DETERMINATION BY^1H-NMR OF BINDING SITES OF LOCAL ANESTHETICS ON LIPID BILAYER MEMBRANE MODEL

局所麻酔薬の作用機序についてはさまざまな仮説があるが,どの仮説も十分な説明をしていない。そこで我々は核磁気共鳴装置(NMR)を用いて,局所麻酔薬と神経膜モデルであるリン脂質二重膜との結合状態を検索した。この結果,局所麻酔薬分子中にある窒素原子とリン脂質二重膜の外側にある親水性部分の酸素原子とが静電結合をおこすことが分かった。また我々が作用持続時間の延長を目的に合成した,リドカインのエステル誘導体では窒素原子との結合に加えて,エステルカルボニル部分の酸素原子でも膜と結合することもわかった。さらに,この結合力の強さは局所麻酔薬の作用持続時間に影響することもわかった。これらの事実は一分子の局所麻酔薬が一つのNaイオンチャネルを閉鎖して局所麻酔作用を発現するのではなく,リン脂質二重膜と結合した多くの局所麻酔薬がNaイオンチャネルを構成するタンパク質の流動性を変化させ,結果的にNaイオンの通過を阻害して,局所麻酔作用を発現する可能性を示唆している。This is a study of the binding mode of local anesthtics to the phospholipid bilayer membrane model by proton nuclear masrnetic resonance spectroscopy (1^H-NMR). There was evidence of ionic interaction between the polar external hydrophilic part of the membrane and positively charged nitrogen atom of N-ethyl substituent of lidocaine molecule. Lidocaine ester derivatives, synthesized for prologed duration of action, indicated interaction with the membrane not only by positively charged nitrogen atoms but also by an electrostatic effect of the ester carbonyl oxygen atom. This may be related to the prolonged duration of lidocaine ester derivative action. The results indicate that a single molecule of local anesthetic does not close a single sodium channel. Many local anesthetic molecules bind to the phospholipid bilayer surounding sodium channels, and may bring some change in sodium channel protein comformation, and lead to the obstruction of the sodium ion passage

Examination of the Effective Utilization of the CARELINK® Remote Monitoring System after its Introduction

AbstractBackground: Japan started using the CARELINK® (Medtronic, Inc, Minneapolis, MN, USA) remote monitoring system in April 2009. However, in some cases, the device failed to transmit a message after registration or according to schedule. We investigated the difference between patients who could make effective use of CARELINK® system and those who could not.Subjects and Method: Sixty patients who had registered until December 2009 at our institution were analyzed. These patients were divided into two groups: those who were able to use the device effectively (group G, n = 49) and those who were not (group F = 11). Patient background, automatic or manual telemetries, new or existing implant patient, presence of adverse events, and the use or non-use of a checklist at the time of introduction were compared between the two groups.Results: In group G, more patients used a checklist at the time of introduction than that in group F (use of checklist/total, 31/49 in group G vs. 3/11 in group F; P, 0.029). No significant difference was observed in other factors between the two groups.Conclusion: We consider that the method used to explain the system are important to make the patients understand handling methods of CARELINK® system. The number of patients introduced to remote monitoring of implantable devices will continue to increase in the future; therefore, we must continue to develop innovative approaches for their effective us

Expression of a Cross-reactive Antigen on the Surface of Human Carcinomas Overproducing Epidermal Growth Factor Receptors Shared with RSV induced Tumors

Analysis based on the complement-dependent cytotoxicity (CDC) assays using syngeneic antiserum against a Rous sarcoma virus (RSV)-induced mouse tumor (CSA1M) showed that a cross-reactive antigen with a common tumor-associated cell surface antigen (TASA) of RSV-induced mouse tumors was shared with two human tumors A431 and MDA-468 overexpressing epidermal growth factor receptors (EGFRs). The TASA, however, was not expressed on four human choriocarcinomas, a human lung cancer A2182, and human embryo fibroblasts HEF. Immunofluorescent studies demonstrated that A431 did not express a src gene product detected by rabbit anti-pp60V-src serum. Two variant clones derived from A431 reducing number of EGFRs (cl-15 and cl-16) had almost the same growth rate and expression of transferrin receptor (Tf-R) in comparison with parental A431 cells. These clones, however, decreased the expression of the TASA. Furthermore, CDC assays and enzyme-linked immunosorbent assays (ELISA) revealed that A431 reduced the expression of the TASA by pretreatment of EGF, but not with insulin. A truncated form corresponding to extracellular domain of the EGFR blocked the cytotoxicity of anti-CSA1M serum to A431 and RSV-induced tumor cells. All these findings indicate a close association between a cross-reactive antigen with the TASA of RSV-induced tumors and the EGFR expression

