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Background: The pathogenesis of stroke-like episodes in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) remains unknown. Methods: Fourteen stroke-like episodes in six patients with MELAS were studied using clinical, neuroradiologic, and electrophysiologic approaches. In two patients postmortem examination was done. Results: Headache and epileptic seizure were the most common presenting symptoms. In 13 of 14 episodes the cerebral cortex was primarily involved with variable subcortical edema particularly in the temporal, occipital, and parietal cortex. Repeated MRI performed in two episodes revealed progressive spread of the cortical lesion to the surrounding cortex for a few weeks after the onset of symptoms. In 6 of 11 episodes T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis was seen during subacute stage of the episode. Fat-suppression MRI confirmed intracortical gyral hemorrhage in one episode. Petechial gyral microhemorrhages were also pathologically confirmed in the autopsy of another patient. In 9 of 11 episodes focal epileptiform discharges on EEG were noted in the acute brain lesion. In seven of nine episodes focal cortical hyperperfusion was seen in SPECT studies. Conclusion: The stroke-like episodes in MELAS may reflect neuronal hyperexcitability, which increases energy demand and creates energy imbalance between energy requirement and adequate availability of adenosine triphosphate due to oxidative phosphorylation defect particularly in the susceptible neuronal population, causing cortical necrosis. The episodic nature of stroke-like episodes is unexplained.

Objective. To evaluate individualized growth assessment using the Rossavik growth model for detection of growth-retarded neonates with poor perinatal outcomes. Methods. Rossavik growth models derived from second-trimester ultrasound measurements were used to predict birth characteristics of 154 singleton neonates. Individual fetal growth curve standards for head and abdominal circumference and weight were determined from the data of two scans obtained before 25 weeks' menstrual age and separated by an interval of at least 5 weeks. Comparisons between actual and predicted birth characteristics were expressed by the Growth Potential Realization Index and the Neonatal Growth Assessment Score (NGAS). The proportions of perinatal outcomes (mechanical delivery, low Apgar score, abnormal fetal heart rate [FHR] patterns, neonatal acidosis, meconium staining of amniotic fluid, neonatal intensive care unit admission, and maternal complications), using NGAS, were compared with those by the traditional birth weight-for-gestational age method and the ponderal index, respectively. Results. Of the 154 fetuses studied, 120 had normal growth outcomes at birth; 18 showed evidence of intrauterine growth retardation; and 16 had macrosomia, based on NGAS. According to birth weight-for-gestational age classification, 32 fetuses were small for gestational age; 118 were appropriate for gestational age; and only 4 were large for gestational age. According to the ponderal index, 55 fetuses had growth retardation, 99 showed appropriate growth and there was no macrosomia. There was a significant increase in mechanical deliveries in cases of growth-retarded neonates, determined using the NGAS classification, when compared with events related to normally grown or macrosomic neonates. However, there were no significant differences in mechanical deliveries among the groups by birth weight classification or ponderal index. Both birth weight classification and NGAS classification showed a significant increase in the low Apgar score, abnormal FHR patterns, and neonatal acidosis in infants classified as growth retarded when compared with appropriately grown or macrosomic infants. However, there were no significant differences in the low Apgar score, abnormal FHR patterns, and neonatal acidosis between growth-retarded and appropriately grown infants when they had been so classified by ponderal index. Three growth category classification methods failed to reveal significant differences in meconium staining of amniotic fluid, neonatal intensive care unit admission, and maternal complications among the groups. Conclusion. We do cast doubt on the usefulness of the ponderal index for detection of growth-retarded neonates with poor perinatal outcomes, and individualized growth assessment seems to perform at least as well as the traditional birth weight-for-gestational age method.

