Prognostic factors for overall survival in clinical node-positive patients with upper tract urothelial carcinoma.

BACKGROUND: There is sparse evidence regarding optimal management and prognosticators for oncologic outcomes in patients with clinical node-positive (cN+) upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analyzed the data from 105 UTUC patients with cN1-2M0 between June 2010 and June 2022 at multiple institutions affiliated with our university. At the time of diagnosis, all patients received standard-of-care treatment including radical nephroureterectomy (RNU), chemotherapy, and/or palliative care. We employed a Cox regression model to analyze the prognostic importance of various factors on overall survival (OS). RESULTS: Of 105 patients, 54 (51%) underwent RNU, while 51 (49%) did not. RNU was likely to be selected in patients with younger and higher G8 score, resulting in better median OS in patients who underwent RNU than in those who did not (42 months vs. 15 months, p < 0.001). Multivariable analysis among the entire cohort revealed that low G8 score (≤14) (hazard ratio [HR]: 2.07, 95% confidence interval [CI]: 1.08-3.99), elevated pretreatment C-reactive protein (CRP) (HR: 3.35, 95%CI: 1.63-6.90), and failure to perform RNU (HR: 2.16, 95%CI: 1.06-4.42) were independent prognostic factors for worse OS. In the subgroup analyses of cohorts who did not undergo RNU, elevated pretreatment CRP was the only independent prognostic factor for worse OS in cN+ UTUC patients. CONCLUSIONS: RNU seems to be a reasonable treatment option in cN+ UTUC patients where applicable. Elevated pretreatment CRP appears to be a reliable prognosticator of worse OS and may be helpful in optimizing candidate selection for intensified treatment in this setting.

Docetaxel versus abiraterone for metastatic hormone-sensitive prostate cancer with focus on efficacy of sequential therapy.

PURPOSE: We aimed to assess the oncologic efficacy of combining docetaxel (DOC) versus abiraterone (ABI) with androgen deprivation therapy (ADT) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC), with a focus on the efficacy of sequential therapy, in a real-world clinical practice setting. METHODS: The records of 336 patients who harbored de novo high-risk mHSPC, based on the LATITUDE criteria, and had received ADT with either DOC (n = 109) or ABI (n = 227) were retrospectively analyzed. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), time to 2nd-line progression (PFS2), and 2nd- and 3rd-line PFS, were compared. We used one-to-two propensity score matching to minimize the confounders. The differential efficacy of 2nd-line therapy based on agents in each arm was evaluated using the unmatched cohort as an additional interest. RESULTS: After propensity score matching, 86 patients treated with DOC + ADT and 172 with ABI + ADT were available for analyses. The 3-year OS and CSS for DOC versus ABI were 76.2% versus 75.1% (p = 0.8) and 78.2% versus 78.6% (p = 1), respectively. There was no difference in the median PFS2 (49 vs. 43 months, p = 0.39), while the median time to CRPC in patients treated with ABI was significantly longer compared to those treated with DOC (42 vs. 22 months; p = 0.006). The median 2nd-line PFS (14 vs. 4 months, p < 0.001) and 3rd-line PFS (4 vs. 2 months, p = 0.012) were significantly better in the DOC group than in the ABI group. Among the unmatched cohort, after ABI for mHSPC, the median 2nd-line PFS did not differ between the patients treated with DOC and those treated with enzalutamide as 2nd-line therapy (both 3 months, p = 0.8). CONCLUSIONS: ADT with DOC or ABI has comparable oncologic outcomes in terms of OS, CSS, and PFS2 in patients with de novo high-risk mHSPC. Compared to DOC, ABI resulted in longer time to CRPC but worse 2nd and 3rd-line PFS. Further studies are needed to clarify the optimal sequence of therapy in the upfront intensive treatment era.

Combination of docetaxel versus nonsteroidal antiandrogen with androgen deprivation therapy for high-volume metastatic hormone-sensitive prostate cancer: a propensity score-matched analysis.

PURPOSE: The aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting. METHODS: The records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared. RESULTS: After matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups. CONCLUSIONS: Our analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC.

Association between nocturnal falls and hypnotic drug use in older patients at acute care hospitals.

