Pharmacokinetic analysis of new synthetic antimalarial N-251

Background With the emergence and growing number of drug-resistant Plasmodium falciparum, a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice. Results PK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. Cmax was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability (F) was approximately 23%. Additionally, Tmax, Cmax, AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251. Conclusions N-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis

Images Formed of Neonates and Infants in Child Health Nursing Practice utilizing Neonate and Infant Models

本研究は新生児・乳児モデルを使用した小児看護学演習において,学生が新生児および乳児をどのようにイメージしたかを明らかにし,対象理解の導入としての効果を検討することを目的とした.短期大学看護学科2年生67名を対象に,小児の養護の演習終了後の感想をデータとし,質的・帰納的に分析した.結果,【小児看護技術の特徴】,【子どもの特性】,【感想・課題】,【愛着】,【養育者への思い】のカテゴリが得られた.【小児看護技術の特徴】が最も多く記述され,演習は学生にとって技術習得の意味が大きかった.【子どもの特性】では,子どもの成長発達上の特徴を示す内容が記述され,学生は子どもの特性を具体的にイメージできた.【愛着】,【養育者への思い】では,学生は子どもに対する愛着を喚起し,養育者へも思いを及ばせていることから,子どもとその家族も含めて,看護対象の理解を深めたと思われる.以上より,モデルを使用することは,子どもの早期イメージ化をはかり,対象理解の導入としても有効な教授方法であることが示唆された.The present study aims to determine the images that students form of neonates and infants after completing a course on child health nursing practice utilizing neonate and infant models. Furthermore, the effect as introduction of object understanding is examined. Sixty-seven second-year college nursing students were surveyed after completing the child health nursing practice course, and data were qualitatively and inductively analyzed. The following categories were identified: "characteristics of child health nursing techniques", "characteristics of children", "impressions and topics", "affection" and "concerns for guardians". Content was highest for the category of "characteristics of child health nursing techniques", suggesting that students valued most the nursing techniques taught on the course. The category of "characteristics of children" contained items that were related to the growth and development of children, and enabled the students to form concrete images of children. The categories of "affection" and "concerns for guardians" included items that were related to affection toward children and concerns for their guardians, suggesting that the students gained an understanding of children and their families within the scope of nursing. Taken together, the findings indicate that the use of models for introducing study subjects may be an effective teaching method enabling students to quickly form images of children

Impact of a president’s attributes on leadership roles in private universities : Results of a questionnaire survey

In recent years, Japanese higher education policy has encouraged the strengthening of the leadership role of the university president; however, the meaning of “leadership role” has not always been very clear. To clarify the understanding of what is expected of university presidents; we must first understand what roles they are playing now and which factors affect the ways in which they fulfill their position. The purpose of this study was to clarify the influence of the university president’s job description and number of years in office on what the president actually does and on his or her abilities using a questionnaire-based survey. The results revealed notable differences in the duties and capabilities of university presidents, depending on their professional experience and number of years of service

MicroRNA-351 Regulates Two-Types of Cell Death, Necrosis and Apoptosis, Induced by 5-fluoro-2'-deoxyuridine.

Cell-death can be necrosis and apoptosis. We are investigating the mechanisms regulating the cell death that occurs on treatment of mouse cancer cell-line FM3A with antitumor 5-fluoro-2'-deoxyuridine (FUdR): necrosis occurs for the original clone F28-7, and apoptosis for its variant F28-7-A. Here we report that a microRNA (miR-351) regulates the cell death pattern. The miR-351 is expressed strongly in F28-7-A but only weakly in F28-7. Induction of a higher expression of miR-351 in F28-7 by transfecting an miRNA mimic into F28-7 resulted in a change of the death mode; necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in the morphology change, apoptosis to necrosis, in this death-by-FUdR. Possible mechanism involving lamin B1 in this miR-351's regulatory action is discussed