Lysine and Arginine Reduce the Effects of Cerebral Ischemic Insults and Inhibit Glutamate-Induced Neuronal Activity in Rats

Intravenous administration of arginine was shown to be protective against cerebral ischemic insults via nitric oxide production and possibly via additional mechanisms. The present study aimed at evaluating the neuroprotective effects of oral administration of lysine (a basic amino acid), arginine, and their combination on ischemic insults (cerebral edema and infarction) and hemispheric brain swelling induced by transient middle cerebral artery occlusion/reperfusion in rats. Magnetic resonance imaging and 2,3,5-triphenyltetrazolium chloride staining were performed 2 days after ischemia induction. In control animals, the major edematous areas were observed in the cerebral cortex and striatum. The volumes associated with cortical edema were significantly reduced by lysine (2.0 g/kg), arginine (0.6 g/kg), or their combined administration (0.6 g/kg each). Protective effects of these amino acids on infarction were comparable to the inhibitory effects on edema formation. Interestingly, these amino acids, even at low dose (0.6 g/kg), were effective to reduce hemispheric brain swelling. Additionally, the effects of in vivo microiontophoretic (juxtaneuronal) applications of these amino acids on glutamate-evoked neuronal activity in the ventromedial hypothalamus were investigated in awake rats. Glutamate-induced neuronal activity was robustly inhibited by microiontophoretic applications of lysine or arginine onto neuronal membranes. Taken together, our results demonstrate the neuroprotective effects of oral ingestion of lysine and arginine against ischemic insults (cerebral edema and infarction), especially in the cerebral cortex, and suggest that suppression of glutamate-induced neuronal activity might be the primary mechanism associated with these neuroprotective effects

A STUDY OF OVER THE COUNTER-PHARMACEUTICAL SALES ON THE INTERNET IN CHINA

Purpose of Study: The Pharmaceutical industry in China has been increasing its market: Aging society, urbanization, upgrading of structure of consumption, reform for pharmaceutical market by the government. However, it is still under development regarding e-commerce in china. The objectives of this research is to consider the future trends of Over the Counter (OTC) pharmaceutical sales on the internet in China. Methodology: Questionnaire survey regarding pharmaceutical sales on the internet. Investigated 260 respondents live in China. The questions mainly asked about the purchase of medicines during respondents’ lifetimes and how respondents made decisions about the purchases of general medicine on the Internet. Main Findings: We found that regarding the age of 26­­­­­­­‑35 have the strong potential of purchasing on the internet.At the same timefound that the retail shop has becoming convenient, based on walking distance to drugstore. Implications of study: This study can apply for decision making regarding the purchase of OTC pharmaceutical sales on the internet in China. Also, this study can be refereed when concerning about the system of online pharmaceutical sales. Originality of study: The originality of study is that we designed the questionnaire survey based on abundant lows which connected to pharmaceutical sales on the internet. And we conducted the survey to the consumers so that we can understand the consciousness of the consumers

A STUDY ON THE CULTURAL TOURISM OF THE CHINESE TOURISTS IN JAPAN

The Japanese tourism industry is becoming an important pillar of the Japanese economy. To increase the number of Chinese visitors to Japan, emphasizing the charm of the Japanese culture will be key. Promoting “cultural tourism” as the main reason for Chinese tourists to take vacation trips to Japan will be a major factor in helping Japan reach its international tourism goals by 2020 and beyond. Earlier studies on cultural tourism have offered several conclusions, but few have addressed the subject of cultural tourism as it relates to Chinese visitors to Japan. There appears to be little existing research on Japanese tourism from the perspective of cultural exploration. In most studies on Chinese visitors to Japan, the focus is primarily on economics and policies; very few studies address “cultural tourism.” So in this study, we attempt to expand our understanding of “cultural tourism” among Chinese tourists coming to Japan by identifying factors influencing tourism from a cultural point of view. We conducted a questionnaire survey of Chinese tourists who visited Japan. Before analyzing using multiple regression analysis, we analyzed In order to grasp the visiting factors of Chinese tourists. Based on the results of the survey described here. It was established that increasing numbers of Chinese tourists now visit Japan to pursue “cultural tourism.” The specific elements of this cultural tourism were identified.&nbsp

