Primary cilia control glucose homeostasis via islet paracrine interactions.

Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking ß-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the ß-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of ß-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate ß-cell-intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.

Multi-scale causality analysis between COVID-19 cases and mobility level using ensemble empirical mode decomposition and causal decomposition.

The global spread of the coronavirus disease 2019 (COVID-19) pandemic has affected the world in many ways. Due to the communicable nature of the disease, it is difficult to investigate the causal reason for the epidemic's spread sufficiently. This study comprehensively investigates the causal relationship between the spread of COVID-19 and mobility level on a multi time-scale and its influencing factors, by using ensemble empirical mode decomposition (EEMD) and the causal decomposition approach. Linear regression analysis investigates the significance and importance of the influential factors on the intrastate and interstate causal strength. The results of an EEMD analysis indicate that the mid-term and long-term domain portrays the macroscopic component of the states' mobility level and COVID-19 cases, which represents overall intrinsic characteristics. In particular, the mobility level is highly associated with the long-term variations of COVID-19 cases rather than short-term variations. Intrastate causality analysis identifies the significant effects of median age and political orientation on the causal strength at a specific time-scale, and some of them cannot be identified from the existing method. Interstate causality results show a negative association with the interstate distance and the positive one with the airline traffic in the long-term domain. Clustering analysis confirms that the states with the higher the gross domestic product and the more politically democratic tend to more adhere to social distancing. The findings of this study can provide practical implications to the policymakers that whether the social distancing policies are effectively working or not should be monitored by long-term trends of COVID-19 cases rather than short-term.

Elevated levels of serum tumor markers CA 15-3 and CEA are prognostic factors for diagnosis of metastatic breast cancers.

To investigate the prognostic value of tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels at diagnosis of systemic recurrence. After primary treatments of locoregional breast cancers, serum CA 15-3 and/or CEA concentrations were regularly measured, and systemic recurrences were identified in 351 patients between January 1999 and December 2009. The association between tumor marker levels at systemic recurrence and survival were investigated by univariate and multivariate analyses. Elevated CA 15-3 and CEA levels were identified in 194 of 349 (55.6 %) and 111 of 308 (36.0 %) patients, respectively, at diagnosis of systemic recurrence. Elevated levels of CA 15-3 and CEA were correlated with visceral or multiple recurrences and elevated preoperative levels. Elevation of CA 15-3 was more prominent in younger patients and in primary node-positive tumors, while CEA was elevated in older patients at diagnosis and in estrogen receptor (ER)-positive tumors. Elevated tumor markers as well as ER negativity, short disease-free interval, and advanced stage at initial diagnosis showed independent prognostic significance on multivariate analysis. Among 306 patients for whom levels of both tumor markers at recurrence were available, 106 patients without elevation of either marker showed significantly better overall survival than those with elevated levels of either one or both markers, and the significance persisted in multivariate analysis. Elevated serum CA 15-3 and CEA levels at recurrence suggest increased tumor burden and may be prognostic for survival for metastatic breast cancer patients.

Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer at diagnosis.

BACKGROUND: The performance of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NCT) was investigated in patients with locally advanced breast cancer (LABC). METHODS: After NCT of 178 patients with cytology-proven axillary/supraclavicular nodes metastasis at the time of diagnosis, SLNB using radioisotope was performed including completion node dissection between 2008 and 2011. The detection rate, sensitivity, false negative rate (FNR), negative predictive value (NPV) and accuracy of SLNB were analyzed. RESULTS: SLNB was successfully performed in 169 (94.9%) patients. Tumor nonresponse and extensive residual nodal disease were found to be significantly associated with detection failure of sentinel nodes. Sensitivity, FNR, NPV, and accuracy of SLNB were 78.0, 22.0, 75.8, and 87.0%, respectively, and a greater number of retrieved SLNs increased all four of these performance measures. Conversion to node-negative disease was achieved in 69 (40.8%) patients: 24% of patients with the luminal A subtype, 51.6% of patients with the luminal B, 51.7% of patients with the HER2-enriched, and 58.5% of patients with the triple-negative breast cancer (TNBC) subtype. Luminal B, HER2-enriched, and TNBC subtypes showed comparable responses to NCT; however, the TNBC subtype had a significantly better FNR and accuracy. CONCLUSIONS: SLNB was found to be technically feasible, but its routine use was not recommended for LABCs after NCT. However, acceptable performance was noted for locally advanced TNBCs, and thus SLNB might be safely considered in these selected patients.

