Continuous administration of mirabegron has advantages in inhibition of central sensitization compared with short-term treatment cessation in a mouse model of overactive bladder.

AIMS: There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. METHODS: Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, ß-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. RESULTS: OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, the CON group exhibited reduced ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, the CON group showed better improvements in nonvoiding contractions (0.16 ± 0.09 vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder ß3 receptors and CCL2 of L6-S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to the CES group. CONCLUSIONS: Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

TP53-dependence on the effect of doxorubicin and Src inhibitor combination therapy.

The anticancer effects of Src kinase inhibitors are controversial. This study found an association between alterations in the TP53 gene and the synergy score for combination treatment with doxorubicin and an Src kinase inhibitor using human osteosarcoma cell lines (MG63 and U2OS) and human colon cancer cell line. Doxorubicin was found to activate signal transducer and activator of transcription 3 via Src kinase in cancer cells harboring alterations in TP53. A drug combination study using patient-derived cells confirmed that an Src kinase inhibitor synergizes with doxorubicin in cancer cells harboring alterations in TP53, while antagonizing its effect in cancer cells expressing wild-type TP53. Our findings suggest that genetic alterations in TP53 are a critical factor in determining the use of a combination treatment of doxorubicin and Src inhibitors.

Biomechanical and clinical considerations in deep bite treatment using temporary skeletal anchorage devices.

Deep bite is usually treated by intrusion of the anterior teeth, extrusion of the posterior teeth, or a combination thereof. Various traditional methods have been used to correct deep bites, but they can cause negative side effects. Recently, temporary skeletal anchorage devices (TSADs) have been used to intrude the anterior teeth simply and efficiently without side effects. The amount of incisal exposure at rest should be considered as the first factor in determining which tooth segment should be intruded to correct a deep bite. The center of resistance of the anterior teeth should be considered to achieve the proper biomechanics when intruding them. The location of TSADs should be determined to ensure sufficient interradicular bone to achieve the desired tooth movement. Therefore, clinicians should understand the biomechanical and clinical considerations to correct a deep bite using TSADs.

Thread embedding acupuncture for herniated intervertebral disc of the lumbar spine: A multicenter, randomized, patient-assessor-blinded, controlled, parallel, clinical trial.

BACKGROUND: and purpose: Although several studies have reported that thread embedding acupuncture (TEA) is effective for lumbar herniated intervertebral disc (LHIVD), the evidence remains limited because previous studies had a high risk of bias. This study aimed to investigate the efficacy and safety of TEA for LHIVD through a rigorously designed trial. MATERIALS AND METHODS: This was a randomized, patient-assessor-blinded, sham-controlled trial. Participants were screened according to eligibility criteria, and 70 patients with LHIVD were randomly allocated to the TEA and sham TEA (STEA) groups in a 1:1 ratio. Both groups received TEA or STEA treatment at 23 acupoints once per week for eight weeks. Changes in low back pain, radiating pain, Oswestry disability index, Roland-Morris disability questionnaire, EuroQol 5-Dimensions 5-Levels, and global perceived effect were measured at baseline and at 4, 8, 12, and 16 weeks after screening and compared between the two groups. RESULTS: TEA showed no significant difference in all outcomes compared to STEA immediately after eight weeks of treatment. After an additional eight weeks of follow-up, TEA showed a more significant effect on the low back pain than STEA (p < 0.05) and showed a better tendency in maintaining or enhancing the improvement of radiating pain, function, and quality of life even after the end of treatment. No serious adverse events were observed. CONCLUSION: TEA is effective in improving low back pain in patients with LHIVD and may help improve function and quality of life, especially in the long term.

Korean Medicine Clinical Practice Guidelines for Lumbar Herniated Intervertebral Disc in Adults: Based on Grading of Recommendations Assessment, Development and Evaluation (GRADE).