PURPOSE: Although hypnotic drug use is a known risk factor for falls, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. Here, we aimed to assess the influence of various hypnotic drugs on fall risk in older patients admitted to acute care hospitals. METHODS: We investigated the relationship between nocturnal falls and sleeping pill use in 8,044 hospitalized patients aged > 65 years. We used a propensity score matching method to homogenize characteristics of patients with and without nocturnal falls (n = 145 patients per group) using 24 extracted factors (excluding hypnotic drugs) as covariates. RESULTS: Our analysis of fall risk for each hypnotic drug revealed that benzodiazepine receptor agonists were the only drugs significantly associated with falls, suggesting that use of the drugs is a risk factor for falls in older adults (p = 0.003). In addition, a multivariate analysis of 24 selected factors, excluding hypnotic drugs, revealed that patients with advanced recurrent malignancies were at greatest risk of experiencing falls (OR: 2.62; 95% CI: 1.23-5.60; p = 0.013). CONCLUSION: Benzodiazepine receptor agonists should be avoided in older hospitalized patients since they increase fall risk, with melatonin receptor agonists and orexin receptor antagonists used instead. Particularly, fall risk associated with hypnotic drugs should be considered in patients with advanced recurrent malignancies.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

[Incidence of Immune-Related Adverse Events after Switching from a Conventional Regimen of Nivolumab and Pembrolizumab to the Extended Dosing Interval Regimen].

A new nivolumab and pembrolizumab monotherapy regimen with double the conventional dose and longer dosing intervals( the new regimen)has been approved. Here, we report the incidence of immune-related adverse events(irAEs)in the early phase of switching from the conventional regimen to the new regimen at Ogaki Municipal Hospital. Thirty-seven patients switched to the new regimen between October 2020 and February 2021: 7(18.9%)switched to nivolumab and 5 (14.3%)to pembrolizumab. Two of the 7 patients treated with nivolumab developed irAEs. One patient developed Grade 3 colitis on day 51 following the switch to the new regimen, and the treatment was discontinued. The other patient developed Grade 3 adrenal insufficiency on day 72 and was hospitalized. No irAEs were observed with pembrolizumab treatment. These results suggest that high-severity grade irAEs may occur early after switching to the new regimen.

Risk Factors for Adverse Events in Patients with Chronic Constipation Following Lubiprostone Administration.

INTRODUCTION: Lubiprostone is an effective treatment of chronic constipation (CC). However, as with other stimulant or osmotic laxatives, adverse events (AEs) can make it difficult to continue treatment. This article investigates AE risk factors associated with lubiprostone. METHODS: We retrospectively analyzed all 1,338 Japanese patients with CC treated at our hospital from October 2013 to July 2017. All patients were diagnosed with constipation as defined by the Roma III criteria. Enrolled patients received lubiprostone orally (24 or 48 µg daily), after which we investigated the incidence of AEs. The causative factors for diarrhea and nausea, the most common AEs, were examined by the backward logistic regression model. RESULTS: Two hundred eight (15.5%) experienced at least 1 AE. No serious AEs were associated with the study drug. The AEs reported by >1% of patients overall were diarrhea (6.1%) and nausea (4.2%). We performed a multivariate logistic regression using a backward variable selection method to investigate AE risk factors. Factors associated with higher incidence of diarrhea were patient age of 65 years or more (odds ratio: [95% confidence interval]; p value) (2.09: [1.05-4.16]; 0.035). Factors associated with greater likelihood of nausea included female gender (1.99: [1.10-3.61]; 0.023), and the chief complaint was a patient complaining of abdominal pain and fullness (2.07: [1.01-4.22]; 0.046). CONCLUSIONS: Understanding AE risk factors can help avoid unnecessary AEs and promote more effective treatment.

Effects of in-hospital exercise on sarcopenia in hepatoma patients who underwent transcatheter arterial chemoembolization.

BACKGROUND AND AIM: Sarcopenia is a prognostic factor in hepatocellular carcinoma (HCC) patients. HCC patients who underwent transcatheter arterial chemoembolization (TACE) are at a risk of muscle atrophy. We aimed to investigate the effects of in-hospital exercise on muscle mass and factors associated with muscle hypertrophy in HCC patients who underwent TACE. METHODS: We enrolled 209 HCC patients who underwent TACE. Patients were classified into either an exercise (n = 102) or control (n = 107) group. In the exercise group, patients were treated with in-hospital exercise (median 2.5 metabolic equivalents/20-40 min/day). The effects of exercise on muscle mass were evaluated by changes in skeletal muscle index (ΔSMI) between before and after TACE. Factors associated with an increase in SMI were analyzed by logistic regression and decision-tree analyses. RESULTS: There was no significant difference in serum albumin and bilirubin levels between the two groups. ΔSMI was significantly higher in the exercise group than in the control group (0.28 cm2 /m2 vs -1.11 cm2 /m2 , P = 0.0029). In the logistic regression analysis, exercise was an independent factor for an increase in SMI (hazard ratio 2.13; 95% confidence interval 1.215-3.846; P = 0.0085). Moreover, the decision-tree analysis showed that exercise was the initial divergence variable for an increase in SMI (the ratio of increased SMI: 53% in the exercise group vs 36% in the control group). CONCLUSIONS: In-hospital exercises increased muscle mass in HCC patients who underwent TACE. In addition, exercise was an independent factor for muscle hypertrophy. Thus, in-hospital exercise may prevent sarcopenia in HCC patients who underwent TACE.