Oncologic safety of breast-conserving surgery compared to mastectomy in patients receiving neoadjuvant chemotherapy for locally advanced breast cancer.

BACKGROUND: Breast-conserving surgery (BCS) in patients with large tumors shrunk by neoadjuvant chemotherapy (NCT) remains controversial. We investigated oncologic outcomes of BCS in patients receiving NCT to treat locally advanced breast cancer (LABC). METHODS: We reviewed 1,994 patients who underwent surgery with/without NCT. Patients were categorized into three groups according to treatment methods: initial BCS, BCS after NCT (NCT-BCS), and mastectomy after NCT (NCT-MX). Their characteristics and outcomes were analyzed. RESULTS: The NCT-BCS group had earlier stage cancer, more hormone receptor-negative and triple-negative breast cancers (TNBC) than the NCT-MX group. However, outcomes did not differ statistically between the two groups. BCS patients receiving NCT were younger, and had more advanced, hormone receptor-negative, HER2-positive, and TNBC breast cancers than BCS patients without NCT. Patients with pathological complete remission (pCR) in the NCT-BCS group had better survival outcomes than non-pCR patients and the initial BCS group. By multivariate analysis in patients receiving NCT, final stage and TNBC were associated with poor overall survival (stage III: P = 0.008; TNBC: P = 0.01), however surgery type was not (P = 0.20). CONCLUSIONS: BCS after NCT is a safe option for LABC that responded well to NCT. Shrinking tumors with NCT allows more opportunities to apply BCS without compromising outcomes.

Homeodomain-interacting protein kinase 1 (HIPK1) expression in breast cancer tissues.

OBJECTIVE: This study investigated the incidence and clinical significance of homeodomain-interacting protein kinase 1 expression in breast cancer patients. METHODS: We investigated immunohistochemical homeodomain-interacting protein kinase 1 expression from tissue microarrays of 1032 patients. The association of homeodomain-interacting protein kinase 1 expression pattern, clinicopathologic factors and survival outcome was evaluated. Tumors with ≥10% stained cells were considered positive for homeodomain-interacting protein kinase 1. RESULTS: Non-cancerous breast tissue, pTis and pT1mic lesions did not show homeodomain-interacting protein kinase 1 expression at any sites. Of the 859 invasive tumors, 124 (14.4%) showed homeodomain-interacting protein kinase 1 expression with three different expression patterns: cytoplasmic (2.4%), nuclear (6.3%), and both cytoplasmic and nuclear (5.7%). Cytoplasmic homeodomain-interacting protein kinase 1-positive tumors showed distinctive features such as fewer nodal metastases, but were frequently Grade III, estrogen receptor-negative, progesterone receptor-negative, HER2-positive, highly proliferative and molecular apocrine tumors. No significant difference in clinicopathologic features was identified between negative and nuclear homeodomain-interacting protein kinase 1-positive tumors. Both cytoplasmic and nuclear HIPK1-positive tumors represent frequent small size, node negativity and moderately differentiated features. Survival was not significantly different by homeodomain-interacting protein kinase 1 expression patterns. CONCLUSIONS: Homeodomain-interacting protein kinase  1 expression was identified only in invasive breast cancer cells with three different patterns: cytoplasmic, nuclear, and both cytoplasmic and nuclear. Although the mechanism is not certain, the subcellular localization of HIPK1 expression is associated with tumor histopathologic characteristics and different functions.

Cilia Action in Islets: Lessons From Mouse Models.

