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Background and Aim The aim of the present study was to examine the lifestyle‐ and comorbidity‐related determinant factors of the prescription of proton pump inhibitors (PPIs) for patients in whom Helicobacter pylori has been eradicated, and to evaluate the relationship between PPI prescription and the severity of endoscopic esophagitis. Methods This retrospective study included patients who underwent H. pylori eradication from May 2012 to September 2016 at Saiseikai Karatsu Hospital. All patients received upper gastrointestinal endoscopy before H. pylori eradication. Patients with open peptic ulcers and/or malignant diseases were excluded, and a final total of 389 patients were evaluated. Medical records were reviewed to determine the prescription of PPIs after H. pylori eradication, lifestyle‐related factors, and comorbidities. Lifestyle‐related factors were confirmed by a questionnaire. Results PPIs were administered to 124 of 389 patients (31.9%). The only lifestyle‐related risk factor for the prescription of PPIs after H. pylori eradication was older age (P, The lifestyle‐ and comorbidity‐related risk factors for the prescription of proton pump inhibitors after Helicobacter pylori eradication were older age and hypertension, while mild endoscopic esophagitis had no influence on proton pump inhibitor prescription.

Vonoprazan (VPZ)-based regimen for Helicobacter pylori (H. pylori) is safe and more efficacious than the proton pump inhibitor-based regimen mainly in adults. This study aimed to evaluate the efficacy and safety of a VPZ-based regimen for H. pylori eradication therapy in adolescents.An H. pylori screening and treatment longitudinal project for third-year junior high school students in Saga Prefecture began in 2016. Students who tested positive for both urine and stool tests received a VPZ-based regimen. On the checklist, students were asked for diarrhea, fever, abdominal pain, nausea, vomiting, urticaria, dysgeusia, or bloody stool occurrence during the therapy.The longitudinal project for H. pylori screening and treatment among third-grade students in Saga Prefecture targeted 41,115 students from 2017 to 2021 and 836 as positive. Of the 645 students, 542 (84.0% in per protocol [PP] analysis and 73.6% in intention-to-treat [ITT] analysis) were successful in primary eradication therapy. The secondary eradication therapy was successful in 79 (96.3% in PP analysis and 76.7% in ITT analysis) of 82 students. In the primary eradication therapy, abdominal pain occurred in 164 (27.9%), diarrhea in 217 (36.9%), nausea or vomiting in 7 (1.2%), and urticaria in 13 (2.2%) students. In the secondary eradication therapy, abdominal pain occurred in 12 (19.4%) and diarrhea in 17 (27.4%) students. The eradication therapy of 5 students was interrupted due to adverse events only by primary eradication therapy.VPZ-based regimen for H. pylori was efficacious and safe for adolescents, as in adults, for both primary and secondary eradication therapies.

Objective: The aim of this study was to determine the characteristics of patients without Helicobacter pylori infection who were prescribed antacid medications (potassium-competitive acid blockers, proton pump inhibitors, and/or H2 receptor antagonist) and had no upper gastrointestinal lesions detected by endoscopy. Methods: This cross-sectional study included the patients who underwent upper gastrointestinal endoscopy in our institution between August 2017 and July 2018. They were aged from 55 to 89 years, had no upper gastrointestinal lesions detected by endoscopy, and no H. pylori infection. Exclusion criteria comprised low-dose aspirin and/or nonsteroidal anti-inflammatory drugs. The subjects were allocated to middle-aged (55–69 years) and older age groups (70–89 years). The relationships between antacid medications and patient lifestyle and comorbidities were evaluated by multivariate analyses. Results: Of the 420 patients, 272 were in the middle-aged group and 148 patients in the older age group. Age was found to be a risk factor for antacid medications in both groups (p = 0.002, p = 0.007). No other lifestyle related factors were risk factors. As to comorbidities, hiatal hernia was positively associated with antacid medications in the middle-aged group (p = 0.002). Hypertension and Ca-blockers were positively associated with prescription of antacids in the older age group (p = 0.013); this association was not significant in the middle-aged group. Conclusions: Three lifestyle-related and/or comorbidity-associated factors known to exacerbate gastroesophageal reflux, namely, age, hiatus hernia, and Ca-blockers, were associated with prescription of antacid medications, even in patients without endoscopic reflux esophagitis.

Bioterrorism attacks become more probable when important high-profile international or political events are held, such as G7 summit meetings or mass gathering events including Olympic and Paralympic games and FIFA World Cup tournaments. Outbreaks of infectious disease and widespread incidents of food poisoning are also public health concerns at such times. In Japan, the Tokyo Metropolitan Government operates Ambulance Transfer Syndromic Surveillance (ATSS), which can help monitor such incidents. The present study presents and assesses the ATSS framework. During the study period of October 2017 through November 2018, we monitored 33 areas for symptoms of 9 categories: vomiting/nausea, dizziness, palpitation, unconsciousness, breathing disorder, fever, spasm/paralysis, collapse/weakness, and bloody emesis/nasal hemorrhage. Among all symptoms, we found 9929 low-level aberrations, 2537 medium-level aberrations, and 577 high-level aberrations, with respective frequencies of 9.2%, 2.3%, and 0.5%. Of those, Tokyo Metropolitan Institute of Public Health reported the information to Tokyo Metropolitan Government 28 times during the period. Of the 28 identified clusters, Tokyo Metropolitan Government judged the necessity for investigating 7. All of those were investigated at hospitals by the jurisdictional public health center. Because ATSS covers almost the entire Tokyo metropolitan area, with about 13.8 million residents, it is definitely the largest syndromic surveillance in the world.

