Analgesic Effect of the Kampo Formula Yokukansan via the Suppression of Substance P in an Experimental Rat Model of Hunner-Type Interstitial Cystitis.

INTRODUCTION: Yokukansan (YKS), a Kampo formula used in traditional Japanese medicine, has an analgesic effect, and is used for various pain disorders. This study investigated its analgesic effects on Hunner-type interstitial cystitis (HIC) and its mechanism of action in animal models.   Methods: Rats with toll-like receptor-7 agonist (loxoribine)-induced HIC were used. Eight-week-old female Wistar rats were divided into three groups: control, HIC, and HIC-administered YKS (YKS + HIC). Bladder pain was assessed based on escape behavior using the von Frey test. Three days after HIC induction, the bladder and spinal cord were excised, and the expression of substance P (SP) was examined.   Results: The pain threshold decreased significantly in the HIC group compared to that in the control group, but this decrease was suppressed by further YKS administration. The expression of SP in the bladder wall and spinal cord increased significantly in the HIC group compared to that in the control group; however, this increase was suppressed by YKS administration. CONCLUSION: SP is involved in the onset of bladder pain via neurokinin 1 receptors in bladder tissue. YKS may be useful for managing HIC-induced pain, and the suppression of SP secretion is one of its mechanisms of action.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios alone or combined with prostate-specific antigen for the diagnosis of prostate cancer and clinically significant prostate cancer.

Objective: We evaluated whether the blood parameters before prostate biopsy can diagnose prostate cancer (PCa) and clinically significant PCa (Gleason score [GS] ≥7) in our hospital. Methods: This study included patients with increased prostate-specific antigen (PSA) up to 20 ng/mL. The associations of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) alone or with PSA with PCa and clinically significant PCa were analyzed. Results: We included 365 patients, of whom 52.9% (193) had PCa including 66.8% (129) with GS of ≥7. PSA density (PSAD) and PSA had better the area under the curve (AUC) of 0.722 and 0.585, respectively with p=0.001 for detecting PCa compared with other blood parameters. PSA combined with PLR (PsPLR) and PSA with NLR (PsNLR) had better AUC of 0.608 and 0.610, respectively with p<0.05, for diagnosing GS≥7 population, compared with PSA, free/total PSA, NLR, PLR, and PsNPLR (PSA combined with NLR and PLR). NLR and PLR did not predict PCa on multivariate analysis. For GS≥7 cancer detection, in the multivariate analysis, separate models with PSA and NLR (Model 1: PsNLR+baseline parameters) or PSA and PLR (Moder 2: PsPLR+baseline parameters) were made. Baseline parameters comprised age, digital rectal exam-positive lesions, PSA density, free/total PSA, and magnetic resonance imaging. Model 2 containing PsPLR was statistically significant (odds ratio: 2.862, 95% confidence interval: 1.174-6.975, p=0.021) in finding aggressive PCa. The predictive accuracy of Model 2 was increased (AUC: 0.734, p<0.001) than that when only baseline parameters were used (AUC: 0.693, p<0.001). Conclusion: NLR or PLR, either alone or combined with PSA, did not detect PCa. However, the combined use of PSA with PLR could find the differences between clinically significant and insignificant PCa in our retrospective study limited by the small number of samples.

The Japanese Herbal Medicine Yokukansan Exerted Antioxidant and Analgesic Effects in an Experimental Rat Model of Hunner-Type Interstitial Cystitis.

Background and Objectives: The Japanese herbal medicine Yokukansan (YKS) has analgesic properties and is used for various pain disorders. The purpose of the present study was to investigate the effects of YKS in Hunner-type interstitial cystitis (HIC) using an experimental rat model of HIC and to explore its antioxidant activity and role as the underlying mechanism of action. Materials and Methods: The antioxidant capacity of YKS was evaluated by determining its hydroxyl radical (·OH) scavenging capacity using electron spin resonance (ESR). Next, the effects of YKS administration were explored using a toll-like receptor-7 agonist-induced rat model of HIC. The von Frey test was performed to assess bladder pain. Three days after HIC induction, the bladder was removed, and the expression of oxidative stress parameters in the bladder wall was investigated (reactive oxygen metabolites (ROMs), ·OH, and 8-hydroxy-2'-deoxyguanosine (8-OhdG)). Results: YKS had a ·OH scavenging capacity according to the ESR study. In the von Frey test, a significant decrease in the withdrawal threshold was observed in the HIC group compared with the control group; however, the decrease was ameliorated by the administration of YKS. Oxidative stress parameters showed increasing tendencies (ROMs test and 8-OHdG) or a significant increase (·OH) in the HIC group compared with the control group; however, the increase was significantly suppressed by the administration of YKS. Conclusions: These findings suggest that YKS is effective against HIC and that its antioxidant activity is involved in the mechanism of action.

