Near-Infrared Metabolic Profiling for Discrimination of Apricot and Peach Kernels.

Apricot and Peach Kernels are commercial crude drugs used in many formulas of traditional Japanese medicine, Kampo. Although their applications are quite different, it is difficult to distinguish them using conventional methods such as HPLC. The study aimed at near-infrared (NIR) metabolic profiling to discriminate Apricot and Peach Kernels (Armeniacae Semen and Persicae Semen) collected from Japanese markets. A fast, simple, non-destructive, and robust NIR measurement of kernel surface with no sample pre-treatment was achieved in situ. Principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) models showed discrimination between the two crude drugs with good fitting and prediction values. These results indicate that NIR metabolic profiling is useful for discriminating Apricot and Peach Kernels based on their chemical constituents using a simple and non-destructive procedure.

Stability of masticatory movements after placement of implant-supported denture.

The purpose of this study was to clarify the stability of masticatory movement after placement of implant-supported denture. Fourteen patients (patient group) with mandibular implants denture and maxillary complete denture and 30 dentate adults (control group) were asked to chew a boiled fishpaste, and the masticatory movement was recorded using MKG. For the 10 cycles beginning with the 5th cycle of mastication, the parameters representing the stability of masticatory movement were calculated. Data collected at 1, 3, 6, 9 months and 1, 2, 3 years after insertion of implants denture were compared between sessions and also between the patient and control groups. The mean and standard deviation of the values in the patient group at 1 month after insertion of implants denture were large, but gradually decreased 6 to 9 months after insertion of implants denture. Each parameter maintained almost the same value from 1 to 3 years. The parameter values of the patient group were significantly larger than those of control group from 1 to 9 months after insertion of implants denture, but 1 year after insertion of implants denture, there was no significant difference between the two groups in 5 out of 7 parameters. From these results, it was suggested that a certain duration, about 9 months to 1 year, was necessary for patients with implants denture to adapt to the new masticatory function and that the timing of functional evaluation should be set to 1 year after insertion of implants denture.

Preparation of Tenuifolin from Polygala senega L. Root Using a Hydrolytic Continuous Flow System under High-Temperature, High-Pressure Conditions.

An improved process for preparing tenuifolin (presenegenin 3-ß-d-glucopyranoside) from the root of Polygala senega L. was developed. A crude saponin mixture extracted from P. senega was subjected to hydrolysis, and the reactivity of compounds in the extract was controlled by utilizing the combination of a flow reactor and experimental design. In addition, column chromatography with HP 20, a synthetic polystyrenic adsorbent, allowed the gram-scale preparation of tenuifolin in a continuous manner with fewer steps. This approach shortens the total time required for gram-scale preparation from 16 to 5 h in a continuous manner while improving the yield from 0.59% to 2.08% (w/w).

Permanent pacemaker implantation and its predictors in patients admitted for complete atrioventricular block: a report from the Tokyo Cardiovascular Care Unit Network multi-center registry.

Little is known about the permanent pacemaker implantation rate and predictors of permanent pacemaker implantation in patients admitted for complete atrioventricular block (cAVB). The present study was a retrospective analysis based on a multicenter cohort of 797 patients with cAVB (mean age: 79.6 ± 10.7 years; males: 48.4%) registered with the Tokyo Cardiovascular Care Unit Network multicenter registry between 2013 and 2016. Secondary cAVB due to acute coronary syndrome was excluded. The permanent pacemaker implantation rate was 82.9%. Multivariable logistic regression analysis revealed that systolic blood pressure (SBP) > 140 mmHg [odds ratio (OR) 2.10; 95% confidence interval (CI) 1.38-3.22; P < 0.001], male gender (OR 1.63; 95% CI 1.07-2.49; P = 0.023), and left ventricular ejection fraction (LVEF) ≥ 50% (OR 2.19; 95% CI 1.16-2.06; P = 0.016) were predictors of permanent pacemaker implantation while pre-admission ß-blocker use (OR 0.28; 95% CI 0.17-0.47; P < 0.001) was associated with a lower risk of permanent pacemaker implantation. Reversible cAVB was not rare in patients admitted for cAVB. Data on SBP on admission, gender, LVEF, and pre-admission ß-blocker use may be important for assessing the requirement for permanent pacemaker implantation in the emergency care setting.

