Cross-cultural adaption, validity, and reliability of the Japanese version of the Central Aspects of Pain in the Knee (CAP-Knee-J) questionnaire in patients with knee pain: a validation study.

BACKGROUND: Knee pain is a prominent concern among older individuals, influenced by the central nervous system. This study aimed to translate the Central Aspects of Pain in the Knee (CAP-Knee) questionnaire into Japanese and investigate its reliability and validity in older Japanese individuals with knee pain. METHODS: Using a forward-backward method, CAP-Knee was translated into Japanese, and data from 110 patients at an orthopedic clinic were analyzed. The Japanese version (CAP-Knee-J) was evaluated regarding pain intensity during walking, central sensitization inventory, and pain catastrophizing scale. Statistical analyses confirmed internal validity and test-retest reliability. Concurrent validity was assessed through a single correlation analysis between CAP-Knee-J and the aforementioned measures. Exploratory factor analysis was employed on each CAP-Knee-J item to examine structural validity. RESULTS: CAP-Knee-J showed good internal consistency (Cronbach's α = 0.86) and excellent test-retest reliability (intraclass correlation coefficient = 0.77). It correlated significantly with pain intensity while walking, central sensitization inventory scores, and pain catastrophizing scale scores. Exploratory factor analysis produced a three-factor model. CONCLUSIONS: CAP-Knee-J is a reliable and valid questionnaire for assessing central pain mechanisms specific to knee pain in older Japanese individuals, with moderate correlations with the CSI and weak with the PCS, thus indicating construct validity. This study supports the development of effective knee pain treatments and prognosis predictions.

Comparison of time courses in postoperative functional outcomes between simultaneous bilateral and unilateral total knee arthroplasty with propensity score matching.

INTRODUCTION/OBJECTIVES: No consensus has been reached on which is better in terms of functional outcomes between simultaneous bilateral and unilateral total knee arthroplasty (TKA). As patient characteristics, such as age, sex, and body mass index, have significant effects on functional outcomes after TKA, these factors should be matched before comparisons are made. This study aimed to compare time courses in functional outcomes between simultaneous bilateral TKA and unilateral TKA after matching the patient characteristics. MATERIALS AND METHODS: In this retrospective study, the clinical records of patients admitted to a hospital were reviewed. Of 425 patients, 43 underwent simultaneous bilateral TKA, whereas 382 underwent unilateral TKA. Propensity score matching was performed for age, sex, and body mass index between simultaneous bilateral and unilateral TKA patients. Therapists measured pain intensity, knee extensor strength, and knee-specific functional outcomes by using the new knee society score, including total score, symptoms, patient satisfaction, patient expectations, and functional activities preoperatively and 3 and 12 months postoperatively. Two-way repeated analysis of variance was performed to compare the time courses in functional outcomes between simultaneous bilateral and unilateral TKA. RESULTS: After propensity score matching, 40 patients each for underwent bilateral TKA and unilateral TKA were selected. Knee extensor strength in simultaneous bilateral TKA patients was significantly lower than that in unilateral TKA patients at 3 months postoperatively (p = 0.04). A significant interaction was observed between the effects of time and group on knee extensor strength (F [1, 78] = 3.338; interaction: p = 0.042; η2 = 0.052). No significant interactions were found among the other variables measured. CONCLUSIONS: Patients who underwent simultaneous bilateral TKA should undergo postoperative rehabilitation focused on alleviating delayed recovery in knee extensor strength during the acute phase.

Association between knee function and kinesiophobia 6 months after anterior cruciate ligament reconstruction.

[Purpose] Kinesiophobia after anterior cruciate ligament reconstruction has been identified as an inhibitor of return to sports. This study aimed to clarify the relationship between kinesiophobia and knee function 6 months after anterior cruciate ligament reconstruction when the patient intends to return to sports. [Participants and Methods] A total of 66 patients who underwent primary anterior cruciate ligament reconstruction (mean age 17.3 ± 2.6 years, 17 males and 49 females, Tegner activity score ≥7) were included in the study. The 11-item version of Tampa scale of kinesiophobia was used to evaluate kinesiophobia 6 months postoperatively. Knee function was evaluated with knee extension muscle strength, tibial anterior displacement, heel buttock distance, heel height difference, anterior knee pain score, and single-leg hop test. The relationship between Tampa scale of kinesiophobia, patient characteristics, and knee function was investigated. [Results] A low Anterior knee pain score and low single-leg hop test, male gender, and age were significant factors associated with kinesiophobia. [Conclusion] Kinesiophobia was associated with a low anterior knee pain score and low single-leg hop test 6 months after anterior cruciate ligament reconstruction. Patients with a low single-leg hop test score or severe pain may need rehabilitation to reduce kinesiophobia.