A significant number of individuals suffer from low back pain throughout their lifetime, and the medical costs related to low back pain and disc herniation are gradually increasing in Korea. Korean medicine interventions have been used for the treatment of lumbar intervertebral disc herniation. Therefore, we aimed to update the existing Korean medicine clinical practice guidelines for lumbar intervertebral disc herniation. A review of the existing guidelines for clinical treatment and analysis of questionnaires targeting Korean medicine doctors were performed. Subsequently, key questions on the treatment method of Korean medicine used for disc herniation in actual clinical trials were derived, and drafts of recommendations were formed after literature searches using the Grading of Recommendations, Assessment, Development and Evaluation. An expert consensus was reached on the draft through the Delphi method and final recommendations were made through review by the development project team and the monitoring committee. Fifteen recommendations for seven interventions for lumbar disc herniation were derived, along with the grade of recommendation and the level of evidence. The existing Korean medicine clinical practice guidelines for lumbar intervertebral disc herniation have been updated. Continuous updates will be needed through additional research in the future.

Ophthalmomyiasis caused by a Phormia sp. (Diptera: Calliphoridae) larva in an enucleated patient.

Ophthalmomyiasis rarely occurs worldwide, and has not been reported in Korea. We present here a case of ophthalmomyiasis caused by Phormia sp. fly larva in an enucleated eye of a patient. In June 2010, a 50-year-old man was admitted to Dankook University Hospital for surgical excision of a malignant melanoma located in the right auricular area. He had a clinical history of enucleation of his right eye due to squamous cell carcinoma 5 years ago. During hospitalization, foreign body sensation developed in his right eye, and close examination revealed a fly larva inside the eye, which was evacuated. The larva was proved to be Phormia sp. based on the morphology of the posterior spiracle. Subsequently, no larva was found, and the postoperative course was uneventful without any complaints of further myiasis. This is the first case of ophthalmomyiasis among the literature in Korea, and also the first myiasis case caused by Phormia sp. in Korea.

A nasal myiasis in a 76-year-old female in Korea.

On July 2009, 5 fly larvae were discovered inside the nose of a 76-year-old female. She was living in Cheonan-si, and in a state of coma due to rupture of an aortic aneurysm. Surgery was performed on the day of admission, and the larvae were found 4 days later. By observing their posterior spiracle, the larvae were identified as Lucilia sericata. Considering the rapid development of this species, the infection was likely acquired during hospitalization. Further investigation on the hospital environment should be needed to know the origin of the infection.

Thread-embedding acupuncture for lumbar herniated intervertebral disc: Protocol for a systematic review and meta-analysis.

BACKGROUND: Lumbar herniated intervertebral disc (LHIVD) is a frequent disease among patients attending Korean medicine hospitals, and it is associated with considerable medical expenses for the patients. Although several recent randomized clinical trials (RCTs) have reported that thread-embedding acupuncture (TEA) has a more favorable therapeutic effect on LHIVD than other types of acupuncture or other treatments, the evidence remains limited because these trials used poor assessment methods and had a high risk of bias. This study aims to evaluate the evidence for the effectiveness and safety of TEA for LHIVD. In this article, we describe our methods and plan for a systematic review. METHODS: We will conduct an electronic search of the following databases from their inception to May 2018: MEDLINE; EMBASE; COCHRANE; China National Knowledge Infrastructure (CNKI) (a Chinese database); CiNii and J-STAGE (Japanese databases); and KoreaMed, Korean Medical Database (KMbase), Korean Studies Information Service System (KISS), National Digital Science Library (NDSL), Korea Institute of Science and Technology Information (KISTI), Oriental Medicine Advanced Searching Integrated System (OASIS). RCTs investigating any type of TEA will be included. The risk of bias in each study will be evaluated using the Cochrane risk of bias tool. Risk ratios or mean differences with 95% confidence intervals will be used to show the effects of TEA if it will be possible to conduct a meta-analysis. Sensitivity analyses will also be conducted in this study. ETHICS AND DISSEMINATION: Ethical approval is not necessary as this paper does not involve patient data. The review will be published in a peer-reviewed journal or presented in a conference. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019133060.

Clinical research on the efficacy and safety of thread-embedding acupuncture for treatment of herniated intervertebral disc of the lumbar spine: a protocol for a multicenter, randomized, patient-assessor blinded, controlled, parallel, clinical trial.

