Clinicopathological Significance and Prognostic Role of High Mobility Group Box 1 (HMGB1), Toll-Like Receptor (TLR) 2 and TLR4 in Breast Cancer.

High-mobility group box 1 (HMGB1) functions as damage-associated molecular pattern (DAMPs), released into extracellular space during cellular stress. Extracellular HMGB1 act as signal molecules through Toll-like receptor (TLR) 2 or TLR4, exerting diverse functions in both normal cells and malignant cells including breast cancer. However, their comprehensive examination in breast cancer tissues is lacking. Thus, we immunolocalized them in 112 breast cancer tissues, correlating their immunoreactivity with clinicopathological parameters and clinical outcomes to clarify their significance in breast cancer. We demonstrated that nuclear HMGB1 immunoreactivity was correlated with tumor progression and longer disease-free survival. In contrast, TLR2 immunoreactivity was correlated with increased cell proliferation and shorter disease-free survival, dependent on cytoplasmic HMGB1 immunoreactivity. Additionally, TLR4 immunoreactivity correlated with chemoresistance, regardless of cytoplasmic HMGB1 immunoreactivity. It was therefore considered that TLR2 collaboratively contributed to breast cancer progression with HMGB1-DAMPs to become a worse prognostic factor. Meanwhile, TLR4 served as a worse prognostic factor associated with chemoresistance, irrespective of HMGB1.

Factors associated with the introduction of visiting-pharmacist services in older adults in Japan: A nested case-control study.

AIM: To investigate the factors associated with introducing visiting-pharmacist services for community-dwelling older adults in Japan. METHODS: We conducted a nested case-control study using claims data in a cohort from a city in Tokyo. Patients aged ≥65 years who received visiting-pharmacist services for the first time between April 2014 and March 2020 were considered case patients. A maximum of four controls to each case patient were randomly selected on the basis of sex, age, health insurance systems, and month-year. Medical and long-term care service usage and patient condition were assessed using claims data from the index and preceding months, along with long-term care needs certification data. Multivariable conditional logistic regression analysis was conducted to estimate the adjusted odds ratios with 95% confidence intervals for factors associated with visiting-pharmacist service introduction. RESULTS: A total of 22 949 participants (4591 cases and 18 358 controls) were included, with a median age of 85 years; 59.3% were women. The adjusted odds ratios (95% confidence intervals) of the three most related factors were 27.61 (23.98-31.80) for physicians' home visits, 5.83 (5.08-6.70) for hospitalization, and 4.97 (4.16-5.95) for designated-facility admission. Factors such as prescribing ≧10 medications, visiting nursing, and cancer were positively associated. In contrast, low household income and a high need for support due to cognitive function or disability were negatively associated. CONCLUSIONS: This study provides insights into the introduction of visiting-pharmacist services for older adults in Japan. Geriatr Gerontol Int 2024; 24: 344-351.

Literature Review of Studies Using the National Database of the Health Insurance Claims of Japan (NDB): Limitations and Strategies in Using the NDB for Research.

The use of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) for research has increased over time. Researchers need to understand the characteristics of the data to generate quality-assured evidence from the NDB. In this review, we mapped and characterized the limitations and related strategies using the NDB for research based on the descriptions of published NDB studies. To find studies that used Japanese healthcare claims data, we searched MEDLINE, EMBASE, and Ichushi-Web up to June 2023. Additionally, we hand-searched the NDB data publication list from the Ministry of Health, Labour and Welfare (2017-2023). We abstracted data based on the NDB data type, research themes, age of the study sample or population, targeted disease, and the limitations and strategies in the NDB studies. Ultimately, 267 studies were included. Overall, the most common research theme was describing and estimating the prescriptions and treatment patterns (125 studies, 46.8%). There was a variation in the frequency of themes according to the type of NDB data. We identified the following categories of limitations: (1) lack of information on confounders/covariates, outcomes, and other clinical content, (2) limitations regarding patients not included in the NDB, (3) misclassification of data, (4) lack of unique identifiers and register of beneficiaries, and (5) others. Although the included studies noted several limitations of using the NDB for research, they also provided some strategies to address them. Organizing the limitations of NDB in research and the related strategies across research fields can help support high-quality NDB studies.

A mixed-methods study on the pharmacological management of pain in Australian and Japanese nursing homes.