Primary cilia as a signaling organelle have garnered recent attention as a regulator of pancreatic islet function. These rod-like sensors exist on all major islet endocrine cell types and transduce a variety of external cues, while dysregulation of cilia function contributes to the development of diabetes. The complex role of islet primary cilia has been examined using genetic deletion targeting various components of cilia. In this review, we summarize experimental models for the study of islet cilia and current understanding of mechanisms of cilia regulation of islet hormone secretion. Consensus from these studies shows that pancreatic cilia perturbation can cause both endocrine and exocrine defects that are relevant to human disease. We discuss future research directions that would further elucidate cilia action in distinct groups of islet cells, including paracrine and juxtacrine regulation, GPCR signaling, and endocrine-exocrine crosstalk.

Fluorescence imaging of beta cell primary cilia.

Primary cilia are slender cell-surface organelles that project into the intercellular space. In pancreatic beta cells, primary cilia coordinate a variety of cell responses including GPCR signaling, calcium influx, and insulin secretion, along with likely many underappreciated roles in islet development and differentiation. To study cilia function in islet biology, direct visualization of primary cilia by microscopic methods is often a necessary first step. Ciliary abundance, distribution, and morphology are heterogeneous among islet cells and are best visualized by fluorescence microscopy, the tools for which are readily accessible to most researchers. Here we present a collection of fluorescence imaging methods that we have adopted and optimized for the observation of primary cilia in mouse and human islets. These include conventional confocal microscopy using fixed islets and pancreas sections, live-cell imaging with cilia-targeted biosensors and probes, cilia motion recordings, and quantitative analysis of primary cilia waveform in the ex vivo environment. We discuss practical considerations and limitations of our approaches as well as new tools on the horizon to facilitate the observation of primary cilia in pancreatic islets.

Islet primary cilia motility controls insulin secretion.

Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here, we show that primary cilia in human and mouse pancreatic islets exhibit movement that is required for glucose-dependent insulin secretion. Islet primary cilia contain motor proteins conserved from those found in classic motile cilia, and their three-dimensional motion is dynein-driven and dependent on adenosine 5'-triphosphate and glucose metabolism. Inhibition of cilia motion blocks beta cell calcium influx and insulin secretion. Human beta cells have enriched ciliary gene expression, and motile cilia genes are altered in type 2 diabetes. Our findings redefine primary cilia as dynamic structures having both sensory and motile function and establish that pancreatic islet cilia movement plays a regulatory role in insulin secretion.

Glutamate decarboxylase 67 contributes to compensatory insulin secretion in aged pancreatic islets.

Pancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO2. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic ß-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to ß-cell responses to impaired glucose homeostasis caused by advanced aging.

Effect of young exosomes injected in aged mice.

INTRODUCTION: Exosomes, nanosized extracellular vesicles, are known to circulate through the blood stream to transfer molecular signals from tissue to tissue. METHODS: To determine whether exosomes affect aging in animals, we primarily identified the changes in exosomal miRNA contents during the aging process. In exosomes from 12-month-old mice, mmu-miR-126-5p and mmu-miR-466c-5p levels were decreased and mmu-miR-184-3p and mmu-miR-200b-5p levels were increased significantly compared with those of 3-month-old mice. Their levels in exosomes were partially correlated with those in tissues: levels of only mmu-miR-126-5p and mmu-miR-466c-5p in lungs and/or liver were decreased, but those of mmu-miR-184-3p and mmu-miR-200b-5p in tissues did not coincide with those of exosomes. RESULTS AND DISCUSSION: In the aged tissues injected with young exosomes isolated from serum, mmu-miR-126b-5p levels were reversed in the lungs and liver. Expression changes in aging-associated molecules in young exosome-injected mice were obvious: p16Ink4A, MTOR, and IGF1R were significantly downregulated in the lungs and/or liver of old mice. In addition, telomerase-related genes such as Men1, Mre11a, Tep1, Terf2, Tert, and Tnks were significantly upregulated in the liver of old mice after injection of young exosomes. CONCLUSION: These results indicate that exosomes from young mice could reverse the expression pattern of aging-associated molecules in aged mice. Eventually, exosomes may be used as a novel approach for the treatment and diagnosis of aging animals.

Reverse Expression of Aging-Associated Molecules through Transfection of miRNAs to Aged Mice.