Kamikihito rescued depressive-like behaviors and hippocampus neurogenesis in chronic restraint stress rats.

Background and aim: Substantial evidence suggests the effectiveness of plant-based medicine in stress-related diseases. Kamikihito (KKT), a Japanese traditional herbal medicine (Kampo), has been used for anemia, insomnia, and anxiety. Recent studies revealed its ameliorating effect on cognitive and memory dysfunction in several animal models. We, therefore, determined whether daily supplementation of KKT has an antidepressant-like effect on the stress-induced behavioral and neurological changes in rats. Experimental procedure: The effect of KKT against the stress-induced changes in anxiety- and depressive-like behaviors and hippocampal neurogenesis were determined using a rat model of chronic restraint stress (CRS). KKT was orally administered daily at 300 or 1000 mg/kg during 21 consecutive days of CRS (6 h/day). The effect of CRS and KKT on physiological parameters, including body weight gain, food/water consumptions, plasma corticosterone (CORT) levels, and percentage of adrenal gland weight to body weight, were firstly measured. Anxiety- and depressive-like behaviors in rats were assessed in the open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). Hippocampal neurogenesis was determined by immunohistochemistry. Results and conclusion: CRS for 21 days caused a significant decrease in body weight gain and increase in plasma CORT levels and percentage of adrenal gland weight to body weight, which were rescued by KKT treatment. KKT also suppressed the CRS-induced anxiety- and depressive-like behaviors and impairment of hippocampal neurogenesis. These results suggest that daily treatment of KKT has a protective effect against physiological, neurological, and behavioral changes in a rat model of depression.

A case of complete response following the administration of pembrolizumab and metastasectomy for lung and bone metastases of bladder cancer.

INTRODUCTION: Patients with metastatic urothelial carcinoma have poor prognosis and limited treatment options. CASE PRESENTATION: The patient was a 60-year-old male with bladder cancer and multiple lung metastases. He underwent three courses of gemcitabine and cisplatin chemotherapy, despite left femoral bone metastases. Tumor resection and bone replacement surgery was performed. Following the administration of four courses of pembrolizumab, lung metastasis completely resolved. However, after nine courses, right femoral neck bone metastasis was observed; therefore, tumor resection and bone replacement surgery were repeated. Pathologically, PD-L1 expression was low in lung biopsy tissue and bone metastases. Pembrolizumab treatment continued for up to 20 courses; cancer recurrence and adverse events were not observed upon follow-up examination after 1 year. CONCLUSION: Patients responding well to systemic therapy may have resectable metastatic sites, and long-term survival might be achieved with adjunctive metastasectomy. The effect of pembrolizumab was not associated with positive PD-L1 expression.

Hard bilateral syphilitic testes with vasculitis: a case report and literature review.

BACKGROUND: We report the case of a patient with syphilitic testicular gumma and vasculitis with adrenal failure due to chronic steroid use. CASE PRESENTATION: A 63-year-old male presented with hard right eye swelling and very firm bilateral testes on palpation, which he had for 2 years. Testicular tumor markers were negative; syphilis test was positive. Radiological examination suggested aortitis and bilateral testicular malignancy. The patient received ampicillin for the infection and prednisolone for vasculitis. Left orchidectomy was performed to confirm the presence of testicular tumor; histological examinations revealed granulomatous orchitis. The prednisolone doses were adjusted because of relapses and adverse effects of steroid use. Unfortunately, the patient died in the intensive care unit because of uncontrolled blood pressure and pneumonia. CONCLUSIONS: This is a rare case of syphilis with testicular involvement and vasculitis. This report shows the importance of broadening the differential diagnoses of testicular firmness.

Influences of Lavender Essential Oil Inhalation on Stress Responses during Short-Duration Sleep Cycles: A Pilot Study.