BACKGROUND: Understanding how analgesics are used in different countries can inform initiatives to improve the pharmacological management of pain in nursing homes. AIMS: To compare patterns of analgesic use among Australian and Japanese nursing home residents; and explore Australian and Japanese healthcare professionals' perspectives on analgesic use. METHODS: Part one involved a cross-sectional comparison among residents from 12 nursing homes in South Australia (N = 550) in 2019 and four nursing homes in Tokyo (N = 333) in 2020. Part two involved three focus groups with Australian and Japanese healthcare professionals (N = 16) in 2023. Qualitative data were deductively content analysed using the World Health Organization six-step Guide to Good Prescribing. RESULTS: Australian and Japanese residents were similar in age (median: 89 vs 87) and sex (female: 73% vs 73%). Overall, 74% of Australian and 11% of Japanese residents used regular oral acetaminophen, non-steroidal anti-inflammatory drugs or opioids. Australian and Japanese healthcare professionals described individualising pain management and the first-line use of acetaminophen. Australian participants described their therapeutic goal was to alleviate pain and reported analgesics were often prescribed on a regular basis. Japanese participants described their therapeutic goal was to minimise impacts of pain on daily activities and reported analgesics were often prescribed for short-term durations, corresponding to episodes of pain. Japanese participants described regulations that limit opioid use for non-cancer pain in nursing homes. CONCLUSION: Analgesic use is more prevalent in Australian than Japanese nursing homes. Differences in therapeutic goals, culture, analgesic regulations and treatment durations may contribute to this apparent difference.

Symptomatic and preventive medication use according to age and frailty in Australian and Japanese nursing homes.

OBJECTIVE: To investigate symptomatic and preventive medication use according to age and frailty in Australian and Japanese nursing homes (NHs). METHODS: Secondary cross-sectional analyses of two prospective cohort studies involving 12 Australian NHs and four Japanese NHs. Frailty was measured using the FRAIL-NH scale (non-frail 0-2; frail 3-6; most-frail 7-14). Regular medications were classified as symptomatic or preventive based on published lists and expert consensus. Descriptive statistics were used to compare the prevalence and ratio of symptomatic to preventive medications. RESULTS: Overall, 550 Australian residents (87.7 ± 7.3 years; 73.3% females) and 333 Japanese residents (86.5 ± 7.0 years; 73.3% females) were included. Australian residents used a higher mean number of medications than Japanese residents (9.8 ± 4.0 vs 7.7 ± 3.7, p < 0.0001). Australian residents used more preventive than symptomatic medications (5.5 ± 2.5 vs 4.3 ± 2.6, p < 0.0001), while Japanese residents used more symptomatic than preventive medications (4.7 ± 2.6 vs 3.0 ± 2.2, p < 0.0001). In Australia, symptomatic medications were more prevalent with increasing frailty (non-frail 3.4 ± 2.6; frail 4.0 ± 2.6; most-frail 4.8 ± 2.6, p < 0.0001) but less prevalent with age (< 80 years 5.0 ± 2.9; 80-89 years 4.4 ± 2.6; ≥ 90 years 3.9 ± 2.5, p = 0.0042); while preventive medications remained similar across age and frailty groups. In Japan, there was no significant difference in the mean number of symptomatic and preventive medications irrespective of age and frailty. CONCLUSIONS: The ratio of symptomatic to preventive medications was higher with increasing frailty but lower with age in Australia; whereas in Japan, the ratio remained consistent across age and frailty groups. Preventive medications remained prevalent in most-frail residents in both cohorts, albeit at lower levels in Japan.

Studies of Health Insurance Claims Data in Japan: A Scoping Review.