Ebf3⁺ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells

Lympho-hematopoiesis is regulated by cytokines; however, it remains unclear how cytokines regulate hematopoietic stem cells (HSCs) to induce production of lymphoid progenitors. Here, we show that in mice whose CXC chemokine ligand 12 (CXCL12) is deleted from half HSC niche cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, HSCs migrate from CXCL12-deficient niches to CXCL12-intact niches. In mice whose CXCL12 is deleted from all Ebf3+/leptin receptor (LepR)+ CAR cells, HSCs are markedly reduced and their ability to generate B cell progenitors is reduced compared with that to generate myeloid progenitors even when transplanted into wild-type mice. Additionally, CXCL12 enables the maintenance of B lineage repopulating ability of HSCs in vitro. These results demonstrate that CAR cell-derived CXCL12 attracts HSCs to CAR cells within bone marrow and plays a critical role in the maintenance of HSCs, especially lymphoid-biased or balanced HSCs. This study suggests an additional mechanism by which cytokines act on HSCs to produce B cells.Nakatani T., Sugiyama T., Omatsu Y., et al. Ebf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells. Nature Communications 14, 6402 (2023); https://doi.org/10.1038/s41467-023-42047-2

Effect of Thermal Neutrons on Fusion Power Measurement using the Micro-Fission Chamber in ITER

Abstract A Micro-fission Chamber (MFC) provides time-resolved measurements of global neutron source strength and fusion power in ITER. The MFC is a pencil-sized gas counter containing the fissile material, 235 U. MFCs will be installed behind blanket modules at upper and lower outboard positions due to interface considerations with other equipment and the vacuum vessel. Measurements of the neutron source strength could be affected by cooling water in branch pipes, which will be installed near the MFC. The effect of the branch pipes upon the MFC is assessed by neutron transport calculation using MCNP 5. Results indicate a significant increase in the MFC response rate (up to ~ 40% higher) due to the branch pipe. The increase in the MFC response is caused by the slowing down of the neutrons due to the cooling water in the branch pipes. The effect of the thermal neutrons on the MFC response is especially significant. One possible solution to reduce the effect is to cover the MFC with a material that absorbs thermal neutrons such as cadmium. The ways in which the absorbent material may affect MFC response is analyzed through neutron transport calculation. Results indicate that the increase in the MFC response can be reduced to < 10 % through cadmium coating

Carotid artery occlusion and colateral circulation in C57black/6J mice detected by synchrotron radiation microangiography

Using monochromatic synchrotron radiation, we performed microangiography inC57BL/6J mice and investigated their vasculature after unilateral and bilateral carotidartery occlusion. Bilateral occlusion of the carotid artery was made by a ligation of theleft common carotid artery followed by a ligation of the right internal carotid artery(ICA) two days later (n=12). Five days after the second surgery, angiography wasperformed. Unilateral occlusion was made by clipping the right ICA and thenangiography was performed immediately (n=5). The control mice did not undergo anyocclusion (n=5). We removed the brain of the bilateral occlusion mice afterangiography and examined the infarction area. The cerebral microvessels in all animalswere clearly visualized. In the control mice, the posterior communicating artery (Pcom)was not visualized. In the unilateral occlusion mice, the anastomosis of thepterygopalatine artery (PPA) and the external carotid artery (ECA) were recognized.The PPA is thus considered to play a role in the collateral vessel between the ICA andthe ECA. The Pcom was not visualized. In the bilateral occlusion mice, the Pcom wasobserved either unilateraly (n=5) or bilateraly (n=5). The Pcom supplied blood flow tothe anterior circulation from the vertebrobasilar arteries. The bilateral occlusion micethat had at least one visualized Pcom did not have any infarction. We could successfullyvisualize the cerebral vasculature of normal mice and carotid artery occluded mice inan in vivo study. Microangiography can demonstrate the development of vasculatureand the blood flow dynamics in mice

Noninvasive Tracking of Donor Cell Homing by Near-Infrared Fluorescence Imaging Shortly after Bone Marrow Transplantation

BACKGROUND: Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases. METHODOLOGY/PRINCIPAL FINDINGS: Freshly harvested near-infrared fluorescence-labeled cells were noninvasively observed for 24 h after BMT using a photon counting device to track their homing process. In a congenic BMT model, the homing of Alexa Fluor 750-labeled donor cells in the tibia was detected less than 1 h after BMT. In addition, subsequent cell distribution in an intraBM BMT model was successfully monitored for the first time using this method. In the allogeneic BMT model, T-cell depletion decreased the near-infrared fluorescence (NIRF) signals of the reticuloendothelial system. CONCLUSIONS/SIGNIFICANCE: This approach in several murine BMT models revealed that the transplanted cells homed within 24 h after transplantation. NIRF labeling is useful for tracking transplanted cells in the initial phase after BMT, and this approach can contribute to in vivo studies aimed at improving the therapeutic outcomes of BMT

Rapid detection of hypoxia-inducible factor-1-active tumours: pretargeted imaging with a protein degrading in a mechanism similar to hypoxia-inducible factor-1alpha