Comparison of Acute-Phase Pain Intensity, Pain Trajectory, and the Number of Analgesics Administered between Total and Unicompartmental Knee Arthroplasties.

We aimed to compare the variables of pain intensity, pain trajectory, and the number of analgesics administered during the acute phase between total and unicompartmental knee arthroplasties. This prospective cohort study recruited 445 patients who planned to undergo knee arthroplasty. Pain intensity was evaluated during hospitalization, and 1 month postoperatively using a numerical rating scale. Pain trajectory (slope and intercept) was calculated using pain intensity data from postoperative days 1 to 4. The number of analgesics administered for worsening pain was monitored during hospitalization. Multiple linear regression analysis with adjustment for potential confounders was conducted to investigate the impact of surgery type on pain variables. Data for 208 and 189 patients who had undergone total and unicompartmental knee arthroplasties, respectively, were included in this study. Pain intensity and pain trajectory were similar between the two surgeries. The number of analgesics administered on postoperative day 3 (p = 0.01) and day 4 (p = 0.03), as well as total number (p = 0.01), were lower for unicompartmental knee arthroplasty than for total knee arthroplasty. Multiple linear regression analysis showed that the type of surgery affected the total number of analgesics administered (ß = - 1.24, p < 0.01, 95% confidence interval: -1.80 to -0.62). This study suggests that pain characteristics observed during the acute phase differ between total and unicompartmental knee arthroplasties. Postoperative pain should be managed, and rehabilitation should be provided at similar levels after the second postoperative day in total and unicompartmental knee arthroplasty patients.

Frequency of working at home, body mass index, and productivity in Japanese office workers: A cohort study.

BACKGROUND: Since the start of the COVID-19 pandemic, the number of people working at home has grown significantly. OBJECTIVE: This cohort study aimed to investigate whether the frequency of working at home was associated with changes in body mass index (BMI) and productivity from 2018 to 2020. METHOD: Frequency of working at home was self-reported. Participants were classified into three groups based on mean frequency of working at home per week (no working at home: ≦ 0.5 days, low frequency: 0.5 to 2.5 days, and high frequency: >2.5 days). Productivity was measured using a numerical rating scale, and BMI was calculated using height and weight. Changes in BMI and productivity were calculated by subtracting 2018 data from 2020 data. Linear regression analysis was performed by considering BMI and productivity change as outcomes and frequency of working at home as explanatory variable. RESULTS: BMI change in the high frequency group was significantly smaller than in the group that did not work at home (crude; coefficient: -0.27; 95% CI: -0.55--0.01, adjusted; coefficient: -0.30; 95% CI: -0.60--0.01). Frequency of working at home was not associated with productivity change. CONCLUSION: Working at home may be a solution for preventing BMI from increasing significantly.

Value of the 3-min walk test and its association with motor functions in older adults.

BACKGROUND: The 3-min walk test (3MWT) has been used in the clinical setting. OBJECTIVE: To present the 3MWT value and investigate its association with motor and respiratory functions of healthy older adults. METHODS: Two hundred six older adults and 27 younger adults were enrolled. The 3MWT was assessed by the walking distance within 3 min. Knee extension muscle strength (KEMS), 5-repetition sit-to-stand (5 R-STS), Timed Up and Go (TUG), forced vital capacity (FVC), forced expiratory volume 1.0 (FEV1.0), maximal expiratory pressure (MEP), and maximal inspiratory pressure (MIP) were measured. The 3MWT distance was examined by age group (18-39, 60-69, 70-79, and 80-89 years). A multivariate regression analysis investigated the association between 3MWT and motor function test. RESULTS: The 3MWT values in each age group were 273-385, 233-414, 93-351, and 171-345 m for men and 215-375, 220-349, 198-325, and 174-332 m for women respectively. The 3MWT values were correlated with age, body mass index (BMI), KEMS, 5 R-STS, TUG, FVC, FEV1.0, MEP, and MIP. On the multivariate regression analysis, 3MWT was significantly associated with BMI (standard beta = -0.18; 95% confidence interval [CI], -3.20 to 0.83), KEMS (standard beta = 0.37; 95% CI, 0.06-0.13), 5 R-STS (standard beta = -0.13; 95% CI, -5.70 to -0.13), and TUG (standard beta = -0.36; 95% CI, -17.15 to -7.73) in older adults (adjusted R2 = 0.47). CONCLUSIONS: The 3MWT distance decreased with age and was associated with motor and respiratory functions. No range trends were observed among groups. Our findings suggest that 3MWT reflects functional capacity.