Background: Health insurance claims data are used in various research fields; however, an overview on how they are used in healthcare research is scarce in Japan. Therefore, we conducted a scoping review to systematically map the relevant studies using Japanese claims data. Methods: MEDLINE, EMBASE, and Ichushi-Web were searched up to April 2021 for studies using Japanese healthcare claims data. We abstracted the data on study characteristics and summarized target diseases and research themes by the types of claims database. Moreover, we described the results of studies that aimed to compare health insurance claims data with other data sources narratively. Results: A total of 1,493 studies were included. Overall, the most common disease classifications were "Diseases of the circulatory system" (18.8%, n = 281), "Endocrine, nutritional, and metabolic diseases" (11.5%, n = 171; mostly diabetes), and "Neoplasms" (10.9%, n = 162), and the most common research themes were "medical treatment status" (30.0%, n = 448), "intervention effect" (29.9%, n = 447), and "clinical epidemiology, course of diseases" (27.9%, n = 417). Frequent diseases and themes varied by type of claims databases. A total of 19 studies aimed to assess the validity of the claims-based definition, and 21 aimed to compare the results of claims data with other data sources. Most studies that assessed the validity of claims data compared to medical records were hospital-based, with a small number of institutions. Conclusions: Claims data are used in various research areas and will increasingly provide important evidence for healthcare policy in Japan. It is important to use previous claims database studies and share information on methodology among researchers, including validation studies, while informing policymakers about the applicability of claims data for healthcare planning and management.

Trends in antihypertensive prescription for pregnant women with hypertension and their peripartum outcomes before and after label and guideline revisions in Japan.

We investigated the trends in the proportion of antihypertensive prescriptions listed in the guidelines for pregnant patients and their pregnancy outcomes before and after regulatory actions in Japan. This retrospective cohort study used the Japan Medical Data Center claims data from January 2005 to April 2020. We identified women who had delivered and had hypertensive disorders before childbirth. To evaluate the influence of regulatory actions (label revision in 2011 and guideline updates in 2014), we divided the study period into three terms based on the year of the last menstrual period. We assessed the time trend of the prescription proportion of antihypertensives and conducted multivariable logistic regression analyses to assess the impact of the investigation terms on pregnancy outcomes (preterm birth, cesarean section, emergency cesarean section, and Hemolysis, Elevated Liver enzymes, and Low Platelets syndrome). Among the 13,797 eligible patients, 1739 (12.6%) were treated with oral antihypertensives during pregnancy. Before the policy revisions, the most frequently prescribed antihypertensive medication was methyldopa, but after the label and guideline revisions, nifedipine was the most frequently prescribed. The trend in the prescription proportion of nifedipine increased (P < 0.001) and that of hydralazine decreased (P < 0.001), while those of methyldopa and labetalol showed no significant trend. The adjusted odds ratios for all four pregnancy outcomes showed no significant differences according to the investigation terms. By investigating the three terms before and after the label and guideline revisions, significant changes were identified in the trend of the prescription proportion for pregnant women-an increase in nifedipine and a decrease in hydralazine-but not in pregnancy outcomes.

Acupuncture and Laser Acupuncture as Treatments for Emotional Distress in Infertile Women in Japan.

Objectives: Needle and laser acupuncture are often used to improve the success rate of assisted reproductive technology (ART). This study examined whether needle or laser acupuncture ameliorated the emotional distress experienced by infertile women undergoing in vitro fertilization and embryo transfer (IVF-ET) or intracytoplasmic sperm injection (ICSI). Materials and Methods: Fifty-one infertile women who were undergoing IVF-ET or ICSI received needle acupuncture (needle-acupuncture group; n = 32) or laser acupuncture treatment (laser-acupuncture group; n = 19). The emotional distress experienced by the infertile women was evaluated using 2 questionnaires-the Profile of Mood States (POMS) and the State-Trait Anxiety Inventory (STAI)-both before and after 3 months of treatment. Results: In the needle-acupuncture group, the POMS detected significant post-treatment reductions in tension/anxiety (P < 0.001), depression/dejection (P < 0.001), anger/hostility (P < 0.001), confusion (P < 0.05), and total mood disturbance (TMD; p < 0.001). However, the POMS scores for vigor/activity and fatigue were not altered significantly after the treatment. In the STAI, both State and Trait scores had significantly decreased after the acupuncture (P < 0.001 and P < 0.05, respectively). In the laser-acupuncture group, the POMS detected significantly lower tension/anxiety (P < 0.05) and vigor/activity (P < 0.05) scores after the treatment. However, the POMS did not detect significant changes in depression/dejection, anger/hostility, fatigue, confusion, or TMD after the treatment. Furthermore, neither the STAI-State nor the STAI-Trait score had significantly decreased after the laser acupuncture treatment. Conclusions: These results indicate that needle and laser acupuncture ameliorate the emotional distress experienced by women who are undergoing IVF-ET or ICSI.