Molecular changes during aging have been studied to understand the mechanism of aging progress. Herein, changes in microRNA (miRNA) expression in the whole blood of mice were studied to systemically reverse aging and propose them as non-invasive biomarkers. Through next-generation sequencing analysis, we selected 27 differentially expressed miRNAs during aging. The most recognized function involved was liver steatosis, a type of non-alcoholic fatty liver disease (NAFLD). Among 27 miRNAs, six were predicted to be involved in NAFLD, miR-16-5p, miR-17-5p, miR-21a-5p, miR-30c-5p, miR-103-3p, and miR-130a-3p; alterations in their blood and liver levels were confirmed by real-time qPCR. The expression of the genes associated in the network of these miRNAs, Bcl2, Ppara, E2f1, E2f2, Akt, Ccnd1, and Smad2/3, also was altered in the liver of aged mice. Following transfection of these miRNAs into 18-month-old mice, levels of miR-21a-5p, miR-103-3p, and miR-30c-5p increased, and their related genes exhibited a reversed expression in the liver. Expression of Mre11a, p16INK4a, and Mtor, reported to be aging-associated molecules, also was reversed in the livers of miRNA-transfected mice. These miRNAs could be non-invasive biomarkers for aging, and they might induce a reverse regulation of aging-associated pathways. This study provides preliminary data on reverse aging, which could be applied further for treatments of adult diseases.

Enhanced Therapeutic Treatment of Colorectal Cancer Using Surface-Modified Nanoporous Acupuncture Needles.

Acupuncture originated within the auspices of Oriental medicine, and today is used as an alternative method for treating various diseases and symptoms. The physiological mechanisms of acupuncture appear to involve the release of endogenous opiates and neurotransmitters, with the signals mediating through electrical stimulation of the central nervous system (CNS). Earlier we reported a nanoporous stainless steel acupuncture needle with enhanced therapeutic properties, evaluated by electrophysiological and behavioral responses in Sprague-Dawley (SD) rats. Herein, we investigate molecular changes in colorectal cancer (CRC) rats by acupuncture treatment using the nanoporous needles. Treatment at acupoint HT7 is found most effective at reducing average tumor size, ß-catenin expression levels, and the number of aberrant crypt foci in the colon endothelium. Surface modification of acupuncture needles further enhances the therapeutic effects of acupuncture treatment in CRC rats.

Oncologic Outcomes of a Laparoscopic Right Hemicolectomy for Colon Cancer: Results of a 3-Year Follow-up.

PURPOSE: The purpose of the study is to evaluate the oncologic outcomes of a laparoscopic-assisted right hemicolectomy for the treatment of colon cancer and compare the results with those of previous randomized trials. METHODS: From June 2006, to December 2008, 156 consecutive patients who underwent a laparoscopic right hemicolectomy with a curative intent for colon cancer were evaluated. The clinicopatholgic outcomes and the oncologic outcomes were evaluated retrospectively by using electronic medical records. RESULTS: There were 84 male patients and 72 female patients. The mean possible length of stay was 7.0 ± 1.5 days (range, 4 to 12 days). The conversion rate was 3.2%. The total number of complications was 30 (19.2%). Anastomotic leakage was not noted. There was no mortality within 30 days. The 3-year overall survival rate of all stages was 93.3%. The 3-year overall survival rates according to stages were 100% in stage I, 97.3% in stage II, and 84.8% in stage III. The 3-year disease-free survival rate of all stages was 86.1%. The 3-year disease-free survival rates according to stage were 96.2% in stage I, 90.3% in stage II, and 75.6% in stage III. The mean follow-up period was 36.3 (3 to 60) months. CONCLUSION: A laparoscopic right hemicolectomy for the treatment of colon cancer is technically feasible and safe to perform in terms of oncologic outcomes. The present data support previously reported randomized trials.

Effect of acupuncture on heart rate variability in primary dysmenorrheic women.