Summary of 17 chemicals evaluated by OECD TG229 using Japanese Medaka, Oryzias latipes in EXTEND 2016.

In June 2016, the Ministry of the Environment of Japan announced a program "EXTEND2016" on the implementation of testing and assessment for endocrine active chemicals, consisting of a two-tiered strategy. The aim of the Tier 1 screening and the Tier 2 testing is to identify the impacts on the endocrine system and to characterize the adverse effects to aquatic animals by endocrine disrupting chemicals detected in the aquatic environment in Japan. For the consistent assessment of the effects on reproduction associated with estrogenic, anti-estrogenic, androgenic, and/or anti-androgenic activities of chemicals throughout Tier 1 screening to Tier 2 testing, a unified test species, Japanese medaka (Oryzias latipes), has been used. For Tier 1 screening, the in vivo Fish Short-Term Reproduction Assay (OECD test guideline No. 229) was conducted for 17 chemicals that were nominated based on the results of environmental monitoring, existing knowledge obtained from a literature survey, and positive results in reporter gene assays using the estrogen receptor of Japanese medaka. In the 17 assays using Japanese medaka, adverse effects on reproduction (i.e., reduction in fecundity and/or fertility) were suggested for 10 chemicals, and a significant increase of hepatic vitellogenin in males, indicating estrogenic (estrogen receptor agonistic) potency, was found for eight chemicals at the concentrations in which no overt toxicity was observed. Based on these results, and the frequency and the concentrations detected in the Japanese environment, estrone, 4-nonylphenol (branched isomers), 4-tert-octylphenol, triphenyl phosphate, and bisphenol A were considered as high priority candidate substances for the Tier 2 testing.

Effectiveness of workplace active rest programme on low back pain in office workers: a stepped-wedge cluster randomised controlled trial.

OBJECTIVE: This study aimed to investigate the effectiveness of workplace active rest programme (WARP) on chronic low back pain (LBP) among office workers. DESIGN: A closed cohort, stepped-wedge cluster randomised trial was conducted. The total duration of the study was 16 weeks (4 weeks for each step). Sequence allocation was randomised, but no one was blinded. SETTING: This study was conducted in three offices in a Japanese electronics company. One office was for the administrative department, the others are for the engineering department. PARTICIPANTS: We recruited 29 office workers with LBP greater than 3 months. LBP due to specific injury or disease was excluded. The median age was 38 years, and 26 (90%) were male. All participants completed the study. INTERVENTIONS: In the intervention phase, participants performed WARP comprising frequent stand-up and individualised brief exercise/physical activity during work. Physical therapists held an LBP workshop and developed tailor-made programmes before introducing WARP. We instructed participants to perform WARP at five timings during work. Control phase was set before the intervention and participants stayed as usual. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was pain intensity of LBP assessed using the Brief Pain Inventory. The secondary outcomes were work productivity loss measured using the Work Limitations Questionnaire, LBP disability assessed using the Roland-Morris Disability Questionnaire, psychosocial subscale assessed using the STarT Back Screening Tool and physical activity measured using triaxial accelerometers. These outcomes were collected at baseline and at 4-month follow-up evaluation. RESULTS: In the intention-to-treat analysis, WARP did not show any significant effects on pain intensity (ß, 0.01; 95% CI -0.50 to 0.52) and on the secondary outcomes. The median adherence to WARP was 28.6% (IQR, 16.8-41.1), which was equal to 1.43 times per day. No adverse effect was observed. CONCLUSIONS: The present study was unable to confirm the effectiveness of active rest in improving LBP. Hence, further study needs to investigate its effectiveness. TRIAL REGISTRATION NUMBER: UMIN000033210.

Association of objectively measured physical activity with combined bilateral knee and low-back pain in older adults with knee osteoarthritis: A cross-sectional study.