Relationships between endogenous CYP3A markers and plasma amlodipine exposure and metabolism in early postpartum and non-peripartum women with hypertension.

OBJECTIVE: This study aimed to evaluate the relationship between endogenous CYP3A markers and plasma amlodipine (AML) exposure and metabolism parameters in early postpartum and non-peripartum women. METHODS: Twenty-four AML-treated early postpartum women with hypertensive disorders of pregnancy and 30 non-peripartum women with essential hypertension were enrolled. Blood samples for determination of CYP3A markers including total cholesterol-adjusted 4ß-hydroxycholesterol (4ß-OHC/TC), 25-hydroxyvitamin D (25-OHD), and AML and its metabolites in plasma were collected at 24 h after the AML treatment. RESULTS: The plasma 4ß-OHC/TC in postpartum women was higher than that in non-peripartum women, while the plasma 25-OHD was lower. The postpartum women had a lower plasma AML concentration and its metabolic ratio was higher. The plasma 4ß-OHC/TC decreased as the number of days post-delivery increased. The plasma AML concentration increased as the number of days post-delivery increased, while the metabolic ratio of AML declined slightly. Tendency toward negative correlations between the plasma 4ß-OHC/TC but not 25-OHD, and AML concentration were observed in both postpartum and non-peripartum women. In both groups, the plasma 4ß-OHC/TC was correlated with the metabolic ratio of AML. CONCLUSIONS: The early postpartum women had higher plasma 4ß-OHC and AML metabolism. The plasma 4ß-OHC had positive relationships with amlodipine metabolism in both women groups. AML metabolism and plasma 4ß-OHC may be useful as CYP3A markers in early postpartum and non-peripartum women.

Validated LC-MS/MS Method for the Simultaneous Determination of Amlodipine and Its Major Metabolites in Human Plasma of Hypertensive Patients.

BACKGROUND: No information on the pharmacokinetic characteristics of amlodipine (AML) metabolites is available. This study aimed to develop a method based on isocratic liquid chromatography coupled to tandem mass spectrometry for the simultaneous determination of AML and its 2 major metabolites, dehydroamlodipine (DH-AML) and O-des[2-aminoethyl]-O-carboxymethyl DH-AML (CM-DH-AML), and to use it for monitoring this drug in hypertensive patients. METHODS: Acetonitrile-deproteinized plasma specimens were separated using an octadecyl-silica column (3-µm particle size) with a mobile phase consisting of 50% methanol containing 0.15% of formic acid in water. The run time was 9 minutes. The mass spectrometer was run in the positive ion electrospray ionization mode. This method was applied for the determination of AML and its metabolites in plasma samples from patients treated with this drug. RESULTS: The calibration curves in human plasma of AML, DH-AML, and CM-DH-AML were linear over the concentration ranges of 0.5-64, 1-64, and 0.5-64 ng/mL, respectively, and their lower limits of quantification were 0.5, 1, and 0.5 ng/mL, respectively. Their extraction recovery rates and matrix factors in human plasma were 94.8%-109.0% and 97.0%-101.4%, respectively. The intra-assay and interassay imprecisions and accuracies were within 10.8% and 95.4%-111.2%, respectively. The plasma concentration ranges of AML, DH-AML, and CM-DH-AML were 6.5-20.9, 1.4-10.9, and 5.6-38.3 ng/mL, respectively. CONCLUSIONS: The present method with acceptable analytical performance can be helpful for monitoring the plasma concentration of AML, including the determination of its metabolites in patients with hypertension.

Involvement of peripheral opioid receptors in electroacupuncture analgesia for carrageenan-induced hyperalgesia.

