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Iron complexes bearing new silyl-NHC bidentate ligands were synthesised by treating Fe 3 (CO) 12 with a mixture of N -(hydrosilyl)methyl imidazolium salts and a base. These complexes showed high performance in the catalytic double hydroboration of nitrile with pinacolborane (HBpin) to produce N , N -bis(boryl)amine by a combination of UV irradiation and mild heating (60 °C). The product yields for the hydroboration of aromatic and aliphatic nitriles reached 85%-95% (NMR) using an iron complex (5 mol%). Reducing the loading amount of the iron complex to 0.5 mol% still afforded the products in high yields. An analogous ruthenium complex, which was similarly synthesised using Ru 3 (CO) 12 , showed lower activity. Stoichiometric reactions of the iron complex with nitriles afforded Fe(0)- N -silylimine complexes, which may be dormant states in nitrile hydroboration. A catalytic mechanism including Fe(0) N -silylimine species is proposed.

Background and Objectives: Control of burn wound infection is difficult due to the increase in drug-resistant bacteria and deteriorated immune responses. In this study, we examined the usefulness of methylene blue (MB)-mediated antimicrobial photodynamic therapy (aPDT) with illumination by a light-emitting diode (LED) array for controlling invasive infections from the wound to inside the body for rats with an extended deep burn infected with Pseudomonas aeruginosa., Study Design/materials and Methods: An MB solution with the addition of ethanol, ethylene-diamine-tetra-acetic acid disodium salt, and dimethyl sulfoxide was used as a photosensitizer (PS). An extended deep burn was made on the dorsal skin in rats and the wounds were infected with P. aeruginosa. The rats were divided into three groups: control (no treatment; n = 14), PS mixture application alone (PS alone group; n = 10), and aPDT group (n = 14). For aPDT, after the PS mixture was applied onto the surface of infected wounds, the wounds were illuminated with a 665-nm LED array at an intensity of 45 mW/cm 2 three times per treatment, with an illumination duration of 20 minutes and an interval of 10 minutes. The treatment was repeated each day for 7 consecutive days (day 0-day 6). Bacterial numbers on the wound surface and the weights and survival rates of the animals were evaluated daily. At the endpoints, bacterial numbers in the liver and blood were counted. Since the PS mixture showed high dark toxicity against P. aeruginosa in vitro, the influence of the PS mixture application onto healthy skin was also examined in vivo., Results: Even in the aPDT group, rapid bacterial regrowth was observed on the wound surface after each day's treatment, but the geometric mean values of the bacterial numbers before and after each aPDT were considerably lower than those in the control group. Application of the PS mixture alone showed a clear bactericidal effect only at day 0, which is attributable to the formation of biofilms after day 1. Rats in the aPDT group showed a smaller weight loss, a higher ratio of no bacterial migration at the endpoints, and significantly higher survival rates than those in the other two groups. Effects of repeated application of the PS mixture onto healthy skin were not evident., Conclusions: Application of MB-mediated aPDT with illumination by a high-intensity LED array daily for seven consecutive days was effective for suppressing invasive infection from the wound to inside the body in rats with an extensive deep burn infected with P. aeruginosa, resulting in significant improvement of their survival. Lasers Surg. Med. © 2021 Wiley Periodicals LLC., (© 2021 Wiley Periodicals LLC.)

Aim: To determine the relationship between multiple medications and falls., Methods: This case-control and case-crossover study was carried out at Kudanzaka Hospital in Chiyoda, Tokyo, Japan. A total of 325 patients who experienced their first falls when hospitalized between January 2016 and November 2018, and 1285 controls matched by sex, age and clinical departments were included in this study. Hospitalization duration and fall risk score were adjusted for in the analyses., Results: In the case-control study, multivariable logistic regression showed that increasing the intake of oral medications was not significantly associated with the incidence of falls (odds ratio 1.02, 95% confidence interval 0.998-1.049). In contrast, drugs prescribed with special caution in accordance with the Elderly Oral Medication Guidelines were significantly associated with falls (odds ratio 1.17, 95% confidence interval 1.09-1.26). A similar pattern was observed in the case-crossover analysis. Among the drugs to be prescribed with special caution according to the guidelines, atypical antipsychotics, non-benzodiazepine hypnotics and magnesium oxide were significantly associated with the risk of falls., Conclusion: The drugs to be prescribed with special caution according to the guidelines were associated with an increased fall risk. The risk of falls in hospitalized older people due to multiple medications varies among medications. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2021; ••: ••-••., (© 2021 Japan Geriatrics Society.)

