Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models.

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

Suppression of Hepatocellular Carcinoma Progression through FOXM1 and EMT Inhibition via Hydroxygenkwanin-Induced miR-320a Expression.

Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid's cancer suppression mechanisms were further investigated through gain- and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor 'forkhead box protein M1' (FOXM1) and downstream FOXM1-regulated proteins related to epithelial-mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.

The ecology of gynecological care for women.

Gynecological care is vital to women's health but utilization of gynecological care has been seldom addressed. We applied the population-based "ecology model" to demonstrate the utilization of gynecological care of women, with examples from Taiwan. We analyzed the claims data from the cohort datasets within the National Health Insurance Research Database in Taiwan. Women's utilization of gynecological care in 2009 was computed. Of 1000 women, 319 utilized gynecological care at least once, 277 visited Western medicine clinics, 193 visited physician clinics, 118 visited hospital-based outpatient clinics, 73 visited traditional Chinese medicine clinics, eight were hospitalized, four were hospitalized in an academic medical center, and four visited emergency departments. More than 90% of young and middle-aged women who sought gynecological care visited gynecologist clinics. Elderly women were less likely to utilize gynecological care in all settings of medical care, but were more likely to be attended by non-gynecologists. Young women tended to visit emergency departments. The ecology model highlighted age disparities in women's utilization of gynecological care in various settings of medical care. Since gynecological conditions were common among women, more attention should be paid on the availability of gynecologists and continuing medical education in gynecological care for non-gynecologists to guarantee women's health.

Old habits die hard: a nationwide utilization study of short-acting nifedipine in Taiwan.

BACKGROUND: To investigate the nationwide trend of ambulatory prescriptions of short-acting nifedipine on a PRN (pro re nata) order over a fifteen-year period in Taiwan. METHODS: The systematic sampling claims datasets (0.2% sampling ratio) of ambulatory care visits within Taiwan's National Health Insurance from 1997 to 2011 were analyzed. The prescriptions of short-acting capsule-form nifedipine on a PRN order were stratified by the patient's age, the prescribing physician's specialty, and the setting of healthcare facility for each year. RESULTS: During the study period, 8,189,681 visits were analyzed. While the utilization rate of calcium channel blockers changed with time from 2.8% (13,767/489,636) in 1997 to 5.1% (31,349/614,719) in 2011, that of short-acting nifedipine were from 1.0% (n = 5,070) to 0.2% (n = 1,246). However, short-acting capsule-form nifedipine on a PRN order still existed (from 447 prescriptions in 1997 to 784 in 2011). More than one half of these PRN nifedipines were prescribed by the internists and to the elderly patients; almost four-fifths of PRN nifedipines were prescribed during non-emergent consultations. CONCLUSION: The physicians in Taiwan still had the habit of prescribing short-acting nifedipines for PRN use. The reason for such practices and the impact on patients' health deserve attention.

The ecology of medical care in Taiwan.

BACKGROUND: In regular administrative statistics for medical services, utilization data are usually presented as aggregate data and lack an individual perspective. The aim of this study was to provide an overview of medical care utilization in Taiwan using a long-established analytical framework, the so-called ecology model. METHODS: Claims data for a cohort of one million people from the National Health Insurance (NHI) Research Database were used to estimate the yearly and monthly prevalence of health care utilization in Taiwan in 2005. Analyses were extended to different types of healthcare settings and were stratified by age and sex. Results are presented per 1000 of the population. RESULTS: Per 1000 people, 74 did not utilize any NHI services during the year. In a month, 503 people on average utilized at least once NHI service of any kind, 329 visited a physician's clinic (Western medicine), 152 visited a hospital-based outpatient clinic, 19 visited an emergency department, 10 were hospitalized and 3 were hospitalized in an academic medical center. Women were more likely to utilize NHI services than men (274/504 vs. 229/496 in a month). In a month on average, 40.3% (146/362) of young people, 52.2% (166/318) of middle-aged people, 53.3% (121/227) of children and 75.0% (70/93) of elderly people utilized NHI services. Over the whole year, 22.0% (21/93) of elderly people were hospitalized and nearly one-third of them were hospitalized in academic medical centers. CONCLUSION: People in Taiwan utilized NHI services frequently and tended to seek medical help in hospitals. Although these features might reflect the higher availability and accessibility of medical care within the NHI in Taiwan, the possibility of overuse deserves further attention.