Glycemic Profiling in Patients with Drug-Naïve Type 2 Diabetes by Continuous Glucose Monitoring.

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

[Role of Surgery in Multimodality Treatment for Non-small Cell Lung Cancer;Current Status and Future Perspectives].

Recent improvement of outcomes for resected non-small cell lung cancer (NSCLC) has been contributed not only by increased detection of early-stage disease and improvement of preoperative diagnosis/perioperative management but also by improvement of multimodality treatment. The introduction of newly developed systemic therapies including molecular targeted agents and immune checkpoint inhibitors dramatically changed clinical outcomes of advanced NSCLC. Accordingly, the role of surgery during the multimodality treatment will be changed more than ever. In this article, we overviewed the current status of the multimodality treatment for clinical stageⅢ (N2)disease and postoperative adjuvant therapy and discussed the role of surgery during these situations. We also discussed the future perspectives of the role of surgery during the multimodality treatment for advanced NSCLC.

Point-to-Point Ultra-Remote Asymmetric Control with Flexible Linker.

An ultra-remote intramolecular (point-to-point) asymmetric control through 38 bonds (1,39-asymmetric induction) has been achieved by using the principle of direct supramolecular orientation of catalytic and reactive moieties in asymmetric autocatalysis. We found the highly stereoselective diisopropylzinc addition reaction using designed molecules possessing pyrimidine sites at each terminal of a conformationally flexible simple methylene chain.

Comparison Between Effectiveness of 100 mg/day Sitagliptin and a Switch to Mitiglinide Calcium Hydrate/Voglibose from 50 mg/day Sitagliptin in Patients with Type 2 Diabetes.

We analyzed the effects of 100 mg/day sitagliptin and a switch to mitiglinide calcium hydrate/voglibose compound tablets (MIT/VOG) in patients with type 2 diabetes mellitus (T2DM) treated with 50 mg/day sitagliptin. Five patients with T2DM treated with 50 mg/day sitagliptin and hemoglobin A1c (HbA1c) of ≥6.5% were switched to MIT/VOG, or the dose of sitagliptin was increased to 100 mg/day. The effects of the changes in therapy were compared in a crossover fashion by continuous glucose monitoring. The primary endpoint was mean amplitude of glycemic excursions (MAGE), and the secondary end points were 24-hour mean blood glucose level and mean blood glucose level from 0:00 a.m. to 7:00 a.m. and from 7:00 a.m. to 0:00 a.m., percentage of time with blood glucose level of ≥200 mg/dl and <70 mg/dl, maximum and minimum blood glucose levels, and increases in postprandial blood glucose levels. MAGE was significantly lower with MIT/VOG (P = 0.016), whereas mean blood glucose levels were lower between 0:00 a.m. and 7:00 a.m. with 100 mg/day sitagliptin. The percentage of time with blood glucose level ≥200 mg/dl was significantly shorter with MIT/VOG (P = 0.041). The maximum blood glucose level was significantly lower with MIT/VOG (P = 0.043), and the minimum was significantly lower with 100 mg/day sitagliptin (P = 0.043). Blood glucose levels after dinner and mean increases in postprandial blood glucose levels were significantly lower with MIT/VOG (P = 0.090 and P = 0.045 respectively). In patients with T2DM, treatment with MIT/VOG improves MAGE and postprandial hyperglycemia and 100 mg/day sitagliptin lowers early morning glucose levels. This trial was registered with the University Hospital Medical Information Network (UMIN) (No. UMIN R000008274).

Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus.

