Development of clinical practice guidelines for Korean medicine: Towards evidence-based complementary and alternative medicine.

Background: Since evidence-based medicine has been pursued in complementary and alternative medicine, the clinical practice guideline (CPG) has become a key factor in providing standardized and validated practices in Korean Medicine (KM). We aimed to review the current status and characteristics of the development, dissemination, and implementation of KM-CPGs. Methods: We searched KM-CPGs and relevant publication via web-based databases. We organized the searching results focused on the year of publications and the development programs to show which and how KM-CPGs have been development. We also reviewed the manuals for KM-CPG development to introduce concise characteristics of the KM-CPGs published in Korea. Results: The KM-CPGs have been developed according to manuals and standard templates for developing evidence-based KM-CPGs. First, CPG developers reviews the previously published CPGs for a clinical condition of interest and plans the CPG development. After finalizing the key clinical questions, the evidence is searched, selected, appraised, and analyzed following the internationally standardized methods. The quality of the KM-CPGs is controlled by a tri-step appraisal process. Second, the CPGs were submitted for the appraisal of the KM-CPG Review and Evaluation Committee. The committee evaluates the CPGs according to the AGREE II tool. Finally, the Steering Committee of the KoMIT project reviews the entire process of developing the CPGs and confirms it for public disclosure and dissemination. Conclusion: Evidence-based KM from research to practice can be achieved with the attention and effort of multidisciplinary entities such as clinicians, practitioners, researchers, and policymakers for the CPGs.

Contracted thalamic shape is associated with early development of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson's disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Drug screening by uniform patient derived colorectal cancer hydro-organoids.

As the importance of organoids increases, the need to develop organoid culture systems suitable for basic biological and clinical applications is being emphasized. However, there is still an unmet need to produce functionally complex and scalable uniform organoids. Here, we demonstrate a scalable organoid production platform with 8 well strips and a total of 8 × 9 microwells per strip using organoids derived from colorectal cancer tissue. The new culture platform is a format in which single cells are self-organized into organoids in culture medium supplemented with 2% Matrigel. It is functionally compatible with existing 96 well plates and Matrigel based conventional organoid culture methods. The consistency, uniformity and reproducibility of organoid produced on the new platform have been significantly improved compared to those of conventional plates. Importantly, Hydro-organoids are functionally identical to conventional Matrigel organoids, but show better consistency in drug screening. Our results show the possibility that Hydro-organoids can be used in high-throughput assays and incorporated into drug screening models to predict clinical outcomes.

Effect of Fatty Acid-Binding Protein 4 Inhibition on Rotator Cuff Muscle Quality: Histological, Biomechanical, and Biomolecular Analysis.

BACKGROUND: A rotator cuff tear (RCT) induces fatty acid-binding protein 4 (FABP4) expression, resulting in ectopic fat accumulation in the rotator cuff muscle. PURPOSE: To evaluate whether FABP4 inhibition reduces fatty infiltration and improves muscle physiology after RCT in a rat model. STUDY DESIGN: Controlled laboratory study. METHODS: Human supraspinatus muscle and deltoid muscle tissues were acquired from patients with RCTs during arthroscopic surgery, and FABP4 expression in the supraspinatus muscle was evaluated as compared with the intact deltoid muscle. A rat RCT model was established by detaching the supraspinatus tendon, after which a specific FABP4 inhibitor was locally injected into the supraspinatus muscle 4 times at 3-day intervals starting 2 weeks after the surgery. Body weight and blood glucose levels were measured at 2 and 4 weeks after the RCT, and the mRNA and protein expressions of various target molecules (including FABP4), histological changes, and biomechanical tensile strength were assessed in the supraspinatus muscles at 4 weeks after the RCT. RESULTS: The expression of human FABP4 was significantly increased in the torn rotator cuff muscle as compared with the intact deltoid muscle. In the rat model, the mRNA and protein expressions of FABP4 and HIF1α were significantly increased by the RCT as compared with the control. The FABP4 inhibitor treatment significantly decreased FABP4 expression when compared with the vehicle treatment; however, HIF1α expression was not significantly decreased versus the vehicle treatment. Histologically, RCT induced noticeable muscle fatty infiltration, which was remarkably reduced by the local injection of the FABP4 inhibitor. Biomechanically, the tensile strength of the rotator cuff muscle after the RCT was significantly improved by the FABP4 inhibitor in terms of load to failure and total energy to failure. CONCLUSION: RCT induces FABP4 expression in human and rat rotator cuff muscles. The FABP4 inhibitor drastically decreased the histological fatty infiltration caused by RCT and improved the tensile strength of the rotator cuff muscle. CLINICAL RELEVANCE: FABP4 inhibitor may have a beneficial effect on the muscle quality after RCT.