Aerobic Intramolecular Oxidative Coupling Using Heterogeneous Catalyst for Synthesis of N-Substituted 2,3,6,7-Tetramethoxycarbazoles.

A heterogeneous metal catalyst enabled the intramolecular oxidative coupling of diarylamines to form carbazoles with molecular oxygen as the sole oxidant. Rh/C had efficient catalytic activity and allowed the catalyst loading to be reduced to 0.1 mol% while maintaining excellent yields of carbazoles. This reaction is operationally simple in an open-to-air setup, and provides a green and atom-economical process for an efficient synthetic approach to N-substituted carbazoles.

Quality Evaluation and Characterization of Fractions with Biological Activity from Ephedra Herb Extract and Ephedrine Alkaloids-Free Ephedra Herb Extract.

Previously, we reported that the c-Met inhibitory effect of Ephedra Herb extract (EHE) is derived from ingredients besides ephedrine alkaloids. Moreover, analgesic and anti-influenza activities of EHE and ephedrine alkaloids-free Ephedra Herb extract (EFE) have been reported recently. In this study, we examined the fractions containing c-Met kinase inhibitory activity from EHE and the fractions with analgesic and anti-influenza activities from EFE, and elucidated the structural characteristics of the active fractions. Significant c-Met kinase activity was observed in 30, 40, and 50% methanol (MeOH) eluate fractions obtained from water extract of EHE using Diaion HP-20 column chromatography. Similarly, 20 and 40% MeOH, and MeOH eluate fractions obtained from water extract of EFE were found to display analgesic and anti-influenza activities. Reversed phase-HPLC analysis of the active fractions commonly showed broad peaks characteristic of high-molecular mass condensed tannin. The active fractions were analyzed using 13C-NMR and decomposition reactions; the deduced structures of active components were high-molecular mass condensed tannins, which were mainly procyanidin B-type and partly procyanidin A-type, including pyrogallol- and catechol-type flavan 3-ols as extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9 : 2, and the weight-average molecular weight based on the polystyrene standard was >45000. Furthermore, GPC-based analysis was proposed as the quality evaluation method for high-molecular mass condensed tannin in EHE and EFE.

Analgesic Effects of Ephedra Herb Extract, Ephedrine Alkaloids-Free Ephedra Herb Extract, Ephedrine, and Pseudoephedrine on Formalin-Induced Pain.

The analgesic effect of Ephedra Herb (EH) is believed to be derived from the anti-inflammatory action of pseudoephedrine (Pse). We recently reported that ephedrine alkaloids-free EH extract (EFE) attenuates formalin-induced pain to the same level as that achieved by EH extract (EHE), which suggests that the analgesic effect of EH may not be due to ephedrine alkaloids (EAs). To examine the contribution of EAs to the analgesic effect of EH, mice were injected with formalin to induce a biphasic pain reaction (first phase, 0-5 min; second phase, 10-45 min) at various time points after oral administration of the following test drugs: ephedrine (Eph), Pse, "authentic" EHE from Tsumura & Co. (EHE-Ts), EFE, and EHE that was used as the source of EFE (EHE-To). Biphasic pain was suppressed at 30 min after administration of Eph, EHE-Ts, and EHE-To. At 6 h after administration of EFE, EHE-To, and Pse-and at 4 to 6 h after administration of EHE-Ts-only second-phase pain was suppressed; however, the effect of Pse at 6 h was not significant. These results suggested that EHE has a biphasic analgesic effect against biphasic formalin-induced pain: in the first phase of analgesia (30 min after administration), biphasic pain is suppressed by Eph; in the second phase of analgesia (4-6 h after administration), second-phase pain is alleviated by constituents other than EAs, although Pse may partially contribute to the relief of second-phase pain.

Indication for voiding cystourethrography during first urinary tract infection.