BACKGROUND: Basic studies have shown that glucagon-like peptide-1 (GLP-1) analogs exert a direct protective effect on the vascular endothelium in addition to their indirect effects on postprandial glucose and lipid metabolism. GLP-1 analogs are also reported to inhibit postprandial vascular endothelial dysfunction. This study examined whether the GLP-1 analog exenatide inhibits postprandial vascular endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). METHODS: Seventeen patients with T2DM underwent a meal tolerance test to examine changes in postprandial vascular endothelial function and in glucose and lipid metabolism, both without exenatide (baseline) and after a single subcutaneous injection of 10 µg exenatide. Vascular endothelial function was determined using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide tests. RESULTS: The natural logarithmically-scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. The use of exenatide resulted in a significant decrease in triglycerides (TG) area under the curve and coefficient of variation (CV). The change in L_RHI correlated with changes in CV of triglycerides and HDL-cholesterol. Multivariate analysis identified changes in triglyceride CV as the only determinant of changes in L_RHI, contributing to 41% of the observed change. CONCLUSIONS: Exenatide inhibited postprandial vascular endothelial dysfunction after the meal loading test, suggesting that exenatide has a multiphasic anti-atherogenic action involving not only glucose but also lipid metabolism. TRIAL REGISTRATION: ClinicalTrials.gov: UMIN000015699.

Efficacy and safety of sublingual immunotherapy for two seasons in patients with Japanese cedar pollinosis.

BACKGROUND: Japanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Standardized JC pollen extract is available for subcutaneous immunotherapy, but this treatment is limited by potentially serious side effects. The aim of this double-blind, randomized comparative study was to evaluate the efficacy and safety of standardized JC pollen extract in a new oral formulation (CEDARTOLEN®, Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for sublingual immunotherapy (SLIT) for JC pollinosis. METHODS: A total of 531 subjects with JC pollinosis were randomized into 2 groups at a ratio of 1:1 to receive daily sublingual administration of standardized JC pollen extract with a maintenance dose of 2,000 Japanese allergy units (JAU) or placebo for 2 consecutive pollen seasons. The efficacy was evaluated using the total nasal symptom and medication score (TNSMS) as the primary end point. Secondary end points included the total ocular symptom and medication score (TOSMS) and scores for individual symptoms and medication. RESULTS: The TNSMS was significantly lower (p < 0.0001) in the SLIT group than in the placebo group in the peak symptom period by 18 and 30% in the first and second seasons, respectively. All secondary end points were also significantly lower in the SLIT group in both seasons. No systemic anaphylaxis occurred. CONCLUSIONS: SLIT with daily administration of standardized JC pollen extract was effective for improving nasal and ocular symptoms of JC pollinosis and reducing the use of relief medication. The JC pollen extract was well tolerated with only local adverse events.

[Risk Factors Analysis for Hypermagnesemia with Magnesium Oxide].

While decreased renal function is a known risk factor for hypermagnesemia caused by magnesium oxide (MgO), few studies have comprehensively investigated other contributing factors. In this study, the researchers analyzed the risk factors for hypermagnesemia development in 256 inpatients receiving MgO treatment at the Matsuyama Shimin Hospital. Multivariate analysis identified blood urea nitrogen ≧22 mg/dL, estimated glomerular filtration rate ≦43.1 mL/min, and MgO ≧1000 mg/d as risk factors. Additionally, the researchers' findings suggest a correlation between the number of risk factors and the incidence of hypermagnesemia, including the prevalence of Grade 3 cases. Interestingly, low body mass index emerged as a potential risk factor even in patients without the three identified factors. These findings highlight the importance for pharmacists to advocate for routine serum Mg level monitoring in patients with the risk factors identified in this study.

Practical selective hydrogenation of α-fluorinated esters with bifunctional pincer-type ruthenium(II) catalysts leading to fluorinated alcohols or fluoral hemiacetals.

Selective hydrogenation of fluorinated esters with pincer-type bifunctional catalysts RuHCl(CO)(dpa) 1a, trans-RuH2(CO)(dpa) 1b, and trans-RuCl2(CO)(dpa) 1c under mild conditions proceeds rapidly to give the corresponding fluorinated alcohols or hemiacetals in good to excellent yields. Under the optimized conditions, the hydrogenation of chiral (R)-2-fluoropropionate proceeds smoothly to give the corresponding chiral alcohol without any serious decrease of the ee value.

Androgen receptor W741C and T877A mutations in AIDL cells, an androgen-independent subline of prostate cancer LNCaP cells.

The androgen-independent LNCaP (AIDL) cell line was generated by maintaining prostate cancer LNCaP cells in a hormone-deprived medium. Notably, synthetic androgen R1881-related gene response is attenuated in AIDL cells as compared to the parental LNCaP cells. The aim of this study was to clarify the mechanisms underlying androgen sensitivity in AIDL cells. We first examined the expression of androgen receptor (AR) and its co-regulators. However, no significant difference in mRNA expression was found between LNCaP and AIDL cells. Remarkably, AR protein levels were induced by R1881 and DHT in LNCaP cells, but not in AIDL cells. We next performed the cDNA sequencing to detect mutations in the AR gene. The T877A mutation was detected both in LNCaP and AIDL cells. Furthermore, AIDL cells harbored a missense substitution (TGG → TGT) in the AR gene, which caused a point mutation at codon 741 (W741C). Double T877A and W741C AR mutants have been previously reported to exhibit reduced androgen sensitivity. Hence, the low-androgen-sensitive responses of AIDL cells may be explained, at least in part, by AR gene mutations.