In vitro nasal mucosa gland-like structure formation on a chip.

The emergence of microfluidic epithelial models using diverse types of cells within a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug screening and pathophysiological studies. However, to date, few studies have reported the development of a complicated in vitro human nasal epithelial model. The aim of this study was to produce an in vitro human nasal mucosa model for reliable drug screening and clinical applications. Here, we integrated and optimized several culture conditions such as cell type, airway culture conditions, and hydrogel scaffolds into a microfluidic chip to construct an advanced in vitro human nasal mucosa model. We observed that the inducing factors for nasal gland-like structures were secreted from activated human dermal microvascular endothelial cells. Furthermore, our in vitro nasal mucosa presented different appearance and characteristics under hypoxic conditions. Morphological and functional similarities between in vivo nasal mucosa and our model indicated its utilization as a reliable research model for nasal diseases including allergic rhinitis, chronic sinusitis, and nasal polyposis.

Spheroid Formation of Hepatocarcinoma Cells in Microwells: Experiments and Monte Carlo Simulations.

The formation of spherical aggregates during the growth of cell population has long been observed under various conditions. We observed the formation of such aggregates during proliferation of Huh-7.5 cells, a human hepatocarcinoma cell line, in a microfabricated low-adhesion microwell system (SpheroFilm; formed of mass-producible silicone elastomer) on the length scales up to 500 µm. The cell proliferation was also tracked with immunofluorescence staining of F-actin and cell proliferation marker Ki-67. Meanwhile, our complementary 3D Monte Carlo simulations, taking cell diffusion and division, cell-cell and cell-scaffold adhesion, and gravity into account, illustrate the role of these factors in the formation of spheroids. Taken together, our experimental and simulation results provide an integrative view of the process of spheroid formation for Huh-7.5 cells.

Effect of modified fasting therapy on body weight, fat and muscle mass, and blood chemistry in patients with obesity.

OBJECTIVE: The aim of this study was to investigate the effects and safety of modified fasting therapy using fermented medicinal herbs and exercise on body weight, fat and muscle mass, and blood chemistry in obese subjects. METHODS: Twenty-six patients participated in a 14-day fast, during which they ingested a supplement made from fermented medicinal herbs and carbohydrates (intake: 400-600 kcal/d). The schedule included 7 prefasting relief days and 14 days of stepwise reintroduction of food. The patients also took part in an exercise program that incorporated Qigong, weight training, and walking exercises. The efficacy of treatments was observed by assessing body fat mass and muscle mass, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and triglycerides in each study period. Specific symptoms or side effects were reported. RESULTS: Body weight and body fat mass both decreased significantly by (5.16 ± 0.95) and (3.89 ± 0.79) kg (both P < 0.05), while muscle mass decreased by an average of (0.26 ± 0.22) kg, without statistical significance. ALT levels were significantly decreased (P < 0.05), while AST levels decreased without statistical significance (P = 0.052). The levels of total cholesterol and triglycerides were also significantly decreased (both P < 0.05). There were few adverse events except for mild dizziness, which did not affect everyday living. CONCLUSION: These results suggest that modified fasting therapy using fermented medicinal herbs and exercise could be effective and safe on obese patients.

Acupuncture for postoperative pain following total knee arthroplasty: a systematic review protocol.

INTRODUCTION: Total knee arthroplasty (TKA) is a common surgical method in orthopaedics; however, pain management after TKA remains a significant challenge. This review provides a comprehensive evaluation of the effects of acupuncture for postoperative pain after TKA. METHODS AND ANALYSIS: The following 10 databases will be searched until August 2015: MEDLINE, EMBASE, CENTRAL, AMED, CINAHL, three Chinese databases (the China National Knowledge Infrastructure Database, the Chongqing VIP Chinese Science and Technology Periodical Database, and Wanfang Database) and five Korean databases (the Korean Medical Database, the Korean Studies Information Service System, the National Discovery for Science Leaders, the Database Periodical Information Academic, and the Oriental Medicine Advanced Searching Integrated System). All eligible randomised controlled trials related to the use of acupuncture for postoperative pain after TKA will be included. Assessment of risk of bias will be performed with the Cochrane risk-of-bias method. Mean differences or standardised mean differences will be calculated with 95% CIs for continuous data; the risk ratio will be used with 95% CIs for dichotomous data. DISSEMINATION: This systematic review will be presented in a peer-reviewed journal. The result of this review will also be disseminated at a relevant conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO 2015: CRD42015020924.