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment., Competing Interests: Rie Nishitani, Ayano Takeuchi, Mamoru Touko, Takashi Kato, Satoshi Ohtani, Sahoko Chiba, Keiko Ashidate, Tomoyasu Ichijo, Takanori Shirai, Nobuo Ishiwata, Masataka Sasabe. declares that they have no conflicts of interest. Yoshiki Ishibashi, reports personal fees from Children and Future co., Ltd. Akiyoshi Shimura reports personal fees from Dainippon Sumitomo Pharma, Yoshitomiyakuhin, and Meiji Seika Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

We developed an accurate and precise system for controlling dew points by using an active pressure control system in a primary standard humidity generator. By using this system, an adjustment capability to a target value of 0.0008 °C was attained for dew-point generation, compared with the previous value of approximately 0.01 °C. In a two-pressure humidity generator, the drift in the dew point with time owing to a rapid drop in the water level in the presaturator and to fluctuations in atmospheric pressure was greatly suppressed. The standard deviation of the dew point obtained with our dew-point control system was 10 times smaller than the drift observed in the absence of the system. This dew-point control system makes it possible to calibrate humidity sensors at target values with greater efficiency.

Background: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan., Methods: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma., Results: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01)., Conclusions: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 µg·kg⁻¹·min⁻¹) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 µg·kg⁻¹·min⁻¹) and flecainide (0.13 mg·kg⁻¹·min⁻¹) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling.

Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC(50) of 0.05 µM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC(50) of 0.1 µM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans.

Controlling the position of a magnetic domain wall with electric current may allow for new types of non-volatile memory and logic devices. To be practical, however, the threshold current density necessary for domain wall motion must be reduced below present values. Intrinsic pinning due to magnetic anisotropy, as recently observed in perpendicularly magnetized Co/Ni nanowires, has been shown to give rise to an intrinsic current threshold J(th)(0). Here, we show that domain wall motion can be induced at current densities 40% below J(th)(0) when an external magnetic field of the order of the domain wall pinning field is applied. We observe that the velocity of the domain wall motion is the vector sum of current- and field-induced velocities, and that the domain wall can be driven against the direction of a magnetic field as large as 2,000 Oe, even at currents below J(th)(0). We show that this counterintuitive phenomenon is triggered by Walker breakdown, and that the additive velocities provide a unique way of simultaneously determining the spin polarization of current and the Gilbert damping constant.

Controlling the displacement of a magnetic domain wall is potentially useful for information processing in magnetic non-volatile memories and logic devices. A magnetic domain wall can be moved by applying an external magnetic field and/or electric current, and its velocity depends on their magnitudes. Here we show that the applying an electric field can change the velocity of a magnetic domain wall significantly. A field-effect device, consisting of a top-gate electrode, a dielectric insulator layer, and a wire-shaped ferromagnetic Co/Pt thin layer with perpendicular anisotropy, was used to observe it in a finite magnetic field. We found that the application of the electric fields in the range of ± 2-3 MV cm(-1) can change the magnetic domain wall velocity in its creep regime (10(6)-10(3) m s(-1)) by more than an order of magnitude. This significant change is due to electrical modulation of the energy barrier for the magnetic domain wall motion.