1. Species-, gender- and strain-related differences in amine sulphoconjugations were studied in 105,000 g supernatants of liver samples isolated from mouse, rat, guinea pig, rabbit, dog, monkey and man and were compared with those of alcoholic and phenolic compounds. Substrates examined were desipramine (an alkylamine), piperazine and piperidine derivatives (alicyclic amines), aniline (an arylamine), tiaramide and dehydroepiandrosterone (alcoholic compounds) and 2-naphthol (a phenolic compound). 2. Sulphoconjugating activities of alicyclic and aryl-amines and tiaramide varied depending on the animal species, sex and strain used. In all animal species examined, the activity for desipramine was low or negligible but for 2-naphthol was consistently detected and high. Amine sulphoconjugations were higher in rabbit than in other animal species. Dog hepatic 105,000g supernatants exhibited low or neglible activities for amines and tiaramide. Females showed higher sulphoconjugating activities for all substrates in mouse and for amines and tiaramide in rat; males exhibited higher activities for 2-naphthol in rat and monkey and for amines in rabbit; there were no clear sex-related differences in other sulphoconjugations. 3. Among BALB/c, C57BL/6, DBA/2, and AKR mouse strains, the AKR strain showed higher activities towards amines and tiaramide than others. 4. In human liver 105,000g supernatants, sulphoconjugating activities for alicyclic amines, dehydroepiandrosterone, and 2-naphthol were detected. Among them, higher activities were observed in piperazine and phenol sulphoconjugations. There were no sex-related differences in the activities of all substrates examined. Good correlations were observed in activities between alicyclic amine and dehydroepiandrosterone sulphoconjugations. 5. These results indicate that activities of amine and alcohol sulphoconjugations vary considerably depending on the substrate, species, sex and strain but phenol sulphoconjugation is consistently detected in all species examined.

1. To clarify the mechanism of sex-dependent and independent kidney secretion of major nilvadipine metabolites (3, 7) in rat, renal clearance corrected for protein binding and glomerular filtration rate (GFR) was measured in both sexes. The effect of probenecid, an inhibitor of organic anion transport, on these measurements was also investigated. 2. Clear sex-dependent active secretion was observed in the renal excretion of 3 (3-carboxylic acid pyridine derivative). In the female rat, 3, clearance was approximately 32-fold greater than GFR and was markedly decreased by probenecid. Conversely, in the male rat, renal clearance of 3 was only a fraction of GFR and was unaffected by probenecid. 3. Sex-independent active secretion was observed in the renal excretion of 7 (5-carboxylic acid pyridine derivative). In both sexes of rat 7 clearance was about 22-fold greater than GFR and was markedly reduced by probenecid. 4. A clear presence of sex-dependent and independent active secretion mechanisms in the kidney has been demonstrated in rat. The female rat is able to eliminate 3 and 7 in urine by an active secretion mechanism that is inhibited by probenecid. In the male rat, a transport mechanism for 7 is present, but either lacks or is apparently inactive for 3.

1. The relationship between dose and plasma concentrations is important in extrapolating toxicity between species. Therefore, we determined this relationship for zenarestat in animals and man. 2. The biopharmaceutics of zenarestat was assessed prior to toxicity testing. The bioavailability of zenarestat in rat administered zenarestat in 0.5% (w/v) methyl cellulose suspension and aqueous solution was similar. Bioavailability in dog administered zenarestat treated with excipients and in aqueous solution was similar. 3. Cmax increases dose-relatedly both in animals and man. AUC increased almost in proportion to the dose in mouse, rat and man, but increased to a greater extent at the highest dose in dog. Cmax, AUC and C24h were not significantly different during/after multiple dosing. 4. After 13 and 53 weeks of toxicity testing, plasma concentrations were not significantly different between the days and sexes except at 560 mg/kg in the female rat and at 56 mg/kg in the female dog in 13 week toxicity tests. 5. The exposure of zenarestat in man, administered 300 mg b.i.d., seemed to be no more than that in animals at non-toxic doses.

Early detection and treatment of melanoma is important for optimal clinical outcome, leading to biopsy of pigmented lesions deemed suspicious for the disease. The vast majority of such lesions are benign. Thus, a more objective and accurate means for detection of melanoma is needed to identify lesions for excision.To provide proof-of-principle that epidermal genetic information retrieval (EGIR™; DermTech International, La Jolla, CA, U.S.A.), a method that noninvasively samples cells from stratum corneum by means of adhesive tape stripping, can be used to discern melanomas from naevi.Skin overlying pigmented lesions clinically suspicious for melanoma was harvested using EGIR. RNA isolated from the tapes was amplified and gene expression profiled. All lesions were removed for histopathological evaluation.Supervised analysis of the microarray data identified 312 genes differentially expressed between melanomas, naevi and normal skin specimens (P0·001, false discovery rate q0·05). Surprisingly, many of these genes are known to have a role in melanocyte development and physiology, melanoma, cancer, and cell growth control. Subsequent class prediction modelling of a training dataset, consisting of 37 melanomas and 37 naevi, discovered a 17-gene classifier that discriminates these skin lesions. Upon testing with an independent dataset, this classifier discerned in situ and invasive melanomas from naevi with 100% sensitivity and 88% specificity, with an area under the curve for the receiver operating characteristic of 0·955.These results demonstrate that EGIR-harvested specimens can be used to detect melanoma accurately by means of a 17-gene genomic biomarker.