Primary dysmenorrhea is a common gynecological complaint among young women that is related to an autonomic nervous system (ANS) disturbance. Acupuncture is one of several therapeutic approaches for primary dysmenorrhea, since it can modulate ANS function. The heart rate variability (HRV) parameters such as high frequency (HF), low frequency (LF) and LF/HF ratio are generally accepted tools to assess ANS activity. The purpose of this study was to investigate the effects of acupuncture applied at Hegu (LI4) and Sanyinjiao (SP6) points on HRV of women with primary dysmenorrhea during the late luteal phase. The experimental design was a crossover and patient-blinded procedure. All subjects participated in Sham (SA) and Real Acupuncture (RA) procedure, separated by one month, in a crossover sequence. The participants included 38 women (mean age 22.3 years; weight 53.8 kg; height 162.6 cm). HRV measurement was 15 min before and 15 min after an acupuncture procedure. The RA procedure was performed at two bilateral acupoints, but needles were inserted subcutaneously to the acupuncture points for the SA procedure. The RA induced a significant decrease in LF/HF ratio and a significant increase in the HF power, while SA treatment caused a significant increase only in the HF power. Manual acupuncture at bilateral acupoints of LI4 and SP6 may play a role in dysmenorrhea treatment with autonomic nervous system involvement.

Heat stimulation on the skin for medical treatment: can it be controlled?

OBJECTIVES: It has become increasingly important for evidence-based medicine to have a proper control for randomized-controlled trials. However, appropriately controlling manual therapies such as moxibustion has proved challenging. Our team designed a novel device based on sensory illusion, and tested its feasibility. DESIGN AND RESULTS: A sham moxibustion device was constructed to allow participants to feel moxibustion treatment without actually stimulating the corresponding acupoint. The device consisted of two pieces of aluminum, each shaped like a horseshoe, so that the center of the device would not touch the skin. Participants perceived two heat stimuli as one when the distances of two heat sources were within 15 mm on the forearm. The thermal stimulation of the sham device was adjusted to the lowest possible temperature, but enough to elicit a heat sensation (39°C), while that of verum was set at around 44°C. The subject blinding, tested in 30 healthy volunteers, was successful. With the exception of 1 subject, subjects in the sham group described the sensation as a warm solid circle, unable to differentiate between two-pieced sham moxibustion and verum moxibustion. CONCLUSIONS: This preliminary study indicates that this device may serve as an appropriate control for clinical studies of moxibustion, but more research is clearly needed. A validated sham moxibustion device based on sensory illusion may contribute in expanding knowledge of somatosensory studies.

Eupatilin, a dietary flavonoid, induces G2/M cell cycle arrest in human endometrial cancer cells.

This study is the first to investigate the antiproliferative effect of eupatilin in human endometrial cancer cells. Eupatilin, a naturally occurring flavonoid isolated from Artemisia princeps, has anti-inflammatory, anti-oxidative, and anti-tumor activities. In the present study, we investigated the potential effect of eupatilin on cell growth and its molecular mechanism of action in human endometrial cancer cells. Eupatilin was more potent than cisplatin in inhibiting cell viability in the human endometrial cancer cell lines Hec1A and KLE. Eupatilin showed relatively low cytotoxicity in normal human endometrial cells HES and HESC cells when compared to cisplatin. Eupatilin induced G2/M phase cell cycle arrest in a time- and dose-dependent manner, as indicated by flow cytometry analysis. In addition, treatment of Hec1A cells with eupatilin resulted in a significant increase in the expression of p21(WAF1/CIP1) and in the phosphorylation of Cdc25C and Cdc2. Knockdown of p21 using specific siRNAs significantly compromised eupatilin-induced cell growth inhibition. Interestingly, levels of mutant p53 in Hec1A cells decreased markedly upon treatment with eupatilin, and p53 siRNA significantly increased p21 expression. Moreover, eupatilin modulated the phosphorylation of protein kinases ERK1/2, Akt, ATM, and Chk2. These results suggest that eupatilin inhibits the growth of human endometrial cancer cells via G2/M phase cell cycle arrest through the up-regulation of p21 by the inhibition of mutant p53 and the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway.

Dangguijakyak-san, a medicinal herbal formula, protects dopaminergic neurons from 6-hydroxydopamine-induced neurotoxicity.

