An organic transistor for detecting the oxidation of an organic sulfur compound at a solid-liquid interface and its chemical sensing applications.

The development of chemical sensors has advanced due to an increase in demand; however, the potential of chemical sensors as devices to monitor organic reactions has not been revealed yet. Thus, we aim to propose a chemical sensor platform for facile monitoring of chemical reactions, especially at a solid-liquid interface. In this study, an extended-gate-type organic field-effect transistor (OFET) has been employed as a platform to detect chemical reactions at an interface between the extended-gate electrode and an aqueous solution. The OFET device functionalized with 4,4'-thiobisbenzenthiol has shown time- and concentration-dependent shifts in transistor characteristics upon adding H2O2. In a selectivity test using seven oxidant agents, the transistor responses depended on the oxidation of the organic sulfur compound (i.e., 4,4'-thiobisbenzenthiol) stemming from the ability of the oxidant agents. Therefore, the observed changes in the transistor characteristics have suggested the generation of sulfur-oxidized products at the interface. In this regard, the observed responses were caused by disulfide formation accompanied by changes in the charges under neutral pH conditions. Meanwhile, weak transistor responses derived from the generation of oxygen adducts have also been observed, which were caused by changes in the dipole moments. Indeed, the yields of the oxygen adducts have been revealed by X-ray photoelectron spectroscopy. The monitoring of gradual changes originating from the decrease in the disulfide formation and the increase in the oxygen adducts implied a novel aspect of the OFET device as a platform to simultaneously detect reversible and irreversible reactions at interfaces without using large-sized analytical instruments. Sulfur oxidation by H2O2 on the OFET device has been further applied to the indirect monitoring of an enzymatic reaction in solution. The OFET-based chemical sensor has shown continuous changes with an increase in a substance (i.e., lactate) in the presence of an enzyme (i.e., lactate oxidase), which indicates that the OFET response depends on the H2O2 generated through the enzymatic reaction in the solution. In this study, we have clarified the versatility of organic devices as platforms to monitor different chemical reactions using a single detection method.

Location of the Shared Proton in Proton-Bound Dimer Compound of Hydrogen Sulfate and Formate: Path Integral Molecular Dynamics Study.

The structure of the proton-bound dimer compound of hydrogen sulfate and formate has been studied by considering nuclear quantum effects (NQEs) using the path integral molecular dynamics method. This study unveiled the location of the shared proton and answered the following question: "Is the shared proton localized on either an anion or located around the center of two anions?" We have elucidated that the shared proton is distributed in the region beyond the transition state due to the NQEs, even though the shared proton did not completely overcome the transition state for the proton shuttle.

Development of a score model to predict long-term prognosis after community-onset pneumonia in older patients.

BACKGROUND AND OBJECTIVE: The identification of factors associated with long-term prognosis after community-onset pneumonia in elderly patients should be considered when initiating advance care planning (ACP). We aimed to identify these factors and develop a prediction score model. METHODS: Patients aged 65 years and older, who were hospitalized for pneumonia at nine collaborating institutions, were included. The prognosis of patients 180 days after the completion of antimicrobial treatment for pneumonia was prospectively collected. RESULTS: The total number of analysable cases was 399, excluding 7 outliers and 42 cases with missing data or unknown prognosis. These cases were randomly divided in an 8:2 ratio for score development and testing. The median age was 82 years, and there were 68 (17%) deaths. A multivariate analysis showed that significant factors were performance status (PS) ≥2 (Odds ratio [OR], 11.78), hypoalbuminemia ≤2.5 g/dL (OR, 5.28) and dementia (OR, 3.15), while age and detection of antimicrobial-resistant bacteria were not associated with prognosis. A scoring model was then developed with PS ≥2, Alb ≤2.5, and dementia providing scores of 2, 1 and 1 each, respectively, for a total of 4. The area under the curve was 0.8504, and the sensitivity and specificity were 94.6% and 61.7% at the cutoff of 2, respectively. In the test cases, the sensitivity and specificity were 91.7% and 63.1%, respectively, at a cutoff value of 2. CONCLUSION: Patients meeting this score should be considered near the end of life, and the initiation of ACP practices should be considered.

Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

Nuclear quantum and H/D isotope effects on intramolecular hydrogen bond in curcumin.