BACKGROUND: A lumbar herniated intervertebral disc (LHIVD) is a common problem that usually causes lower back pain and neurological symptoms that manifest as radiating pain. Several studies have reported that thread-embedding acupuncture (TEA) is effective in the treatment of LHIVD. However, these studies were of low quality and there is therefore little clinical evidence for the effectiveness of TEA in this regard. The aim of the present study is to establish the clinical evidence regarding the efficacy and safety of TEA in the treatment of pain, function, and quality of life in patients with LHIVD. The study uses a rigorously designed, full-scale, randomized clinical trial (RCT) protocol. METHOD/DESIGN: This is a multicenter, randomized, patient-assessor blinded, sham-controlled trial with two parallel arms. Seventy patients with LHIVD who have lower back pain more severe than 40 mm on the 100-mm visual analogue scale (VAS), and who are aged 19-70 years, will be recruited and randomly allocated to a TEA group and sham TEA (STEA) group. Both groups will receive treatment on 23 predefined acupoints once a week for eight weeks; needles with the thread removed will be used in the STEA group, while normal TEA will be employed in the TEA group. Changes in the 100-mm VAS for lower back pain after eight weeks will be assessed as the primary outcome. Furthermore, the 100-mm VAS for radiating pain, Oswestry Disability Index, Roland-Morris disability questionnaire, EuroQol 5 Dimensions 5 Levels, and global perceived effect will be measured and analyzed as secondary outcomes. All outcomes will be assessed at baseline and at 4, 8, 12, and 16 weeks after screening. DISCUSSION: The results of this trial will help to establish the clinical evidence regarding TEA in the treatment of patients with LHIVD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236753 . Registered on August 2, 2017. Clinical Research Information Service of the Republic of Korea, KCT0002439 . Registered on August 1, 2017.

A Novel Endoluminal Ultrasound Imaging Technique to Determine Urethral Luminal Cross-Sectional Area.

INTRODUCTION AND OBJECTIVES: Retrograde urethrogram (RUG) and voiding cystourethrogram (VCUG) are currently the gold standard imaging technique for diagnosis of urethral stricture and determination of stricture location. However, RUG and VCUG have multiple limitations. These techniques require exposure to ionizing radiation, the quality is operator and patient dependent, there is a moderate degree of invasiveness with urethral catheterization, can have artifacts because of patient positioning that underestimates stricture length. The development of novel imaging modalities without ionizing radiation to accurately evaluate the presence, location, length, and lumen cross-sectional area (CSA) of the urethral stricture would be of great value. The objective of this study was to develop a novel endoluminal ultrasound (ELUS) imaging technique that permits the accurate quantitation of urethral stricture. METHODS: Urethral strictures were created in rabbits (n = 5) by electrocautery and an ELUS technique was developed for subsequent luminal imaging. A 3.2F 40 MHz ultrasound (US) probe was introduced transurethrally and infused with US contrast agent. Images were recorded as the catheter was pulled back at a constant speed to acquire tomographic images. Lumen CSA over the entire urethral length was calculated using a custom methodology and validated in our laboratory. RESULTS: Urethral luminal CSA over the entire length of urethra before and after experimental stricture development was quantified including the length of stenosis. Intra- and interobserver variability (r = 0.99 for both) was excellent. CONCLUSIONS: Feasibility of ELUS as a quantitative technique to determine healthy urethral lumen and stricture CSA was demonstrated. The translational potential for a nonionizing imaging modality to better describe CSA, length, location, and uninvolved urethral CSA of the stricture is a significant improvement over current methodology.

Clinical research on the efficacy and safety of Bosinji for low back pain with radiculopathy caused by herniated intervertebral disc of the lumbar spine: A protocol for a multicenter, randomized, controlled equivalence trial.