Acupuncture is widely used to relieve pain; however, the mechanism underlying electroacupuncture analgesia (EAA) during inflammatory pain is unclear. We investigated whether endogenous peripheral opioid receptors participated in EAA during hyperalgesia elicited by carrageenan-induced inflammation. Moreover, we investigated which subtype of opioid receptor was involved in EAA. Carrageenan was subcutaneously administered by intraplanter (i.pl.) injection into the left hind paw. Nociceptive thresholds were measured using the paw pressure threshold (PPT). Rats received 3Hz electroacupuncture (EA) for 1h after carrageenan injection. The nonselective peripheral opioid receptor antagonist, naloxone methiodide, was administered by i.pl. injection of the inflamed paw 5min before EA. Also, animals received i.pl. or intravenous (i.v.) injection of selective antagonists against µ(D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), δ(naltrindole, NTI), or κ (nor-Binaltorphimine, nor-BNI) opioid receptors 1h before EA. PPT decreased significantly 3h after carrageenan injection. EA resulted in significant increases of PPT, moreover, PPT elevations persisted for 9h after carrageenan injection. PPT elevations produced by EA were antagonized by local i.pl. injection of naloxone methiodide at 3 and 5h after cessation of EA. NTI, nor-BNI and CTOP blocked EAA from immediately, 1h, and 3h after EA cessation, respectively. The EAA in the inflamed paw could not be blocked by i.v. injection of NTI, nor-BNI and CTOP. These findings suggest that peripheral µ, δ and κ receptors on peripheral nerve terminals are activated by EA, although there is a time difference among these activations.

Acupuncture for premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD), a severe type of premenstrual syndrome (PMS), is characterized mainly by psychological symptoms confined to the premenstrual period, which reduce not only patients' quality of life, but also their working activities. Although various therapies have been employed for PMDD, some patients do not respond to them. We recently employed acupuncture treatment for a patient in PMDD. Symptoms ameliorated during the acupuncture (+) period, but deteriorated during the acupuncture (-) period. This review describes the clinical course of this case. The diagnosis and treatment of PMDD are briefly summarized and previous acupuncture treatment for PMS are reviewed. The difficulties in evaluating the effectiveness of acupuncture for PMS/PMDD are addressed. It is suggested that acupuncture may be a treatment option for PMDD.

Acupuncture anesthesia and analgesia for clinical acute pain in Japan.

Acupuncture anesthesia has been practiced in China since about 1960. In Japan, Hyodo reported 30 cases of acupuncture anesthesia in 1972. However, from around 1980, the direction of acupuncture investigations turned from anesthesia to analgesia. Acupuncture analgesia is presently considered a way to activate the body's endogenous analgesic system. Recently, with the rise of acupuncture as one of the most well known CAM therapies, acupuncture or moxibustion treatment has been reported for both acute and chronic pain. Even so, few clinical reports and original articles have been reported in Japan. This review illustrates how acupuncture is being used in Japan for acute pain such as surgical operations, post- operative pain (POP), neuropathic pain, pain associated with teeth extractions and after the extraction of impacted wisdom teeth.

Effect of varying frequency and duration of electroacupuncture stimulation on carrageenan-induced hyperalgesia.

OBJECTIVE: Although electroacupuncture (EA) therapy is used to relieve various kinds of pain, the optimal frequency and duration of EA remain unclear. We investigated the effect of varying frequency and duration of EA during hyperalgesia elicited by carrageenan-induced inflammation. METHODS: Carrageenan was administered by subcutaneous intraplantar injection to induce inflammation. Nociceptive thresholds were measured using the paw pressure threshold (PPT) (Randall-Selitto Test). EA was applied at 3, 15, or 100Hz to the left anterior tibial muscles for 1, 15, or 60 minutes. Intensities used were chosen within the known tolerance of the animal, and increased up to 3mA for 3Hz, and up to 1.5mA for 15 and 100Hz. EA was started three hours after carrageenan injection. RESULTS: Three hours after carrageenan injection, a marked ipsilateral inflammatory response appeared and PPT decreased significantly. This decrease persisted for at least 24 hours after carrageenan injection. EA at 3Hz (60 minutes) resulted in significant increases of PPT which persisted for 24 hours after injection. EA at 3Hz (15 minutes) also induced PPT elevations immediately and for one hour after EA compared to the control group. However, no other variety of EA significantly increased PPT. CONCLUSION: These results show that EA produces electroacupuncture analgesia of carrageenan-induced hyperalgesia. These findings also suggest that, among the frequencies and durations tested, EA at 3Hz (60 minutes) is the most suitable frequency and duration for carrageenan-induced inflammation. It seems that EA has different analgesic effects and mechanisms according to the parameters of stimulation. For EA in the clinical induction of analgesia, it is especially important that an effective frequency and duration are selected.