A calmodulin-dependent nitric oxide synthase was significantly induced in the liver of rats treated intravenously with heat-killed Propionibacterium acnes and 5 days later with Escherichia coli lipopolysaccharide. The apparent calmodulin-dependent and -independent isozymes were separated by Mono Q column chromatography after their partial purification by 2',5'-ADP-agarose affinity chromatography. Both enzymes had a molecular weight of 125,000 as determined by SDS-polyacrylamide gel electrophoresis and required NADPH, tetrahydrobiopterin, and dithiothreitol as cofactors. Their activities were completely inhibited by the specific nitric oxide synthase inhibitors NG-monomethyl-L-arginine and N omega-nitro-L-arginine at 80 and 800 microM, respectively. The peptide maps of these two isozymes with lysylendopeptidase and their reverse-phase column chromatographic profiles were indistinguishable. In the presence of bovine calmodulin, the purified calmodulin-dependent isozyme behaved as a calmodulin-independent isozyme on Mono Q column chromatography. The purified calmodulin-independent isozyme was converted to a calmodulin-dependent isozyme by EDTA and EGTA. Calmodulin blot analysis using 125I-calmodulin showed that the two isozymes bound calmodulin equally efficiently.

Because the Na+ pump is considered to modulate the contractile force development by the cardiac muscle and depressed cardiac pump function is the hallmark of congestive heart failure, we characterized the sarcolemmal Na(+)-K(+)-ATPase activity in failing rat hearts after myocardial infarction. For this purpose, the left ventricular coronary artery was ligated, and hearts were examined 4, 8, and 16 wk later; sham-operated animals served as controls. Hemodynamic assessment revealed the presence of abnormal cardiac function at 4, 8, and 16 wk. Although accumulation of ascites in the abdominal cavity was present in experimental animals at 4 wk, other clinical signs of congestive heart failure in experimental rats including lung congestion and cardiac dilatation were evident 8 and 16 wk after induction of myocardial infarction. The depression in Na(+)-K(+)-ATPase activity in purified sarcolemmal membrane from the uninfarcted experimental left ventricle at 8 wk was associated with depressed Vmax without any changes in the affinities for Mg-ATP, Na+, and K+ or the pH optimum for the enzyme. The Kd values of both the high- and low-affinity binding sites for [3H]ouabain, which is believed to interact with Na(+)-K(+)-ATPase, were increased; however, no change in the density of either class of ouabain binding site was evident. The depression of Na(+)-K(+)-ATPase activity in failing hearts at 16 wk of myocardial infarction was not different from that observed at 8 wk but the enzyme activity was not altered at 4 wk of coronary occlusion. These data support the view that depression of Na(+)-K(+)-ATPase activity may serve as an adaptive mechanism during the development of congestive heart failure.

We stated that SART-stressed guinea pigs showing nasal mucosal hypersensitivity would serve as an animal model for the in vivo evaluation of antiallergic drugs. In the present study, the mode of action of Neurotropin on nasal allergy compared with those of antiallergic drugs was studied by using SART-stressed guinea pigs. Daily administrations of Neurotropin improved the methacholine-induced hypersecretion and histamine-evoked sneeze response, which are parameters of nasal mucosal hypersensitivity, and increased the density of muscarinic ACh receptors located on the nasal mucosa caused by SART stress. In addition, the inhibitory action on nasal secretion in a passively sensitized model was more intense in SART-stressed guinea pigs than in normal ones. Ketotifen and tranilast were also found to have marked effects on nasal secretion in the passively sensitized SART-stressed model, but only had weak effects on nasal mucosal hypersensitivity. Neurotropin significantly potentiated the action of ketotifen or tranilast. Thus, at least part of the inhibitory effect of Neurotropin on nasal symptoms such as watery secretion and sneezing is thought to have been brought forth through the regulatory action on nasal mucosal hypersensitivity, and its combined use with antiallergic drugs would be a very effective therapeutic regimen for nasal allergy.