OBJECTIVE: Knee pain (KP) and low-back pain (LBP) are common sites of pain and major public health issues among older adults. We investigated the combined association of bilateral KP and LBP with objectively measured physical activity (PA) among adults with knee osteoarthritis (OA). METHODS: We recruited 150 knee OA adults and measured steps and PA intensity, including sedentary behavior (SB), low PA (LPA), and moderate-to-vigorous PA, using an accelerometer. KP and LBP were measured using a numerical rating scale. They were classified into 4 groups based on the presence of KP and LBP: with the only unilateral KP (UKP), with the combined UKP and LBP (UKP and LBP), with the bilateral KP (BKP), and with the combined bilateral KP and LBP (BKP and LBP). One-way analysis of covariance was performed to compare physical activity variables (intensity or steps) between the four groups. RESULTS: Overall, 126 patients were enrolled. The prevalence of UKP, BKP, UKP and LBP, and BKP and LBP were 29.4%, 23.8%, 18.3%, and 28.6%. The proportion of SB was higher in the BKP and LBP group than in the other groups (F = 6.51, p < 0.01). The proportion of LPA was lower in the BKP and LBP group than in the other groups (F = 6.21, p < 0.01). CONCLUSIONS: The proportions of SB and LPA were significantly worse in knee OA adults with BKP and LBP than in those with UKP. Our findings may be a basis for considering knee OA adults for improving PA.

Comparison of voluntary cough function in community - dwelling elderly and its association with physical fitness.

OBJECTIVE: To compare the association of cough peak flow (CPF) with aging in community-dwelling older adults and to investigate the relationship between physical fitness and CPF in these individuals. METHOD: Two hundred twenty two community-dwelling older adults were enrolled. CPF was assessed as a cough function parameter. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1.0) were assessed as respiratory function. Maximal expiratory pressure (MEP) and inspiratory pressure (MIP) were assessed as respiratory muscle strength. The 3-minute walk test (3MWT) performance was assessed as a physical fitness. Participants were divided into the following age groups: 60-64, 65-69, 70-74, 75-79 and 80-89 years. One way analysis of variance were computed for comparison between age group, sex and CPF. Multivariate regression analyses were used to investigate the association of CPF with 3MWT. RESULTS: The value of CPF significantly decreased in the 75-79 and 80-89 years group than 60-64 years group in men and in the 80-89 years group than 65-69 years group in women. The value of CPF were 545.5, 497.2, 403.3, 354.8 and 325.4 L/min in the 60-64, 65-69, 70-74, 75-79 and 80-89-year group in men and 263.4, 278.8, 264.5, 214.0, and 193.6 L/min in the corresponding age groups in women, respectively. 3MWT (p = 0.041) was significantly associated with CPF. CONCLUSIONS: Cough function tends to decrease with aging in community-dwelling elderly. Physical fitness is associated with cough function.

Effect of self-calf massage on the prevention of deep vein thrombosis after total knee arthroplasty: A randomized clinical trial.

OBJECTIVE: Deep vein thrombosis (DVT) is a severe complication after total knee arthroplasty (TKA). Performing self-calf massage may decrease the incidence of DVT. The purpose of this study was to investigate whether self-calf massage is effective for preventing DVT after TKA. METHOD: In all, 165 patients participated in the present study. Patients were randomized to one of two groups: the self-calf massage group or the control group. In the control group, patients started regular physical therapy. In the self-calf massage group, in addition to regular physical therapy, patients were instructed to massage their calf muscles 30 times from the distal to proximal side. This procedure was repeated three times and was completed in 2 mins during the 2 days following TKA. All patients were evaluated for DVT on postoperative day 3 using lower limb vein ultrasonography. RESULTS: The incidence of DVT was significantly lower in the self-calf massage group than in the control group. Self-calf massage was associated with a lower incidence of DVT, whereas age and female sex were risk factors for DVT. CONCLUSION: This study showed that the self-calf massage may be beneficial for the prevention of DVT after TKA.

Navicular drop is negatively associated with flexor hallucis brevis thickness in community-dwelling older adults.