BACKGROUND AND AIM Barrett's esophagus and colorectal polyps have several overlapping risk factors. Whereas several reports in Western countries have indicated a close relationship between Barrett's esophagus and colorectal polyps, the relationship between these two diseases remains unclear in Japan. This study was performed to determine whether the prevalence of Barrett's esophagus is related to that of colorectal polyps in Japanese patients. METHODS The present retrospective chart review included 1582 Japanese patients who underwent both total colonoscopy and esophagogastroduodenoscopy from January 2010 to December 2016. The data on colorectal polyps and Barrett's esophagus were obtained from the endoscopic findings. The medical record of each patient was checked for age, sex, body mass index, smoking, alcohol drinking, use of acid suppression agents, and comorbidities including a history of diabetes, ischemic heart disease, gastroesophageal reflux disease, hiatal hernia, and Helicobacter pylori infection. RESULTS Colorectal polyps were detected in 789 of the 1582 patients (49.9%). Barrett's esophagus was detected in 233 patients (14.7%), and most cases of Barrett's esophagus (n = 229) were classified as short-segment Barrett's esophagus. Colorectal polyps were more frequent in patients with than without Barrett's esophagus (odds ratio, 1.79; 95% confidence interval, 1.31-2.46; P

BACKGROUND The screening and treatment of Helicobacter pylori infection for all junior high students in Saga Prefecture, Japan, were started in 2016. The present study aims to evaluate the influence of adverse reactions on the success of the eradication therapy. METHODS From 2017 to 2019, 25,006 third-grade junior high school students were tested for urinary anti-H. pylori antibodies. Positive cases were confirmed by H. pylori stool antigen tests. Of the 531 students who were found to be H. pylori-positive, 390 (358 in first-line and 32 in second-line therapy) underwent eradication therapy, and 274 (242 in first-line and 32 in second-line) students actually completed a self-reported form to rate stool consistency (based on the Bristol Stool Scale), the maximum number of bowel movements, and abdominal symptoms during the 7 days of treatment. RESULTS Among the 274 students, the total of primary and secondary eradication success rates was 87% (95% confidential interval: 82.9-90.1) in intention-to-treat analysis. On days 4, 5, and 6, stool consistency was looser in the primary eradication failure group than in the success group (p

Aims: The influence of lifestyle-related factors, including smoking and drinking, was evaluated for Helicobacter pylori eradication therapy with vonoprazan or proton pump inhibitors (PPIs). Methods: Between 2012 and 2016, the medical records of 620 patients receiving H. pylori eradication therapy at Saiseikai Karatsu Hospital were evaluated. Patients had received vonoprazan (20 mg) or PPIs with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 days. The influence of lifestyle-related factors on eradication failure was determined in the 2 groups. Results: The eradication rates for vonoprazan and lansoprazole, rabeprazole, and esomeprazole were, respectively, 91.0, 73.8, 72.0, and 84.6%. The vonoprazan eradication rate was significantly higher than those for the PPIs (p < 0.01). Habitual smoking and drinking did not increase eradication failure, and smoking and drinking during the eradication period did not reduce the eradication rate. Metabolic syndrome-related factors including obesity, hypertension, and diabetes mellitus had no negative influence on the eradication rate. Eradication with vonoprazan was more effective compared with that achieved through the use of PPIs. Conclusion: Lifestyle-related factors including smoking and drinking did not exacerbate the H. pylori eradication failure, and vonoprazan was more effective than the PPIs.

Background: The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) has been used in various Asia-Pacific countries for more than 20 years. Although ICD-10 is a powerful tool, clinical coding processes are complex; therefore, many developing countries have not been able to implement ICD-10-based health statistics (WHO-FIC APN, 2007). Objective: This study aimed to simplify ICD-10 clinical coding processes, to modify index terms to facilitate computer searching and to provide a simplified version of ICD-10 for use in developing countries. Method: The World Health Organization Family of International Classifications Asia-Pacific Network (APN) developed a simplified version of the ICD-10 and conducted field testing in Cambodia during February and March 2016. Ten hospitals were selected to participate. Each hospital sent a team to join a training workshop before using the ICD-10 simplified version to code 100 cases. All hospitals subsequently sent their coded records to the researchers. Results: Overall, there were 1038 coded records with a total of 1099 ICD clinical codes assigned. The average accuracy rate was calculated as 80.71% (66.67–93.41%). Three types of clinical coding errors were found. These related to errors relating to the coder (14.56%), those resulting from the physician documentation (1.27%) and those considered system errors (3.46%). Discussion: The field trial results demonstrated that the APN ICD-10 simplified version is feasible for implementation as an effective tool to implement ICD-10 clinical coding for hospitals. Conclusion: Developing countries may consider adopting the APN ICD-10 simplified version for ICD-10 code assignment in hospitals and health care centres. The simplified version can be viewed as an introductory tool which leads to the implementation of the full ICD-10 and may support subsequent ICD-11 adoption.

This study aimed to evaluate the influence of Helicobacter pylori infection and its eradication on the upper gastrointestinal symptoms of relatively healthy Japanese subjects. A total of 3,005 subjects (male/female: 1,549/1,456) undergoing medical health checkups were enrolled in the present study, at five hospitals in Saga, Japan, from January to December 2013. They had no significant findings following upper gastrointestinal endoscopy. All subjects completed a questionnaire that addressed a frequency scale for symptoms of gastroesophageal reflux disease. The questionnaire comprised seven questions regarding reflux symptoms and seven regarding acid-related dyspepsia, which were answered with a score based on the frequency of symptoms. Helicobacter pylori infection was identified by a rapid urease test and/or H. pylori antibody titer, and an eradication history was confirmed by the subjects’ medical records. Helicobacter pylori infection was positive in 894 subjects out of 3,005 (29.8%). Eradication of Helicobacter pylori was successfully achieved in 440 subjects of 458 treated. Helicobacter pylori infection had no influence on the acid-related dyspepsia evaluated by the questionnaire, whereas the mean reflux score was relatively high in the Helicobacter pylori native negative subjects compared to Helicobacter pylori native positive. Eradication of Helicobacter pylori and time span after the eradication had no effect on the upper gastrointestinal symptoms evaluated by the questionnaire. Helicobacter pylori infection and history of eradication did not affect acid-related dyspepsia symptoms in Japanese healthy subjects.

