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SUMMARY Background and objectives The effect of leukoreduction and storage periods on the accumulation of bioactive lysophospholipids and substances in human autologous blood ( AB units) has not been fully investigated. Materials and methods The accumulation of bioactive lysophospholipids such as sphingosine 1-phosphate ( S1P) and lysophosphatidylserine ( LysoPS) in AB units during the storage was investigated. The time-dependent changes and the effect of the filtration in pre-storage leuckoreduction ( LR) and unmodified samples derived from 46 AB units were analysed. Additionally, the changes of lysophospholipids and platelet releasate, namely β-thromboglobulin (β- TG), induced by exposure of whole blood ( WB) or platelet-rich plasma ( PRP) to the filter material were analysed. Results LysoPS, but not S1P levels, time-dependently and significantly increased in both unmodified and LR samples. LysoPS significantly decreased in LR compared with unmodified samples, whereas S1P increased in LR compared with unmodified samples. In addition, exposure of WB and/or PRP to the filter material in vitro resulted in increased levels of S1P, LysoPS and β- TG. Conclusions LR effectively reduced the accumulation of LysoPS in AB units. On the other hand, it increased concentrations of S1P due to platelet activation by exposure to the filter material. These suggest that increases of S1P levels in LR and LysoPS in the unmodified samples were mainly caused by the leukocytes and/or platelets and that LR was effective in inhibiting the accumulation of LysoPS. [ABSTRACT FROM AUTHOR]

Immune-mediated thrombocytopenia is commonly caused by platelet-reactive antibodies mostly against polymorphic structures residing on platelet glycoproteins such as human leucocyte antigen and human platelet antigen ( HLA class I and HPA). In the Japanese population, some individuals do not express CD36 ( CD36 null also known as Naka) on the cell surface. Immunization of these individuals can lead to the development of CD36 isoantibodies (anti-Naka) which play a role in the mechanism of platelet transfusion refractoriness, post-transfusion purpura and fetal/neonatal alloimmune thrombocytopenia. Until today, however, little is known about the clinical relevance of CD36 deficiency and CD36 isoantibodies among other South-East Asian populations. Therefore, multinational study was organised under the aegis of the ISBT to study the distribution of CD36 deficiency in this region. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD) differs from Alzheimer’s disease (AD) in larger fluctuations of cognitive impairment, hypothetically because of deteriorated vigilance control. Vigilance levels are reflected by locations of EEG sources. Transition from alertness to sleep might be particularly sensitive to degradations of vigilance control. Twelve AD and 12 VaD patients (medication free, mean age 75.6 and 77.6 years, respectively, difference = n.s.), and 12 healthy elderly subjects (mean age 70.6 years), who served as controls, were studied (each group comprised 2 males and 10 females). A twenty-one-channel EEG was recorded from full alertness to the onset of sleep stage 2. Dipole source modeling, based on Fast Fourier Transform dipole approximation, yielded 3D source localizations in 7 EEG frequency bands. For each brain axis, means of source location differences between successive 20-second periods were calculated (fluctuation magnitude). EEG band-wise MANCOVAs (3 brain axes, 3 subject groups, covariate: age) showed differences in fluctuation magnitude between groups in the 10.5- to 12-Hz α2 frequency band (p = 0.0066). Post hoc ANCOVAs for the axes (3 subject groups, covariate: age) were significant on the superior-inferior axis: VaD patients had higher fluctuations than AD patients and controls, without significant difference between the latter two. Thus, larger source fluctuations in VaD might reflect the patients’ decreased vigilance control, accounting for their increased fluctuations of cognitive impairment. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs), known to inhibit cyclooxygenase (COX), reduce the risk of colorectal cancer. COX is a key enzyme in prostaglandin biosynthesis, and two isoforms of COX, COX-1 and COX-2, have been identified. Recently COX-2 has been reported to frequently overexpress in colorectal neoplasms and to play a role in colorectal tumorigenesis and tumor progression. In this study, using immunohistochemistry, we examined COX-2 expression in advanced human colorectal cancer and its correlation with clinicopathological features. COX-2 expression was observed mainly in the cytoplasm of cancer cells in all the specimens examined, but some stromal cells and endothelial cells were also stained. According to the grade of COX-2 expression of the cancer cells, patients were divided into high- and low-COX-2 expression groups. High-COX-2 expression significantly correlated with tumor recurrence, especially haematogenous metastasis. These results suggest that a selective COX-2 inhibitor can be a novel class of therapeutic agents not only for tumorigenesis but also for haematogenous metastasis of cololectal cancer. To our knowledge, this is the first report on the correlation between COX-2 overexpression and recurrence of colorectal cancer. [ABSTRACT FROM AUTHOR]