Lavender essential oil (LEO) was reported to improve sleep quality. We investigated the influence of aromatherapy by testing the effects of LEO on stress responses during a short-duration sleep in a single-blind, randomized, crossover trial. The subjects were twelve healthy adults who were nonsmokers without any known disease and who were not prescribed medications, and nine of these completed the study. After the subjects had fallen asleep, they were sprayed with LEO using an aroma diffuser. Before and after 90 min of sleep, α-amylase, chromogranin A (CgA), and cortisol levels in saliva were measured as objective stress indicators, and the Japanese version of the UWIST Mood Adjective Checklist was used as a subjective indicator. A comparison of changes before and after sleep, with and without LEO, revealed that the cortisol level did not significantly change; however, α-amylase (p < 0.05) and CgA (p < 0.01) levels significantly decreased after LEO inhalation. A mood test indicated no change in mood before and after sleep, with or without LEO. Since α-amylase and CgA reflect the sympathetic nervous system response, these results indicate that LEO aromatherapy during a short-duration sleep cycle suppresses the stress response, especially that of the sympathetic nervous system.

Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. MATERIALS AND METHODS: Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. RESULTS: AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. CONCLUSIONS: These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

Lung adenocarcinoma diagnosed incidentally after renal biopsy for suspected right renal cancer.

We present a case of lung adenocarcinoma metastasizing to the right clear cell renal cell carcinoma diagnosed by computed tomography (CT)-guided renal biopsy and immunohistochemistry. A 72-year-old male patient had right lower abdominal pain for 3 days, followed by right loin pain for 10 days. On CT scan, renal cell cancer was suspected with multiple metastases. Renal cell cancer with metastatic lung adenocarcinoma was diagnosed on CT-guided renal biopsy with positive immunohistochemical markers. The patient, unfortunately, expired after few days of diagnosis. Tumor-to-tumor metastasis is an unusual disease, and its tumors are aggressive. A definite diagnosis of tumor-to-tumor metastasis is a clinical challenge. Immunohistochemistry helped us in the diagnosis without the primary lesion biopsy.

MRI-guided conservative management of a left segmental testicular infarction.

Segmental testicular infarction is a rare condition. Patients present with clinical features similar to torsion and testicular tumors, with most undergoing surgery. A 55-year-old male patient presented with left scrotal pain. We did a Doppler ultrasonogram and magnetic resonance imaging to diagnose his condition and rule out testicular torsion and tumor. We decided not to operate and asked the patient for follow-up. There was no pain in the left testis, and magnetic resonance imaging showed a reduction in the left testicular lesion after 4 months.

The long-run heterogeneous effects of a cholera pandemic on stature: Evidence from industrializing Japan.

The recent COVID-19 pandemic poses the general question on how infectious diseases can persistently affect human health. A growing body of literature has found a significant amount of evidence on the long-term adverse effects of infectious diseases, such as influenza, typhoid fever, and yellow fever. However, we must be careful about the fact that little is known about the long-term consequences of the acute diarrheal disease pandemic cholera - Vibrio cholerae bacillus - which still threatens the health of the population in many developing countries. To bridge this gap in the body of knowledge, we utilized unique census-based data on army height at age 20 in early 20th-century Japan, with a difference-in-differences estimation strategy using regional variation in the intensity of cholera pandemics. We found that early-life exposure to a cholera pandemic had heterogeneous stunting effects on the final height of men; the magnitude of the stunting effects increased as the intensity of exposure increased.

Prostate cancer detection rate and Gleason score in relation to prostate volume as assessed by magnetic resonance imaging cognitive biopsy and standard biopsy.

OBJECTIVE: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy. MATERIAL AND METHODS: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV. RESULTS: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p<0.001), respectively. ISUP Grade group ≥2 (Gleason score ≥3+4) detection rates for increased PVs of ≤40 cc and >40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p<0.05). On multivariable logistic regression, MRI (p=0.014) and PSA (p=0.039) predicted ISUP Grade group ≥2 in patients with PV>40 cc. CONCLUSION: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

Particulate air pollution, birth outcomes, and infant mortality: Evidence from Japan's automobile emission control law of 1992.

This study investigates the impacts of the Automobile NOx Law of 1992 on ambient air pollutants and fetal and infant health outcomes in Japan. Using panel data taken from more than 1500 monitoring stations between 1987 and 1997, we find that NOx and SO2 levels reduced by 5% and 11%, respectively in regulated areas following the 1992 regulation. In addition, using a municipal-level panel data set from Japan's Vital Statistics Survey and a difference-in-differences approach, we find that the regulation explains most of the improvements in the fetal death rate after the regulation came into effect. This study provides evidence on the positive impacts of this large-scale automobile regulation policy on fetal health.

