Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey.

BACKGROUND: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs. METHODS: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception. RESULTS: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported. CONCLUSIONS: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Effects of Photobiomodulation on Root Resorption Induced by Orthodontic Tooth Movement and RANKL/OPG Expression in Rats.

The aim of this study was to evaluate the effects of photobiomodulation on the repair of induced root resorption (RR) after orthodontic tooth movement. Twenty male rats were used in this study. Forty right and left upper first molars were evaluated and divided into four groups (n = 10): negative control group (NC), no tooth movement or irradiation; positive control group (PC), induced tooth movement and root resorption; conventional treatment group (CT), force was removed after 7 days; and photobiomodulation group (PBM) after force removal molars were irradiated every 48 h for 7 days using GaAlAs diode laser (810 nm). Energy per point was 1.5 J (100 mW, 15 s, 75 J cm-2 ). NC and PC were euthanized on day 7; CT and PBM on day 14. Histomorphometric and immunohistochemsitry analyses showed increase in area of root resorption in all groups (P < 0.05) compared to NC. RR lacunae were larger in CT compared to PC and PBM at the compression side of the distal root. OPG was higher in PBM group (P < 0.05). PBM group showed low expression of RANKL compared to PC and CT on the tension side. PBM can potentially affect RR progression by increasing OPG expression in the compression area and decreasing number of clastic cells in the root surface.

Photobiomodulation increases intrusion tooth movement and modulates IL-6, IL-8 and IL-1ß expression during orthodontically bone remodeling.

This study investigated the effects of photobiomodulation (PBM) on upper molar intrusion movement, regarding acceleration of orthodontic movement and its molecular effects. The sample consisted of 30 patients with indication of tooth intrusion for oral rehabilitation. Teeth were divided into three different groups: G1 (n = 10) pre-molars without force or laser application (control); G2 (n = 10) upper molar intrusion; and G3 (n = 10) upper molar intrusion and PBM. On PBM treated molars, the teeth were irradiated with a low-power diode laser (808 nm, 100 mW), receiving 1 J per point, density of 25 J/cm2 , with application of 10 s per point, 10 points (5 per vestibular and 5 per palatal region). Orthodontic force of intrusion applied every 30 days and PBM was performed immediately, 3 and 7 days after force application for 3 months. Gingival crevicular fluid was collected at the same time periods as the laser applications and interleukins (IL) 1-ß, -6 and -8 were evaluated by enzyme-linked immunosorbent assay. Clinical measures were performed monthly to verify the amount of intrusion. The levels of IL-6, IL-8 and IL-1ß increased under orthodontic force (G2 and G3) when compared to control group (G1), however, the cytokines levels were significantly higher after PBM (G3). The mean intrusion velocity was 0.26 mm/month in the irradiated group (G3), average duration of 8 months vs 0.17 mm/month for the non-irradiated group (G2), average duration of 12 months. This study suggests that PBM accelerates tooth movement during molar intrusion, due to modulation of IL-6, IL-8 and IL-1ß during bone remodeling.

The preventive effect of Qing Dai on bisphosphonate-induced gastric cellular injuries.

The Chinese herbal medicine Qing Dai has been traditionally used for the treatment of various inflammatory diseases. We previously reported that reactive oxygen species play an important role in bisphosphonate-induced gastrointestinal injuries and that Qing Dai improved ulcerative colitis by scavenging reactive oxygen species. In this study, we investigated whether Qing Dai prevented bisphosphonate-induced gastric cellular injuries. Risedronate (a bisphosphonate) was added to rat gastric mucosal cells. Risedronate-induced cellular injury, cellular lipid peroxidation, mitochondrial membrane potential, and reactive oxygen species production in rat gastric mucosal cells were examined via viable cell counting, specific fluorescent indicators, and electron spin resonance. Pretreatment with Qing Dai attenuated the fluorescence intensity of diphenyl-1-pyrenylphosphine and MitoSox as well as the signal intensities of electron spin resonance. Cell viability improved from 20% to 80% by pretreatment with Qing Dai. Thus, Qing Dai prevented this injury by suppressing mitochondrial reactive oxygen species production, which is the main cause of cellular lipid peroxidation. Qing Dai also maintained mitochondrial potential, reducing reactive oxygen species production. We conclude that Qing Dai has protective effects on bisphosphonate-induced gastrointestinal injury and thus has the potential for clinical application.