Use of traditional Chinese medicine among pregnant women in Taiwan.

OBJECTIVE: To investigate the patterns of traditional Chinese medicine (TCM) use among pregnant women in the National Health Insurance program in Taiwan. METHODS: Women who gave birth in Taiwan in 2006 were identified from the National Health Insurance Research Database. Claims for reimbursement following TCM ambulatory visits by these women were analyzed. RESULTS: In total, 20.9% of women in the study who gave birth in 2006 used TCM during pregnancy, with older women more likely to utilize this form of care (23.9% of women >35 years of age vs 16.2% of women <20 years of age). There was an increase in the use of TCM for pregnancy-related problems such as hypertension (194 women before pregnancy vs 2163 during) and nausea/vomiting (220 women before vs 1648 during). The predominant modality (88.4%) of TCM treatment during pregnancy was herbal preparation. CONCLUSION: Traditional Chinese medicine, with the exception of acupuncture, is popular among pregnant women in Taiwan. In addition to its efficacy, the safety of TCM during pregnancy requires future investigation.

Patterns of traditional Chinese medicine use in patients with inflammatory bowel disease: a population study in Taiwan.

BACKGROUND/AIMS: Many researchers have reported on the utilization of complementary and alternative medicine by patients with inflammatory bowel disease (IBD). The aim of this study was to investigate the use of traditional Chinese medicine (TCM) by all IBD patients within the National Health Insurance in Taiwan. METHODOLOGY: The complete ambulatory visits records of TCM in 2004 were obtained from the National Health Insurance Research Database. For all IBD patients identified from the registry for catastrophic illness patients, patterns of TCM visits were analyzed. RESULTS: The prevalence of IBD in Taiwan was 5.6 per 100,000 persons at the end of 2004. Of 1,206 IBD patients, 440 (37%) patients have in total 3,169 TCM visits in 2004. Women were more likely to use TCM than men (40.5% vs. 34.3%). Among the TCM users of the IBD patients, 200 (45.5%) patients had gastroenterological diagnoses at their TCM visits. Most of their TCM visits contained herbal remedies (90%), followed by manual therapy (11.7%) and acupuncture (9.8%). CONCLUSIONS: The high utilization rate of TCM among the IBD patients in Taiwan implied that their needs of medical care were not satisfied by the mainstream Western medicine. The TCM herbal regimens deserve further studies.

Intra-articular hyaluronic acid for treatment of osteoarthritis: a nationwide study among the older population of Taiwan.

BACKGROUND: Although intra-articular treatment with hyaluronic acid (HA) for symptomatic osteoarthritis has become widely accepted in recent decades, the pattern of its use has seldom been reported. We have explored the epidemiology of intra-articular HA treatment in Taiwan by using the rich data source from nationwide insurance claims. METHODS: Taiwan's National Health Insurance (NHI), which covers 97% of inhabitants, offers extensive hospitalisation and ambulatory care. We identified the beneficiaries aged 60 years and older who received intra-articular HA within the NHI during 2004. The number of visits in which HA was administered were analysed by patient's age and gender and by the physician's specialty and practice site. RESULTS: Among the 73,410,777 ambulatory visits by 2,909,219 beneficiaries aged 60 years and older in 2004, 35,782 (1.2%) patients received intra-articular HA treatment in 205,012 (0.3%) visits. The highest prevalence of HA use was in the 70-79 year age group in both sexes. Women received intra-articular HA treatment more frequently than men in all age groups, especially in the 60-69 and 70-79 year groups (1.6% vs. 0.5%, 2.2% vs. 1.0%, respectively). Most intra-articular HA procedures were performed by orthopaedic surgeons (75.1%) and physical medicine and rehabilitation physicians (15.2%), and at metropolitan hospitals (34.5%) and local community hospitals (38.2%). CONCLUSION: One out of 100 older patients in Taiwan received intra-articular HA treatment for osteoarthritis of the knee during the course of the year. There were age-gender differences in use of HA treatment. The completion rate of this treatment in our study was high, and thus intra-articular HA might be a good alternative for patients for whom conventional treatment fails. Further research is needed to examine the age-gender differences in use of intra-articular HA in Taiwan.