Effect of capsular release in the treatment of shoulder stiffness concomitant with rotator cuff repair: diabetes as a predisposing factor associated with treatment outcome.

BACKGROUND: In spite of the high prevalence of shoulder stiffness during rotator cuff repair, optimal management remains unclear. PURPOSE: To identify the effect of capsular release during rotator cuff repair on the outcomes of patients with both shoulder stiffness and a rotator cuff tear, based on subgroup analyses. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Forty-nine consecutive patients (mean age, 61.5 ± 8.3 years) were enrolled who underwent arthroscopic repair of a small- to large-sized full-thickness rotator cuff tear and manipulation for concomitant shoulder stiffness (passive forward flexion ≤120°, external rotation at the side ≤45°). The first 21 consecutive patients underwent manipulation alone to treat stiffness; the second 28 consecutive patients underwent capsular release with manipulation. Among the 49 patients, 25 showed severe stiffness (forward flexion ≤100°, external rotation at the side ≤30°; 11 in the first series and 14 in the second series), and 15 had diabetes mellitus (30.6%; 6 in the first series and 9 in the second series). Shoulder range of motion was measured 6 weeks, 3 months, 6 months, and 1 year postoperatively and at final follow-up visit. Simultaneously, functional outcome was evaluated by visual analog scale for pain, American Shoulder and Elbow Surgeons score, Constant score, and muscle strength ratio (involved/uninvolved), and cuff integrity was assessed ultrasonographically at least 1 year postoperatively. RESULTS: All range of motion measurements, functional scores, and muscle strength ratios significantly improved postoperatively regardless of the treatment method of stiffness. No outcome measure differed significantly between patients who did and did not undergo capsular release, regardless of the severity of stiffness, except for a temporary improvement in external rotation at side 3 months postoperatively in favor of those who underwent capsular release in cases with severe stiffness. Among patients with diabetes mellitus however, those who underwent capsular release showed greater improvement in forward flexion after 3 months and 1 year and in external rotation at the side for all time points (all P < .05), except for 6 weeks postoperatively; these patients also had a significantly higher final American Shoulder and Elbow Surgeons score (P = .03). Of 21 patients who underwent manipulation alone and of 28 who underwent capsular release and manipulation, 2 and 1 developed retears, respectively. CONCLUSION: Both manipulation and capsular release with manipulation significantly improved range of motion and produced satisfactory functional outcomes. The outcomes did not differ between treatment methods for stiffness regardless of the severity of stiffness. In patients with diabetes mellitus however, capsular release at the time of rotator cuff repair seems to be beneficial, especially for external rotation and final postoperative function.

[The influence of Donguibogam during the middle Joseon era based on clinical records on low back pain in Seungjeongwon ilgi].

The recently increasing interest in historical records has led to more research on historical records in various fields of study. This trend has also affected medical research, with the medical climate and popular treatment modalities of the past now being revealed based on historical records. However, most research on medical history during the Joseon era has been based on the most well-known record, Joseon wangjo sillok or Annals of the Joseon Dynasty. Joseon wangjo sillok is a comprehensive and organized record of society during the Joseon era and contains key knowledge about medical history during the period, but it lacks details on the treatment of common disorders at the time. Seungjeongwon ilgi or Diary of the Royal Secretariat has detailed records of daily events and is a valuable resource for the daily activities of the era. And in the middle Josoen era, a variety of medical books - especially Donguibogam - was published. Therefore, the authors focused on the under-researched Seungjeongwon ilgi, Donguibogam and attempted to assess and evaluate low back pain treatment performed on Joseon royalty. The most notable characteristic of low back treatment records within the Seungjeongwon ilgi is that diagnosis and treatment was made based on an independent Korean medicine, rather than conventional Chinese medicine. This paradigm shift is represented in Dongeuibogam, and can be seen in the close relationship between Dongeuibogam and national medical exams of the day. Along with the pragmatism of the middle Joseon era, medical treatment also put more focus on pragmatic treatment methods, and records show emphasis on acupuncture and moxibustion and other points in accord with this. The authors also observed meaning and limitations of low back pain treatment during that era through comparison with current diagnosis and treatment.