Eltrombopag (ELT) is a novel thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Previous reports indicate that ELT is mainly eliminated in the liver, although its pharmacokinetic profile has not yet been clarified in detail. The purpose of the present study is to investigate the overall elimination mechanism of ELT. After intravenous administration of ELT to rats, approximately 40% of unchanged ELT was excreted into the bile in 72 h, whereas less than 0.02% of the dose was excreted in urine, indicating that liver is the major elimination organ for ELT. The total clearance was much lower than the hepatic blood flow rate and comparable with hepatic uptake clearance obtained from integration plot analysis. Coadministration of rifampicin, an organic anion transporter inhibitor, reduced both total clearance and hepatic uptake clearance of ELT. These results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT. To further characterize the uptake mechanism, uptake of ELT by freshly isolated mouse hepatocytes was examined. The ELT uptake showed concentration and energy dependence and was inhibited by various compounds, including not only organic anions but also organic cations. Hepatic uptake clearance in vivo was reduced by coadministration of an organic cation, tetrapentylammonium. Finally, uptake of ELT was observed in human embryonic kidney 293 cells transfected with human hepatic transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1 and organic cation transporter OCT1. These results suggest that multiple transporters, including organic anion transporters and organic cation transporters, are involved in hepatic ELT uptake.

Background: The acetylcholine-activated K(+) current (I(K,ACh)) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement of I(K,ACh) in atrial fibrillation (AF) using NTC-801, a novel potent and selective I(K,ACh) blocker., Methods and Results: The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol, on I(K,ACh) and other cardiac ionic currents (I(Na), I(CaL), I(to), I(Kur), I(Kr), I(Ks), I(Kl), I(KATP), and I(f)) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-induced I(K,ACh) in guinea pig atrial cells and the GIRK1/4 current in Xenopus oocytes with IC(50) values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibited I(K,ACh) >1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD(90)) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD(90) at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in 3 AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period without affecting ventricular effective refractory period under vagal nerve stimulation. NTC-801 dose-dependently converted AF to normal sinus rhythm in both vagal nerve stimulation-induced (0.3 to 3 μg · kg(-1) · min(-1) IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg(-1) · min(-1) IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent., Conclusions: A selective I(K,ACh) blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest that I(K,ACh) may be important in the development and maintenance of AF.

Objective: The signaling by thrombopoietin (TPO) via its receptor, c-MPL, plays a crucial role in the maintenance of hematopoietic stem cells (HSCs). Small-molecule c-MPL agonists have recently been shown to be beneficial in the treatment of thrombocytopenia. However, their effects on HSCs have not yet been explored. In this study, we evaluated the effects of NR-101, a novel small-molecule c-MPL agonist, on the ex vivo expansion of human cord blood (hCB) HSCs., Materials and Methods: hCB CD34(+) or CD34(+)CD38(-) hematopoietic stem and progenitor cells were cultured for 7 days in the presence of thrombopoietin (TPO) or NR-101, and then subjected to flow cytometric analyses, colony-forming cell assays, and severe combined immunodeficiency-repopulating cell assays., Results: During a 7-day culture of CD34(+) or CD34(+)CD38(-) hematopoietic stem and progenitor cells, NR-101 efficiently increased their numbers, with a greater than twofold increase compared to TPO, although its effect on megakaryocytopoiesis was comparable to that of TPO. Correspondingly, severe combined immunodeficiency-repopulating cells were increased 2.9-fold during a 7-day culture with NR-101 compared to freshly isolated CD34(+) cells, and 2.3-fold compared to that with TPO. Of note, NR-101 persistently activated signal transducer and activator of transcription (STAT) 5 but not signal transducer and activator of transcription 3. Furthermore, NR-101 induced a long-term accumulation of hypoxia-inducible factor-1alpha protein and enhanced activation of its downstream target genes., Conclusion: This is the first time that a small-molecule c-MPL agonist has been demonstrated to promote net expansion of HSCs. NR-101 is more efficient in ex vivo expansion of HSCs than TPO. NR-101 could be a useful tool for the therapeutic manipulation of human HSCs.