BACKGROUND: Flatfoot is characterized as a lower longitudinal arch and is a common foot deformity in older adults. Foot intrinsic muscle dysfunction has been considered as one of the factors for a lower medial longitudinal arch. The objective of this study was to investigate the association of the navicular drop with the thickness of foot intrinsic muscles in older adults. RESEARCH QUESTION: Which intrinsic muscle contributes most to support the medial longitudinal arch in older adults? METHODS: We studied 88 community-dwelling older adults (mean age 74.2 ± 6.2 years). We measured the navicular height, the calcaneus inclination, and hallux valgus angle on the right foot in the sitting and standing positions using a 3D foot scanner. Then, we calculated the navicular drop and changes in the calcaneus inclination from the sitting to the standing position. The muscle thickness of the flexor hallucis brevis (FHB), flexor digitorum brevis (FDB), and abductor hallucis (AbH) was measured on the right foot using Bmode ultrasonography. RESULTS: Multiple regression analysis demonstrated that FHB thickness was significantly associated with navicular height in the standing positions (ß = 8.568, P = 0.016) as well as navicular drop (ß = -9.495, P = 0.037) after adjusting for age, sex, height, weight, and hallux valgus angle. There was no association with FDB or AbH. The thickness of any intrinsic muscle was not associated with the calcaneus inclination or changes in the calcaneus inclination. SIGNIFICANCE: Our data suggest that FHB plays an important role in preventing navicular drop and that intrinsic muscles likely do not contribute to the rearfoot angle in older adults.

Importance of knee flexion range of motion during the acute phase after total knee arthroplasty.

BACKGROUND: We investigate the association with knee flexion range of motion (ROM) during the acute phases and that at 12 months after total knee arthroplasty (TKA). We also clarified the cut-off ROM during the acute phases in predicting the goal of knee flexion ROM at 12 months. METHODS: In this retrospective study, 193 patients with knee osteoarthritis (female:144 patients, age:73.2 ± 7.7 years) who underwent unilateral TKA at an orthopedic clinic were recruited. They underwent assessments of knee flexion ROM at 5 days, 1 month, and 12 months after TKA. The goal of knee flexion ROM at 12 months after TKA was set at 120°. Single and logistic-regression analyses were performed with the dependent variables including the outcome of the goal of knee flexion ROM at 12 months, and the independent variables included knee flexion ROM at 5 days and 1 month, separately. We calculated the cut-off ROM at 5 days and 1 month for predicting the goal of knee flexion ROM at 12 months with receiver operating curve analysis. RESULTS: Knee flexion ROM at 5 days and 1 month were significantly associated with the goal of that at 12 months (p < 0.01). The cut-off ROM were 85° at 5 days and 105° at 1 month separately. CONCLUSIONS: Our results suggest the importance of early improvement in knee flexion ROM after TKA, and that at 1 month postoperatively indicates the likelihood of achievement of the goal of knee flexion ROM at 12 months after TKA.

Effect of preoperative sedentary behavior on clinical recovery after total knee arthroplasty: a prospective cohort study.

OBJECTIVES: Prolonged sedentary behavior (SB) may affect clinical improvements following total knee arthroplasty (TKA). We aim to assess preoperative SB effect on improvements in clinical outcomes after TKA. We hypothesized that patients with high proportion of preoperative SB have small improvements in clinical outcomes after TKA. METHODS: We recruited 115 adults with knee osteoarthritis (OA), planning to undergo TKA. Knee-specific functional outcomes were assessed using the new knee society score (KSS), including total score, symptoms, patient satisfaction, patient expectations, and functional activities. Gait function was assessed using the timed up and go (TUG) test. SB was measured using a triaxial accelerometer. Multiple linear regression analysis was performed to investigate preoperative SB effect on improvements in clinical outcomes 6 months postoperatively by adjusting for several factors as potential confounders. RESULTS: Of 115 patients, 82 were included. High proportion of preoperative SB had a significant negative effect on recovery at 6 months in the new KSS total score [ß, -0.83, 95% confidence interval (CI), -1.53 to -0.12; p = 0.02], symptoms (-0.15, -0.28 to -0.02; p = 0.03), patient satisfaction (-0.22, -0.42 to -0.02; p = 0.03), and functional activities (-0.40, -0.76 to -0.04; p = 0.03) after adjusting for potential confounders. CONCLUSIONS: A high proportion of preoperative SB was a risk factor for reduced improvements in knee-specific functional outcomes after TKA. To prevent poor functional recovery after TKA, it is essential to understand the preoperative lifestyle factors and intervene proactively during acute postoperative phase in patients with high SB proportion.Key Points• Preoperative high proportion of SB had a negative effect on improvement in new KSS total scores, symptoms, patient satisfaction, and functional activities.• When considering clinical outcomes after TKA, clinicians should closely monitor patients with high proportions of preoperative SB to prevent poor functional recovery.