PURPOSE: Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-(123)I-iodobenzoyl)norbiotinamide ((123)I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and (123)I-IBB for rapid imaging of HIF-1-active tumours. METHODS: Tumour-implanted mice were pretargeted with POS. After 24 h, (125)I-IBB was administered and subsequently, the biodistribution of radioactivity was investigated at several time points. In vivo planar imaging, comparison between (125)I-IBB accumulation and HIF-1 transcriptional activity, and autoradiography were performed at 6 h after the administration of (125)I-IBB. The same sections that were used in autoradiographic analysis were subjected to HIF-1alpha immunohistochemistry. RESULTS: (125)I-IBB accumulation was observed in tumours of mice pretargeted with POS (1.6%ID/g at 6 h). This result is comparable to the data derived from (125)I-IBB-conjugated POS-treated mice (1.4%ID/g at 24 h). In vivo planar imaging provided clear tumour images. The tumoral accumulation of (125)I-IBB significantly correlated with HIF-1-dependent luciferase bioluminescence (R=0.84, p<0.01). The intratumoral distribution of (125)I-IBB was heterogeneous and was significantly correlated with HIF-1alpha-positive regions (R=0.58, p<0.0001). CONCLUSION: POS pretargeting with (123)I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours

Synthesis and Luminescence Properties of Near-Infrared N-Heterocyclic Luciferin Analogues for In Vivo Optical Imaging

As a means of achieving highly sensitive bioluminescence imaging of deep tissues utilizing the firefly luciferin-luciferase (L-L) reaction, we previously reported a luciferin analogue, AkaLumine, which exhibits high cell-permeability and emits near-infrared (NIR) light with high tissue-penetration by the L-L reaction. However, while AkaLumine enables us to observe targets in deep tissues, its poor solubility in aqueous media limits its utility for in vivo imaging. Herein, to address this issue, we have synthesized three AkaLumine derivatives with N-heterocyclic aromatic rings as new red luciferin analogues that have substantially higher solubility than that of AkaLumine in phosphate buffered saline solution. One of the derivatives (herein termed seMpai) exhibits an emission maximum at 675 nm upon L-L reaction with Photinus pyralis luciferase and presents an activity in mouse-tissue imaging similar to that of AkaLumine. It is hoped that seMpai will extend the application of high-sensitivity NIR bioluminescence imaging in a wide range of biomedical research fields

The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial

<p>Abstract</p> <p>Background</p> <p>Our phase III clinical trial of pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) revealed the efficacy in reducing the decline of vital capacity (VC) and increasing the progression-free survival (PFS) time by pirfenidone. Recently, marginal decline in forced VC (FVC) has been reported to be associated with poor outcome in IPF. We sought to evaluate the efficacy of pirfenidone from the aspects of 5% change in VC.</p> <p>Methods</p> <p>Improvement ratings based on 5% change in absolute VC, i.e., "improved (VC ≥ 5% increase)", "stable (VC < 5% change)", and "worsened (VC ≥ 5% decrease)" at month 3, 6, 9 and 12 were compared between high-dose pirfenidone (1800 mg/day; n = 108) and placebo (n = 104) groups, and (high-dose and low-dose (1200 mg/day; n = 55)) pirfenidone (n = 163) and placebo groups. PFS times with defining the disease progression as death or a ≥ 5% decline in VC were also compared between high-dose pirfenidone and placebo groups, and low-dose pirfenidone and placebo groups. Furthermore, considering "worsened" and "non-worsened (improved and stable)" of the ratings at months 3 and 12 as "positive" and "negative", respectively, and the positive and negative predictive values of the ratings were calculated in each group.</p> <p>Results</p> <p>In the comparison of the improvement ratings, the statistically significant differences were clearly revealed at months 3, 6, 9, and 12 between pirfenidone and placebo groups. Risk reductions by pirfenidone to placebo were approximately 35% over the study period. In the comparison of the PFS times, statistically significant difference was also observed between pirfenidone and placebo groups. The positive/negative predictive values in placebo and pirfenidone groups were 86.1%/50.8% and 87.1%/71.7%, respectively. Further, the baseline characteristics of patients worsened at month 3 had generally severe impairment, and their clinical outcomes including mortality were also significantly worsened after 1 year.</p> <p>Conclusions</p> <p>The efficacy of pirfenidone in Japanese phase III trial was supported by the rating of 5% decline in VC, and the VC changes at month 3 may be used as a prognostic factor of IPF.</p> <p>Trial Registration</p> <p>This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13^th, 2005 (Registration Number: JAPICCTI-050121).</p