The aim of this study was to determine the characteristics of patients without Helicobacter pylori infection who were prescribed antacid medications (potassium-competitive acid blockers, proton pump inhibitors, and/or H2 receptor antagonist) and had no upper gastrointestinal lesions detected by endoscopy.This cross-sectional study included the patients who underwent upper gastrointestinal endoscopy in our institution between August 2017 and July 2018. They were aged from 55 to 89 years, had no upper gastrointestinal lesions detected by endoscopy, and no H. pylori infection. Exclusion criteria comprised low-dose aspirin and/or nonsteroidal anti-inflammatory drugs. The subjects were allocated to middle-aged (55-69 years) and older age groups (70-89 years). The relationships between antacid medications and patient lifestyle and comorbidities were evaluated by multivariate analyses.Of the 420 patients, 272 were in the middle-aged group and 148 patients in the older age group. Age was found to be a risk factor for antacid medications in both groups (p = 0.002, p = 0.007). No other lifestyle related factors were risk factors. As to comorbidities, hiatal hernia was positively associated with antacid medications in the middle-aged group (p = 0.002). Hypertension and Ca-blockers were positively associated with prescription of antacids in the older age group (p = 0.013); this association was not significant in the middle-aged group.Three lifestyle-related and/or comorbidity-associated factors known to exacerbate gastroesophageal reflux, namely, age, hiatus hernia, and Ca-blockers, were associated with prescription of antacid medications, even in patients without endoscopic reflux esophagitis.

Background/Aims: This study aimed at (i) clarifying the factors associated with high scores on the modified frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) among 3,505 relatively healthy subjects undergoing routine medical health checkups with gastrointestinal endoscopy and (ii) comparing risk factors for high FSSG scores between subjects with and without reflux esophagitis. Methods: In total, 3,505 subjects (male/female: 1,922/1,583) who underwent upper gastrointestinal endoscopy during health medical checkups at 5 hospitals in Saga, Japan from January 2013 to December 2013 were enrolled. All subjects completed a modified FSSG questionnaire, which comprised 7 questions regarding reflux symptoms and 7 questions regarding acid-related dyspepsia. Each question was assigned a score based on the frequency of symptoms. Results: Younger age, female gender, hiatal herniation, and endoscopic reflux esophagitis were risk factors for a FSSG score with a high total. Subjects with high scores but without esophagitis were women, and hiatal herniation and Barrett's esophagus were frequently seen in patients with reflux esophagitis. Conclusion: Younger age, female gender, hiatal hernia, and endoscopic esophagitis were risk factors for a high FSSG score, and women tended to complain of upper gastrointestinal symptoms more frequently than did men among subjects without endoscopic esophagitis.

The ability of the human malarial parasite Plasmodium falciparum to adapt to environmental changes depends considerably on its ability to maintain within-population genetic variation. Strong selection, consequent to widespread antimalarial drug usage, occasionally elicits a rapid expansion of drug-resistant isolates, which can act as founders. To investigate whether this phenomenon induces a loss of within-population genetic variation, we performed a population genetic analysis on 302 P. falciparum cases detected during two cross-sectional surveys in 2002/2003, just after the official introduction of sulphadoxine/pyrimethamine as a first-line treatment, and again in 2010/2011, in highly endemic areas in Papua New Guinea. We found that a single-origin sulphadoxine-resistant parasite isolate rapidly increased from 0% in 2002/2003 to 54% in 2010 and 84% in 2011. However, a considerable number of pairs exhibited random associations among 10 neutral microsatellite markers located in various chromosomes, suggesting that outcrossing effectively reduced non-random associations, albeit at a low average multiplicity of infection (1.35–1.52). Within-population genetic diversity was maintained throughout the study period. This indicates that the parasites maintained within-population variation, even after a clonal expansion of drug-resistant parasites. Outcrossing played a role in the preservation of within-population genetic diversity despite low levels of multiplicity of infection.

The influence of lifestyle-related factors, including smoking and drinking, was evaluated for Helicobacter pylori eradication therapy with vonoprazan or proton pump inhibitors (PPIs).Between 2012 and 2016, the medical records of 620 patients receiving H. pylori eradication therapy at Saiseikai Karatsu Hospital were evaluated. Patients had received vonoprazan (20 mg) or PPIs with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 days. The influence of lifestyle-related factors on eradication failure was determined in the 2 groups.The eradication rates for vonoprazan and lansoprazole, rabeprazole, and esomeprazole were, respectively, 91.0, 73.8, 72.0, and 84.6%. The vonoprazan eradication rate was significantly higher than those for the PPIs (p0.01). Habitual smoking and drinking did not increase eradication failure, and smoking and drinking during the eradication period did not reduce the eradication rate. Metabolic syndrome-related factors including obesity, hypertension, and diabetes mellitus had no negative influence on the eradication rate. Eradication with vonoprazan was more effective compared with that achieved through the use of PPIs.Lifestyle-related factors including smoking and drinking did not exacerbate the H. pylori eradication failure, and vonoprazan was more effective than the PPIs.

This chapter provides a commentary on the present state and challenges regarding the acceptance of international patients in Japan. Despite some heightened expectations that medical tourism could be an engine of growth for Japan, various challenges have emerged to stymie such aspirations. However, it is necessary to open up Japanese medical institutions so that people are more willing to visit Japan and undergo examination and treatment in environments that are accredited as secure and safe. In addition to Japan’s advanced medical devices and technology, international patients also have high expectations of ordinary medical services available to everyone under Japan’s universal health insurance system. Treating international patients within Japan’s medical institutions will also pave the way for objective evaluations of healthcare in Japan according to global criteria. Appropriate development of medical tourism is expected to help strengthen Japan’s global presence in the field of medical services and at the same time to improve the quality of medical services offered domestically, thereby gaining greater support and understanding of the Japanese people and those in the medical profession for such an outward-looking initiative.

Background In resource-limited settings with a high prevalence of human immunodeficiency virus (HIV) infection such as Zambia, decentralization of HIV/acquired immunodeficiency syndrome (HIV/AIDS) treatment and care with effective use of resources is a cornerstone of universal treatment and care. Objectives This research aims to analyse the cost effectiveness of the National Mobile Antiretroviral Therapy (ART) Services Programme in Zambia as a means of decentralizing ART services. Methods Cost-effectiveness analyses were performed using a decision analytic model and Markov model to compare the original ART programme, ‘Hospital-based ART’, with the intervention programme, Hospital-based plus ‘Mobile ART’, from the perspective of the district government health office in Zambia. The total cost of ART services, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were examined. Results The mean annual per-patient costs were 1259.16 USD for the original programme and 2601.02 USD for the intervention programme, while the mean number of QALYs was 6.81 for the original and 7.27 for the intervention programme. The ICER of the intervention programme relative to the original programme was 2965.17 USD/QALY, which was much below the willingness-to-pay (WTP), or three times the GDP per capita (4224 USD), but still over the GDP per capita (1408 USD). In the sensitivity analysis, the ICER of the intervention programme did not substantially change. Conclusion The National Mobile ART Services Programme in Zambia could be a cost-effective approach to decentralizing ART services into rural areas in Zambia. This programme could be expanded to more districts where it has not yet been introduced to improve access to ART services and the health of people living with HIV (PLHIV) in rural areas. Electronic supplementary material The online version of this article (doi:10.1186/s12962-017-0065-8) contains supplementary material, which is available to authorized users.

