Objective: Extract from cultured Lentinula edodes mycelia (L.E.M.) is a food ingredient possessing various pharmacologic actions such as immunomodulatory properties, antitumor and hepatoprotective effects. In Japan, it has been used as a health food for 30 years or more.
In the present study to evaluate the safety of L.E.M., a genotoxicity study and acute toxicity study were conducted. In addition, the inhibitory effect of drug-metabolizing enzyme by L.E.M. was tested in vitro, to gain insight on the interaction with medicines.
Methods: The genotoxicity study was performed using a bacterial reverse mutation assay and a in vivo mammalian bone marrow cell chromosomal mutation assay. The acute toxicity study was performed using a single-dose oral toxicity test in rats. Inhibitory activity of cytochrome P-450 3A4 (CYP3A4), one of the most important drug-metabolizing enzymes, by L.E.M. was tested using a baculovirus-expressed system.
Results: In the genotoxicity study, mutagenicity was negative for both bacterial reverse mutation assay and in vivo mammalian bone marrow cell chromosomal mutation assay. In the acute toxicity study, no toxic symptoms were observed by single dose oral administration of L.E.M. at a dose of 10,000 mg/kg BW in rats. This implies LD₅₀>10,000 mg/kg BW. No inhibitory activity of CYP3A4 by L.E.M. was observed at in the in vitro screening system to investigate drug-L.E.M. interaction.
Conclusion: It is believed L.E.M. is a safety ingredient for foods used in complementary and alternative medicine, since it was toxicologically safe and showed no inhibitory activity of CYP3A4 in the studies conducted.

To identify the most frequently reported preferred terms （PTs） in the cases of rheumatoid arthritis （RA） patients treated with immunosuppressive biological drugs as suspected drugs, we analyzed the cases in the Japanese Adverse Drug Event Report （JADER） database. We found that pneumonia, interstitial lung disease, Pneumocystis jiroveci pneumonia （PCP), cellulitis, sepsis, and herpes zoster were the most frequently reported PTs. We obtained the reporting odds ratio （ROR） and the time to onset of these six PTs and compared them in the cases reported for each immunosuppressant as a suspected drug. We focused on RA treatment, including five tumor necrosis factor （TNF） antagonists （infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol). For pneumonia, interstitial lung disease and sepsis, no specific correlation was observed for each immunosuppressant for RA. In the case of PCP, the highest ROR was observed in the patients treated with infliximab. The time to onset of PCP in the infliximab-treated patients （median, 0.19 yr） was significantly shorter than the onset time in the patients treated with tocilizumab, an interleukin-6 receptor blocker that is another type of drug for RA（0.32 yr, p<0.01, Mann-Whitney test). The onset time in the patients treated with golimumab （0.24 yr） was also significantly shorter than the onset time for tocilizumab（p<0.05), but the ROR was not as high. These results suggested a correlation between PCP and infliximab. In the cases of cellulitis and herpes zoster, a similar correlation was observed with tocilizumab and certolizumab pegol, respectively. We should consider these results when patients have a respiratory disorder or skin/subcutaneous tissue disorder.

Background/Aims: Unsedated transnasal esophagogastroduodenoscopy (EGD) is affected by a poor scope lens-cleaning function. We have previously reported good, albeit limited, effects of an oolong tea washing solution; here, we evaluated the effectiveness of a 5% lens cleaning solution for cleaning an EGD lens. Methods: Five percent lens cleaning solution (C), 5% dimethicone solution (D), and distilled water (W) were prepared. Study I: Lenses were soiled with pork grease, washed with each washing solution, and their image quality was judged. Study II: Patients (n=996) scheduled for transnasal EGD were randomly assigned to the C- or W-group. Lens cleanliness level, washing solution volume used, and endoscopist stress due to lens contamination were determined. Results: Study I: The image quality of the lenses washed with (C) was significantly superior. (D) was clinically unsuitable because of spray nozzle clogging. Study II: Lens cleaning in the C-group was significantly superior (p<0.0001) and the solution volume required was significantly reduced (p<0.0001), while endoscopist stress was also lower (p<0.0001). Conclusions For transnasal small-caliber EGD, the present 5% lens cleaning solution provided good visibility. It features a high detergency level and is simple to formulate for therapeutic endoscopy applications, such as endoscopic submucosal dissection.

Background/Aims: Unsedated transnasal esophagogastroduodenoscopy (EGD) is affected by a poor scope lens-cleaning function. We have previously reported good, albeit limited, effects of an oolong tea washing solution; here, we evaluated the effectiveness of a 5% lens cleaning solution for cleaning an EGD lens. Methods: Five percent lens cleaning solution (C), 5% dimethicone solution (D), and distilled water (W) were prepared. Study I: Lenses were soiled with pork grease, washed with each washing solution, and their image quality was judged. Study II: Patients (n=996) scheduled for transnasal EGD were randomly assigned to the C- or W-group. Lens cleanliness level, washing solution volume used, and endoscopist stress due to lens contamination were determined. Results: Study I: The image quality of the lenses washed with (C) was significantly superior. (D) was clinically unsuitable because of spray nozzle clogging. Study II: Lens cleaning in the C-group was significantly superior (p<0.0001) and the solution volume required was significantly reduced (p<0.0001), while endoscopist stress was also lower (p<0.0001). Conclusions For transnasal small-caliber EGD, the present 5% lens cleaning solution provided good visibility. It features a high detergency level and is simple to formulate for therapeutic endoscopy applications, such as endoscopic submucosal dissection.

