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

An operative case of hepatic pseudolymphoma difficult to differentiate from primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue

Hepatic pseudolymphoma (HPL) and primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are rare diseases and the differential diagnosis between these two entities is sometimes difficult. We herein report a 56-year-old Japanese woman who was pointed out to have a space occupying lesion in the left lateral segment of the liver. Hepatitis viral-associated antigen/antibody was negative and liver function tests including lactic dehydrogenase, peripheral blood count, tumor markers and soluble interleukin-2 receptor were all within normal limit. Imaging study using computed tomography and magnetic resonance imaging were not typical for hepatocellular carcinoma, cholangiocarcinoma, or other metastatic cancer. Fluorodeoxyglucose-positron emission tomography examination integrated with computed tomography scanning showed high standardized uptake value in the solitary lesion in the liver. Under a diagnosis of primary liver neoplasm, laparoscopic-assisted lateral segmentectomy was performed. Liver tumor of maximal 1.0 cm in diameter was consisted of aggregation of lymphocytes of predominantly B-cell, containing multiple lymphocyte follicles positive for CD10 and bcl-2, consistent with a diagnosis of HPL rather than MALT lymphoma, although a definitive differentiation was pending. The background liver showed non-alcoholic fatty liver disease/early non-alcoholic steatohepatitis. The patient is currently doing well with no sign of relapse 13 months after the surgery. Since the accurate diagnosis is difficult, laparoscopic approach would provide a reasonable procedure of diagnostic and therapeutic advantage with minimal invasiveness for patients. Considering that the real nature of this entity remains unclear, vigilant follow-up of patient is essential

Cardiac involvement in Beagle-based canine X-linked muscular dystrophy in Japan (CXMD(J)): electrocardiographic, echocardiographic, and morphologic studies

BACKGROUND: Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes. We therefore established a line of dogs with Beagle-based canine X-linked muscular dystrophy in Japan (CXMD(J)) and examined the cardiac involvement. METHODS: The cardiac phenotypes of eight CXMD(J )and four normal male dogs 2 to 21 months of age were evaluated using electrocardiography, echocardiography, and histopathological examinations. RESULTS: Increases in the heart rate and decreases in PQ interval compared to a normal littermate were detected in two littermate CXMD(J )dogs at 15 months of age or older. Distinct deep Q-waves and increase in Q/R ratios in leads II, III, and aVF were detected by 6–7 months of age in all CXMD(J )dogs. In the echocardiogram, one of eight of CXMD(J )dogs showed a hyperechoic lesion in the left ventricular posterior wall at 5 months of age, but the rest had not by 6–7 months of age. The left ventricular function in the echocardiogram indicated no abnormality in all CXMD(J )dogs by 6–7 months of age. Histopathology revealed myocardial fibrosis, especially in the left ventricular posterobasal wall, in three of eight CXMD(J )dogs by 21 months of age. CONCLUSION: Cardiac involvement in CXMD(J )dogs is milder and has slower progression than that described in GRMD dogs. The distinct deep Q-waves have been ascribed to myocardial fibrosis in the posterobasal region of the left ventricle, but our data showed that they precede the lesion on echocardiogram and histopathology. These findings imply that studies of CXMD(J )may reveal not only another causative mechanism of the deep Q-waves but also more information on the pathogenesis in the dystrophin-deficient heart