Chain effects of clean water: The Mills-Reincke phenomenon in early 20th-century Japan.

This study explores the validity of chain effects of clean water, which are known as the "Mills-Reincke phenomenon," in early 20-century Japan. Recent studies have reported that water purifications systems are responsible for huge contributions to human capital. Although some studies have investigated the instantaneous effects of water-supply systems in pre-war Japan, little is known about the chain effects of these systems. By analyzing city-level cause-specific mortality data from 1922 to 1940, we find that a decline in typhoid deaths by one per 1000 people decreased the risk of death due to non-waterborne diseases such as tuberculosis and pneumonia by 0.742-2.942 per 1000 people. Our finding suggests that the observed Mills-Reincke phenomenon could have resulted in the relatively rapid decline in the mortality rate in early 20-century Japan.

Long-run effects of early childhood exposure to cholera on final height: Evidence from industrializing Japan.

Pandemic cholera is one of the most topical and urgent issues in many developing countries. However, although a growing body of research has shown the negative long-run effects of infectious disease exposure on human health, the long-run influences of early childhood exposure to cholera have thus far been understudied. To bridge this gap in the body of knowledge, we draw both on new data describing adult height from 1899 to 1910 from comprehensive official Japanese army records and on data recording the regional variation in the intensity of cholera pandemics. By using a difference-in-differences estimation strategy, we find that exposure to pandemic cholera had stunting effects on the final height of men at that time. Our estimates also suggest that early-infancy exposure to cholera seems to have a stronger long-run effect on adult height than late-infancy exposure.

Brief hourly exercise during night work can help maintain workers' performance.

Increased night work is an important issue because of its implications on workers' health, safety and performance. This study examined the effects of brief hourly exercise as a countermeasure against the adverse effects of night work, especially for workers requiring sustained attention while working in a prolonged sitting posture. During simulated night work (22:00-08:00), participants were required to follow an hourly schedule comprising a 30-min task, 15-min test and 15-min break. The study included 2 experimental conditions: (1) hourly exercise (HE; hourly exercise for 3 min during breaks) and (2) control (without exercise during breaks). Throughout the test period, work performance in the last 10 min of each 30-min task was better under the HE condition than under the control condition (p<0.01). During the second half of the test period, exercise showed an effect on sustained attention (p=0.02). Parasympathetic nerve activity under the HE condition was less than that under the control condition (p<0.01). However, exercise was not effective in reducing subjective fatigue and sleepiness. These results suggest that brief hourly exercise acts as a restraint on parasympathetic nerve activity and is capable of sustaining attention levels during the circadian rhythm nadir that occurs during early morning.

Characterizing recovery of sleep after four successive night shifts.

The purpose of this study was to characterize the recovery pattern of sleep following simulated, four successive night shifts in ten healthy men (22.9 + or - 3.2 yr). Poor sleep was defined as sleep efficiency of 80% or lower as determined actigraphically. The results showed that four (rapid, slow, pseudo, and incomplete) patterns of sleep recovery were observed over three recovery sleep periods. The rapid and slow recovery pattern represented immediate and slow return to baseline level prior to the nightshifts, respectively. The pseudo recovery pattern demonstrated poor sleep at the 3rd recovery sleep period, despite transient recovery at the 2nd sleep period. The incomplete recovery pattern was characterized by consistently poorer sleep during the entire recovery period. The correlation analysis indicated that sleep habits (bed time and variation of wake time) prior to the experiment were significantly related to the recovery patterns, rather than performance and alertness during the night shifts.

Effects of a modified ambulance night shift system on fatigue and physiological function among ambulance paramedics.