Curcumin and its derivatives possess intramolecular low-barrier hydrogen bonds for intramolecular proton transfer. The π-delocalization in the OCCCO framework of the hydrogen bond in these compounds is reorganized concomitantly with the proton transfer. To characterize the hydrogen bond and π-delocalization, we performed path integral molecular dynamics simulations, revealing that although the proton migration and reorganization of the π-delocalized structure showed a positive correlation, the correlation was weak.

Direct Elucidation of the Vibrationally Averaged Structure of Benzene: A Path Integral Molecular Dynamics Study.

Path integral molecular dynamics (PIMD) simulations for C6H6, C6D6, and C6T6 have been carried out to directly estimate the distribution of projected C-H(D,T) bond lengths onto the principal axis plane. The average values of raw C-H(D,T) bond lengths obtained from PIMD simulations are in the order of ⟨RC-H⟩ > ⟨RC-D⟩ > ⟨RC-T⟩ due to the anharmonicity of the potential energy curve. However, the projected C-H(D,T) bond lengths are almost the same as those reported by Hirano et al. [J. Mol. Struct. 2021, 1243, 130537]. Our PIMD simulations directly and strongly support the explanation by Hirano et al. for the experimental observations that almost the same projected C-H(D) bond lengths are found for C6H6 and C6D6. The PIMD simulations also predicted the same projected bond lengths for C6T6 as those of C6H(D)6. In addition to the previous local mode analysis, the present PIMD simulations predicted, for benzene isotopologues, that the vibrationally averaged structure is planar but non-flat.

Negative Inotropic Effects of Class I Antiarrhythmics on Guinea Pig Ventricular Myocardium: Correlation with L-Type Ca2+ Channel Blockade.

The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel rather than the Na+ channel. The effects of drugs were roughly the same when examined under a high extracellular K+ solution, which inactivates the Na+ channel. Furthermore, the attenuation of the extracellular Ca2+-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Mechanisms for the α-Adrenoceptor-Mediated Positive Inotropy in Mouse Ventricular Myocardium: Enhancing Effect of Action Potential Prolongation.

Mechanisms for the α-adrenoceptor-mediated positive inotropy in neonatal mouse ventricular myocardium were studied with isolated myocardial preparations. The phenylephrine-induced positive inotropy was suppressed by prazosin, nifedipine, and chelerythrine, a protein kinase C inhibitor, but not by SEA0400, a selective Na+/Ca2+ exchanger inhibitor. Phenylephrine increased the L-type Ca2+ channel current and prolonged the action potential duration, while the voltage-dependent K+ channel current was not influenced. In the presence of cromakalim, an ATP-sensitive K+ channel opener, the phenylephrine-induced prolongation of action potential duration, as well as the positive inotropy, were smaller than in the absence of cromakalim. These results suggest that the α-adrenoceptor-mediated positive inotropy is mediated by an increase in Ca2+ influx through the L-type Ca2+ channel, and the concomitant increase in action potential duration acts as an enhancing factor.

Chronic Volume Overload Caused by Abdominal Aorto-Venocaval Shunt Provides Arrhythmogenic Substrates in the Rat Atrium.

Atrial enlargement is thought to provide arrhythmogenic substrates, leading to the induction of atrial fibrillation (AF). In this study, we investigated the anatomical, molecular biological, and electrophysiological characteristics of remodeled atria in an animal model with chronic volume overload. We used rats that underwent abdominal aorto-venocaval shunt (AVS) surgery. In the in vivo studies, marked changes in electrocardiogram parameters, such as the P-wave duration, PR interval, and QRS width, as well as prolongation of the atrial effective refractory period were observed 12 weeks after the creation of AVS (AVS-12W), which were undetected at 8 weeks postoperative (AVS-8W) despite obvious atrial and ventricular enlargement. Moreover, the duration of AF induced by burst pacing in the AVS-12W rats was significantly longer than that in the Sham and AVS-8W rats. In the isolated atria, a longer action potential duration at 90% repolarization was detected in the AVS-12W rats compared with that in the Sham group. The mRNA levels of the Kv and Kir channels in the right atrium were mostly upregulated in the AVS-8W rats but were downregulated in the AVS-12W rats. These results show that chronic volume overload caused by abdominal AVS provides arrhythmogenic substrates in the rat atrium. The difference in gene expression in the right atrium between the AVS-8W and AVS-12W rats may partly explain the acquisition of arrhythmogenicity.