["Exclusivity" and quantifier float in bakari"Exclusivity" and quantifier float in bakari]. / 「ばかり」の「限定」と遊離数量詞.

This paper presents a descriptive study that analyzes the semantic meaning of Toritate focus particle bakari. Previous studies reported that, although bakari expresses exclusivity, it is characterized by the fact that it permits non-applicable cases, thereby drawing the conclusion that the meaning of bakari is not exclusivity. This paper argues that bakari does indeed denote "exclusivity" as bakari is supported by the phenomenon that non-applicable cases are unacceptable when bakari co-occurs with floating quantifiers. Considering existing research on this subject, the following was observed. Even though the subjective set, as established by the speaker's past experiences to interpret the meaning of bakari, may not be consistent with the real world, the number of events that form the said set match the number of real-world events when bakari co-occurs with floating quantifiers due to the characteristics of floating quantifiers. In such cases, bakari does not permit non-applicable cases. The interpretation that permits non-applicable cases applies to situations where the set established by the speaker is fixed at a narrower range than the real world, and the non-applicable cases exist outside the set. We thus conclude that bakari denotes "exclusivity" that does not permit non-applicable cases.

A novel bone-thinning technique for transcranial stimulation motor-evoked potentials in rats.

Transcranial electrical stimulated motor-evoked potentials (tcMEPs) are widely used to evaluate motor function in humans, and even in animal studies, tcMEPs are used to evaluate neurological dysfunction. However, there is a dearth of reports on extended tcMEP recordings in both animal models and humans. Therefore, this study examined a new technique for stably recording tcMEPs over several weeks in six healthy female Sprague-Dawley rats. We thinned the skull bone using the skull base and spinal surgery technique to reduce electrical resistance for electrical stimulation. tcMEPs were recorded on days 1, 7, 14, 21, and 28 after surgery. The onset latency and amplitude of tcMEPs from the hindlimbs were recorded and evaluated, and histological analysis was performed. Stable amplitude and onset latency could be recorded over several weeks, and histological analysis indicated no complications attributable to the procedure. Thus, our novel technique allows for less invasive, safer, easier, and more stable extended tcMEP recordings than previously reported techniques. The presently reported technique may be applied to the study of various nerve injury models in rats: specifically, to evaluate the degree of nerve dysfunction and recovery in spinal cord injury, cerebral infarction, and brain contusion models.

Comparisons of Neurotrophic Effects of Mesenchymal Stem Cells Derived from Different Tissues on Chronic Spinal Cord Injury Rats.

Cell-based therapies with mesenchymal stem cells (MSCs) are considered as promising strategies for spinal cord injury (SCI). MSCs have unique characteristics due to differences in the derived tissues. However, relatively few studies have focused on differences in the therapeutic effects of MSCs derived from different tissues. In this study, the therapeutic effects of adipose tissue-derived MSCs, bone marrow-derived MSCs, and cranial bone-derived MSCs (cMSCs) on chronic SCI model rats were compared. MSCs were established from the collected adipose tissue, bone marrow, and cranial bone. Neurotrophic factor expression of each MSC type was analyzed by real-time PCR. SCI rats were established using the weight-drop method and transplanted intravenously with MSCs at 4 weeks after SCI. Hindlimb motor function was evaluated from before injury to 4 weeks after transplantation. Endogenous neurotrophic factor and neural repair factor expression in spinal cord (SC) tissue were examined by real-time PCR and western blot analyses. Although there were no differences in the expression levels of cell surface markers and multipotency, expression of Bdnf, Ngf, and Sort1 (Nt-3) was relatively higher in cMSCs. Transplantation of cMSCs improved motor function of chronic SCI model rats. Although there was no difference in the degree of engraftment of transplanted cells in the injured SC tissue, transplantation of cMSCs enhanced Bdnf, TrkB, and Gap-43 messenger RNA expression and synaptophysin protein expression in injured SC tissue. As compared with MSCs derived other tissues, cMSCs highly express many neurotrophic factors, which improved motor function in chronic SCI model rats by promoting endogenous neurotrophic and neural plasticity factors. These results demonstrate the efficacy of cMSCs in cell-based therapy for chronic SCI.