BACKGROUND: A lumbar herniated intervertebral disc (LHIVD) is a common problem that usually causes low back pain and radiating pain. The effectiveness of Bosinji, one of the herbal medicines used for low back pain and radiating pain in patient with LHIVD, has been reported in several studies; however, little clinical evidence is available owing to the methodological limitations in previous studies. Hence, the present study aims to establish the clinical evidence regarding the efficacy and safety of Bosinji in improving pain, function, and quality of life in LHIVD patients. METHOD/DESIGN: This is a multicenter, open-label, randomized, controlled, and equivalence trial with 2 parallel arms. A total of 74 patients who have low back pain and radiating pain due to LHIVD will be recruited and randomly allocated to the experimental group and control group. The patients in the experimental group and control group will take 2.5 g of Bosinji granule (1.523 g of Bosinji extract) or Loxonin tablet (60 mg of loxoprofen) 3 times a day for 6 weeks. Additionally, both groups will receive the same acupuncture treatment once a week for 6 weeks as a concurrent treatment. Changes in the 100-mm visual analogue scale (VAS) for low back pain after 6 weeks from baseline will be assessed as the primary outcome. Furthermore, the 100-mm VAS for radiating pain, Oswestry disability index (ODI), Roland-Morris disability questionnaire (RMDQ), EuroQol 5 Dimensions 5 Levels (EQ-5D-5L), global perceived effect (GPE), and deficiency syndrome of kidney index (DSKI) will be used to evaluate secondary outcomes. Outcomes will be assessed at baseline and at 3, 6, and 10 weeks after screening. For the safety evaluation, laboratory examinations including complete blood count, liver function test, renal function test, blood coagulation test, inflammation test, and urine analysis will be conducted before and after taking the medications. DISCUSSION: The results of this trial will be used to establish clinical evidence regarding the use of Bosinji with acupuncture treatment in the treatment of patients with LHIVD. TRIAL REGISTRATION NUMBER: NCT03386149 (clinicaltrials.gov) and KCT0002848 (Clinical Research Information Service of the Republic of Korea).

A 12-Week, Open Label, Multi-Center Study to Evaluate the Clinical Efficacy and Safety of Silodosin on Voiding Dysfunction in Patients with Neurogenic Bladder.

OBJECTIVES: The purpose of this study is to evaluate clinical effect and safety of α1A -adrenoceptor blocker, silodosin, in patients with voiding dysfunction caused by neurogenic bladder. METHODS: From April 2011 to January 2012, patients who were diagnosed as potential voiding dysfunction associated with neurogenic bladder, aged ≥ 20 years were enrolled. Silodosin (8 mg/day) was administered once daily in the morning with food. The efficacy was assessed at the baseline and after 12 weeks of the treatment having following parameters of international prostate symptom score and other measures including the maximum flow rate and the postvoid residual urine volume. RESULTS: A total of 97 patients were screened and 95 were enrolled. Of these 95 patients, 82 patients were completed and included in analysis. After 12-weeks of treatment, mean total international prostate symptom score decreased significantly from 22.23 ± 6.80 to 14.98 ± 9.48 (P = 0.0002). Voiding symptoms and storage symptoms were also improved by decreasing in international prostate symptom score-QoL from 4.62 ± 0.92 to 3.48 ± 1.63 (P < 0.0001). Maximum flow rate increased significantly from 10.72 ± 2.66 to 15.14 ± 6.63 (P < 0.0001). The main adverse event was ejaculation disorder. No serious adverse events related to silodosin were noted. CONCLUSIONS: This study indicates that silodosin was significantly effective, well tolerated and safe in patients who have voiding dysfunction associated with neurogenic bladder.

Effects of atractylodis rhizoma pharmacopuncture on an acute gastric mucosal lesion induced by compound 48/80 in rats.

OBJECTIVES: This study was designed to investigate the protective effects of Atractylodis Rhizoma pharmacopuncture (ARP) against acute gastric mucosal lesions induced by compound 48/80 in rats. METHODS: The ARP was injected in Joksamni (ST36) and Jungwan (CV12) 1 hr before treatment with compound 48/80. The animals were sacrificed under anesthesia 3 hrs after treatment with compound 48/80. The stomachs were removed, and the amounts of gastric adherent mucus, gastric mucosal hexosamine, thiobarbituric acid reactive substances (TBARS), xanthine oxidase (XO), and superoxide dismutase (SOD) were measured. Also, histological examination were performed. RESULTS: Gastric adherent mucus, gastric mucosal hexosamine and histological defects of gastric mucosa declined significantly after ARP treatment. Changes in gastric mucosal TBARS were also reduced by ARP treatment, but this result was not statistically significant. ARP treatment did not change the XO and the SOD activities. CONCLUSIONS: ARP showed protective effects for acute gastric mucosal lesions induced by compound 48/80 in rats. These results suggest that ARP may have protective effects for gastritis.

Modulatory Effects of Chrysanyhemi Flos Pharmacopuncture on Nitric-oxide (NO) Production in Murin Macrophagy Cells.