Association of fear of falling with acceleration-derived gait indices in older adults with knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (OA) and fear of falling (FoF) are important factors contributing to trunk oscillation during walking. It is of a clinical importance to clarify the association of FoF with trunk oscillation during walking in older adults with knee OA (knee OA adults). AIM: The purpose of this study was to investigate the association of FoF with trunk oscillation during walking in knee OA adults. METHODS: Forty-one patients who met the criteria participated in the study and were classified into two groups based on their answer to a question on FoF. An accelerometer was attached at the level of the third lumbar vertebra (L3) and the seventh cervical vertebra (C7), and the accelerations at L3 and C7 were measured during a 10-m gait test. Using these data, the acceleration-derived gait indices, such as stride time variability (STV), root mean square (RMS), and autocorrelation at the trunk in the anteroposterior (AP) and mediolateral (ML) directions, were computed. RESULTS: FoF was associated with a higher STV value and a smaller RMS value in the ML direction at L3. DISCUSSION: The decreased trunk oscillation in the ML direction in knee OA adults with FoF may reflect a positive, compensatory adaptation for trunk control. CONCLUSION: Knee OA adults with FoF decreased trunk oscillation during walking than those without FoF.

Study of mizoribine therapy in elderly patients with membranous nephropathy: comparison with patients not receiving mizoribine.

BACKGROUND: We have previously reported the results of mizoribine (MZR) treatment for elderly patients with membranous nephropathy (MN). Here, we retrospectively compared these patients with those who had been initially treated with prednisolone (PSL) alone. METHODS: The subjects were patients with MN aged ≥65 years who were examined between April 2007 and September 2010 and followed for at least 1 year. RESULTS: The median period until the start of treatment in the MZR group (MZR-G) was 60 days. The urinary protein level at the start of MZR treatment was 3.89±2.3 g/gCr. Urinary protein in the group not treated with MZR (N-MZR-G) was 1.0±1.1 g/gCr, showing a tendency to improve in patients with nephrotic syndrome relative to the MZR-G (p=0.055). The PSL dose in the MZR-G versus N-MZR-G at 1 year was 5.7±3.0 versus 6.25±2.5 mg/day, the urinary protein level was 0.19±0.2 versus 0.13±0.1 g/gCr, and the remission rate was 80 versus 75%. In the MZR-G, the total PSL dose at 1 year after the start of MZR treatment was 5,058±1,904 versus 6,649±875 mg in the N-MZR-G. Adverse events occurred in 3/5 patients (60%) in the MZR-G and in 3/4 patients (75%) in the N-MZR-G. CONCLUSION: Elderly patients with MN who respond poorly to PSL treatment may be treated successfully with MZR.

Diofenolan induces male offspring production through binding to the juvenile hormone receptor in Daphnia magna.

Juvenile hormone (JH) and JH agonists have been reported to induce male offspring production in various daphnid species including Daphnia magna. We recently established a short-term in vivo screening assay to detect chemicals having male offspring induction activity in adult D. magna. Diofenolan has been developed as a JH agonist for insect pest control, but its male offspring induction activity in daphnids has not been investigated yet. In this study, we found that the insect growth regulator (IGR) diofenolan exhibited a potent male offspring induction activity at low ng/L to µg/L concentrations, as demonstrated by the short-term in vivo screening assay and the recently developed TG211 ANNEX 7 test protocol. A two-hybrid assay performed using the D. magna JH receptor confirmed that diofenolan had a strong JH activity. Global whole body transcriptome analysis of D. magna exposed to 10 ng/L diofenolan showed an up-regulation of JH-responsive genes and modulation of several genes involved in the ecdysone receptor signaling pathway. These results clearly demonstrate that diofenolan has strong JH activity and male offspring induction activity, and that a combination of modified standardized regulatory testing protocols and rapid in vitro and in vivo screening assays are able to identify potential endocrine disruptors in D. magna. The observation that diofenolan modulates multiple endocrine signaling pathways in D. magna suggests that further investigation of potential interference with growth, development and reproduction is warranted.

Effects of different administration protocols on the plasma concentration of donepezil hydrochloride in dementia patients with stage 5 chronic kidney disease.