It is proposed that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal tumorigenesis by inhibition of cyclooxygenase (COX). COX is a key enzyme in the conversion of arachidonic acid to prostaglandins and two isoforms of COX have been characterized, COX-1 and COX-2. Multiple studies have shown that COX-2 is expressed at high levels in colorectal tumours and play a role in colorectal tumorigenesis. Recently it has been reported that selective inhibition of COX-2 inhibits colon cancer cell growth. In this study we investigated the effect of a selective COX-2 inhibitor (JTE-522) on haematogenous metastasis of colon cancer. For this purpose, we selected a murine colon cancer cell line, colon-26, that constitutively expresses the COX-2 protein. The subclone P expressed a high level of COX-2 and the subclone 5 expressed a low level. The colon-26 subclones were injected into the tail vein of BALB/c mice. JTE-522 was given intraperitoneally every day from the day prior to cancer cell injection, and the mice were sacrificed 16 days after cell injection. Lung metastases were compared between groups with and without JTE-522. In the mice injected with subclone P, the number of lung metastatic nodules was significantly reduced in the treated group. However, in the mice injected with subclone 5, there was little difference between the control and the treated groups. These results indicate that there may be a direct link between inhibition of haematogenous metastasis of colon cancer and selective inhibition of COX-2, and that selective COX-2 inhibitors may be a novel class of therapeutic agents not only for colorectal tumorigenesis but also for haematogenous metastasis of colon cancer. [ABSTRACT FROM AUTHOR]

Under the physiological shear condition, cultured colon cancer cells bound to laminin (LM), but not to fibronectin or vitronectin. Most of the tethered cells did not roll, but arrested immediately and spread within 10-30 min on LM under the continuous presence of shear flow. The tethering of Colo201 was partially inhibited by monoclonal antibodies (mAbs) to α6 integrin and a combination of mAbs to β1 and β4 integrins, but not by mAb to 67KD laminin receptor. Some Colo201 cells still tethered at 4°C. This suggests that α6β1 and α6β4 integrins participate in Colo201 tethering on LM, although other non-integrin molecules play roles. In contrast, the spread of Colo201 was effectively inhibited by the mAbs to integrin α2, α6 and β1 chains. The effect of anti-α2 plus anti-α6 mAbs was almost equal to anti-β1, suggesting that Colo201 cells mainly use α2β1 and α6β1 integrins for spreading on LM. When the cells were perfused on subconfluent endothelial cells (HUVEC) cultured on LM, they did not tether on HUVEC but did on coated LM exposed at intercellular gap area. Immunohistochemistry revealed that LM abundantly existed in the cytosol of human portal and hepatic vein endothelial cells. These data suggest that LM can mediate from tethering to spreading of colon cancer cells under the blood flow and plays an essential role in haematogeneous metastasis. [ABSTRACT FROM AUTHOR]

The major operative indication for ulcerative colitis is intractability. Although steroid side effects appear to be closely associated with surgical indications for intractable ulcerative colitis, this relationship has yet to be analyzed in detail. To elucidate this relationship, we investigated 39 surgical patients with intractable ulcerative colitis, as defined by the Research Committee for Intractable Diseases of the Ministry of Health and welfare of Japan, and 66 conservatively treated patients with ulcerative colitis, of whom 6 had intractable disease. All patients with major steroid side effects and 17/24 (71%) patients with minor side effects underwent surgery. The median number of admissions was higher in patients with major side effects than in those with less severe or no side effects in the operative series, while this value was lower in the non-operative series than in the operative series. This tendency was similar for the total duration of hospitalization and the number of relapses. In the operative series, markedly higher steroid doses were administered to patients with side effects than to those without, and lower doses were given in the non-operative series. On multivariate regression analysis, the presence of steroid side effects, disease extent, and disease duration were significantly associated with surgery. Patients without side effects had a higher postoperative complication rate than those with minor side effects. We conclude that major side effects are a surgical indication for patients with intractable ulcerative colitis, and that even minor side effects should be taken as a surgical indication in view of the patient's quality of life. [ABSTRACT FROM AUTHOR]