Objectives: Equol, a metabolite of the isoflavone daidzein, is hypothesized to play a major role in the health benefits of soy. We examined the effect of a new S-equol supplement on menopausal symptoms and mood states., Design: We conducted a randomized, double-blind, placebo-controlled trial with our new equol supplement for 12 weeks with 134 Japanese women (aged 40-59 years). They were randomly assigned to three groups: placebo (n = 44), 10 mg of equol per day (EQ-1; n = 44), and 10 mg of equol three times per day (EQ-3; n = 46). Habitual isoflavone intake was limited to 20 mg/d. Participants completed menopausal symptom and Profile of Mood States questionnaires at baseline and postintervention. Physical examination and blood and 24-hour urine collection were performed at baseline and postintervention., Results: At baseline, total menopausal symptom score varied by menopausal and equol producer status (34.3% producers). A total of 127 participants (94.8%) completed the trial. No adverse effects were reported, except for a systemic rash in one EQ-3 woman. The anxiety scores of equol producers were lower than those of nonproducers (P < 0.05). Significant differences between premenopausal and perimenopausal/postmenopausal symptom scores were observed for anxiety, somatic, and total scores. After the EQ-3 intervention, perimenopausal/postmenopausal equol nonproducers showed significant decreases from baseline in all menopausal symptom scores except depression (P < 0.01). Compared with placebo, the EQ-3 group showed significant decreases in depression scores (P < 0.05), as well as significant decreases in Tension-Anxiety (P < 0.05), Depression-Dejection (P < 0.05) and Fatigue (P < 0.01) and increases in Vigor (P < 0.05) of the Profile of Mood States., Conclusion: S-equol supplement improved mood-related symptoms in perimenopausal/postmenopausal equol nonproducers.

Purpose: To evaluate the chemotherapeutic regimens suitable for the outpatient settings, we conducted a randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel., Methods: Group CP(n=25): carboplatin AUC 6.0 day 1 and paclitaxel 70 mg/m2 day 1, 8, 15 every 4 weeks followed by gemcitabine 1.0 g/m2 day 1, 8, 15 every 4 weeks; group CG(n=26): carboplatin AUC 2.0 and gemcitabine 0.8 g/m2 day 1, 8 every 3 weeks followed by docetaxel 60 mg/m2 day 1, 8 every 3 weeks., Results: The response rate of the first line therapy was 18.0% in group CP and 21.7% in group CG and that of the second line therapy was 10.0% and 14.3%, respectively. Time to progression of the first line therapy was 4.0 months in group CP and 4.3 months in group CG, that of the second line therapy was 2.1 months and 2.8 months, respectively. The median survival time was 10.9 months in group CP and 10.3 months in group CG. No statistically significant differences were documented in the response rate, time to progression, and overall survival between these two groups. Severe hematologic toxicity was rare in both groups and no symptomatic peripheral neuropathy was documented in carboplatin/paclitaxel therapy., Conclusion: Carboplatin /paclitaxel followed by gemcitabine and carboplatin/gemcitabine followed by docetaxel were well tolerated and equal in efficacy. Both regimens in this study seemed to be suitable for the outpatient settings because of their mild hematologic toxicity and peripheral neuropathy.

A 66-year-old man who had been given a clinical diagnosis of vasculitis at another hospital after presenting with high fever and rash was admitted to our hospital for further examination following a relapse of fever during steroid reduction. The biopsy specimens of the leg with crusts showed the presence of epithelioid granuloma, and because of a negative tuberculin test, increased serum angiotensin converting enzyme (ACE) and lysozyme levels, and pulmonary Ga uptake, the patient was given a diagnosis of sarcoidosis. Although the patient had been treated on an outpatient basis following resolution of fever with NSAIDs and 5 mg prednisolone (PSL), he suffered acute respiratory failure during follow-up and required emergency admission. Chest CT revealed bilateral ground-glass opacity and pleural effusion, and serum ACE and soluble IL2R levels were significantly elevated. We diagnosed acute exacerbation of sarcoidosis and given high dose steroid therapy. The patient's symptoms, image findings, blood test results, and other findings promptly improved. Here we reported a highly unusual presentation of acute respiratory failure in sarcoidosis.

NT-702 (parogrelil hydrochloride, NM-702), 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride, a novel phosphodiesterase (PDE) inhibitor synthesized as a potent vasodilatory and antiplatelet agent, is being developed for the treatment of intermittent claudication (IC) in patients with peripheral arterial disease. We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo. NT-702 selectively inhibited PDE3 (IC(50)=0.179 and 0.260 nM for PDE3A and 3B) more potently than cilostazol (IC(50)=231 and 237 nM for PDE3A and 3B) among recombinant human PDE1 to PDE6. NT-702 inhibited in vitro human platelet aggregation induced by various agonists (IC(50)=11 to 67 nM) and phenylephrine-induced rat aortic contraction (IC(50)=24 nM). Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM, respectively. NT-702 (3 mg/kg or more) significantly inhibited ex vivo rat platelet aggregation after a single oral dose. For cilostazol, 300 mg/kg was effective. In a rat femoral artery ligation model, NT-702 at 5 and 10 mg/kg repeated oral doses twice a day (BID) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more. Cilostazol also improved the walking distance and surface temperature at 300 mg/kg BID but significant difference was only observed for surface temperature on day 8. These results suggest that NT-702 can be expected to have therapeutic advantage for IC.