New acoustic respiratory sound monitoring with artificial intelligence

Monitored anesthesia care (MAC) often causes airway complications, particularly posing an elevated risk of aspiration and airway obstruction in obese patients. This study aimed to quantify the levels of aspiration and airway obstruction using an artificial intelligence (AI)-based acoustic analysis algorithm, assessing its utility in identifying airway complications in obese patients. To verify the correlation between the stridor quantitative value (STQV) calculated by acoustic analysis and body weight, and to further evaluate fluid retention and airway obstruction, STQV calculated exhaled breath sounds collected at the neck region, was compared before and after injection of 3 ml of water in the oral cavity and at the start and end of the MAC procedures. STQV measured immediately following the initiation of MAC exhibited a weak correlation with body mass index. Furhtermore, STQV values before and after water injection increased predominantly after injection, further increased at the end of MAC. AI-based analysis of cervical respiratory sounds can enhance the safety of airway management during MAC by quantifying airway obstruction and fluid retention in obese patients

All local anesthetics bind to the biomembrane by its nitrogen atom in the molecule

The interaction between various local anesthetics and the phospholipid membrane was examined by ^1HNMR (Nuclear Magnetic Resonance) spectroscopy. In order to measure the extent of proximity of various local anesthetics to the membrane, We examinined the chemical shift value and broadening of half-width of choline methyl signal of the membrane. Electrostatic interaction was seen between positively charged nitrogen atom of local anesthetics and negatively charged oxygen atom of phospholipid membrane. It was also determined that binding ability to the membrane of tetracaine and dibucaine, both of which possess two positively charged nitrogen atoms, was stronger than that of anesthetics such as lidocaine, procaine and bupivacaine, possessing only one positively charged nitrogen atom. On the other hand, when the positively charged nitrogen atom is surrounded by bulky carbon chains, such as cocaine, the chemical shift and broadening of half-width of choline methyl signal in the membrane were virtually unaffected. The binding ability of local anesthetics to the phospholipid membrane was found to be directly proportional to the anesthetic potency, suggesting that positively charged nitrogen atom of local anesthetics plays an important role in the action mechanism of local anesthetics

Numerical study for the c-dependence of fractal dimension in two-dimensional quantum gravity

We numerically investigate the fractal structure of two-dimensional quantum gravity coupled to matter central charge c for $-2 \leq c \leq 1$. We reformulate Q-state Potts model into the model which can be identified as a weighted percolation cluster model and can make continuous change of Q, which relates c, on the dynamically triangulated lattice. The c-dependence of the critical coupling is measured from the percolation probability and susceptibility. The c-dependence of the string susceptibility of the quantum surface is evaluated and has very good agreement with the theoretical predictions. The c-dependence of the fractal dimension based on the finite size scaling hypothesis is measured and has excellent agreement with one of the theoretical predictions previously proposed except for the region near $c\approx 1$.Comment: 41 pages, 16 figure

Improved long-term performance of pulsatile extracorporeal left ventricular assist device

SummaryBackground and purposeThe majority of heart transplant (HTx) candidates require left ventricular assist device (LVAD) support for more than 2 years before transplantation in Japan. However, the only currently available device is the extracorporeal pulsatile LVAD. The long-term management of extracorporeal LVAD support has improved remarkably over the years. To determine which post-operative management factors are related to the long-term survival of patients on such LVAD, we retrospectively compared the incidence of complications and their management strategies between the initial and recent eras of LVAD use, classified by the year of LVAD surgery.MethodsSixty-nine consecutive patients supported by extracorporeal pulsatile LVAD as a bridge to HTx between 1994 and 2007 were reviewed retrospectively. The patients were assigned according to the time of LVAD surgery to either group A (n=30; between 1994 and 2000) or group B (n=39; between 2001 and 2007).ResultsPatients in group B survived significantly longer on LVAD support than those in group A (674.6 vs. 369.3 days; p<0.001). The 1- and 2-year survival rates were significantly higher in group B than that in group A (82% vs. 48%, p<0.0001; 68% vs. 23%, p<0.0001, respectively). The proportion of deaths due to cerebrovascular accidents was lower (17% vs. 50%, p<0.001) in group B compared with group A. The incidences of systemic infection were similar in both groups, but the proportions of patients alive and achieving transplant surgery after systemic infection were higher in group B than those in group A (55% vs. 14%, p<0.01; 14% vs. 36%, p<0.05, respectively).ConclusionsThe long-term survival of patients even on “first-generation” extracorporeal LVAD has improved significantly in the recent era. Careful management of cerebrovascular accidents and systemic infection will play important roles in the long-term LVAD management