Inhibitory Effect of a Late Sodium Current Blocker, NCC-3902, on the Automaticity of the Guinea Pig Pulmonary Vein Myocardium.

The effect of blocking the persistent component of the sodium channel current (late INa) on the automatic activity of the isolated guinea pig pulmonary vein myocardium was examined. NCC-3902 blocked late INa, but did not affect other major ion channel currents stably expressed in cell lines. In isolated pulmonary vein cardiomyocytes, NCC-3902 blocked the late INa induced by a ramp depolarizing voltage clamp pulse similar to that of the pacemaker depolarization observed in the pulmonary vein myocardium. In isolated pulmonary vein tissue, NCC-3902 decreased the frequency of automatic firing of the myocardium through a reduction of the pacemaker depolarization slope. In isolated pulmonary vein cardiomyocytes, NCC-3902 significantly reduced the firing frequency of Ca2+ transients, but had no effect on Ca2+ sparks. NCC-3902 affected neither the spontaneous beating rate of the right atrium nor the contractile force of the ventricular myocardium. Selective blockers of late INa like NCC-3902, which inhibit the automatic activity of the pulmonary vein myocardium, appear to be promising as drugs for the pharmacological treatment of atrial fibrillation.

Japanese infants' attachment insecurity and externalizing/internalizing problems: Using strange situation and attachment Q-sort methods.

According to attachment theory, an infant-mother attachment is universal, and infants who develop an insecure attachment relationship with their mother are likely to show mental health problems compared to those who develop a secure attachment relationship. These hypotheses have been empirically supported in Western cultures. However, the cross-cultural evidence is still insufficient. The purpose of this study was to examine the association between Japanese infants' attachment insecurity and mental health problems. We studied 81 Japanese infants (Mage = 14.64 months, SD = 1.43, females = 54%) mostly from middle-class families. The Strange Situation Procedure (SSP) and Attachment Q-sort (AQS) assessed infant attachment security. Infant externalizing and internalizing problems were rated concurrently by the mother and 6 months later by the mother and another adult (father or grandmother). Japanese infants' attachment insecurity measured by the AQS was associated with their externalizing problems concurrently and 6 months later. Infants with insecure-resistant attachment measured by the SSP had higher externalizing problems compared to those with secure attachment concurrently (not 6 months later). Attachment insecurity was not related to internalizing problems. These findings partly supported the association between attachment insecurity and mental health problems. This research also recommends observing infant attachment at home.

De acuerdo con la teoría de la afectividad, una unión afectiva infante-madre es universal y los infantes que desarrollan una insegura relación de afectividad con sus madres están propensos a mostrar problemas de salud mental, comparados con aquellos que desarrollan una relación afectiva segura. Estas hipótesis han sido empíricamente apoyadas en las culturas occidentales. Sin embargo, la evidencia entre las culturas es aún insuficiente. El propósito de este estudio fue examinar la asociación entre la inseguridad de la afectividad de los infantes japoneses y los problemas de salud mental. Estudiamos a 81 infantes japoneses (edad promedio = 14.64 meses, SD = 1.43, niñas = 54%), principalmente de familias de clase media. El Procedimiento de la Situación Extraña (SSP) y la Afectividad Q-sort (AQS) evaluaron la seguridad de afectividad del infante. Las madres, concurrentemente, les dieron un puntaje a los problemas de externalización e internalización del infante, y seis meses después los hicieron la madre y otro adulto (el padre o la abuela). La inseguridad de la afectividad de los infantes japoneses, tal como se midió por medio de AQS, se asoció con sus problemas de externalización concurrentemente y seis meses después. Los infantes con una afectividad insegura y de resistencia, tal como se midió por SSP, tenían más altos problemas de externalización comparados con aquellos con una afectividad segura concurrentemente (no a los seis meses después). La inseguridad de la afectividad no se relacionó con problemas de internalización. Estos resultados en parte apoyan la asociación entre la inseguridad de la afectividad y los problemas de salud mental. Esta investigación también recomienda observar la afectividad del infante en casa.

