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Kenji Takeyoshi,1,2 Masatake Kurita,1–3 Satoshi Nishino,2,3 Mika Teranishi,1 Yukio Numata,2 Tadahiro Sato,2 Yoshiro Okubo11Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, 2Sato Hospital, Koutokukai, Nanyo, Yamagata, 3Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, JapanAbstract: Although three drugs, risperidone, yokukansan, and fluvoxamine, have shown equal efficacy in treating behavioral and psychological symptoms of dementia (BPSD) in our previous study, their mechanisms of action are different from one another. Monoamines have attracted attention for their key roles in mediating several behavioral symptoms or psychological symptoms through synaptic signaling. We aimed to clarify the monoamines changed by treatment with each drug in patients with BPSD. The main purpose of this study was to determine whether plasma levels of catecholamine metabolites are correlated with pharmacological treatments. This was an 8-week, rater-blinded, randomized, flexible-dose, triple-group trial. In total, 90 subjects were recruited and subsequently three different drugs were allocated to 82 inpatients with BPSD. We examined BPSD data from patients who completed 8 weeks of treatment. Eventually, we analyzed 42 patients (yokukansan: 17; risperidone: 9; fluvoxamine: 16). Homovanillic acid, a metabolite of dopamine, and 3-methoxy-4-hydroxyphenylglycol, a metabolite of noradrenaline, in their plasma were analyzed by high-performance liquid chromatography with electrochemical detection. All three drugs showed equal significant efficacy between baseline and study endpoint. By contrast, biomarkers showed mutually different changes. Patients in the yokukansan group had significantly decreased plasma homovanillic acid levels from baseline. Conversely, patients in the risperidone and fluvoxamine groups exhibited no significant changes in plasma homovanillic acid levels from baseline. Yokukansan contains geissoschizine methyl ether, which is known to have a partial agonist effect on dopamine D2 receptors. An improvement in BPSD condition with the intake of yokukansan is suggested to occur through a suppressed dopaminergic function, which is similar to the effect of aripiprazole.Keywords: herbal medicine, MHPG, homovanillic acid, HVA, noradrenaline, BPSD

Deep learning algorithms have been successfully used in medical image classification and cancer detection. In the next stage, the technology of acquiring explainable knowledge from medical images is highly desired. Herein, fully automated acquisition of explainable features from annotation-free histopathological images is achieved via revealing statistical distortions in datasets by introducing the way of pathologists’ examination into a set of deep neural networks. As validation, we compared the prediction accuracy of prostate cancer recurrence using our algorithm-generated features with that of diagnosis by an expert pathologist using established criteria on 13,188 whole-mount pathology images. Our method found not only the findings established by humans but also features that have not been recognized so far, and showed higher accuracy than human in prognostic prediction. This study provides a new field to the deep learning approach as a novel tool for discovering uncharted knowledge, leading to effective treatments and drug discovery.

Medial meniscectomy was undertaken in adult merino sheep and after 16 weeks exercise each group was administered five weekly intra-articular injections of saline, pentosan polysulphate (PPS), hyaluronic acid (HA) or a combination of PPS + HA. Gait analysis and x-rays were undertaken before and after drug treatment. At sacrifice (26 weeks), joints were examined for gross pathological and histochemical changes. Only the PPS-treated group showed an improvement in gait, with low radiological and histology scores. The HA-treated group showed similar but less significant changes to these parameters.

The effects of medial versus lateral meniscectomy on articular cartilage (AC) of adult sheep was investigated. In vitro incorporation of 35S into proteoglycans (PGs) and their release into media was used to assess cartilage metabolism. Lateral meniscectomy produced higher loss of PGs from AC and lower 35S-PG biosynthesis than for AC from medial meniscectomized joints. These findings were consistent with the proposed role of the lateral meniscus in joint mechanics.