NIP-004 is a novel synthetic compound developed to display human thrombopoietin (TPO) receptor (c-Mpl) agonist activity. NIP-004 displays species specificity, stimulating proliferation or differentiation of human c-Mpl-expressing cells such as UT-7/TPO and human CD34(+) cells but not murine c-Mpl-expressing cells or cynomolgus monkey cells. To test the mechanism of its action, we constructed mutant forms of c-Mpl; murine c-Mpl(L490H) dis-played a response to NIP-004, whereas human c-Mpl(H499L) lost this response, indicating that histidine in the transmembrane domain of c-Mpl is essential for its activity. Because histidine is not present in the c-Mpl transmembrane domain of rats, hamsters, rhesus macaques, and cynomolgus monkeys, we examined the in vivo efficacy of NIP-004 using mice that received xenotransplants. In immunodeficient nonobese diabetic (NOD)/Shi-scid, IL-2Rgamma(null) (NOG) mice receiving transplants of umbilical cord blood-derived CD34(+) cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes, and circulating human platelets 6-fold, the latter being morphologically and functionally indistinguishable from normal human platelets. These observations indicate that NIP-004 is a novel human c-Mpl activator and induces human thrombopoiesis.

Four xanthocillins (1-4), including a new compound 4, were isolated from cultured marine fungus Basipetospora sp. as thrombopoietin (TPO) mimics. Compounds 1-4 promoted the proliferation of a TPO-sensitive human leukemia cell line, UT-7/TPO, and UT-7/EPO-mpl, genetically engineered to express c-Mpl, a receptor for TPO in dose-dependent manners. However, the proliferation of UT-7/EPO, a parental cell line of UT-7/EPO-mpl that was devoid of TPO receptor, was not affected by them. Thrombopoietic action of compound 1 was nearly as potent as that of TPO, inducing cell proliferation at a concentration ranging from 1 to 100nM. Compound 1 also induced the phosphorylation of several proteins, including Janus kinase 2 (Jak2), signal transducers, and activators of transcription-3 (STAT3) and STAT5 in the UT-7/EPO-mpl cell line, but not in the UT-7/EPO cell line. These data indicated that xanthocillins are putative agonists for c-Mpl, as their cellular actions were analogous to those of TPO.

A double-blind, placebo-controlled crossover study on the effects of 40~mg/d isoflavone supplements was carried out by 58 climacteric Japanese women. A questionnaire and an interview concerning climacteric symptoms, health status, dietary and exercise habit, and medical history were carried out, and the physical check-up and biochemical tests including sex-hormone analysis were made at baseline and after 4 and 8 weeks of treatment. Urinary isoflavones were separately measured from the frozen samples. Isoflavone treatment did not cause any adverse effects on anthropometric measures or blood chemistry. Urinary deoxypyridinoline, a marker of bone resorption decreased significantly with isoflavone treatment. This tendency was remarkable among equol producers. Plasma osteocalcin and bone mineral density did not change by the four-weeks treatment. As for climacteric symptoms, hot flash decreased significantly. Systolic and diastolic blood pressure of hypertensive participants decreased significantly after isoflavone treatment compared with baseline and the placebo treatment. Isoflavone supplementation offers benefits to reduce effectively on bone resorption enhanced by menopause. The treatment also showed an improvement of climacteric hot flash and hypertension. Equol producers showed better results.

