findings, the shapes of the protruding lesions were as follows: 10 Yamada (Y) I, 4 Y-II, 1 Y-III, and 1 flat lesion. Histological examination of the protruding lesions revealed regenerating hyperplasia in 5 lesions, intestinal metaplasia in 5, and both in 6. 3. The incidence of these lesions was higher in cases of tubular adenomas with focal high-grade dysplasia than in cases of tubular adenomas without dysplasia (p<0.05). 4. The incidence of H. pylori infection was higher in patients ($81.7\%$) who developed a protruding lesion than in those ($51.8\%$) who did not develop (p=0.029); also, the incidence of use of PPI was higher in those patients (p=0.045). However, eradication therapy for H. pylori and duration of use of PPI or H2-blocker showed no difference between groups. Conclusions: It may be possible that the potential hyperplasia that may reside in normal mucosa surrounding EGC or a gastric adenoma might awaken during the healing process of the EMR ulcer and develop to benign protruding lesions. And, H. pylori and PPI might also be related to the development of the protruding lesions.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.5 no.1
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• pp.19-25
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• 2002

Purpose: The triple therapy with proton pump inhibitor (PPI) has been recognized as the treatment of choice in Helicobacter pylori (H. pylori) infection in adults. However, the effect of triple therapy with omeprazole, amoxicillin and clarithromycin (OAC) on eradication of H. pylori infection in children has not been established yet. This study was performed to evaluate the efficacy of OAC triple therapy and to compare the effect of one-week with two-week therapy on H. pylori eradication. Methods: From July 1998 to July 2000, 34 children with upper gastrointestinal symptoms, who underwent upper gastrointestinal endoscopy with biopsy at entry and 4 or more weeks after therapy, were enrolled in this study. H. pylori infection was assessed by CLO test and histologic examination (Hematoxylin-Eosin stain or Alcian yellow stain) with biopsy specimens. The regimen consisted of omeprazole (0.7 mg/kg/day), amoxicillin (50 mg/kg/day), and clarithromycin (25 mg/kg/day) for 1 week (n=21) or 2 weeks (n=13). Eradication of H. pylori was determined after the termination of treatment by the CLO test and histologic examination. Results: One-week treatment group consisted of 21 children (11 male, 10 female) with a mean age of $9.5{\pm}3.0$ years. Two-week group consisted of 13 children (4 male, 9 female) with a mean age of $9.9{\pm}4.0$ years. The endoscopic diagnoses included nodular gastritis in 19 cases, superficial gastritis in 7 cases, gastric ulcer in 4 cases, purpuric duodenitis in 2 cases, and normal in 2 cases. H. pylori was eradicated in 28 of total 34 children (82.4%). In 1-week group, H. pylori was eradicated in 17 of 21 children (81%). In 2-week group, H. pylori was eradicated in 11 of 13 children (84.6%). In remaining 6 cases in whom H. pylori had not been eradicated with OAC regimen, H. pylori infection persisted despite of the treatment with additional drugs such as colloidal bismuth subcitrate ($Denol^{(R)}$) and metronidazole. Conclusion: In this study, eradication rate of H. pylori with OAC regimen was 82.4%, and the triple therapy would be highly effective as primary treatment. However, there was no significant difference in the eradication rate between the 1-week and 2-week treatment group (P=0.785).