It has been reported that anti-A and anti-B (ABO antibody) titers decrease with age, but little is known about the association between ABO antibody titers and physiologic/biochemical parameters such as body mass index (BMI), gamma-glutamyl transpeptidase (GGT), and total cholesterol (T-Cho). We investigated the present situation of ABO antibody titers among healthy blood donors in Japan and the physiologic/biochemical factors that may be associated with changes in ABO antibody titers. Plasma from 7450 Japanese blood donors was tested for ABO antibody titers using ABO reverse typing reagents by an automated microplate system; donor samples were classified into low, middle, and high titers according to the agglutination results obtained with diluted plasma samples. Multivariate regression analysis was performed to analyze the association between ABO antibody titers and age, gender, biochemical parameters (alanine transaminase [ALT], GGT, globulin, T-Cho, and glycosylated albumin [GA]), and BMI according to the ABO blood groups. A significant correlation between ABO antibody titers and age/gender, except for gender in anti-A of blood group B donors, was observed. BMI showed significant but negative correlations with anti-A and anti-B (β = -0.085 and -0.062, respectively; p < 0.01) in blood group O donors. In addition, significant but negative correlations between GGT and T-Cho with anti-B of blood group A donors (β = -0.055 and -0.047, respectively; p < 0.05) were observed. Although differences existed among the ABO blood groups, ABO antibody titers seem to be associated with physiologic and biochemical parameters of healthy individuals., (© 2023 M. Mikame et al., published by Sciendo.)

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel activated by various physical stimuli such as cell swelling and shear stress. TRPV4 is expressed in bladder sensory nerves and epithelium, and its activation produces urinary dysfunction in rodents. However, there have been few reports regarding its involvement in bladder pain. Therefore, we investigated whether TRPV4 is involved in bladder pain in mouse cystitis model. Intraperitoneal injection of cyclophosphamide (CYP; 300 mg/kg) produced mechanical hypersensitivity in the lower abdomen associated with a severe inflammatory bladder in mice. The mechanical threshold was reversed significantly in Trpv4-knockout (KO) mice. Repeated injections of CYP (150 mg/kg) daily for 4 days provoked mild bladder inflammation and persistent mechanical hypersensitivity in mice. Trpv4-KO mice prevented a reduction of the mechanical threshold without an alteration in bladder inflammation. A selective TRPV4 antagonist also reversed the mechanical threshold in chronic cystitis mice. Although expression of Trpv4 was unchanged in the bladders of chronic cystitis mice, the level of phosphorylated TRPV4 was increased significantly. These results suggest involvement of TRPV4 in bladder pain of cystitis mice. A TRPV4 antagonist might be useful for patients with irritable bladder pain such as those with interstitial cystitis/painful bladder syndrome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cocrystal engineering can alter the physicochemical properties of a drug and generate a superior drug candidate for formulation design. Oxyresveratrol (ORV) exhibits a poor solubility in aqueous environments, thereby resulting in a poor bioavailability. Extensive cocrystal screening of ORV with 67 cocrystal formers (coformers) bearing various functional groups was therefore conducted using grinding, liquid-assisted grinding, solvent evaporation, and slurry methods. Six cocrystals (ORV with betaine (BTN), L-proline (PRL), isonicotinamide, nicotinamide, urea, and ethyl maltol) were found, including four novel cocrystals. Powder X-ray diffraction, low frequency Raman spectroscopy, and thermal analysis revealed unique crystal forms in all obtained samples. Conventional Raman and infrared data differentiated the cocrystals by the presence or absence of a hydrogen bond interacting with the aromatic ring of ORV. The crystal structures were then elucidated by single-crystal X-ray diffraction. Two new cocrystals consisting of ORV : BTN (2 : 3) and ORV : PRL : H 2 O (1 : 2 : 1) were identified, and their crystal structures were solved. We report novel cocrystalline solids of ORV with improved aqueous solubilities and the unique cage-like crystal structures.