AIM OF THE STUDY: Dangguijakyak-san (DJS) is a multi-herbal formula that has long been widely used in traditional Oriental medicine to treat gynecologic disorders, including neurological symptoms. Recent clinical and experimental studies have reported aging and anti-neurodegenerative effects of DJS. In this study, we evaluated the neuroprotective effects of DJS on dopaminergic (DA) neurons damaged by 6-hydroxydopamine (6-OHDA). MATERIALS AND METHODS: To evaluate the protective effects of DJS, we analyzed viability in SH-SY5Y neuroblastoma cells and tyrosine hydroxylase (TH) staining in primary DA cells. To explore the possible mechanism(s) of neuroprotection, we assessed anti-oxidant activity by measuring reactive oxygen species (ROS) and glutathione (GSH) levels. To determine mitochondria-mediated apoptotic activity, we examined mitochondrial membrane potential, cytochrome c release, and caspase-3 activation. RESULTS: DJS at 0.05-5 µg/mL significantly protected SH-SY5Y cells from 6-OHDA toxicity, dose-dependently, and attenuated 6-OHDA damage in primary DA cells. DJS reduced 6-OHDA-induced intracellular ROS production and GSH depletion and inhibited mitochondrial membrane instability, cytosolic cytochrome c release, and caspase-3 activation. CONCLUSIONS: These results demonstrate that DJS has neuroprotective effects in DA neurons against 6-OHDA-induced toxicity through anti-oxidant and anti-mitochondrial-mediated apoptotic activities.

Protective effect of Cyperi rhizoma against 6-hydroxydopamine-induced neuronal damage.

Cyperi rhizoma, the rhizome of Cyperus rotundus L. (Family Cyperaceae), is a well-known functional food and traditional herbal medicine in Korea. It has been reported that Cyperi rhizoma has antioxidant and free radical scavenging activities that play a major role in protection of neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, the neuroprotective effects of a water extract of Cyperi rhizoma (CRE) against 6-hydroxydopamine (6-OHDA)-induced neuronal damage were evaluated in an experimental model of PD. In PC12 cells, CRE showed a significant protective effect on cell viability at 50 and 100 microg/mL. CRE inhibited generation of reactive oxygen species and nitric oxide, reduction of mitochondrial membrane potential, and caspase-3 activity, which were induced by 6-OHDA. CRE also showed a significant protective effect against damage to dopaminergic neurons in primary mesencephalic culture. These results suggest that CRE has neuroprotective effects against 6-OHDA-induced toxicity through antioxidant and anti-apoptotic activities in an in vitro PD model.

Therapeutic effects of Chiljehyangbuhwan on primary dysmenorrhea: a randomized, double blind, placebo-controlled study.

OBJECTIVE: This clinical study was conducted to investigate the efficacy and safety of an oriental herbal medicine native to Korea, Chiljehyangbuhwan, in treating primary dysmenorrhea. DESIGN AND SETTING: A total of 100 primary dysmenorrhea patients who visited Kyung Hee University Korean Oriental Medicine Hospital between July 19 2004 and August 27 2004 were recruited. Secondary or drug-related dysmenorrhea was screened out through interviews and examination. The patients were grouped by fixed blocked randomization and administered either Chiljehyangbuhwan or placebo for one menstrual period in a double blind model. Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Multidimensional Verbal Rating Scale (MVRS) were used to evaluate dysmenorrhea severity. A total of 71 patients who passed the screening test and remained to the last were divided into either placebo or Chiljehyangbuhwan group, and each were further split into smaller subsets (indication, non-indication, and unspecified group) according to Korean Oriental medical diagnosis. RESULTS: In the non-indication group, the placebo and Chiljehyangbuhwan group did not show significant difference in VAS, VRS, and MVRS scores before medication (1st VAS, 1st VRS, 1st MVRS), after medication (2nd VAS, 2nd VRS, 2nd MVRS), and in changes in scores before and after (DeltaVAS, DeltaVRS, DeltaMVRS). In the indication group, the placebo and Chiljehyangbuhwan group showed significant difference in change in VAS and MVRS scores (DeltaVAS and DeltaMVRS). No evidence of toxicity could be found, and no serious adverse reactions to Chiljehyangbuhwan were reported. CONCLUSION: The results suggest that Chiljehyangbuhwan is effective and safe in treating primary dysmenorrhea when prescribed appropriately under Korean Oriental medical diagnosis.