Effects of corticopuncture (CP) and low-level laser therapy (LLLT) on the rate of tooth movement and root resorption in rats using micro-CT evaluation.

The aim of this study was to compare the rate of tooth displacement, quantity of root resorption, and alveolar bone changes in five groups: corticopuncture (CP), low-level laser therapy (LLLT), CP combined with LLLT (CP + LLLT), control (C), and negative control (NC). A total of 60 half-maxilla from 30 male Wistar rats (10 weeks old) were divided randomly into five groups: three (CP, LLLT, and CP + LLLT) test groups with different stimulation for accelerated-tooth-movement (ATM), one control (C) group, and one negative control (NC) group with no tooth movement. Nickel-titanium coil springs with 50 g of force were tied from the upper left and right first molars to micro-implants placed behind the maxillary incisors. For the CP and CP + LLLT groups, two perforations in the palate and one mesially to the molars were performed. For the LLLT and CP + LLLT groups, GaAlAs diode laser was applied every other day for 14 days (810 nm, 100 mW, 15 s). The tooth displacements were measured directly from the rat's mouth and indirectly from microcomputer (micro-CT) tomographic images. Bone responses at the tension and compression sites and root resorption were analyzed from micro-CT images. The resulting alveolar bone responses were evaluated by measuring bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular thickness (TbTh). Root resorption crater volumes were measured on both compression and tension sides of mesial and distal buccal roots. The tooth displacement in the CP + LLLT group was the greatest when measured clinically, followed by the CP, LLLT, and control groups (C and NC), respectively (p <0.05). The tooth movements measured from micro-CT images showed statistically higher displacement in the CP and CP + LLLT groups compared to the LLLT and control groups. The BMD, BV/TV, and TbTh values were lower at the compression side and higher at the tension side for all three test groups compared to the control group. The root resorption crater volume of the distal buccal root was higher in the control group, followed by CP, LLLT, and CP + LLLT, mostly at the compression site. Combining corticopuncture and low-level laser therapy (CP + LLLT) produced more tooth displacement and less root resorption at the compression side. The combined technique also promoted higher alveolar bone formation at the tension side.

Effects of Low-Level Laser Therapy in Orthodontic Patients on Immediate Inflammatory Response After Mini-Implants Insertion: A Preliminary Report.

BACKGROUND: The primary stability of a mini-implant is crucial to treatment sequence since most orthodontic mini-implant failures occur at an early stage. Irritation or inflammation of peri-implant tissues has been related to decreasing mini-implant success. PURPOSE: This study evaluates the effect of low-level laser therapy on initial inflammation after orthodontic mini-implants installation. METHODS: Ten volunteers received two mini-implants (1.3 mm diameter, 7 mm length). One mini-implant was inserted on each side of the maxilla following manufacturer recommendation. On the right side, low-level laser therapy (LLLT) was applied (diode laser 660 nm, 40 mW, 1 min, 2.4 J of total energy). Peri-implant crevicular fluid (PGF) was obtained after 24 h (T1), 48 h (T2), and 72 h (T3) to identify levels of interleukin (IL)-6 and IL-8 around mini-implants and around upper first premolars. RESULTS: An increase in interleukin levels was observed for both groups, compared to upper first premolar. PGF around nonirradiated mini-implants showed higher levels of IL-8. Levels of IL-6 24 h after mini-implant insertion were higher for laser group. CONCLUSIONS: LLLT modulates the initial inflammation after the insertion of mini-implant, possibly increasing the mini-implant success prognostic and decreasing patient discomfort.

Low-level laser therapy stimulates bone metabolism and inhibits root resorption during tooth movement in a rodent model.