The protective effect of Cassia obtusifolia on DSS-induced colitis.

Cassia obtusifolia (CO) has been traditionally used in Korea to treat eye inflammation, photophobia, and lacrimation. However, the regulatory effect and molecular mechanism of CO in intestinal inflammation has not been understood. In this study, we investigate the protective effect of CO in dextran sulfate sodium (DSS)-induced colitis. CO reduced clinical signs of DSS-induced colitis, including body weight loss, shortened colon length, and increased disease activity index. The results show that CO significantly suppressed the levels of interleukin (IL)-6 and expression of cyclooxygenase-2 in DSS-treated colon tissues. Additionally, we observed that CO reduced the activation of transcription nuclear factor-κB p65 in DSS-treated colon tissues. Taken together, these findings suggest that CO has improving effects on DSS-induced ulcerative colitis, which may explain its beneficial effect in the regulation of chronic intestinal inflammation.

Hot embossing for fabrication of a microfluidic 3D cell culture platform.

Clinically relevant studies of cell function in vitro require a physiologically-representative microenvironment possessing aspects such as a 3D extracellular matrix (ECM) and controlled biochemical and biophysical parameters. A polydimethylsiloxane (PDMS) microfluidic system with a 3D collagen gel has previously served for analysis of factors inducing different responses of cells in a 3D microenvironment under controlled biochemical and biophysical parameters. In the present study, applying the known commercially-viable manufacturing methods to a cyclic olefin copolymer (COC) material resulted in a microfluidic device with enhanced 3D gel capabilities, controlled surface properties, and improved potential to serve high-volume applications. Hot embossing and roller lamination molded and sealed the microfluidic device. A combination of oxygen plasma and thermal treatments enhanced the sealing, ensured proper placement of the 3D gel, and created controlled and stable surface properties within the device. Culture of cells in the new device indicated no adverse effects of the COC material or processing as compared to previous PDMS devices. The results demonstrate a methodology to transition microfluidic devices for 3D cell culture from scientific research to high-volume applications with broad clinical impact.

Expression of inducible nitric oxide synthase by Corydalis turtschaninovii on interferon-gamma stimulated macrophages.

AIM OF THE STUDY: Corydalis turtschaninovii (CT) has been used for tumor therapy. However, it is still unclear how this herb prevents the diseases in experimental models. Nitric oxide (NO) as a potent macrophage-derived effector molecule against a variety of tumors has received increasing attention. MATERIALS AND METHODS: In this study, using mouse peritoneal macrophages, we have examined the mechanism by which CT regulates NO production. RESULTS: When CT was used in combination with recombinant interferon-gamma (rIFN-gamma), there was a marked cooperative induction of NO production. However, CT had no effect on NO production by itself. The increase in NO synthesis was reflected as an increased amount of inducible NO synthase (iNOS) protein. The increased production of NO from rIFN-gamma plus CT-stimulated peritoneal macrophages was decreased by the treatment with N(G)-monomethyl-L-arginine or N(alpha)-Tosyl-Phe Chloromethyl Ketone, iNOS inhibitor. The increased production of NO from rIFN-gamma plus CT-stimulated cells was almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappa B (NF-kappaB). However, treatment of peritoneal macrophages with rIFN-gamma plus CT had no effect on the increase in tumor necrosis factor-alpha (TNF-alpha) production. CONCLUSIONS: Our findings demonstrate that CT increases the production of NO and TNF-alpha by rIFN-gamma-primed macrophages and suggest that NF-kappaB plays a critical role in mediating these effects of CT.

Effects of bee venom on the maturation of murine dendritic cells stimulated by LPS.