Selon la théorie de l'attachement, l'attachement bébé-mère est universel, et les bébés qui développent une relation d'attachement insécure avec leur mère sont à même de présenter des problèmes de santé mentale comparés à ceux ayant développé une relation d'attachement sécure. Ces hypothèses ont été soutenues empiriquement dans les cultures occidentales. Cependant l'évidence transculturelle demeure insuffisante. Le but de cette étude était d'examiner le lien entre la sécurité de l'attachement des nourrissons japonais et les problèmes de santé mentale. Nous avons étudié 81 nourrissons japonais (Mâge = 14,64 mois, SD = 1.43, filles = 54%) en grande partie issues de la classe moyenne. La Procédure de Situation Etrange (SSP) et l'AQS (en anglais Attachment Q-sort) ont évalué la sécurité de l'attachement du bébé. Les problèmes d'externalisation et d'internalisation du bébé ont été évalués en même temps par la mère et six mois plus tard par la mère et un autre adulte (père ou grand-mère). L'insécurité de l'attachement des bébés japonais mesurée par le AQS était liée à des problèmes d'externalisation simultanément et six mois plus tard. Les bébés avec un attachement insécure-résistant mesuré par le SSP avaient des problèmes d'externalisation plus importants comparé à ceux avec un attachement sécure simultané (pas six mois plus tard). L'insécurité de l'attachement n'était pas liée à des problèmes d'internalisation. Ces résultats soutiennent partiellement le lien entre l'insécurité de l'attachement et les problèmes de santé mentale. Cette recherche recommande aussi d'observer l'attachement du bébé à domicile.

Contribution of ATP-Mediated Positive Feedback to Sympathetic Nerve-Induced Positive Inotropy in Guinea Pig Ventricular Myocardium.

The functional role of ATP released from sympathetic nerve terminals was examined in isolated guinea pig ventricular papillary muscles. The contractile force of papillary muscles was increased by field electrical stimulation of sympathetic nerve endings. This increase was attenuated by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) or suramin, blockers of the P2X receptor, and was abolished by propranolol and prazosin. PPADS, suramin, and ATP affected neither the basal contractile force nor the positive inotropic effect of noradrenaline. These results provide functional evidence that ATP released from sympathetic nerve terminals enhances noradrenaline release and contributes to sympathetic nerve-induced inotropy.

Positive Lusitropic Effect of Quercetin on Isolated Ventricular Myocardia from Normal and Streptozotocin-Induced Diabetic Mice.

The lusitropic effect of quercetin was examined on isolated ventricular myocardial tissue preparations from normal and streptozotocin-induced diabetic mice. The time required for 90% relaxation of the myocardium, which was prolonged in the diabetic mice, was shortened by quercetin in both normal and diabetic myocardia. This effect of quercetin was completely inhibited by cyclopiazonic acid but not by SEA0400. These results indicated that quercetin accelerates myocardial relaxation through activation of the sarco-endoplasmic reticulum Ca2+-ATPase.

Fluorescence Discrimination of Pharmacological Effects on the Na+-Ca2+ Exchanger and Sarco-Endoplasmic Reticulum Ca2+-ATPase in Mouse Ventricular Cardiomyocytes.

We developed a method to evaluate the activity of the Na+-Ca2+ exchanger (NCX) and sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) with fluorescence microscopy in mouse ventricular cardiomyocytes. In non-beating ventricular cardiomyocytes, α-adrenoceptor stimulation by phenylephrine caused a decrease in the cytoplasmic Ca2+ concentration, which was inhibited by SEA0400, an NCX inhibitor, but not cyclopiazonic acid, a SERCA inhibitor. ß-Adrenoceptor stimulation by isoprenaline caused a decrease in the cytoplasmic Ca2+ concentration, which was inhibited by cyclopiazonic acid but not SEA0400. Ellagic acid, a phenolic phytochemical, also decreased the basal Ca2+ concentration, which was inhibited by cyclopiazonic acid, but not SEA0400. Thus, this method using fluorescent microscopy and specific inhibitors would be useful for the evaluation of pharmacological agents acting on NCX and SERCA.

Differential effects of class I antiarrhythmic drugs on the guinea pig pulmonary vein myocardium: Inhibition of automatic activity correlates with blockade of a diastolic sodium current component.

The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of diastolic depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp depolarization mimicking the diastolic depolarization. In conclusion, class I antiarrhythmic drugs which block the diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.

KB-R7943 Inhibits the Mitochondrial Ca2+ Uniporter but Not Na+-Ca2+ Exchanger in Cardiomyocyte-Derived H9c2 Cells.