BACKGROUND: There is confusion surrounding the precise indications for voiding cystourethrography (VCUG) during the assessment of vesicoureteral reflex (VUR) after a first febrile urinary tract infection (UTI). The aim of this study was to determine the combination of clinical, laboratory and ultrasonography factors correlating with grades IV-V VUR in young children with a first febrile UTI. METHODS: Children 0-24 months of age who were brought to the emergency department at National Center for Child Health and Development with the diagnosis of first time febrile UTI between March 2004 and May 2011, were enrolled. We compared clinical, laboratory and ultrasonography findings between children with grades IV-V VUR (high-grade VUR) and those with no or grades I-III VUR (normal or low-grade VUR). RESULTS: A total of 231 patients were eligible and 19 had high-grade VUR. Poor clinical appearance, presence of a uropathogen other than Escherichia coli, positive blood culture, hydroureter and thickened renal pelvic wall were all independently associated with high-grade VUR. When one or more of these factors were present, sensitivity, specificity, positive or negative predictive value, and positive or negative likelihood ratio were 94.7%, 69.4%, 23.1%, 99.3%, 3.1 and 0.1, respectively. When none of the factors was present, the proportion of high-grade VUR was 0.7%; if one factor, 11.3%; two factors, 55.6%; three factors, 85.7%. CONCLUSIONS: In the absence of five specific factors during the first febrile UTI episode in young children, VCUG is not necessary to detect high-grade VUR. When more than one factor is present, however, VCUG is indicated.

In-Hospital Electrical Storm in Acute Myocardial Infarction　- Clinical Background and Mechanism of the Electrical Instability.

BACKGROUND: Recurrent ventricular tachycardia (VT) and fibrillation (VF), the so-called "electrical storm" (ES) occurs at various stages of acute myocardial infarction (AMI), but its incidence, background, and short-term prognosis remain unclear. Methods and Results: A retrospective observational study was performed using the registry database of the Tokyo CCU Network. The individual data of 6,003 patients with AMI during 2011-2012 was corrected. ES was defined as more than 3 episodes of sustained VT/VF during a 24-h period as first documented after hospitalization. ES occurred in 55 patients after admission (0.9%). The ES(+) group had more severe heart failure (Killip class >III), more extensive MI (peak-CK), greater inflammatory reaction (CRP), history of diabetes, and more frequent application of hemodialysis as compared with the ES(-) group (n=5,865). When the ES patients were divided into Early-ES (n=37: ES occurred ≤48 h after the onset of MI) and Late-ES (n=15 >48 h after onset of MI) groups, logistic regression analysis revealed that Early-ES was associated with severity of MI, whereas Late-ES was related to systemic disorders, including inflammation, renal dysfunction, or diabetes. Late-ES was an independent predictor of in-hospital death. CONCLUSIONS: In-hospital ES was a rare clinical manifestation of AMI. The features and background of the ES varied as time elapsed after admission for MI.

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias.

Ephedrine alkaloids-free Ephedra Herb extract (EFE) has been developed to eliminate the adverse effects caused by ephedrine alkaloid-induced sympathetic hyperactivation. Previously, we reported that EFE possesses analgesic, anti-influenza, and cancer metastatic inhibitory effects at comparable levels to that of Ephedra Herb extract (EHE). However, it has not yet been demonstrated that EFE is free from the known side effects of EHE, such as excitation, insomnia, and arrhythmias. In this study, the incidence of these adverse effects was compared between mice administered EHE and those administered EFE. Increased locomotor activity in an open-field test, reduced immobility times in a forced swim test, and reduced sleep times in a pentobarbital-induced sleep test were observed in EHE-treated mice, when compared to the corresponding values in vehicle-treated mice. In contrast, EFE had no obvious effects in these tests. In electrocardiograms, atrial fibrillation (i.e., irregular heart rhythm, absence of P waves, and appearance of f waves) was observed in the EHE-treated mice. It was suggested that this atrial fibrillation was induced by stimulation of adrenaline ß1 receptors, but not by hypokalemia. However, EFE did not affect cardiac electrophysiology. These results suggest that the abovementioned side effects are caused by ephedrine alkaloids in EHE, and that EFE is free from these adverse effects, such as excitation, insomnia, and arrhythmias. Thus, EFE is a promising new botanical drug with few adverse effects.

A comparative study of the biomass properties of Erianthus and sugarcane: lignocellulose structure, alkaline delignification rate, and enzymatic saccharification efficiency.