Additional file 1. Markov Model.

We investigated the relationship between tuberculosis recurrence and Mycobacterium tuberculosis antigen-stimulated interferon-gamma (IFN-γ) responses during treatment.Plasma IFN-γ levels in active pulmonary tuberculosis patients (n = 407) were analyzed using QuantiFERON-TB Gold In-Tube™ (QFT-IT) at 0, 2, and 7 months of the 8-month treatment received from 2007 to 2009 and the patients were followed up for another 16 months after treatment. Risk factors for recurrence were assessed using the log-rank test and Cox proportional hazard models. Random coefficient models were used to compare longitudinal patterns of IFN-γ levels between groups.QFT-IT showed positive results in 95.6%, 86.2%, and 83.5% at 0, 2, and 7 months, respectively. The antigen-stimulated IFN-γ responses varied significantly during the treatment course (P0.0001). Unexpectedly, positive-to-negative conversion of QFT-IT results between 0 and 2 months was significantly associated with earlier recurrence (adjusted hazard ratio, 5.57; 95% confidence interval, 2.28-13.57). Time-dependent changes in IFN-γ levels were significantly different between the recurrence and nonrecurrence groups (P0.0001).Although the IGRA response varies individually, early response during the treatment course may provide an insight into host immune responses underlying tuberculosis recurrence.

Plasmodium falciparum malaria imposes a serious public health concern throughout the tropics. Although genetic tools are principally important to fully investigate malaria parasites, currently available forward and reverse tools are fairly limited. It is expected that parasites with a high mutation rate can readily acquire novel phenotypes/traits; however, they remain an untapped tool for malaria biology. Here, we generated a mutator malaria parasite (hereinafter called a 'malaria mutator'), using site-directed mutagenesis and gene transfection techniques. A mutator Plasmodium berghei line with a defective proofreading 3' → 5' exonuclease activity in DNA polymerase δ (referred to as PbMut) and a control P. berghei line with wild-type DNA polymerase δ (referred to as PbCtl) were maintained by weekly passage in ddY mice for 122 weeks. High-throughput genome sequencing analysis revealed that two PbMut lines had 175-178 mutations and a 86- to 90-fold higher mutation rate than that of a PbCtl line. PbMut, PbCtl, and their parent strain, PbWT, showed similar course of infection. Interestingly, PbMut lost the ability to form gametocytes during serial passages. We believe that the malaria mutator system could provide a novel and useful tool to investigate malaria biology.

Objective To analyse the trends and characteristics of international health issues through agenda items of the World Health Assembly (WHA) from 1970 to 2012. Methods Agendas in Committees A/B of the WHA were classified as Administrative or Technical and Health Matters. Agenda items of Health Matters were sorted into five categories by the WHO reform in the 65th WHA. The agenda items in each category and sub-category were counted. Results There were 1647 agenda items including 423 Health Matters, which were sorted into five categories: communicable diseases (107, 25.3%), health systems (81, 19.1%), noncommunicable diseases (59, 13.9%), preparedness surveillance and response (58, 13.7%), and health through the life course (36, 8.5%). Among the sub-categories, HIV/AIDS, noncommunicable diseases in general, health for all, millennium development goals, influenza, and international health regulations, were discussed frequently and appeared associated with the public health milestones, but maternal and child health were discussed three times. The number of the agenda items differed for each Director-General's term of office. Conclusions The WHA agendas cover a variety of items, but not always reflect international health issues in terms of disease burden. The Member States of WHO should take their responsive roles in proposing more balanced agenda items.

In this study, we investigated the mutation tendency of a mutator rodent malaria parasite, Plasmodium berghei, with proofreading-deficient DNA polymerase δ. Wild-type and mutator parasites were maintained in mice for over 24 weeks, and the genome-wide accumulated mutations were determined by high-throughput sequencing. The mutator P. berghei had a significant preference for C/G to A/T substitutions; thus, its genome had a trend towards a higher AT content. The mutation rate was influenced by the sequence context, and mutations were markedly elevated at TCT. Some genes mutated repeatedly in replicate passage lines. In particular, knockout mutations of the AP2-G gene were frequent, which conferred strong growth advantages on parasites during the blood stage but at the cost of losing the ability to form gametocytes. This is the first report to demonstrate a biased mutation tendency in malaria parasites, and its results help to promote our basic understanding of Plasmodium genetics.

The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisinin pressure.

Background: This retrospective study aimed to determine risk factors associated with serious complications of endoscopic submucosal dissection of gastric tumors in multicenters compared between high- and low-volume centers. Methods: Between 2001 and 2010, gastric endoscopic submucosal dissection was performed in 1,190 lesions of 1,082 patients in five hospitals in Saga, three high-volume and two low-volume centers. Risk factors for serious complications were evaluated. Patients’ background characteristics were evaluated, including anticoagulants use and underlying diseases. Results: Postoperative bleeding was detected in 75 patients (6.9%), and perforation was detected in 40 patients (3.7%). Most postoperative bleeding and perforation cases were recovered with endoscopic procedures, although one case of each complication was treated by emergency surgery. Multivariate analysis indicated that risk factors for perforation were tumor location, massive submucusal invasion, endoscopists’ experience of 100–149 cases and hypertension, and that risk factors for postoperative bleeding were tumor location, resected tumor size, and scar lesion. The serious complications were not different between high- and low-volume centers. Conclusions: The present study indicated that risk factors for perforation during endoscopic submucosal dissection were tumor, endoscopist and patient related, although risk factors for postoperative bleeding were tumor related. There was no difference in complications between high- and low-volume centers.

