Background and Purpose-The detailed role of angiotensin II in salt-exacerbated stroke is unclear. We examined the role of angiotensin II in salt-accelerated stroke of stroke-prone spontaneously hypertensive rats (SHRSP). Methods-Salt-loaded SHRSP were orally given the angiotensin II type 1 (AT1) receptor blocker candesartan (0.3 to 3 mg/kg per day) and calcium channel blocker amlodipine (1 mg/kg per day), and the effects on stroke (nϭ61) and brain superoxide were compared between them. We also examined the effect of angiotensin II infusion (200 ng/kg per min) on brain superoxide production and blood-brain barrier. Results-Despite the comparable hypotensive effect between candesartan and amlodipine, candesartan prolonged survival of salt-loaded SHRSP much more than amlodipine (PϽ0.01), being associated with more improvement of cerebral arteriolar thickening, cerebral arteriolar cell proliferation, and hippocampal CA1 neuronal cell reduction (1024.9Ϯ20.6 versus 724.9Ϯ22.8 cells/mm 2 ; PϽ0.01; nϭ7 to 10 in each group) in SHRSP by candesartan (PϽ0.05) than amlodipine. Salt loading increased superoxide and NADPH oxidase activity in brain cortex and hippocampus of SHRSP, and this increase was prevented by candesartan (PϽ0.01) but not amlodipine. Angiotensin II infusion, via AT1 receptor, directly increased brain superoxide by 1.8-fold (PϽ0.05; nϭ6 to 7 in each group) and impaired blood-brain barrier in salt-loaded SHRSP by 1.7-fold (PϽ0.05), and this increase in brain superoxide and blood-brain barrier impairment was prevented by tempol as well as candesartan. Conclusion-Excess salt, via oxidative stress, accelerates stroke, and angiotensin II, via AT1 receptor, plays a pivotal role in brain superoxide production of SHRSP by excess salt.

Objective: Previously, we suggested that oxaliplatin (L-OHP)-related grade 3/4 hypersensitivity reactions occurred immediately after the initiation, but grade 1/2 reactions did not. This study was conducted to clarify the risk factors for L-OHP-related hypersensitivity reactions.Methods: Clinical data from 108 Japanese patients with colorectal cancer were analyzed, who were treated with L-OHP-containing regimens, FOLFOX4 and/or mFOLFOX6. The risk factors examined included demographic data, preexisting allergies, laboratory test data, treatment regimen, treatment line of therapy, pretreatment with steroids, total number of cycles and cumulative amount of L-OHP.Results: The incidence of grade 1/2 and grade 3/4 hypersensitivity reactions were found at 13.0% (14/108) and 9.3% (10/108), respectively. Female (P=0.037), preexisting allergies (P=0.004) and lower level of lactate dehydrogenase (P=0.003) were risk factors for grade 1/2 hypersensitivity reactions, and higher neutrophil count (P=0.043) and lower monocyte count (P=0.007) were for grade 3/4 reactions. Total number of cycles were larger in the patients with grade 3/4 reactions than those without reactions (P=0.049).Conclusions: Further extensive examination with a large number of patients is needed to establish a patient management strategy.

Aim This study aimed to evaluate the efficacy of pharmacists' assessment and intervention using the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP‐J) to detect and correct potentially inappropriate medications (PIM) compared with the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) criteria version 2. Methods A prospective observational study was carried out at a medical unit of Cardiovascular Surgery and Cardiovascular Internal Medicine in a Japanese university hospital involving new inpatients aged ≥65 years prescribed one or more daily medication. Pharmacists detected PIM based on STOPP‐J and STOPP criteria version 2, and corrected them with physicians. The number of patients with PIM, the content and changes in PIM were compared between both criteria. Results Overall, 230 patients were included (mean age 75.4 years, 162 men, mean number of medications 8.3). STOPP‐J detected significantly more patients with PIM than STOPP criteria version 2 (122 [53%] vs 75 [33%], P < 0.001). The number of PIM based on STOPP‐J was 232, the physicians were recommended to change 61 (26%) and 50 (22%) were changed. Meanwhile, the number of PIM based on STOPP criteria version 2 was 133, the physicians were recommended to change 61 (46%) and 54 (41%) were changed. Several medications detected as PIM using STOPP‐J were not detected using STOPP criteria version 2. Conclusions STOPP‐J detected significantly more patients with PIM than STOPP criteria version 2, and pharmacists' assessment and intervention based on STOPP‐J were suggested to be effective for detecting and correcting PIM. Geriatr Gerontol Int 2019; 19: 1101–1107.

The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.

Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy-and concomitant CRT-induced oral mucositis. Methods: We enrolled healthy volunteers and patients with chemotherapy-and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients. Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was − 1.28 (95% confidence interval: − 2.06, − 0.51), and all patients experienced some degree of pain relief (range: − 0.2 to − 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients. Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo-or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433).

The mitogen-activated protein (MAP) kinase pathways has been shown to be necessary for mitogen-stimulated proliferation, but its role in cell migration has not been fully understood. In this study, we investigated the possible contribution of signaling pathways through c-Jun in platelet-derived growth factor (PDGF)-BB directed cell migration in rat aortic vascular smooth muscle cells (VSMCs) infected with a recombinant adenovirus containing the dominant-negative c-Jun (Ad-DN-c-Jun). DN-c-Jun protein was expressed dose-dependently in VSMCs infected with Ad-DN-c-Jun. Expression of DN-c-Jun significantly inhibited VSMC migration induced by PDGF-BB. Our results provide the first evidence that signaling pathways through c-Jun participates in cell migration induced by PDGF-BB in addition to other MAP kinase pathways in VSMCs.

The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.

Signal transducer and activator of transcription (STAT) 3 is a key factor in homeostasis of the oral mucosa by regulating the production of inflammatory cytokines. Sunitinib is a substrate of P-glycoprotein (multidrug resistance (MDR)-1/ABCB1) and breast-cancer resistance protein (BCRP/ABCG2). In this retrospective study, we evaluated the association between sunitinib-induced stomatitis and STAT3, ABCB1, and ABCG2 polymorphisms in patients with metastatic renal cell carcinoma (mRCC). Fifty-two Japanese patients with RCC treated with sunitinib were retrospectively genotyped to elucidate a potential association between STAT3, ABCB1, and ABCG2 polymorphisms and stomatitis development. Stomatitis occurred in 22 out of 52 patients. The TT TC genotypes at STAT3 rs744166 had an odds ratio of 5.00 against CC genotype for the stomatitis development (95% confident interval, 0.97-25.8). In the Kaplan-Meier method for the cumulative incidence of stomatitis, a statistically significant difference was observed between the TT TC and CC genotypes in STAT3 rs744166 (p 0.037). Both multiple logistic regression analysis and Cox proportional-hazards regression analysis show STAT3 rs744166 TT TC genotypes and serum creatinine in each patient were significant independent factors for stomatitis development. In conclusion, STAT3 polymorphism may be a novel risk factor for sunitinib-induced stomatitis in patients with mRCC.