Use frequency of traditional Chinese medicine in Taiwan.

BACKGROUND: Use of Traditional Chinese medicine (TCM), an important category of complementary and alternative medicine (CAM), has increased substantially in Western countries during the past decade. Use of TCM is also widespread in the Chinese population. However, few informative data have been obtained to date by large-scale investigations of TCM use in the Chinese population. This study was aimed at elucidating the demographics and patterns of TCM use in Taiwan. METHODS: We employed the complete datasets of TCM outpatient reimbursement claims from 1996 to 2001, including the use of Chinese herbal remedies, acupuncture and traumatology manipulative therapy, to analyse use frequencies, the characteristics of TCM users, and the disease categories that were treated by TCM in Taiwan. RESULTS: At the end of 2001, 6,142,829 (28.4%) among the 21,653,555 valid beneficiaries of the National Health Insurance in Taiwan had used TCM during the year. However, 13,536,266 subjects (62.5%) had used TCM at least once during the whole 6-year period from 1996 to 2001, with a total of 156,224,266 visits (mean 11.5 visits per user). The mean number of TCM users per annum was 5,733,602, with a mean increment of 1,671,476 (29.2%) of new users yearly. Among TCM users, female was higher than male (female:male = 1.13:1), and the age distribution displayed a peak at around the 30s, followed by the 20s and 40s. Chinese herbal remedies (85.9%) were the most common TCM modality used by this population, followed by acupuncture (11.0%) and traumatology manipulative therapies (3.1%). Private TCM clinics provided most of the TCM care (82.6%), followed by private TCM hospitals (12.0%). The top ten major disease categories for TCM visits were diseases of the respiratory system, musculoskeletal system and connective tissue; symptoms, signs and ill-defined conditions; injury and poisoning; diseases of the digestive system, genitourinary system, skin and subcutaneous tissue, nervous system and sense organs, circulatory and endocrine system; nutritional and metabolic diseases; and immunological disorders. CONCLUSION: TCM was popular among the Chinese population in Taiwan during the period studied. More than 60% of all subjects had used TCM during the 6-year interval. TCM was widely used by the Chinese population to treat problems and diseases of major human organ systems recognised by western medicine. This study provides information about the use frequencies of TCM and the disease categories treated by TCM, which should be useful for health policy makers and for those considering the integration of TCM and Western medicine.

Health care utilization of home care patients at an academic medical center in Taiwan.

BACKGROUND: Previous surveys of home care patients in Taiwan have primarily concentrated on patients' status and needs. The aim of this study was to review the actual health care utilization of home care patients during the course of 1 year. METHODS: Home care patients at an academic medical center in Taiwan were selected and their insurance claims data at this hospital in 2001 were analyzed. Analyses included the patients' patterns and diagnoses of visits and admissions, and their drug utilization. For diagnoses made at outpatient departments, the grouping system from the National Hospital Ambulatory Medical Care Survey in the United States was used. The Anatomical Therapeutic Chemical Classification system was applied to drug grouping. RESULTS: The home care agency of the hospital cared for 165 patients (66 women, 99 men) in 2001. In total, these 165 patients received 1,358 home visits, 2,751 outpatient visits, and 108 inpatient admissions. While the most frequent diagnoses for all visits were cerebrovascular disease, hypertension, diabetes mellitus, chronic and unspecified bronchitis, psychoses, and other disorders of the central nervous system, the most frequent diagnoses at discharge from the hospital were urinary tract infection and pneumonia. In all visits, 12,282 items of drugs were prescribed in 2,337 prescriptions. On average, each prescription contained 5.3 +/- 2.8 items of drugs. The most frequently prescribed drugs were antacids, expectorants, laxatives, selective calcium channel blockers, and antithrombotic agents. CONCLUSION: The home care agency of the hospital should pay more attention to provision of comprehensive care and review of drug prescribing.