To examine the sex differences in the impact of low back pain (LBP) on health-related quality of life among community-dwelling persons from a nationwide sample. Our analysis enrolled 2,358 participants from among 3,477 randomly selected subjects in Japan. The cumulative days each individual experienced LBP were prospectively measured over 1 month. The Physical Component Summary (PCS) and Mental Component Summary (MCS) in the Short Form 8-item Health Survey were evaluated before and after the study period. Sex differences in the impact of the cumulative number of LBP days on PCS and MCS scores were evaluated using linear regression analysis. Among the 2,170 participants with complete data, the prevalence of LBP in women (32%) was higher than that in men (25%) during the study period. One-day increases in LBP days were associated with greater decreases in PCS scores among men than among women (−0.72 vs. −0.29, sex difference P

Despite a dramatic decrease in incidence of malaria during the last decade, there are still 250 million cases annually, of which nearly 1 million are fatal. The vast majority of these deaths are caused by Plasmodium falciparum, the most virulent malaria parasite species. The antifolate drug combination sulfadoxine/pyrimethamine (SP), although infrequently used for treating acute malaria due to resistance, is still commonly used for intermittent preventive treatment during pregnancy throughout sub-Saharan Africa [1]. SP is also being piloted for intermittent preventive treatment in infants, which has been shown to prevent malaria in pilot studies [2]. However, rising resistance to SP due to the spread of resistant P. falciparum in many endemic regions is a growing concern [3]. Sulfadoxine, a structural analogue of p-aminobenzoic acid, and pyrimethamine, the other component of SP, inhibit dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), respectively, in the P. falciparum folate synthesis pathway. Mutations at the dhps and dhfr loci confer resistance to sulfadoxine and pyrimethamine, respectively [4, 5], and SP treatment failure is strongly associated with the presence of at least 3 mutations in dhfr and 2 in dhps [6, 7]. In the case of pyrimethamine resistance, highly resistant parasites that harbor 3 or more mutations in the dhfr gene emerged in limited geographical foci, probably 1 in Asia and 2 in South America, which then spread worldwide [3, 8–11]. In Africa, almost all parasites harboring pyrimethamine-resistant dhfr alleles with 3 mutations are descendants of resistant parasites introduced from Southeast Asia [12–15]. Mutations associated with sulfadoxine resistance have been observed to occur at 5 amino acid (aa) positions within the dhps gene: positions 436, 437, 540, 581, and 613, with the wild-type represented by the aa sequence SAKAA at these loci [5, 16, 17]. A single mutation at aa position 437, which results in the SGKAA mutant (mutations are underlined), increases the median inhibitory concentration (IC50) of sulfadoxine by 4.8-fold in this parasite, whereas the IC50 of sulfadoxine in the AGEAA triple mutant is 9.8-fold greater than that of the wild-type parasite [17]. In contrast to the knowledge of pyrimethamine-resistant dhfr, studies are limited on the geographical origins and spread of sulfadoxine-resistant dhps. A recent study analyzing P. falciparum parasites from 27 African countries has shown the occurrence of as many as 5 distinct sulfadoxine-resistant dhps lineages in Africa. The flanking microsatellite (MS) haplotype associated with one of these lineages matched that of the K1 P. falciparum laboratory isolate that originated in Southeast Asia. This observation raises the possibility that sulfadoxine resistance was introduced from Asia to Africa in a similar way to pyrimethamine. In contrast, a study from Cambodia, which described 2 major lineages with high sulfadoxine resistance, has shown independent origins of sulfadoxine resistance in Asia and Africa [19]. However, sampling in this study was limited to Cambodia and just 2 African sites (Cameroon and Kenya). Geographically comprehensive characterization of sulfadoxine-resistant dhps is necessary for an accurate understanding of the way in which resistance against the commonly used antimalarial drugs chloroquine, pyrimethamine, and sulfadoxine emerged and spread among populations of P. falciparum. In this study, we sequenced the dhps gene of 893 isolates of P. falciparum from 12 countries from Asia, the Pacific Islands, Africa, and South America and determined the haplotypes of MS markers flanking the dhps locus in parasites bearing mutant dhps alleles. We identified 6 independent sulfadoxine-resistant lineages worldwide, among which highly resistant lineages were found only in Southeast Asia and South America. More important, we obtained evidence for the migration of 2 Southeast Asian lineages to Africa, where it has since spread.

In Bangladesh, despite the official introduction of artemisinin combination therapy in 2004, chloroquine+sulfadoxine/pyrimethamine has been used for the treatment of uncomplicated malaria. To assess the distribution of pfcrt, pfmdr1, dhfr, and dhps genotypes in Plasmodium falciparum, we conducted hospital- and community-based surveys in Bandarban, Bangladesh (near the border with Myanmar) in 2007 and 2008. Using nested PCR followed by digestion, 139 P. falciparum isolates were genotyped. We found fixation of a mutation at position 76 in pfcrt and low prevalence of a mutation at position 86 in pfmdr1. In dhfr, the highest pyrimethamine resistant genotype quadruple mutant was found in 19% of isolates, which is significantly higher prevalence than reported in a previous study in Khagrachari (1%) in 2002. Microsatellite haplotypes flanking dhfr of the quadruple mutants in Bangladesh were identical or very similar to those found in Thailand and Cambodia, indicating a common origin for the mutant in these countries. These observations suggest that the higher prevalence of the dhfr quadruple mutant in Bandarban is because of parasite migration from Myanmar. However, continuous use of sulfadoxine/pyrimethamine would have also played a role through selection for the dhfr quadruple mutant. These results indicate an urgent need to collect molecular epidemiological information regarding dhfr and dhps genes, and a review of current sulfadoxine/pyrimethamine usage with the aim of avoiding the widespread distribution of high levels of resistant parasites in Bangladesh.

Objectives Given that persons with a stronger belief in internal health locus of control (HLC) have been shown to comply well with medical advice, HLC internality may play an important role in low-back pain (LBP) prevention and management because it requires the patient's own commitment. Previous studies in conditions other than LBP have shown that the use of complementary and alternative medicine (CAM) is associated with high HLC internality. Here, we examined the relationship between CAM facility visits and internality of HLC in persons with LBP. Methods We analyzed the data from the Health Diary Study, which surveyed the health-related behavior of 3477 persons sampled from the general population of Japan. Among 2377 participants aged 18 to 75 years, 673 reported LBP during the study period. We examined CAM facility visits and HLC among 81 previously untreated LBP patients who sought care from western medical doctors or CAM providers during the 1-month study period. Results Of the 81 patients, 40 reported at least 1 CAM visit, whereas 41 visited western medical doctors only. Participants who visited CAM facilities had a higher internality score than those who visited western medical doctors after controlling for age, sex, size of residential city, and bodily pain score of the Short Form-8 Health Survey scale. Discussion Visitors to CAM facilities had a stronger belief in internal HLC. This finding suggests that visitors to CAM facilities are more sensitive to educational intervention for the self-management of LBP than those who visit western medicine. In order not to miss the opportunity of reaching these patients, the education should be more emphasized on CAM facilities.