A comprehensive understanding of the structure and properties of gramineous lignocelluloses is needed to facilitate their uses in biorefinery. In this study, lignocelluloses from fractionated internode tissues of two taxonomically close species, Erianthus arundinaceus and sugarcane (Saccharum spp.), were characterized. Our analyses determined that syringyl (S) lignins were predominant over guaiacyl (G) or p-hydroxyphenyl (H) lignins in sugarcane tissues; on the other hand, S lignin levels were similar to those of G lignin in Erianthus tissues. In addition, tricin units were detected in sugarcane tissues, but not in Erianthus tissues. Distributions of lignin inter-monomeric linkage types were also different in Erianthus and sugarcane tissues. Alkaline treatment removed lignins from sugarcane tissues more efficiently than Erianthus tissues, resulting in a higher enzymatic digestibility of sugarcane tissues compared with Erianthus tissues. Our data indicate that Erianthus biomass displayed resistance to alkaline delignification and enzymatic digestion.

Kososan, a Kampo medicine, prevents a social avoidance behavior and attenuates neuroinflammation in socially defeated mice.

BACKGROUND: Kososan, a Kampo (traditional Japanese herbal) medicine, has been used for the therapy of depressive mood in humans. However, evidence for the antidepressant efficacy of kososan and potential mechanisms are lacking. Recently, it has been recognized that stress triggers neuroinflammation and suppresses adult neurogenesis, leading to depression and anxiety. Here, we examined whether kososan extract affected social behavior in mice exposed to chronic social defeat stress (CSDS), an animal model of prolonged psychosocial stress, and neuroinflammation induced by CSDS. METHODS: In the CSDS paradigm, C57BL/6J mice were exposed to 10 min of social defeat stress from an aggressive CD-1 mouse for 10 consecutive days (days 1-10). Kososan extract (1.0 g/kg) was administered orally once daily for 12 days (days 1-12). On day 11, the social avoidance test was performed to examine depressive- and anxious-like behaviors. To characterize the impacts of kososan on neuroinflammation and adult neurogenesis, immunochemical analyses and ex vivo microglial stimulation assay with lipopolysaccharide (LPS) were performed on days 13-15. RESULTS: Oral administration of kososan extract alleviated social avoidance, depression- and anxiety-like behaviors, caused by CSDS exposure. CSDS exposure resulted in neuroinflammation, as indicated by the increased accumulation of microglia, the resident immune cells of the brain, and their activation in the hippocampus, which was reversed to normal levels by treatment with kososan extract. Additionally, in ex vivo studies, CSDS exposure potentiated the microglial pro-inflammatory response to a subsequent LPS challenge, an effect that was also blunted by kososan extract treatment. Indeed, the modulatory effect of kososan extract on neuroinflammation appears to be due to a hippocampal increase in an anti-inflammatory phenotype of microglia while sparing an increased pro-inflammatory phenotype of microglia caused by CSDS. Moreover, reduced adult hippocampal neurogenesis in defeated mice was recovered by kososan extract treatment. CONCLUSIONS: Our findings suggest that kososan extract prevents a social avoidant behavior in socially defeated mice that is partially mediated by the downregulation of hippocampal neuroinflammation, presumably by the relative increased anti-inflammatory microglia and regulation of adult hippocampal neurogenesis. Our present study also provides novel evidence for the beneficial effects of kososan on depression/anxiety and the possible underlying mechanisms.

Synthesis of Bisdesmosidic Oleanolic Acid Saponins via a Glycosylation-Deprotection Sequence under Continuous Microfluidic/Batch Conditions.

We report the first synthesis of a series of bisdesmosidic oleanolic acid saponins using microflow reactor Comet X-01 via a continuous flow glycosylation-batch deprotection sequence. The main results of this study can be summarized as follows: (1) The microfluidic glycosylation of oleanolic acid at C-28 was achieved in quantitative yield and was applied to the synthesis of six C-28-monoglycosidic saponins. (2) The microfluidic glycosylation of oleanolic acid at C-3 was achieved in good yield without orthoester byproduct formation and was applied to the synthesis of three bisdesmosidic saponins. (3) The continuous synthesis of saponins via a microfluidic glycosylation-batch deprotection sequence was achieved in four steps involving two purifications. Thus, the continuous microfluidic glycosylation-deprotection process is expected to be suitable for the preparation of a library of bisdesmosidic oleanolic acid saponins for in vivo pharmacological studies.