Objective: In Japan, pharmaceutical manufacturers have been required to develop a Risk Management Plan (RMP) since April 2013. Publication of the RMP is expected to enable the wide content-sharing of post-marketing risk management and its utilization among medical professionals to further enhance and strengthen post-marketing safety measures. In this study, we examined what points should be focused on for continuous utilization of RMPs after drug approvals by investigating the numbers of safety concerns addition of antineoplastic and immunomodulating agents, and where safety concerns added after approval are listed in package inserts. Furthermore, we investigated the reasons why these safety concerns were considered as such. Methods: Antineoplastics and immunomodulating agents, which account for more than half of all drugs containing new active ingredients approved in recent years, among drugs containing new active ingredients approved from fiscal year (FY) 2013 to FY 2019 were included in the study. The safety concerns (excluding important missing information) in RMPs as of April 1, 2021 for the subject drugs were compared with those at the time of approval. Safety concerns added after approval were investigated where they were listed in package inserts as of April 1, 2021. Furthermore, risks that were added as important potential risks were investigated as to why they were considered as such. Results: There were 117 risks added after approval. Those added to the important identified risks were listed in one of the sections of the package insert, whereas 11 risks were added to the important potential risks that could not be confirmed in the package inserts. Some important potential risks added after approval are suspected to have a causal relationship with the drug, but were not listed in the package inserts. Conclusion: It is important to utilize RMPs continuously to further understand risks of taking the drug.

STUDY DESIGN: Large cohort study. PURPOSE: To clarify spinal sagittal alignment and health-related quality of life (HRQOL) according to sex in volunteers aged >50 years with cervical deformity (CD). OVERVIEW OF LITERATURE: Adult spinal deformities, especially those associated with lumbosacral lesions, are more frequent in females; however, CD is observed to a greater extent in males. METHODS: We divided 656 volunteers (263 males, 393 females; age, 50–89 years [mean, 73 years]) as follows: males with CD (CDM; 82 patients); males without CD (NCDM, 181); females with CD (CDF, 36); and females without CD (NCDF, 357). CD was defined as C2–7 sagittal vertical axis (SVA) ≥40 mm. We measured pelvic tilt (PT), pelvic incidence minus lumbar lordosis (PI−LL), thoracic kyphosis, T1 slope, cervical lordosis, C7 SVA, and C2–7 SVA. HRQOL was evaluated using EuroQOL five dimensions questionnaire (EQ-5D). RESULTS: In CDM, NCDM, CDF, and NCDF groups, the respective parameters were as follows: PT: 15°, 14°, 26°, and 21°; PI−LL: 7°, 5°, 16°, and 10°; C2–7 SVA: 49, 24, 46, and 20 mm; C7 SVA: 61, 40, 75, and 47 mm; and EQ-5D: 0.82, 0.88, 0.78, and 0.81. PT and PI−LL were significantly greater in the CDF group than in the NCDF group (p < 0.05) but were not significantly different between CDM and NCDM groups. The CDF group already showed deterioration of spinopelvic alignment, although it was maintained in the CDM group. EQ-5D in showed significantly greater deterioration the CDM group than in the NCDM group; deterioration of lumbopelvic parameters had less influence in males (p < 0.05). CONCLUSIONS: Sagittal spinal deformity may have different mechanisms in males and females. The deterioration of spinal sagittal alignment in males may originate from the cervical spine, and CD may be associated with HRQOL.
Adult ; Animals ; Cohort Studies ; Congenital Abnormalities* ; Female* ; Humans ; Incidence ; Kyphosis ; Lordosis ; Male* ; Quality of Life* ; Sex Characteristics ; Spine ; Volunteers