To examine the association between poor mental health state and having headache in the Japanese general population, and the association between demographic characteristics and use of medical resources among subjects with headache. The subjects aged 18 through 75 years were chosen from the Japanese general population. We administered a questionnaire to obtain baseline data, an da sked the participants to keep a personal health-diary during October 1–31, 2003. The state of mental health (MH) was examined using the SF-8 Health Survey in the baseline questionnaire. Of the 2371 subjects, 716 had a headache on at least one day during the study period. Of the 716, 52 consulted a physician, 475 used other medical resources, and 189 did nothing about the headache. There wa sa na ssociation between MH score and headache [adjusted odds ratio (OR) = 1.166 (95% confidence interval (CI): 1.010–1.346) for 10-point increment of MH score]. There was also an association between use of medical resources and having a family physician. Poor mental health was associated with headache in the Japanese general population, and one of the predictors of consulting a physician among the headache sufferers was having a family physician whom the subject greatly trusts.

Amyloid A amyloidosis is an obstinate disease complication in chronic inflammatory disease, and there are few effective therapies. The objective of this study was to investigate the effect of oral dimethyl sulfoxide (DMSO) on amyloid A amyloidosis.Fifteen secondary amyloid A amyloidosis patients (4 men, 11 women; age, 23-70 years) were treated with DMSO between 1995 and 2003. DMSO was administered orally in all patients at a dose of 3-20 g/day. The clinical symptoms together with the renal and gastrointestinal functions were evaluated before and after treatment.Among the 15 patients, amyloid A amyloidosis was a complication of rheumatoid arthritis (RA) in 10, of Crohn's disease in 4, and of Adult Still's disease in 1. Nine cases mainly involved the kidney, with renal dysfunction and proteinuria, five mainly involved the gastrointestinal tract, with protein-losing gastroenteropathy and intractable diarrhea, and one involved both gastrointestinal and renal amyloidosis. DMSO treatment was successful in 10 (66.7%) of the 15 patients (RA, 6/10; Crohn's disease, 4/4; Adult Still's disease, 0/1). Eight weeks of DMSO administration improved the renal function and proteinuria in five out of ten renal amyloidosis patients, but had no effect on those patients with severe and/or advanced renal dysfunction. With regard to gastrointestinal amyloidosis, gastrointestinal symptoms, including diarrhea and protein-losing gastroenteropathy, were improved in six patients. No serious side effects were encountered with the DMSO treatment.Oral administration of DMSO is an effective treatment for amyloid A amyloidosis, especially for gastrointestinal involvement and the early stage of renal dysfunction.

Summary The influence of Mycobacterium tuberculosis (MTB) lineages/sublineages on unfavorable tuberculosis (TB) treatment outcomes is poorly understood. We investigated the effects of Beijing genotype sublineages and other factors contributing to treatment outcome. Patients newly diagnosed with sputum smear-positive and culture-positive TB in Hanoi, Vietnam, participated in the study. After receiving anti-TB treatment, they were intensively followed up for the next 16 months. MTB isolates collected before treatment were subjected to drug susceptibility testing, and further analyzed to determine MTB (sub) lineages and their clonal similarities. Of 430 patients, 17 had treatment failure and 30 had TB recurrence. Rifampicin resistance was associated with treatment failure {adjusted odds ratio = 6.64 [95% confidence interval (CI), 1.48–29.73]}. The modern Beijing genotype was significantly associated with recurrent TB within 16 months [adjusted hazard ratio = 3.29 (95% CI, 1.17–9.27)], particularly after adjustment for the relevant antibiotic resistance. Human immunodeficiency virus coinfection and severity on chest radiographs were not significantly associated with unfavorable outcomes. Our findings provide further understanding of the influence of MTB strains on unfavorable treatment outcomes. Multiple risk factors should be considered for the optimal management of TB.

The recent emergence and spread of artemisinin-resistant Plasmodium falciparum isolates is a growing concern for global malaria-control efforts. A recent genome-wide analysis study identified two SNPs at genomic positions MAL10-688956 and MAL13-1718319, which are linked to delayed clearance of parasites following artemisinin combination therapy (ACT). It is expected that continuous artemisinin pressure will affect the distribution of these SNPs. Here, we investigate the worldwide distribution of these SNPs using a large number of archived samples in order to generate baseline data from the period before the emergence of ACT resistance. The presence of SNPs in MAL10-688956 and MAL13-1718319 was assessed by nested PCR RFLP and direct DNA sequencing using 653 global P. falciparum samples obtained before the reported emergence of ACT resistance. SNPs at MAL10-688956 and MAL13-1718319 associated with delayed parasite clearance following ACT administration were observed in 8% and 3% of parasites, respectively, mostly in Cambodia and Thailand. Parasites harbouring both SNPs were found in only eight (1%) isolates, all of which were from Cambodia and Thailand. Linkage disequilibrium was detected between MAL10-688956 and MAL13-1718319, suggesting that this SNP combination may have been selected by ACT drug pressure. Neither of the SNPs associated with delayed parasite clearance were observed in samples from Africa or South America. Baseline information of the geographical difference of MAL10-688956 and MAL13-1718319 SNPs provides a solid basis for assessing whether these SNPs are selected by artemisinin-based combination therapies.