To achieve the specific expression of a transfected suicide gene in malignant mesothelioma cells, we applied the enhancer-promoter fusion sequence of the keratin 19 (K19) gene. Northern blot analysis of three mesothelioma cell lines demonstrated that K19 mRNA was expressed most abundantly in the H2052 mesothelioma cell line. Subsequently, in a luciferase reporting assay, K19 promoter (260 bp) exhibited higher promoter activity in H2052 cells than in the other two cell lines. In addition, ligation of a 3' enhancer (80 bp) of the K19 gene to upstream of the K19 promoter sufficiently enhanced the promoter activity. After transfecting an expression vector containing the K19 enhancer-promoter bound thymidine kinase gene (pK19-TK) into the H2052 cells, the pK19-TK transfected cells became more sensitive to GCV than non-transfected cells in vitro and in vivo. In a mouse peritoneal model of malignant mesothelioma, in vivo transfection of pK19-TK by cationic liposome and systemic administration of GCV inhibited the growth of peritoneal tumors. The K19 enhancer-promoter sequence seemed to be specific and efficient enough for the expression of the transfected suicide gene in malignant mesothelioma cells.

A 68-year-old woman was diagnosed as having empyema on the left side. She had a history of pulmonary tuberculosis and tuberculous pleurisy in 1949. She was treated with artificial pneumothorax and implantation of 7 Lucite-ball plombs in the left upper thorax. A chest radiograph taken 14 years after initial operation, revealed an increase in density inside some of the Lucite-ball plombs. She was again admitted after experiencing fever and dyspnea 48 years after initial operation. The chest radiograph then showed a large mass on the left side, which compressed the mediastinum to the right. Inside the mass, Lucite-ball plombs were detected. The fever and inflammatory findings were improved with antibiotic therapy, but the dyspnea was persistent. The Lucite-ball Plombs and coagulating tissue were removed successfully. The patient's symptoms and respiratory function improved after the second operation.

The relationship between apoptosis and cellular proliferative activity in human non-small cell lung cancer (25 cases) was investigated using the in situ DNA nick-end labeling method and immunohistochemistry for both proliferating cell nuclear antigen (PCNA) and Ki-67 antigen. Comparison of the distribution of Ki-67-positive cells to that of apoptotic cells shows an inverse correlation in semi-serial sections. The PCNA labeling rates were closely correlated with Ki-67 labeling rates in non-small cell lung cancer. It was concluded that the immunostainings of PCNA and Ki-67 were almost equally valuable for assessing the proliferative activity in paraffin-embedded tissue from non-small cell lung cancer and that apoptosis may be related with the cell cycle in this cancer.

We report five cases of hypersensitivity pneumonitis among workers cultivating Tricholoma conglobatum (shimeji). After having worked for 5 to 20 years, they began to notice symptoms of cough, sputum, and dyspnea. They were diagnosed as having a hypersensitivity pneumonitis based on clinical features, bronchoalveolar lavage and transbronchial lung biopsy. By the double immunodiffusion test, precipitating lines between shimeji spore antigen and sera were observed in all of the patients. By enzyme-linked immunosorbent assay, the antibody activities against shimeji and three species of fungi (Cladosporium sphaerospermum, Penicillium frequentans, and Scopulariopsis species) were significantly higher in the sera of the patients than in those of normal subjects who were cultivating shimeji. Although it is not clear what causes this disease, these findings may be helpful in determining the specific antigen.

A plasmid (5.4 kbp) from Salmonella Typhi D4 has been identified as encoding a restriction and modification (R-M) system. DNA fragments (2537 bp) that carried the genes for restriction endonuclease and methyltransferase encoded on the plasmid were sequenced. Two divergently arranged open reading frames of 957 bp for the restriction endonuclease consisting of 318 aa (amino acids) and 1140 bp for the DNA methyltransferase consisting of 379 aa were identified. These sequences were similar to the sequences of the SsoII R-M system, including the interspace between the two genes.

High restriction endonuclease activity was found in a haemolysin-less mutant of the Vibrio parahaemolyticus 1743-1 strain. The endonuclease, named VpaK11BI, recognized the palindromic pentanucleotide sequence of 5'-GGWCC-3' and cleaved double-stranded DNA after the first G, which is exactly the same as the specificity of AvaII. The haemolysin-less mutant of V. parahaemolyticus is now available for producing the valuable restriction endonuclease on a commercial scale.