AIM OF STUDY: This study was performed to elicit the effectiveness of bee venom (BV), a traditional immunosuppressive Korean acupuncture agent, on the maturation of dendrtic cells (DCs). MATERIALS AND METHODS: Immature dendritic cells (iDCs) were generated from mouse bone marrow cells with GM-CSF. After 10 days of initial differentiation, DCs were activated with lipopolysaccharides (LPS) for another 48h in the presence or absence of BV. Surface molecule analysis, intracytoplasmic staining of cytokines, FITC-conjugated antigen uptake, and transwell migration assays were conducted with iDCs and activated DCs. RESULTS: Up-regulation of costimulatory molecules, typical of mature DCs (mDCs) was inhibited by addition of BV. Pro-inflammatory cytokines were also found to be reduced with BV treatment in LPS-stimulated DC. A decrease in antigen uptake upon the maturation of DC was reversed in low dose BV treated mDC. In addition, BV treated mDC demonstrated reduced directional migration in response to CCL21, a lymphoid chemokine which directs mDC. CONCLUSIONS: BV may have a therapeutic effect an on abnormally activated immune status, such as autoimmune rheumatoid arthritis, through an immune-modulatory effect on DC.

Protective effect of shenqi-wan against H2O2-induced apoptosis in hippocampal neuronal cells.

The present study investigated whether Shenqi-wan possesses a protective effect against hydrogen peroxide (H2O2)-induced apoptosis of the hippocampal cell line HiB5. Through morphological and biochemical analyses, it was demonstrated that HiB5 cells treated with H2O2 exhibited several apoptotic features, while cells pre-treated with Shenqi-wan prior to H2O2 exposure showed a decrease in the occurrence of apoptosis. In addition, a patch clamp study revealed that Shenqi-wan inhibited profoundly N-methyl-D-aspartic acid (NMDA) receptor-activated ion current in acutely dissociated hippocampal CA1 neurons. These results suggest that Shenqi-wan may exert its protective effect against H2O2-induced apoptosis via inhibition of NMDA receptors in hippocampal neuronal cells.

Red ginseng inhibits exercise-induced increase in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in dorsal raphe of rats.

Red ginseng has been used as an ergogenic aid for endurance exercise. In this study, the effect of aqueous extract of Red ginseng on the endurance in treadmill exercise and 5-hydroxytryptamine (serotonin) synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats were studied. Rats receiving Red ginseng showed increased time to exhaustion for treadmill running, and Red ginseng treatment inhibited exercise-induced increases in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe. These results suggest that the suppressive effect of Red ginseng on serotonin level during exercise is a possible ergogenic mechanism of Red ginseng.

Effects of Paeonia radix on 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats.

Paeonia radix is the root of Paeonia japonica MIYABE, a perennial plant classified in the family Paeoniaceae. In the present study, the effects of Paeonia radix on performance in treadmill exercise, and 5-hydroxytryptamine (5-HT) synthesis and tryptophan hydroxylase (TPH) expression in the dorsal raphe were investigated. Time to exhaustion in treadmill exercise was increased and exercise-induced increases in 5-HT synthesis and TPH expression in the dorsal raphe were shown to be suppressed by Paeonia radix treatment; 5-HT synthesis and TPH expression were inhibited by Paeonia radix treatment under resting conditions as well. In sum, treatment with Paeonia radix, inhibiting 5-HT synthesis and TPH expression, may bring about reduced fatigue, both during exercise and the resting state.

Effects of acupuncture on the 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats.

In the present study, the effects of acupuncture on the endurance treadmill exercise, serotonin (5-hydroxytryptamine, 5-HT) synthesis, and tryptophan hydroxylase (TPH) expression in the dorsal raphe nuclei were investigated. Acupunctural stimulation were bilaterally inserted into the locus of Zusanli in each hind leg for 20 min. Onset of exhaustion time on the treadmill running was increased significantly by acupunctural stimulation and exercise-induced increments of the 5-HT synthesis and TPH expression in the dorsal raphe were suppressed by acupunctural stimulation. Based on the results, it can be suggested that the suppressive effects of acupunctural stimulation on the 5-HT synthesis and TPH expression in the dorsal raphe during exercise is one of ergogenic mechanisms of acupuncture.

Protective effects of Wuyaoshunqisan against H2O2-induced apoptosis on hippocampal cell line HiB5.

Oxidative stress has been implicated in the pathogenesis of different neurodegenerative disorders. To investigate the protective effects of Wuyaoshunqisan against H2O2-induced apoptosis in the central nervous system, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) method, flow cytometric analysis, and the DNA fragmentation assay were performed on cells of the hippocampal cell line HiB5. Through the morphological and biochemical analyses, it was shown that HiB5 cells treated with H2O2 exhibit classical apoptotic features, while the occurrence of such changes is reduced in cells pre-treated with Wuyaoshunqisan prior to H2O2 exposure.