Development of skeletal cartilage is characterized with coupling growth arrest and cell differentiation. Here, to understand the cyclin-dependent kinase inhibitors involved in the progression of chondrogenic differentiation, we examined changes in the expression levels of cyclin-dependent kinase inhibitor members using mouse ATDC5 prechondrocytes as a widely used in vitro model of cartilage differentiation. Up-regulation of p21 and p27 mRNA was observed following a decrease in growth rate of prechondrocytes, and both transcripts subsequently accumulated during chondrogenic differentiation; p15, p18, and p19 mRNA, in contrast, did not change during differentiation. Only the up-regulation of p21 mRNA during differentiation was prevented by the continuous treatment of early chondrogenic inhibitor, parathyroid hormone, indicating a close correlation between differentiation and p21 induction in ATDC5 cells. Therefore, to examine the role of p21 during chondrogenesis, we established stable cell lines overexpressing full-length p21 antisense RNA in ATDC5. The reduction of endogenous p21 in these cell lines caused inhibition of early chondrogenic differentiation in ATDC5, indicating that p21 gene plays an important role in this process of the cells in vitro. Furthermore, the level of p21 protein and p21.CDK2 complexes transiently increased during differentiation, but not in undifferentiated cells, leading to a decrease in CDK2-associated kinase. However, differentiation-dependent expressed p21 protein was degraded by a proteasome-dependent pathway. Thus, the progression of chondrogenic differentiation requires down-regulation of CDK2-associated kinase with an increase in p21 protein and subsequent degradation of this protein by a proteasomal pathway.

Bone marrow is believed to contain multipotential stromal stem cells which can differentiate into osteoblasts, chondrocytes, adipocytes, and myoblasts (Prockop, D. J. Science 276, 71-74, 1997). Therefore, characterization and identification of the stem-like cell within the stromal cells are important to understand bone marrow function in relation to the hematopoietic microenvironment, and repair/regeneration of tissue defects. TBR31-2 cell, a bone marrow stromal cell line established from bone marrow of transgenic mice harboring temperature-sensitive (ts) simian virus (SV) 40T-antigen gene for immortality, is induced toward both adipocytic and osteogenic cells under conditions of the inactivation of T-antigen (Okuyama, R., Yanai, N., Obinata, M. Exp. Cell Res. 218, 424-429, 1995). In this work, using a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, mRNA expressions of tissue-specific differentiation markers for adipocyte (lipoprotein lipase), osteoblast (type I collagen and osteocalcin), chondrocyte (type II and X collagen), and muscle cell (desmin) were examined during a long-term culture of the cell. In addition, histochemical studies showed the appearance of adipocytic, osteoblastic, chondrocytic, and muscle cells during this long-term culture. Thus, TBR31-2, which has characteristics of an undifferentiated cell, has the potential to express the multipotential cell lineages. These results indicated that a multipotential progenitor cell including potential to differentiate into a muscle cell and which is situated in the mesenchymal cell lineage was first obtained.

The active hormonal form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), has been described as a principal mediator of skeletal homeostasis. Treatment of rat osteosarcoma (ROS)17/2.8, an osteoblast-like cell line, with 1alpha,25(OH)2D3 results in a ligand-dependent increase in transcription of the bone-specific osteocalcin gene. We isolated permanent cell lines that were established by transfecting ROS 17/2.8 cells with plasmids consisting of the human osteocalcin gene promoter containing the vitamin D responsive element linked to a bacterial beta-galactosidase gene. In one of many cell lines, especially in clone NK-31, 1alpha,25(OH)2D3 strongly stimulated beta-galactosidase activity. Reverse transcription-polymerase chain reaction analysis also showed endogenous osteocalcin gene expression and beta-galactosidase gene expression in clone NK-31 cells, which paralleled the increase in beta-galactosidase activity. Using a synthetic analogue of 1alpha,25(OH)2D3, 24,24-difluoro-1alpha,25-dihydroxyvitamin D3, we found that the levels of this activity and these gene expressions were nearly parallel to those of 1alpha,25(OH)2D3. 24R,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 at high doses (concentration: 10(-7) M) also induced beta-galactosidase activity in clone NK-31. These cell lines, harboring the plasmid-carrying beta-galactosidase gene under the control of the osteocalcin gene promoter, may contribute to studies on the regulation by 1alpha,25(OH)2D3 or to the development of synthetic analogues of 1alpha,25(OH)2D3.

Background Linkage of healthcare services for tuberculosis (TB) and human immunodeficiency virus (HIV) remains a major challenge in resource-limited settings. Our operational research aimed to evaluate the linkage between TB and HIV services in a rural area of Zambia, and to explore factors associated with the enrolment of TB/HIV co-infected patients in HIV care services. Methods All TB patients newly diagnosed as HIV-positive in Chongwe district, Zambia between 2009 and 2010 were included. Data from TB registers and medical records were reviewed. Patient referral to HIV services and provision of antiretroviral therapy (ART) were further examined through HIV registers and records. Results Of 621 patients (median age 33.0 years, female 42.4%) who started anti-TB treatment, clinic records indicated that 297 patients were newly diagnosed as HIV-positive, and 176 (59.3%) of these were referred to an ART clinic. Analysis of records at the ART clinic found that only 85 (28.6%) of TB/HIV patients had actually been enrolled in HIV care, of whom only 58 (68.2%) had commenced ART. Logistic regression analyses demonstrated the following factors associated with lower enrolment: “male” sex (aOR, 0.45; 95% CI 0.26-0.78), “previous TB treatment” (aOR, 0.29; 95% CI, 0.11-0.75), “registration at sites that did not provide ART services (non-ART site)” (aOR, 0.10; 95% CI, 0.01-0.77) and “death on TB treatment outcome (aOR, 0.20; 95% CI, 0.06-0.65). However, patient registration at TB clinics in 2010 was associated with markedly higher enrolment in HIV care as compared to registration in 2009 (aOR, 2.80; 95% CI, 1.53-5.12). Conclusions HIV testing for TB patients has been successfully scaled up. However referrals of co-infected patients still remain a challenge due to poor linkage between TB and HIV healthcare services. Committed healthcare workers, a well-organized health services system and patient education are urgently required to ensure a higher rate of referral of TB/HIV co-infected patients for appropriate care.