The prevalence of chronic kidney disease (CKD) as well as Alzheimer's disease (AD) increases with age. With the aging of the population in Japan, there is an increasing likelihood that patients with CKD will receive donepezil hydrochloride (DPZ), an antidementia drug, in the near future. Nevertheless, there have been few reports on how to use DPZ in patients with severe CKD. We report on 2 CKD stage 5 patients who received DPZ under different prescriptions. In case 1, 3 mg/day of DPZ was initially administered for 4 months, after which the dose was increased to 5 mg/day. In case 2, 5 mg was administered twice a week. The plasma concentration of DPZ was measured and the effectiveness was assessed using the Mini-Mental Health State Examination and the Hasegawa Dementia Rating Scale. We found that (1) only a slight increase in the plasma concentration of DPZ was observed with a dose of 3 mg daily, (2) there was a significant increase in the plasma concentration with a dose of 5 mg daily, and (3) when 5 mg of DPZ was administered twice a week, the plasma concentration did not differ significantly from healthy controls who had received 5 mg daily. Although cognitive function was improved best when the 5-mg dose was administered daily with no apparent side effects, the plasma concentration came close to reaching a toxic level at this dose. Careful follow-up may be essential when DPZ is used at 5 mg/day or greater in severe CKD patients.

Establishment of transactivation assay systems using fish, amphibian, reptilian and human thyroid hormone receptors.

Thyroid hormones are essential for the regulation of a wide range of biological processes associated with normal development and metabolism in vertebrates. For the screening of chemicals with a potential thyroid hormone and anti-thyroid hormone activities, we have established transient transactivation assay systems using thyroid hormone receptors (TRα and TRß) from three frog species (Xenopus laevis, Silurana tropicalis and Rana rugosa), a fish (Oryzias latipes), an alligator (Alligator mississippiensis) and a human (Homo sapiens). In all species examined, similar transcriptional activities were found for triiodothyronine (T3 : 10(-11) M in TRα and 10(-10) M in TRß) and thyroxine (T4 : 10(-9) M in TRα and 10(-8) M in TRß). Analogs of thyroid hormone (3,5,3',-triiodothyroacetic acid and 3,3',5,5'-tetraiodothyroacetic acid) exhibited weaker activity, requiring 10-fold higher concentrations for induction of activity when compared with T3 and T4 . These results provide support for the usefulness of in vitro screening assay systems as part of an approach to test chemicals for potential thyroid hormone receptor activity. In addition, we observed that T3 -stimulated transcriptional activity of the O. latipes TRα was inhibited by 10(-5) M tetrabromobisphenol A (TBBPA). In contrast, TR antagonist activities on TRα were not encountered in other species, even with TBBPA concentrations at 10(-5) M. In vitro transactivation assay systems using TRs from various species can be used for the screening of chemicals with thyroid-receptor agonist and antagonist activities. They also can be used for studies that examine evolutionary differences among species in the potency of TR activation.

Comparative responsiveness to natural and synthetic estrogens of fish species commonly used in the laboratory and field monitoring.

Exposure to estrogenic chemicals discharged into the aquatic environment has been shown to induce feminization in wild freshwater fish and although fish species have been reported to differ in their susceptibility for these effects, empirical studies that directly address this hypothesis are lacking. In this study, in vitro ERα activation assays were applied in a range of fish species used widely in chemical testing (including, zebrafish, fathead minnow, medaka) and/or as environmental monitoring species (including, roach, stickleback, carp) to assess their comparative responsiveness to natural (estrone, estradiol, estriol) and synthetic (17α-ethinylestradiol (EE2), diethylstilbestrol (DES)) estrogens. In vivo exposures to EE2 via the water (nominal 2 and 10 ng/L for 7 days) were also conducted for seven fish species to compare their responsiveness for hepatic vitellogenin (VTG) mRNA induction (an ER mediated response). Of the fish species tested, zebrafish ERα was found to be the most responsive and carp and stickleback ERα the least responsive to natural steroid estrogens. This was also the case for exposure to EE2 with an ERα-mediated response sensitivity order of zebrafish > medaka > roach > fathead minnow > carp > stickleback. For VTG mRNA induction in vivo, the order of species responsiveness was: rainbow trout (not tested in the ERα activation assays) > zebrafish > fathead minnow > medaka > roach > stickleback > carp. Overall, the responses to steroid estrogens in vitro via ERα compared well with those seen in vivo (VTG induction for exposure to EE2) showing in vitro screening of chemicals using fish ERα-mediated responses indicative of estrogenic responses (VTG induction) in vivo.