Phellilane L, Sesquiterpene Metabolite of Phellinus linteus: Isolation, Structure Elucidation, and Asymmetric Total Synthesis.

A new cyclopropane-containing sesquiterpenoid, phellilane L (1), was isolated from the medicinal mushroom Phellinus linteus ("Meshimakobu" in Japanese), a member of the Hymenochaetaceae family and a well-known fungus that is widely used in East Asia. The planar structure of 1 was determined on the basis of spectroscopic analysis. The authors achieved the first total synthesis of 1. Our protecting group-free synthesis features a highly stereoselective one-pot synthesis involving an intermolecular alkylation/cyclization/lactonization strategy for construction of the key cyclopropane-γ-lactone intermediate. Additionally, our synthesis determined the absolute configuration of phellilane L (1).

Syntheses and mucosal adjuvant activity of simplified oleanolic acid saponins possessing cinnamoyl ester.

A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant.

Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus.

We encountered a 45-year-old Japanese man who suffered from pulmonary thromboembolism and huge right ventricular thrombus after inferior vena cava (IVC) filter implantation without apparent thrombus in either the deep veins or inside the IVC filter. The biochemical data showed a discrepancy in the level of fibrinogen between the immunological and thrombin time methods, suggesting hypodysfibrinogenemia. The sequencing of the fibrinogen γ-chain gene (FGG) revealed a novel heterozygous missense mutation in exon 8 - a TGT to TCT transversion in codon 326 - resulting in an amino acid substitution of serine for cysteine (γCys326Ser). The characterization of the protein did not show known mechanisms for thrombosis in dysfibrinogenemia, such as dimer or albumin-binding complex formation. In summary, the current case with a life-threatening thrombotic event was found to have a novel heterozygous missense mutation resulting in γCys326Ser, which was suggested as a predisposing factor of the thrombosis. Known mechanisms responsible for thrombosis in the current case were not demonstrated, suggesting other mechanisms including superimposing inherited and/or acquired risk factors. When a patient presents with unusual thrombosis such as breakthrough pulmonary embolism and huge thrombus in the right ventricle, as in the current case, the laboratory process for heritable thrombophilia should be considered.

Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity.

Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3',5'-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T4-by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels.

Safety and Efficacy of Cryoballoon Ablation for Paroxysmal Atrial Fibrillation in Japan　- Results From the Japanese Prospective Post-Market Surveillance Study.

BACKGROUND: Outcomes of cryoballoon ablation for paroxysmal atrial fibrillation (PAF) have been reported in the Western countries but not in Japan. The CRYO-Japan PMS study was a single-arm, observational, multicenter, prospective study of the 2nd-generation cryoballoon Arctic Front Advance(TM). We evaluated device- and procedure-related complications and clinical outcomes at 6 months. METHODS AND RESULTS: The 616 patients (male, 72%; mean age, 63±11 years) were enrolled from 33 Japanese hospitals. Of all patients, 610 had PAF, and procedural data were analyzed in 607. A subset of 328 patients was followed for 6 months for the primary efficacy analysis. AF recurrence outside the 3-month blanking period or repeat ablation was considered treatment failure. Pulmonary vein isolation was achieved in 606/607 patients (99.8%); 1 patient (0.3%) had a repeat ablation during the blanking period. Freedom from AF at 6 months was 88.4% (95% CI: 84.1-91.6%). Device- and/or procedure-related adverse events included phrenic nerve injury unresolved at hospital discharge in 9/616 patients (1.5%), which resolved within 6 months in 7, pericardial effusion in 5/616 (0.8%), and tamponade in 4/616 (0.6%). One non-device-related death from pneumonia was reported 6 days post-procedure. CONCLUSIONS: Cryoballoon ablation is safe and effective for Japanese PAF patients, with 88.4% AF freedom at 6 months post-ablation. (Circ J 2016; 80: 1744-1749).