Sarcolemmal membranes were isolated from skeletal muscle by a sucrose density gradient method from rats with diabetes induced by a streptozotocin injection (65 mg/kg iv). The activities of Na(+)-dependent Ca2+ uptake and Ca2(+)-stimulated adenosine-triphosphatase (ATPase) in the sarcolemmal fraction from diabetic rats was higher than those from the control animals. These changes were apparent at various times of incubation (1-10 min) as well as at different concentrations of free Ca2+ (10(-7) to 10(-5) M) and developed during the third and/or fourth weeks after streptozotocin injection. ATP-dependent Ca2+ uptake in the sarcolemmal vesicles was also increased at 28 and 56 days after inducing diabetes. Treatment of diabetic animals with insulin for 14 days reversed the changes in Ca2+ transport activities toward the control levels. Sarcolemmal Mg2(+)-ATPase and Na(+)-K(+)-ATPase activities remained unchanged in diabetic preparations. Furthermore, no difference in the sarcolemmal phospholipid composition and sodium dodecyl sulfate-gel electrophoretic pattern was evident between the control and experimental groups. These results indicate a higher activity of the sarcolemmal Ca2+ transport, which may be associated with hyperfunction of the skeletal muscle in diabetic rats.

We evaluated the reliability and efficacy of the ultrasonically activated scalpel (Harmonic Scalpel) for pulmonary resection in video-assisted thoracoscopic surgery (VATS). Fifty-six cases of primary or metastatic lung cancer with history of lobectomy or segmentectomy from July 2003 to June 2006 were investigated. The ultrasonically activated scalpel was used to separate aborted lobulation and segment in the surgery. The outcome of the operation using the ultrasonically activated scalpel revealed the mean operation time of 224.5 minutes and mean blood loss volume of 116.7 ml. The chest drainage catheter was removed at the postoperative day 3.4 and hospitalization lasted 10.4 days on average. By means of statistical analysis, no significant differences were noted when compared with the cases using surgical stapler to separate the lobules or segments of the lungs. Histopathological results showed destruction of alveolar structures and denaturation of cells at the cut surface of the resected lung through the use of the ultrasonically activated scalpel. This method resulted in good lung expansion and preservation of the residual lung volume. Furthermore, it prevented postoperative air leakage by appropriate treatment to the cut surfaces of the residual lung. Indeed, the method appears to be useful in the separation of lung tissues in severe aborted lobulation and segmentectomy by VATS.

Recent reports have shown that aortic valve replacement in elderly patients over 65 years with atherosclerotic aortic stenosis and a small aortic annulus is possible by using a small sized bioprosthesis (Carpentier-Edwards pericardial valve). Here we present out surgical technique. Firstly, the native calcified aortic valve was removed completely to gain total exposure of the surrounding aortic root and sinus of Valsalva like Bentall procedure. Secondly, a small sized bioprosthesis was implanted with intermittent noneverting mattress 2-0 sutures with spaghetti and small polytetrafluoroethylene (PTFE) felt. Aortic annulus is the dilated by inserting Hegar dilator sizing from 25 to 27 mm. Therefore, aortic valve replacement for small aortic annulus in intra- or supra-annular position should be easily accomplished. Good surgical results and hemodynamic state were achieved in 25 consecutive cases using this technique.

We report a case of a 40-year-old male with a posterior mediastinal mass that was 8 cm in size and located behind the trachea. The thoracoscopic surgery was performed. The tumor was located from the level of left brachiocephalic vein to the carina. The mediastinal pleura over the tumor was longitudinally opened by cautery-scissors. The azygos vein lying over the tumor was divided by means of an endoscopic stapler. The muscular layer of the esophagus was also longitudinally opened. The tumor was enucleated. Then, the dissected proper muscle layer of the esophagus was suture-closed. The postoperative course was uneventful. On the first postoperative day Gastrografin was swallowed, showing the absence of leaks. The patient was discharged on the fourth postoperative day. The advantages of the thoracoscopic surgery are as follows: rapid, full recovery of the patient; decreased postoperative pain; short postoperative hospital stay. Esophageal leiomyoma in selected patient was suitable for thoracoscopic enucleation.