This study evaluated the biological effects of low-level laser therapy (LLLT) on bone remodeling, tooth displacement and root resorption, occurred during the orthodontic tooth movement. Upper first molars of a total of sixty-eight male rats were subjected to orthodontic tooth movement and euthanized on days 3, 6, 9, 14 and 21 days and divided as negative control, control and LLLT group. Tooth displacement and histomorphometric analysis were performed in all animals; scanning electron microscopy analysis was done on days 3, 6 and 9, as well as the immunohistochemistry analysis of RANKL/OPG and TRAP markers. Volumetric changes in alveolar bone were analyzed using MicroCT images on days 14 and 21. LLLT influenced bone resorption by increasing the number of TRAP-positive osteoclasts and the RANKL expression at the compression side. This resulted in less alveolar bone and hyalinization areas on days 6, 9 and 14. LLLT also induced less bone volume and density, facilitating significant acceleration of tooth movement and potential reduction in root resorption besides stimulating bone formation at the tension side by enhancing OPG expression, increasing trabecular thickness and bone volume on day 21. Taken together, our results indicate that LLLT can stimulate bone remodeling reducing root resorption in a rat model. LLLT improves tooth movement via bone formation and bone resorption in a rat model.

Qing Dai attenuates nonsteroidal anti-inflammatory drug-induced mitochondrial reactive oxygen species in gastrointestinal epithelial cells.

Treatments with nonsteroidal anti-inflammatory drugs (NSAIDs) have increased the number of patients with gastrointestinal complications. Qing Dai has been traditionally used in Chinese herbal medicine for various inflammatory diseases such as ulcerative colitis. We previously reported that Qing Dai suppressed inflammations by scavenging reactive oxygen species (ROS) in ulcerative colitis patients. Thus, Qing Dai can attenuate the production of ROS, which play an important role in NSAID-induced gastrointestinal injuries. In this study, we aimed to elucidate whether Qing Dai decreased mitochondrial ROS production in NSAID-treated gastrointestinal cells by examining cellular injury, mitochondrial membrane potentials, and ROS production with specific fluorescent indicators. We also performed electron paramagnetic resonance measurement in isolated mitochondria with a spin-trapping reagent (CYPMPO or DMPO). Treatments with indomethacin and aspirin induced cellular injury and mitochondrial impairment in the gastrointestinal cells. Under these conditions, mitochondrial alterations were observed on electron microscopy. Qing Dai prevented these complications by suppressing ROS production in gastrointestinal cells. These results indicate that Qing Dai attenuated the ROS production from the NSAID-induced mitochondrial alteration in the gastrointestinal epithelial cells. Qing Dai treatment may be considered effective for the prevention NSAID-induced gastrointestinal injury.

Effects of low-intensity laser therapy over mini-implants success rate in pigs.

The success rate of miniscrews when used as temporary orthodontic anchorage is relatively high, but some factors could affect its clinical success such as inflammation around the miniscrew. Low-intensity laser therapy has been widely used for biostimulation of tissue and wound healing specially for its anti-inflammatory effects. The purpose of this study was to evaluate the effect of low-intensity laser therapy over the miniscrew success rate. Five Landrace's pigs received 50 miniscrews on the buccal side of the mandible and on the palate of the maxilla. All the miniscrews were immediately loaded with 250 gf. The laser group were irradiated with a 780-nm diode laser with 70 mWs for 1 min (dose = 34 J/cm(2)); the contralateral side was used as the control group. The miniscrews were photographed and analyzed clinically every week to determine their stability and presence of local inflammation. After 3 weeks, histological analysis and fluorescent microscopy were performed to compare the laser and the control side. Clinical results showed a success rate of 60% for the control group and 80% for the laser-treated group. The histological analysis and fluorescent microscopy demonstrated that the laser group had less inflammatory cells than the control group and the bone neoformation around the miniscrew was more intense. Low-intensity laser therapy increased the success rate of orthodontic miniscrews, probably due to anti-inflammatory effect and bone stimulation.

Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma.