STUDY DESIGN: Cross-sectional cohort study.PURPOSE: This study aimed to investigate the relationship between hypertension and spino-pelvic sagittal alignment in middle-aged and elderly individuals.OVERVIEW OF LITERATURE: Positive global sagittal alignment is associated with poor health-related quality of life. Hypertension is associated with tissue microcirculation disorders of the skeletal muscle. We hypothesized that hypertension may be involved in positive global sagittal alignment.METHODS: In this institutional review board-approved study, 655 participants (262 men and 393 women; mean age, 72.9 years; range, 50–92 years) who underwent musculoskeletal screening in Toei town, Aichi, Japan were included. Whole spine and pelvic radiographs were taken, and radiographic parameters (thoracic kyphosis, lumbar lordosis, pelvic tilt, sacral slope, pelvic incidence, and sagittal vertical axis [SVA]) were measured using an image-analysis software. Hypertension was assessed using the standard criteria. The study participants were divided into three subgroups as per age (50–64 years, 65–74 years, and ≥75 years). We examined the differences in the radiographic parameters of those with and without hypertension in each age subgroup.RESULTS: In each age subgroup, there was no significant difference in the age and sex of those with and without hypertension. SVA was significantly shifted forward in the hypertension group than in the non-hypertension group in those aged 50–64 years old (32.4 mm vs. 16.0 mm, p=0.018) and in those aged 65–74 years old (42.7 mm vs. 30.6 mm, p=0.012). There was no significant difference between the hypertension and non-hypertension groups in terms of the alignment of the lumbar and thoracic spine in all the subgroups. In multivariate analysis, hypertension was a significant independent factor of forward-shifted SVA (standardized beta 0.093, p=0.015).CONCLUSIONS: This study showed that hypertension was associated with forward-shifted global sagittal alignment.
Aged ; Animals ; Cohort Studies ; Female ; Humans ; Hypertension ; Incidence ; Japan ; Kyphosis ; Lordosis ; Male ; Mass Screening ; Microcirculation ; Multivariate Analysis ; Muscle, Skeletal ; Quality of Life ; Spine

STUDY DESIGN: A retrospective study. PURPOSE: To investigate the incidence of iliac screw loosening with a two-rod vs. multi-rod construct and the effect on clinical and radiographic outcomes after surgery for adult spinal deformity (ASD). OVERVIEW OF LITERATURE: Multi-rod construct is useful for preventing rod fracture in ASD surgery. However, limited information is available regarding the incidence of iliac screw loosening after corrective fusion surgery using a multi-rod construct. METHODS: Total 106 patients with ASD (24 men and 82 women; mean age, 68 years) who underwent corrective fusion surgery using bilateral iliac screws and were followed up for at least 1 year were reviewed. The following variables were compared between patients who underwent surgery with a two-rod and multi-rod construct: age, sex, bone mineral density (BMD), fusion level, high-grade osteotomy, L5/S interbody fusion, screw loosening (upper instrumented vertebra [UIV], S1, and iliac), rod fracture, proximal junctional kyphosis, spinopelvic parameters, and Oswestry Disability Index (ODI) score. We also compared patients with and without iliac screw loosening in the multi-rod construct group. RESULTS: Of the 106 patients, 55 underwent surgery with a conventional two-rod construct and 51 with a multi-rod construct (three rods in 16, four rods in 35). Iliac and UIV screw loosening was observed in 24 patients (21%) and 35 patients (33%), respectively. The multi-rod group showed significantly higher incidence of iliac and UIV screw loosening and lower incidence of rod fracture. Patients with iliac screw loosening had a lower BMD than those without screw loosening; however, no significant differences were observed in the spinopelvic parameters or the ODI score. CONCLUSIONS: The use of multi-rod constructs led to a higher incidence of junctional screw loosening than the use of conventional two-rod constructs, especially in patients with osteoporosis. Iliac screw loosening did not affect sagittal alignment or clinical outcome in the short term.
Adult ; Bone Density ; Congenital Abnormalities ; Female ; Humans ; Incidence ; Kyphosis ; Male ; Osteoporosis ; Osteotomy ; Retrospective Studies ; Spine

Objective: To evaluate the potential of local mosquitoes to act as vectors for dengue transmission in Japan.
Methods: Serotype 2 ThNH28/93 was used to test the dengue susceptibility profiles of Aedes flavopictus miyarai (Ae. f. miyarai), Aedes galloisi (Ae. galloisi) and Aedes albopictus (Ae. albopictus), which were collected in Japan. We used Aedes aegypti from Thailand as a positive control. The mosquitoes were infected with the virus intrathoracically or orally. At 10 or 14 days post infection, the mosquitoes were dissected and total RNA was extracted from their abdomens, thoraxes, heads and legs. Mosquito susceptibility to dengue virus was evaluated using RT-PCR with dengue virus-specific primers. Differences in the infection and mortality rates of the different mosquito species were tested using Fisher's exact probability test.
Results: The infection rates for dengue virus administered intrathoracically to Ae. f. miyarai, Ae. galloisi and Aedes aegypti mosquitoes were identical by RT-PCR on Day 10 post infection. All of the body parts we tested were RT-PCR-positive for dengue virus. For the orally admin-istered virus, the infection rates in the different body parts of the Ae. f. miyarai mosquitoes were slightly higher than those of Ae. albopictus mosquitoes, but were similar to the control mosquitoes (P>0.05). The mortality rates for Ae. f. miyarai and Ae. albopictus mosquitoes were similar (P=0.19). Our data indicated that dengue virus was able to replicate and disseminate to secondary infection sites in all of the four mosquito species (Japanese and Thai).
Conclusions: Ae. albopictus is a well-known candidate for dengue transmission in Japan. However, our data suggest that Ae. f. miyarai from Ishigaki Island (near Okinawa Island) and Ae. galloisi from Hokkaido (Northern Japan) should also be regarded as potential vectors for dengue transmission in these regions. Further studies on these mosquitoes should be conducted.