An in-hospital 72-year-old male with complaint of anterior chest pain was presented with shock. Pericardial effusion was confirmed by echocardiography, and therefore, he was brought to the operating room immediately with diagnosis of ventricular free wall rupture. The repair was performed using fibrin glue, fibrin sheet, and pericardial patch. His post-operative course was uneventful until massive bleeding came through the chest tube on the 5th day from the initial surgery. The emergency sternotomy was made again for hemostasis. In the re-operation, an approximately 20 mm laceration along the proximal circumflex artery was found and this was successfully repaired with 2 pledgetted horizontal mattress sutures. It is important and necessary to treat a postoperative patient taking care of re-rupture.

The appearance of local cerebral dysfunction at remote regions from the focus in the acute stage of stroke (diaschisis) is well known, but its mechanism has not been established. We have analysed serial MR images of the infarcted brain of rats to evaluate the distribution of oedema. Forty-seven Sprague-Dawley rats were anaesthetized with halothane, and the right middle cerebral artery (MCA) was permanently occluded via the intraluminal approach using a nylon 2-0 suture. At 3, 6, 9 and 24 hours after the occlusion, coronal T(2)-weighted MR images were taken and the signal intensity (SI) was computed at each region of the brain. After occlusion of the right MCA, SI increased diachronically up to 24 hours on the occluded side of the cortex (52.9+/-3.2 to 104.8+/-22.4) and striatum, which are within the perfusion territory of the MCA. SI increment was also observed at the hippocampus, alveus hippocampi and pyriform lobe, which are not within the territory of the MCA, and at some regions of the contralateral side (52.5+/-4.8 to 69.4+/-14.8 at the cortex). These changes were prominent in ischaemia-vulnerable portions, mild in the cortex, and minimal in the striatum. This contralateral side SI increment indicates remote oedema, which corresponds to diaschisis. We suggest that the mechanism of this remote contralateral oedema is the movement of extravasated protein from the lesion.

Angioplasty for the unprotected left main trunk remains controversial, but new procedures and devices such as directional coronary atherectomy and stenting have improved the results. We compared the results of angioplasty with the inflexible balloon and new devices.The procedures were performed in 239 consecutive lesions in 160 patients between April 1986 and March 2000. This study excluded emergency cases and repeat angioplasty cases, and included 120 initial and elective cases. Initial and long-term results were compared between the balloon group (n = 29) and the new device group (n = 91).Lesion success rate was lower in the balloon group (90% vs 100%, p0.05), but there were no significant differences in in-hospital results including cardiac death (0% vs 0%), noncardiac death (0% vs 3.3%), Q-wave myocardial infarction (0% vs 2.2%), non-Q wave myocardial infarction (3.4% vs 6.6%), bypass surgery (0% vs 0%) and repeat angioplasty (6.9% vs 1.1%). Quantitative angiography showed significant improvements in minimal lumen diameter (mean 2.17 vs 3.16 mm, p0.001) and percentage diameter stenosis (mean 31% vs 13%, p0.001) in the new device group after the procedures. The minimum lumen diameter remained larger at 3 (p0.001) and 6 months (p0.05) in the new device group. Therefore, angiographic restenosis rate was higher in the balloon group (55% vs 21%, p0.005). Five-year survival rate showed no significant difference between the groups (75.0% vs 83.8%).New devices significantly improved the minimal lumen diameter after angioplasty for unprotected left main trunk disease, and lead to significant improvement of restenosis rate at follow-up.

The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates.The theoretical octanol/water partition coefficients (clog P) of 13 bisphosphonates were calculated by computer software, CLOGP ver. 3.05 (Daylight C.I.S., Inc. Irvine, CA) and related to pharmacokinetic or osteotropic parameters after intravenous injection into rats. On the other hand, to optimize ODDS of diclofenac (DIC-BP), the effects of doses or infusion rates on the in vivo disposition were investigated in relation to solubility product value (Ksp) of DIC-BP-calcium complex.Clog P had good correlations with total plasma clearance, apparent distribution volume and the fraction dose delivered to the whole skeleton after bolus injection into rats (r = -0.868 approximately -0.914). The targetability of bisphosphonates to the skeleton was linearly decreased with an increase in clog P value and the more hydrophilic bisphosphonates were suitable for ODDS in bolus administration. On the other hand, DIC-BP, a relatively lipophilic bisphosphonate, was effectively and selectively delivered to the skeleton only when administered as a slow infusion to keep plasma concentration lower than that calculated from Ksp value where DIC-BP could precipitate with calcium in the plasma circulation.Our results suggest the possibility of a rational design of ODDS via bisphosphonic prodrugs, after consideration of compound lipophilicity and precipitability of bisphosphonate-calcium complex.