Patterns of ambulatory care utilization in Taiwan.

BACKGROUND: We used the insurance claims of a representative cohort to quantify the patterns of ambulatory care visits, especially the doctor-shopping phenomenon, in Taiwan. METHODS: The ambulatory visit files of the 200,000-person cohort datasets from the National Health Insurance Research Database in 2002 were analyzed. Only a visit with physician consultation would be considered. We computed the visit patterns both by visit count and by patient count. RESULTS: In 2002, there were 182,474 eligible people with 2,443,003 physician consultations. During the year, 87.4% of the cohort had visited physician clinics and 57.5% had visited hospital-based outpatient or emergency departments. On average, a person had 13.4 physician consultations and consulted 3.4 specialties, 5.2 physicians, and 3.9 healthcare facilities in a year. In 2002, 17.3% of the cohort had ever visited different healthcare facilities on the same day; 23.5% had ever visited physicians of the same specialty at different healthcare facilities within 7 days and the percentage of second visits was 3.8% of all visits. Besides, 7.6% of the cohort had visited two or more specialties at the same facility on the same day, and such visits make up 2.5% of all visits. CONCLUSION: The people in Taiwan did visit the physicians and outpatient departments frequently. Many patients not only consulted several physicians of different specialties and at different healthcare facilities during the year, but also switched the physicians and facilities quickly. An effective referral system with efficient data exchange between facilities might be the solution.

The ecology of mental health care in Taiwan.

This paper applied the ecology model of general medical care by White et al. to analysis of mental health services utilization within the National Health Insurance in Taiwan. The ambulatory and inpatient claims of a 200,000-person cohort in 2001 were analyzed. The yearly and monthly prevalence estimates included psychotropic drug prescription, diagnosis of mental disorders, psychiatric ambulatory visit and admission, community psychiatric rehabilitation, and certificate of chronic psychosis. The results revealed one-fourth of people had received psychotropic drugs during the year, mostly from non-psychiatrists. Besides, the elderly might be excessively exposed to psychotropic drugs, and community rehabilitation programs were underutilized.

Estimating medical costs of gastroenterological diseases.

AIM: To estimate the direct medical costs of gastroenterological diseases within the universal health insurance program among the population of local residents in Taiwan. METHODS: The data sources were the first 4 cohort datasets of 200,000 people from the National Health Insurance Research Database in Taipei. The ambulatory, inpatient and pharmacy claims of the cohort in 2001 were analyzed. Besides prevalence and medical costs of diseases, both amount and costs of utilization in procedures and drugs were calculated. RESULTS: Of the cohort with 183,976 eligible people, 44.2% had ever a gastroenterological diagnosis during the year. The age group 20-39 years had the lowest prevalence rate (39.2%) while the elderly had the highest (58.4%). The prevalence rate was higher in women than in men (48.5% vs. 40.0%). Totally, 30.4% of 14,888 inpatients had ever a gastroenterological diagnosis at discharge and 18.8% of 51,359 patients at clinics of traditional Chinese medicine had such a diagnosis there. If only the principal diagnosis on each claim was considered, 16.2% of admissions, 8.0% of outpatient visits, and 10.1% of the total medical costs (8,469,909 US dollars/83,830,239 US dollars) were attributed to gastroenterological diseases. On average, 46.0 US dollars per insured person in a year were spent in treating gastroenterological diseases. Diagnostic procedures related to gastroenterological diseases accounted for 24.2% of the costs for all diagnostic procedures and 2.3% of the total medical costs. Therapeutic procedures related to gastroenterological diseases accounted for 4.5% of the costs for all therapeutic procedures and 1.3% of the total medical costs. Drugs related to gastroenterological diseases accounted for 7.3% of the costs for all drugs and 1.9% of the total medical costs. CONCLUSION: Gastroenterological diseases are prevalent among the population of local residents in Taiwan, accounting for a tenth of the total medical costs. Further investigations are needed to differentiate costs in screening, ruling out, confirming, and treating.