OBJECTIVES: In the present study, we modified a night shift system for an ambulance service so that ambulance paramedics were assured of taking a nap, and examined the effects of this new system on the fatigue and physiological function of ambulance paramedics. METHODS: Ten ambulance paramedics at a fire station in the center of a large city in Japan voluntarily enrolled as subjects in this field study. They worked a 24-h shift system. There were two teams of 5 ambulance paramedics in the fire station. Three ambulance paramedics per shift usually provided the emergency services. In the traditional system, the ambulance paramedics had to deal with all emergency calls throughout a 24-h shift (T-shift). In the modified system, 2 ambulance paramedics were allotted time for naps in the 21:00-3:00 (C-shift) or 3:00-8:30 (B-shift) shift by the addition of another a firefighter (D-shift). RESULTS: There were fewer emergency dispatches and nap time was longer in the B- and C-shifts than in the T-shift. Parasympathetic nerve activities during naps in B- and C-shifts were higher than in the T-shift. The results of critical flicker fusion frequency and 3-choice reaction time in the B-shift at 7:30 tended to be higher and shorter than that in T-shift. CONCLUSIONS: The results of this study suggest that the modified night shift which ensured time for ambulance paramedics to take long, restful power naps alleviated subjective fatigue, and improved physiological functions which are often adversely affected by night workload.

Effects of adjustable sit-stand VDT workstations on workers' musculoskeletal discomfort, alertness and performance.

Adjustable sit-stand workstations, which are designed to allow workers to sit and stand autonomously while working, were examined to identify the effects on workers' musculoskeletal discomfort, alertness and performance. Twenty-four healthy subjects participated in the study. The subjects were required to do an English transcription task for 150 min under the following conditions: 1) sitting at standard workstations (Standard), 2) sitting on a chair with the work surface elevated to standing position (High-chair) and 3) a combination of 10-min sitting and 5-min standing with the same setting as that in the high-chair condition (Sit-stand). The subjective musculoskeletal discomfort scores indicated that High-chair and Sit-stand resulted in relatively higher discomfort levels than the Standard condition. Although the ratio between low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.4 Hz) components of heart rate variability (LF/HF ratio) in Sit-stand was higher than that in other conditions, there were no significant differences in subjective sleepiness among the three conditions. As for work performance, there was a tendency to be steadily high under the Sit-stand condition compared with other conditions, but not a significant difference. This study revealed that although the use of sit-stand workstations can contribute to keeping workers' arousal level steady, it has an adverse effect in light of musculoskeletal discomfort.

[Characteristic patterns of fatigue feelings on four simulated consecutive night shifts by "Jikaku-sho shirabe"].

The aim of the present study was to reveal characteristic patterns of fatigue feelings on consecutive night shifts by a questionnaire for work-related fatigue feelings "Jikaku-sho shirabe". Ten healthy males (Mean +/- SD: 22.9 +/- 3.2 years old) participated in the experiment. Participants were required to attend the laboratory for nine consecutive nights under the following conditions: adaptation sleep (0:00-7:00), simulated day shift (10:00-18:00), baseline sleep (0:00-7:00), directly followed by four simulated night shifts (22:00-9:00) and the subsequent daytime sleep (12:00-18:00), three recovery nights (0:00-7:00) and two simulated day shifts (10:00-18:00). During each simulated shift, participants were required to complete an English transcription task (30 min), a performance test battery (20 min) and break (10 min) every hour. Fatigue feelings were evaluated by "Jikaku-sho shirabe", which was proposed by the Industrial Fatigue Research Committee of the Japan Occupational Health in 2002. This questionnaire consists of 25 subjective fatigue symptom items that are categorized into 5 factors: feeling of drowsiness (Factor I), feeling of instability (Factor II), feeling of uneasiness (Factor III), feeling of local pain or dullness (Factor IV), and feeling of eyestrain (Factor V). For each item, respondents are requested to estimate the intensity of the feelings as "Disagree at all," "Agree scarcely," "Agree slightly," "Agree considerably," and "Agree strongly." These five intensities were assigned scores of 1 to 5 points, respectively. Hierarchical cluster analysis suggested that there might be at least three variation patterns of fatigue feelings on the consecutive night shifts (i.e. Clusters A, B and C). On the basis of subjective fatigue symptom items of each cluster, the patterns in Clusters A, B and C might reflect the loads of the reticular activating system, musculoskeletal and central nervous systems, and limbic system, respectively. For Clusters A and C, significant improvements were observed with the increase of the number of night shifts (F(11,99)=3.07, p<0.01, F(11,99)=3.37, p<0.01, respectively). On the other hand, Cluster B deteriorated with the progress of the simulated night shifts. Taken together, we suggest that the characteristic patterns of fatigue feelings on consecutive night shifts might represent dissociation among the feelings induced by several loads.