マンセイ シンフゼン カンジャ ノ ジュウショウド ニヨル ヤカン ムコキュウ ト テイサンソ ケッショウ ノ ヒカク

慢性心不全(CHF)患者の重症度による夜間の酸素飽和度(SaO_2)と無呼吸の比較について検討を行うために安定した慢性軽症心不全患者6例(男4例,女2例63±5.2歳,左室駆出率:49.8±3.4%,NYHA class:IかII,mild-CHF群)と安定慢性重症心不全患者11例(男9例,女2例,62±11.9歳,左室駆出率:25.6±8.6%,NYHA class:III,severe-CHF群)患者を対象とし,両群を比較することにより検討を行った.全例において室内空気下にパルスオキシメーターを用いて24時間のSaO_2と脈拍数を連続記録した.そして夜間のSaO_2が3%あるいは4%以上低下した1時間あたりの回数(3%ODI,4%ODI),SaO_2の最低値を各々分析した.さらにポリソムノグラフィーを用いてSaO_2と睡眠に関する全てのデータを連続的に記録分析した.その結果,severe-CHF群のODIはmild-CHF群に比して有意に高値であった(4%ODI;5.8±5.1 vs 0.6±0.5,p<O.01.3%ODI;8.6±7.1 vs 1.0±O.9,p<0.01.).severe-CHF群のSaO_2の最低値はmild-CHF群に比して有意に低かった(82.2±7.1 vs 91.7±1.0%,p<0.01).severe-CHF群の夜間無呼吸は全例にみられ,大多数が中枢型であった(74.0±3.6%).以上より安定した重症心不全では夜間に低酸素血症と無呼吸がみられ,これらが臨床病像の悪化に影響していることが示唆される.Background : Patients with chronic heart failure (CHF) commonly experience Cheyne- Stokes respiration, central apnea, or obstructive apnea during sleep associated with oxygen desaturation. Nocturnal oxygen therapy and nasal continuous positive airway pressure (NCPAP) reduce sleep-disordered breathing in stable CHF. However, the relation between sleep apnea and nocturnal desaturation inpatients with severe, stable CHF in Japan is unknown. Objectives : To examine nocturnal oxygen saturation (SaO_2) and sleep apnea in Japanese patients with severe, stable CHF. Methods : The subjects were 11 patients with severe, stable CHF (9 men and 2 women, LVEF=25.6±8.6%, NYHA class=III, severe CHF group) and 6 with mild, stable CHF (4 men and 2 women, LVEF=49.8±3.4 %, NYHA class=I or II, mild CHF group). SaO_2 was continuously recorded with a pulse oximeter under room air, and 4 % and 3 % SaO_2 dip rate per hour (GDIs) and the SaO_2 nadir were analyzed. In addition, SaO_2 and sleep variables were continuously recorded with a polysomnograph. Results : ODI frequency in the severe CHF group was significantly higher than that in the mild CHF group (4% ODI, 5.8±5.1 vs 0.6±0.5 times/hour, respectively, p<0.01;3 % ODI, 8.6±7.1 vs 1.0±0.9 times/hour, respectively, p<0.01.). SaO_2 nadir in the severe CHF group was significantly lower than that in the mild CHF group (82.2±7.1 vs 91.7±1.0 %, p<0.01). All severe patients had sleep apnea, predominantly of the central type (74.0±3.6%). Conclusion : The frequency of nocturnal hypoxemia and apnea increases in patients with severe, stable CHF. Nocturnal hypoxemia and apnea may adversely effect the clinical status of these patients

Invasion of Pheochromocytoma from the Caudal Vena Cava to the Right Ventricular Cavity in a Dog

Pheochromocytomas are catecholamine-secreting tumors that are composed of neuroectoderm-derived chromaffin cells. An 8-year-old miniature dachshund with abdominal distension was diagnosed with a neuroendocrine tumor with invasion from the caudal vena cava to the right ventricular cavity. The dog died due to hypotensive shock from the vagal reflex, and on autopsy, an extra-adrenal pheochromocytoma (paraganglioma) was diagnosed in the caudal abdomen. At autopsy, the tumor plug of the caudal vena cava was confirmed. To the best of our knowledge, this is the first case report that echo-captured the extension of pheochromocytoma in the right ventricle and shows it in a figure and video file

Complete atrioventricular block due to primary cardiac lymphoma in a dog

A histological investigation of the atrioventricular (AV) conduction system was performed in an 11-year-old golden retriever with complete AV block. Necropsy revealed a large grayish-white mass with an irregular shape located in the AV junctional area of the lateral aspect of the left heart. Histological and immunohistochemical examinations provided a diagnosis of primary cardiac lymphoma of T-cell origin. Histological findings in the AV conduction system included severe infiltration of neoplastic lymphoid cells into the AV nodal region, causing total destruction of the AV node. Similarly, neoplastic cell infiltration had entrapped the AV bundle, causing various degrees of degeneration, atrophy, and loss of conduction fibers. Such neoplastic lesions of the AV conduction system were associated with complete AV block