AIM: To determine significant indicators for the efficacy of sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 46 patients with Barcelona Clinic Liver Cancer stage C who received sorafenib for more than 30 d at the Iizuka Hospital from June 2009 to December 2012 were enrolled in this study. Multivariate and univariate analyses were performed to evaluate the associations of hepatic function according to Child-Pugh grade, location and size of the largest tumor and adverse events of sorafenib treatment, such as hand-foot syndrome (HFS), hypertension, diarrhea, and alopecia, with the efficacy of treatment, as measured by overall survival (OS) and time to progression (TTP). RESULTS: Patients included 39 men and 7 women whose ages ranged from 48 to 85 years (70.6 ± 9.6 years). HCC was classified according to etiology as follows: hepatitis C virus (n = 26), hepatitis B virus (n = 9), and other (n = 11). Liver function in patients was categorized as Child-Pugh grade A (n = 30) or B (n = 16). Tumors were categorized by size [< 5 cm (n = 33) or >5 cm (n = 13)] and the location of the largest tumor was used to categorize patients with intrahepatic (n = 28) or extrahepatic (n = 18) HCC. HFS, hypertension, diarrhea, and alopecia were present in 22 (47.8%), 19 (41.3%), 15 (32.6%) and 7 patients (15.2%), respectively. The median OS of all patients was 373 d and the median TTP was 112 d. The etiology of HCC did not correlate with the median OS and TPP. The median OS of patients with tumors < 5 cm was significantly longer than those with larger tumors (496 vs 245 d; HR = 0.19, 95%CI: 0.07-0.48; P < 0.01). According to the results of a multivariate analysis, the size of the largest tumor affected OS (HR = 0.22, 95%CI: 0.08-0.59; P < 0.01). The median TTP was significantly longer in patients with extrahepatic compared to intrahepatic major HCC (224 vs 98 d; HR = 0.32; 95%CI: 0.14-0.67; P < 0.01). The median TTP of patients with HFS was significantly longer than those without it (195 d vs 83 d; HR = 0.41, 95%CI: 0.20-0.82; P < 0.05), and the median TTP was significantly longer in patients with hypertension (195 d vs 84 d; HR = 0.43, 95%CI: 0.21-0.84; P < 0.05). According to the results of the multivariate analysis, extrahepatic major HCC (HR = 0.36, P < 0.01) and HFS (HR = 0.44, P < 0.05) prolonged TTP. CONCLUSION: Extrahepatic major HCC and HFS are associated with prolonged TTP and are useful indicators for judging the efficacy of sorafenib treatment.

A case of cap polyposis remission by betamethasone enema after antibiotics therapy including Helicobacter pylori eradication.

We report the case of a 58-year-old woman who was referred to our hospital due to frequent bloody mucus diarrhea. She was diagnosed with cap polyposis based on typical endoscopic and histological findings. Colonoscopy revealed multiple, reddish, mucus-capped polypoid lesions from the rectum to the sigmoid colon. A pathological examination revealed that the polyps were covered by erosive and inflamed granulation tissue with decreased crypt cells. Laboratory data indicated positive values for Helicobacter pylori immunoglobulin G antibody and hypoproteinemia. Metronidazole, H. pylori eradication, and levofloxacin therapies were not effective; however, the subsequent administration of betamethasone enema dramatically improved the clinical symptoms and endoscopic findings. The hypoproteinemia was normalized after the therapy. The dose of the betamethasone enema was tapered gradually, and no recurrence was observed 6 months after discontinuation of the treatment. This case suggests that betamethasone enema may be considered as the second treatment choice for cap polyposis patients after H. pylori eradication, metronidazole or levofloxacin therapy.

Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may become intractable when treated with conventional medications such as aminosalicylates, corticosteroids, and azathioprine. The herbal medicine Qing Dai has traditionally been used in Chinese medicine to treat UC patients, but there is a lack of published data on the efficacy of Qing Dai in UC treatment. We report several cases of patients with intractable UC who take Qing Dai in a retrospective observational study. Furthermore, we explore the mechanisms of action of Qing Dai. Nine patients with active UC who received conventional medications but wished to receive Qing Dai as an alternative medication were included in our analysis. The UC severity level was determined based on the clinical activity index (CAI). Additionally, 5 of the 9 patients were endoscopically evaluated according to the Matts grading system. Each patient received 2 g/d of Qing Dai orally and continued taking other medications for UC as prescribed. Electron spin resonance was applied to explore the mechanisms of action of Qing Dai. After 4 mo of treatment with Qing Dai, the CAI score decreased from 8.3 ± 2.4 to 2.4 ± 3.4 (mean ± SD; P < 0.001). Similarly, the endoscopic Matts grade decreased from 3.4 ± 0.5 to 2.2 ± 0.8 (P = 0.02). Six of 7 patients who were on prednisolone upon enrollment in the study were able to discontinue this corticosteroid. Electron spin resonance revealed that Qing Dai possesses strong hydroxyl radical scavenging activity. Qing Dai showed significant clinical and endoscopic efficacy in patients who failed to respond to conventional medications. Scavenging of hydroxyl radicals appears to be a potential mechanism through which Qing Dai acts, but the significance of the scavenging ability of Qing Dai with respect to the anti-inflammatory effect in UC patients warrants further investigation.