Application of a data-mining technique to analyze coprescription patterns for antacids in Taiwan.

BACKGROUND: Although antacids are popular drugs with a long history of use, their true utilization patterns-including over-the-counter use-have rarely been documented. Because all antacids are reimbursed under the National Health Insurance program in Taiwan, it is possible to access and analyze nationwide data for these drugs. OBJECTIVES: The purposes of this study were to estimate the scale of antacid prescribing in Taiwan using the national insurance claims for outpatient services and to analyze coprescribing patterns of antacids using modern data-mining techniques. METHODS: The National Health Insurance Research Database in Taiwan supplied the visit-based sampling data sets, which had a sampling ratio of 0.2% for all claims for outpatient medical services in the year 2000. In addition to the plain statistics (ie, data from simple calculations) for antacid prescriptions, we also analyzed relationships between prescriptions for antacids and nonantacid drugs. A data-mining technique-association rule mining-was applied to identify the drugs prescribed in combination with antacids. RESULTS: Among a total of 409,049 eligible prescriptions for 1,704,595 drug items to be administered orally, antacids were present in 213,494 prescriptions (52.2%). Antacid users were generally older than nonusers (mean [SD] age, 39.9 [23.4] years vs 32.4 [25.7] years). In all, 88.8% of antacid items (189,531/213,494) were prescribed without claims diagnoses of gastrointestinal disorders. Using association rule mining with a 1.0% minimum support factor, there were 36 strong association rules between prescriptions for antacids and other drug subgroups at the third level of Anatomical Therapeutic Chemical classification. Nonsteroidal anti-inflammatory drugs and drugs for treating upper respiratory infections played dominant roles in the associations with antacid prescriptions; vitamin B complex and antivertigo preparations were also strongly associated with antacids. CONCLUSIONS: Antacid coprescriptions were common in Taiwan in the year 2000. Further study should investigate whether antacid prescribing patterns are influenced by Taiwanese perceptions that Western drugs injure the stomach.

Utilization of hepatoprotectants within the National Health Insurance in Taiwan.

BACKGROUND: Although the hepatoprotectants of Western medicine have centuries of history, their utilization patterns have been seldom documented. Because the National Health Insurance program in Taiwan reimburses hepatoprotectant use, we could estimate the age- and sex-specific prevalence and utilization patterns of hepatoprotectants in Western medicine within the health insurance system in Taiwan. METHODS: We analyzed the outpatient prescription data of 50000 randomly sampled insured patients in 2000. Only patients using drugs indicated for liver diseases and diagnostic codes related to liver diseases on the same visit were considered to be receiving hepatoprotectants. Drugs involved in Chinese medicine were not included. RESULTS: Among the valid cohort of 46614 people, 783 (1.7%) were identified as patients with liver disease and receiving hepatoprotectants. Highest prevalence of hepatoprotectant use was 4.9% in the 60-69 years age group. Silymarin, multivitamins, methionine, ursodeoxycholic acid, and liver hydrolysate accounted for 88.8% of the 3215 prescribed items of hepatoprotectants. Patients receiving hepatoprotectants had, on average, visited the clinics more frequently than those not using hepatoprotectants (30 vs 14 times in a year, P < 0.001), and used more insurance benefits (US dollars 1352 vs US dollars 456, P < 0.001). CONCLUSIONS: The frequency of use of major hepatoprotectants in Taiwan corresponded to the current modalities of treatment under discussion worldwide.