OBJECTIVES: Much evidence exists that herbs have effective immunomodulatory activities. Chrysanthemi Flos (CF) is effective in clearing heat, reducing inflammation, dropping blood pressure and treating headache and is used as a pharmaceutical raw material for an immune enhancer. The purpose of this study was to investigate the modulatory effect of Chrysanthemi Flos pharmacopuncture on nitric-oxide (NO) production in activating macrophages. METHODS: After a murine macrophage cell line, RAW 264.7, was cultured in the presence of lipopolysaccharide (LPS), immune-modulating abilities of CF were evaluated by using NO, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) production and phagocytic activity of macrophages. RESULTS: CF enhanced the activities of macrophages by increasing the phagocytic activity and decreasing NO production. Especially, both LPS and CF, 200 ㎍/ml, treatment could significantly reduce the NO production, but did not change the production of IL-6 and TNF-α. CONCLUSION: The results of this study indicate that CF may be of immunomodulatory value, especially for adverse diseases due to increased NO production. It may have potential for use as immunoenhancing pharmacopuncture.

Effect of Curculigo orchioides on reflux esophagitis by suppressing proinflammatory cytokines.

This study was performed to investigate effects of Curculigo orchioides rhizome (curculiginis rhizome) on acute reflux esophigitis (RE) in rats that are induced by pylorus and forestomach ligation operation. Proinflammatory cytokine, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were all assayed and the expression of TNF-α and COX2 analyzed by RT-PCR. The esophagic tissue damage of reflux esophagitis rat was increased compared to that of normal intact group. However, the esophagic damage percentage from the extract of curculiginis rhizoma (ECR) 600 mg/kg and ECR 300 mg/kg were significantly lower than that of the RE control group. Administration of α-tocopherol (30 mg/kg) and ECR (600 mg/kg, 300 mg/kg, and 150 mg/kg) had a significant effect on the gastric acid pH in rats with induced reflux esophagitis (p < 0.05). The treatment with ECR significantly reduced the production of cytokines TNF-α, IL-1ß and IL-6 levels compared to the model group (p < 0.05). The expression of TNF-α and COX2 in the intact esophageal mucosa was low while those of the RE control group were significantly higher due to an inflammatory reaction in the esophagus. Compare to the model group, treatment with α-tocopherol or ECR significantly inhibited the expression levels of COX2 and TNF-α in a dose-dependent manner. These results suggest that anti-inflammatory and protective effects of ECR could attenuate the severity of reflux esophagitis and prevent esophageal mucosal damage.

Effect of Lonicerae Flos extracts on reflux esophagitis with antioxidant activity.

AIM: To observe the effects of traditional antiinflammatory medicine Lonicerae Flos (LF) on rat reflux esophagitis (RE) induced by pylorus and forestomach ligation compared with the well-known proton antioxidant, alpha-tocopherol. METHODS: Rats were pretreated with three different dosages of LF (500, 250 and 125 mg/kg) orally, once a day for 14 d before pylorus and forestomach ligation. Nine hours after pylorus and forestomach ligation, changes to the stomach and esophagus lesion areas, gastric volumes, acid and pepsin outputs, antioxidant effects, esophageal lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), myeloperoxidase and glutathione (GSH) levels, and collagen contents (marker of flexibility) were observed on the esophageal and fundic histopathology. The results were compared with an alpha-tocopherol (once orally, 1 h before operation, 30 mg/kg) treated group in which the effects on RE were already confirmed. RESULTS: Pylorus and forestomach ligations caused marked increases of gross esophageal and gastric mucosa lesion areas, which corresponded with histopathological changes. In addition, increases of esophageal lipid peroxidation, decreases of SOD, CAT, and GSH-free radical scavengers, increases of collagen were observed. However, these pylorus and forestomach ligation induced RE were dose-dependently inhibited by treatment of 500, 250 and 125 mg/kg of LF extract, mediated by antioxidant effects. RE at 250 mg/kg showed similar effects alpha-tocopherol. CONCLUSION: The results suggest that antioxidant effects of LF could attenuate the severity of RE and prevent the esophageal mucosal damage, and validate its therapeutic use in esophageal reflux disease.