[A pioneer in occupational therapy at mental hospitals in local cities (approaches at Shichiyama Hospital at the beginning of Taisho Era)].

Occupational therapy at mental hospitals in Japan began in 1901, when Shuzo Kure created two sewing rooms in the female section of Sugamo Hospital and allowed patients to sew pillowcases and hospital gowns for use at the hospital. In 1904, Sugamo Hospital added a work section, and occupational therapy became an official part of the hospital. In addition, Kure stated in The Complete Book of Japanese Internal Medicine (Nihon Naika Zensho), published in 1916, that occupational therapy had also become popular at other mental hospitals; however, he did not refer to specifics, such as information on what kind of occupational therapy was being carried out at which hospital. Shichiyama Hospital is a private facility located in Kumatori-cho, Sennan-gun, Osaka. In 1599, some 200 years before Philippe Pinel released lunatics from their chains, Sanai Honda established Soshindo at Jokenji Temple for the treatment of mental disorders using Chinese herbal remedies. Treatment using these remedies was practiced until the 1950's. Evidence suggests that Chinese herbal remedies were being used in combination with occupational therapy, such as farm work and raising poultry, from the end of the Meiji Era. Plans of the hospital in 1913 included descriptions of a farm, and entertainment and recreational areas for patients, confirming this evidence. It also supported Kure's statement about occupational therapy having become popular at mental hospitals at the beginning of the Taisho Era. In Summary, occupational therapy was practiced at mental hospitals in local cities at the beginning of the Taisho Era, and such occupational therapy in this period was significantly influenced by Shuzo Kure; therefore, I pay my respects to this great pioneer of psychiatric medicine.

Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori-infected mice and humans.

The isothiocyanate sulforaphane [SF; 1-isothiocyanato-4(R)-methylsulfinylbutane] is abundant in broccoli sprouts in the form of its glucosinolate precursor (glucoraphanin). SF is powerfully bactericidal against Helicobacter pylori infections, which are strongly associated with the worldwide pandemic of gastric cancer. Oral treatment with SF-rich broccoli sprouts of C57BL/6 female mice infected with H. pylori Sydney strain 1 and maintained on a high-salt (7.5% NaCl) diet reduced gastric bacterial colonization, attenuated mucosal expression of tumor necrosis factor-alpha and interleukin-1beta, mitigated corpus inflammation, and prevented expression of high salt-induced gastric corpus atrophy. This therapeutic effect was not observed in mice in which the nrf2 gene was deleted, strongly implicating the important role of Nrf2-dependent antioxidant and anti-inflammatory proteins in SF-dependent protection. Forty-eight H. pylori-infected patients were randomly assigned to feeding of broccoli sprouts (70 g/d; containing 420 micromol of SF precursor) for 8 weeks or to consumption of an equal weight of alfalfa sprouts (not containing SF) as placebo. Intervention with broccoli sprouts, but not with placebo, decreased the levels of urease measured by the urea breath test and H. pylori stool antigen (both biomarkers of H. pylori colonization) and serum pepsinogens I and II (biomarkers of gastric inflammation). Values recovered to their original levels 2 months after treatment was discontinued. Daily intake of sulforaphane-rich broccoli sprouts for 2 months reduces H. pylori colonization in mice and improves the sequelae of infection in infected mice and in humans. This treatment seems to enhance chemoprotection of the gastric mucosa against H. pylori-induced oxidative stress.

[Combined block of femoral, sciatic, obturator nerves and lateral cutaneous nerve block with ropivacaine for leg amputation above the knee].

A 76-yr-old male presented for leg amputation above the knee. The patient complained of dyspnea due to pulmonary embolism occurring 3 weeks before operation. In addition, the patient could not report paresthesias because he had suffered from a cerebral infarction. Anesthesia was performed with combined block of femoral, sciatic, obturator nerves and the lateral cutaneous nerve of the thigh. The nerves were anesthetized with 0.75% ropivacaine solution 31 ml by use of an electrical nerve stimulator and an insulated needle. Nerve stimulation technique is the best choice for patients who are unable to report paresthesias reliably.