The effect of KB-R7943, an inhibitor of the plasmalemmal Na+-Ca2+ exchanger, on mitochondrial Ca2+ transporters was examined with membrane-permeabilized cardiomyocyte-derived H9c2 cells expressing the fluorescent Ca2+ indicator, yellow cameleon 3.1, in the mitochondria. KB-R7943, as well as ruthenium red, inhibited the rise in mitochondrial Ca2+ on increasing the extramitochondrial Ca2+ concentration from 0 nM to 300 nM. CGP-37157, but not KB-R7943, inhibited the decline in mitochondrial Ca2+on return to Ca2+ free extramitochondrial solution. These results indicated that KB-R7943 has inhibitory effects on the mitochondrial Ca2+ uniporter, but not on the mitochondrial Na+-Ca2+ exchanger.

Involvement of the persistent Na+ current in the diastolic depolarization and automaticity of the guinea pig pulmonary vein myocardium.

The role of the Na+ current in the automaticity of the pulmonary vein myocardium was examined in isolated guinea pig pulmonary vein cardiomyocytes and tissue preparations. Tetrodotoxin inhibited the automaticity of pulmonary vein tissue preparations by suppressing the diastolic depolarization of the action potential. ATX-II, which increased the density of persistent component of the Na+ current (late INa), induced a depolarization of the resting membrane potential followed by spontaneous firing of action potentials. GS-458967, which inhibited the late INa, suppressed the diastolic depolarization and the firing of action potentials. Pilsicainide, which inhibited only the transient component of Na+ current (peak INa), had no effect on the firing frequency. GS-458967 had no effect on the contractile force of the working myocardium. In conclusion, late INa is involved in the diastolic depolarization and automaticity of the pulmonary vein myocardium. Late INa inhibitors appear to be effective therapeutic agents for atrial fibrillation with minimum adverse effects on the working myocardium.

Resistance of Fetal Guinea Pig Ventricular Myocardium to Hypoxia: Maintained Intracellular ATP Prevents the Opening of ATP-Sensitive Potassium Channels.

The presence and function of the ATP-sensitive potassium channel current (IKATP) were examined in the guinea pig myocardium to clarify the mechanisms for the resistance of the fetal myocardium to hypoxia. Experimental hypoxia markedly reduced the action potential duration and contractile force in isolated ventricular myocardium from the adult, but only moderately in those from the fetus. In isolated ventricular cardiomyocytes, the density of the IKATP activated by cromakalim, as well as their sensitivity to intracellular ATP concentration, were not different between the fetus and adult. The tissue ATP content was similar between the fetal and adult myocardium under normal condition, but the hypoxia-induced decrease was smaller in the fetus. Confocal microscopic analysis revealed that the mitochondria in the fetal cardiomyocyte is less in quantity than that in the adult and is more localized to the cell center. These results indicate that IKATP in the fetal guinea pig myocardium has a current density and ATP sensitivity similar to those of the adult, but is not activated under hypoxic conditions because the energy metabolism of the fetal myocardium is less dependent on oxidative phosphorylation.

Angiotensin II Induces Automatic Activity of the Isolated Guinea Pig Pulmonary Vein Myocardium through Activation of the IP3 Receptor and the Na⁺-Ca2+ Exchanger.

The automaticity of the pulmonary vein myocardium is known to be the major cause of atrial fibrillation. We examined the involvement of angiotensin II in the automatic activity of isolated guinea pig pulmonary vein preparations. In tissue preparations, application of angiotensin II induced an automatic contractile activity; this effect was mimicked by angiotensin I and blocked by losartan, but not by PD123,319 or carvedilol. In cardiomyocytes, application of angiotensin II induced an increase in the frequency of spontaneous Ca2+ sparks and the generation of Ca2+ transients; these effects were inhibited by losartan or xestospongin C. In tissue preparations, angiotensin II caused membrane potential oscillations, which lead to repetitive generation of action potentials. Angiotensin II increased the diastolic depolarization slope of the spontaneous or evoked action potentials. These effects of angiotensin II were inhibited by SEA0400. In tissue preparations showing spontaneous firing of action potentials, losartan, xestospongin C or SEA0400 decreased the slope of the diastolic depolarization and inhibited the firing of action potentials. In conclusion, in the guinea pig pulmonary vein myocardium, angiotensin II induces the generation of automatic activity through activation of the IP3 receptor and the Na⁺-Ca2+ exchanger.