Introduction: Resistance of Mycobacterium tuberculosis (MTB) to anti-tuberculosis (TB) drugs presents a serious challenge to TB control worldwide. We investigated the status of drug resistance, including multidrug-resistant (MDR) TB, and possible risk factors among newly diagnosed TB patients in Hanoi, the capital of Viet Nam. Methods: Clinical and epidemiological information was collected from 506 newly diagnosed patients with sputum smear- and culture-positive TB, and 489 (96.6%) MTB isolates were subjected to conventional drug susceptibility testing, spoligotyping, and 15-locus variable numbers of tandem repeats typing. Adjusted odds ratios (aORs) were calculated to analyze the risk factors for primary drug resistance. Results: Of 489 isolates, 298 (60.9%) were sensitive to all drugs tested. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, and MDR accounted for 28.2%, 4.9%, 28.2%, 2.9%, and 4.5%, respectively. Of 24 isolates with rifampicin resistance, 22 (91.7%) were MDR and also resistant to streptomycin, except one case. Factors associated with isoniazid resistance included living in old urban areas, presence of the Beijing genotype, and clustered strains [aOR = 2.23, 95% confidence interval (CI) 1.15–4.35; 1.91, 1.18–3.10; and 1.69, 1.06–2.69, respectively). The Beijing genotype was also associated with streptomycin resistance (aOR = 2.10, 95% CI 1.29– 3.40). Human immunodeficiency virus (HIV) coinfection was associated with rifampicin resistance and MDR (aOR = 5.42, 95% CI 2.07–14.14; 6.23, 2.34–16.58, respectively). Conclusion: Isoniazid and streptomycin resistance was observed in more than a quarter of TB patients without treatment history in Hanoi. Transmission of isoniazid-resistant TB among younger people should be carefully monitored in urban areas, where Beijing strains and HIV coinfection are prevalent. Choosing an optimal treatment regimen on the basis of the results of drug susceptibility tests and monitoring of treatment adherence would minimize further development of drug resistance strains.

KCA-098 (3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoline-6-one), an analogue of coumestrol (a naturally occurring weak phytoestrogen), dose-dependently increased alkaline phosphatase activity of osteoblastic ROS 17 2.8 cells and freshly-isolated osteoblasts from neonatal mouse calvaria, and reduced cell proliferation. In addition, KCA-098 increased the synthesis of collagenese-digestible protein (CDP) of ROS 17 2.8 cells. On the other hand, KCA-098 had no effect on the basal synthesis of osteocalcin but reduced the 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3)-induced increase in osteocalcin synthesized by ROS 17 2.8 cells. Therefore, KCA-098 had a bidirectional effect on the differentiation of osteoblasts (i.e., stimulating both alkaline phosphatase activity and synthesis of CDP and inhibiting osteocalcin synthesis). However, as KCA-098 stimulated the mineralization of chick embryonic bone in organ culture and recovered the bone density reduced by ovariectomy of rats, it would serve overall to stimulate the differentiation of osteoblasts. On the other hand, KCA-098 inhibited the formation of tartrate-resistant, acid phosphate-positive multinucleated cells (TRAP(+)MNC) induced by 1α,25(OH)2D3, parathyroid hormone (PTH), and prostaglandin E2 (PGE2) in cultures of mouse bone marrow cells, showing that it inhibits the formation of osteoclastlike cells. Coumestrol and 17β-estradiol had no effect on the proliferation and alkaline phosphatase activity of ROS 17 2.8 cells. They did, however, dose-dependently inhibit osteoclast-like cell formation as well as KCA-098 did, indicating that the main action of coumestrol and 17β-estradiol on bone tissue is the inhibition of bone resorption.

Seven days' space flight of fertilized chicken eggs pre- incubated for 7 and 10 days on earth caused no differences in the morphology of osteoblasts, osteoclasts, and osteocytes of humerus and tibia from those of control embryos. Bone-resorbing and -forming activities of the femur were not different between control and flight groups. As a consequence, calcium and phosphorus contents of the femora between control and flight groups were not changed. Alkaline phosphatase activity of 3 different regions (resting cartilage, growth cartilage, and cortical bone) of tibia showed no significant difference between control and flight groups. No significant difference of gene expressions of hepatocyte growth factor and receptors of fibroblast growth factor was observed in perichondrium, trabecula, and skeletal muscles and tendons of hind limbs between control and flight groups. Unlike the results of previous space flight experiments in which young growing mammals were used, these morphological and biochemical results indicate that microgravity has little effect on bone metabolism of the chick embryo.

The effects of 3,9-bis( N,N -dimethylcarbamoyloxy)-5 H -benzofuro[3,2- c ]quinoline-6-one (KCA-098), a derivative of coumestrol, on bone resorption was studied in organ cultures of 20-day fetal rat femora. KCA-098 increased the length, dry weight, and calcium and phosphorus contents of parathyroid hormone (PTH)-treated fetal rat femur. As PTH significantly reduced the calcium and phosphorus contents of the femora, probably by stimulating bone resorption, KCA-098 seems to inhibit bone resorption. In fact, KCA-098 inhibited the PTH-induced release of 45 Ca from pre-labeled fetal rat femora into the medium in organ culture. Coumestrol also inhibited the release of 45 Ca from bone into the medium. However, KCA-098 did not increase the uterine weight of ovariectomized rats, whereas coumestrol did so. Thus KCA-098 is a unique, new inhibitor of bone resorption that has no estrogenic activity.

We previously found that 3,9-bis(N,N-dimethylcarbamoyloxy)-5H- benzofuro[3,2-c]quinoline-6-one (KCA-098) inhibited bone resorption in organ culture. In this study, to determine if KCA-098 is therapeutically applicable for the treatment of osteoporosis, we compared the effect of KCA-098 on bone tissues with that of ipriflavone, a drug that is clinically used for the treatment of osteoporosis. Both KCA-098 and ipriflavone inhibited parathyroid hormone-, prostaglandin E2-, 1 alpha,25-dihydroxyvitamin D3- and interleukin 1 beta-induced bone resorption of fetal rat bones, but the inhibitory activity of KCA-098 was more potent than that of ipriflavone. In fact, the effective concentrations of KCA-098 were 10 to 100 times lower than those of ipriflavone. Oral administration of KCA-098 (1 and 3 mg/kg) or ipriflavone (100 mg/kg) to ovariectomized rats on a low-calcium diet increased the breaking force and bone density of the femora, indicating that KCA-098 is an effective on the whole animal as ipriflavone. Furthermore, KCA-098 increased the length and calcium content of 9-day chick embryonic femora cultured in vitro, whereas ipriflavone did not, suggesting that KCA-098 had a direct stimulatory effect on bone mineralization. Therefore, KCA-098 seems to be more potent than ipriflavone in stimulating bone tissue formation and may thus be expected to become a useful agent for the treatment of osteoporosis.