Background: Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan., Objective: To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD., Methods: In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm 2 ; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm 2 ; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24., Results: A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 ( p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period., Conclusion: Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI., Competing Interests: This study was funded by Novartis Pharma K.K. Kengo Ueda, Kazuki Kiyose, and Kazuhiro Toriyama are full-time employees of Novartis Pharma K.K. Ankita Shekhawat and Ayan Das Gupta are full-time employees of Novartis Healthcare Pvt. Ltd. In the past year, Sadao Katayama has received speaking fees from Novartis Pharma K.K., and research fees including payment for clinical trials from Eli Lilly Japan K.K., Biogen Japan Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Boehringer Ingelheim Japan. Tetsuaki Arai has received speaking fees from Eisai Co., Ltd. and Daiichi Sankyo Co., Ltd. Nobuo Furuta has received speaking fees from Janssen Pharmaceutical K.K. Makio Takahashi has received lecture fees from Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. and Novartis Pharma K.K. Toshihisa Tanaka has received fees for research from Biogen Japan Ltd., MSD K.K., Shionogi & Co., Ltd., and speaking fees from Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Meiji Seika Pharma Co., Ltd. Yu Nakamura has received speaking fees from Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., MSD K.K., and research fees including payment for clinical trials from Daiichi Sankyo Co., Ltd., and Biogen Japan Ltd. The other authors have no conflict of interest to declare., (Copyright © 2019 by S. Karger AG, Basel.)

Aim: Most patients with Alzheimer's disease (AD) experience poor food intake and/or loss of appetite, which accelerates cognitive impairment. Several reports have shown that rivastigmine improves appetite in AD patients. The present study investigated the efficacy of a rivastigmine transdermal patch for the treatment of low food intake in AD patients., Methods: AD patients, recruited through the Attitude Towards Food Consumption in Alzheimer's Disease Patients Revive with Rivastigmine Effects study, were recognized as experiencing either a loss of appetite or poor food intake. A rivastigmine transdermal patch was administered to study participants for 16 weeks. Patients' food intake, bodyweight, Mini-Mental State Examination scores and any adverse events were recorded., Results: A total of 38 patients with AD (age 86.2 ± 5.4 years) were examined. Their mean Mini-Mental State Examination score was 10.1 ± 7.0 at baseline. A significant increase in food intake amount (54.9 ± 98.0 g, P < 0.01) and food intake ratio (9.3% ± 17.6%, P < 0.01) was observed by week 1, improvements that were maintained throughout the study duration. A multiple linear regression analysis showed that no independent variables were significantly associated with changes in food intake amount or ratio. Patients in the higher Mini-Mental State Examination subgroup showed a trend change in food intake amount, although this did not reach statistical significance (P = 0.07)., Conclusions: The present study suggests that a rivastigmine transdermal patch might improve poor food intake or loss of appetite in patients with AD. Geriatr Gerontol Int 2019; 19: 571-576., (© 2019 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Background: In this study, we examined the construct validity, concurrent validity concerning other standard scales, intrarater reliability, and changes in scores at 12 weeks of the previously developed ABC Dementia Scale (ABC-DS), a novel assessment tool for Alzheimer's disease (AD)., Methods: Data were obtained from 312 patients diagnosed with either AD or mild cognitive impairment. The scores on the ABC-DS and standard scales were compared., Results: The 13 items of the ABC-DS are grouped into three domains, and the domain-level scores were highly correlated with the corresponding conventional scales. Statistically significant changes in assessment scores after 12 weeks were observed for the total ABC-DS scores., Conclusion: Our results demonstrate the ABC-DS to have good validity and reliability, and its usefulness in busy clinical settings.

A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A series of 2',4'-dimethyl-[4,5'-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2',4'-dimethyl-[4,5'-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold., (Copyright © 2016 Elsevier Ltd. All rights reserved.)