A giant multiseptate cystic mass covering the whole left hemitruncus of fetus was detected by ultrasonography at 23 weeks of gestation. Color and pulsed Doppler ultrasonography revealed marked blood flow in the mass. No other anomaly or chromosomal abnormality was recognized. Although the cystic lesion increased in size with advancing gestation a male infant weighing 4096 g was delivered in good condition at term. Histological examination of the lesion demonstrated hemangiolymphangioma with hyperplasia of both capillaries and lymphoducts. The infant was treated effectively with OK-432 and interferon-alfa-2a.

We evaluated the significance of hepatectomy following hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. The prognosis of 4 cases with initially resectable tumors was discouraging, indicating no benefit of preoperative HAI for resectable tumors. The 2- and 3-year survival of patients who underwent hepatectomy after downstaging by HAI of originally unresectable metastases were 100% and 67%, respectively, suggesting that hepatectomy combined with HAI is a promising modality for those patients. However, it seems that the control of extrahepatic disease and decision making for the timing for surgical therapy are issues requiring improvement.

The short-term and long-term predictors of outcome after coronary angioplasty in the unprotected left main coronary artery were investigated.The procedure was performed in 122 consecutive patients for de novo lesions without myocardial infarction in our hospital between April 1986 and October 1998, including 16 emergency cases. Procedures were directional coronary atherectomy (73 patients), balloon angioplasty (31 patients), and stent implantation (18 patients). There were 101 males and mean age was 68 +/- 10 years. Follow-up angiography was performed in 98% of discharged patients, and all patients were clinically followed up for more than 1 year. Clinical and angiographic predictors of in-hospital and long-term outcome were evaluated.The in-hospital mortality was 5.7% (7 of 122 patients). Multivariate analysis revealed that more patients were admitted as emergency cases (57% vs 10%, p = 0.0088), with left ventricular ejection fractionor = 35% (57% vs 22%, p = 0.029) and renal failure (43% vs 3%, p = 0.0004) finally died. Mean follow-up period was 3.5 years. Estimated survival rate was 77.1%, and cardiac-death free survival rate was 81.0% at 5 years by the Kaplan-Meier method. Univariate analysis showed that the predictors of cardiac death were emergency angioplasty, renal failure, decreased left ventricular ejection fraction, multivessel disease and unstable angina and/or congestive heart failure. Cox's regression model showed that renal failure (p = 0.0004) and multivessel disease (p = 0.0075) were significant predictors of long-term prognosis.Renal failure was the strongest predictor of outcome after unprotected left main coronary artery angioplasty.

A case with the giant aneurysm of the ductus arteriosus combined with severe mitral regurgitation is reported. 58-year-old male underwent MVR and patch closure of the ductal orifice for staged operation. The first operation was MVR and patch closure of the PDA orifice of the pulmonary artery end using retrograde cerebral perfusion (RCP) with deep hypothermic circulatory arrest (DHC). The second operation was performed on 3 months after the first operation using left thoracotomy approach, and patch closure of the ductal orifice via the aorta using RCP with DHC was performed. Upon following-up examination, the patient is now doing well 20 months after the initial surgery.

Between 1990 and 1999, 78 patients underwent combined valvular coronary artery operation. Aortic valve disease was present in 49 patients, mitral valve disease in 23 patients, aortic and mitral valve disease in 6 patients. The average age was 67 years. Twelve patients had had a previous myocardial infarction. The average number of grafts inserted was 1.82 per patients, and the average number of artery grafts inserted was 0.96 per patients. The most number of grafts were placed prior to valve replacement or plasty. And periods of myocardial ischemia were kept at a minimum by coronary perfusion through free grafts. Preoperative mortality was 1.3%. And event fee ratio after operation was 95% (mean follow up 42 month). Therefore the operative risk of combined surgery is, in general, low and the long term results are favorable.

We reported on 2 atomic bomb survivors(a 60-year-old man and 63-year-old woman)suffering myelodysplastic syndrome(MDS) associated with 1p32 chromosomal abnormalities. They were exposed to atomic bomb radiation at distances of 1.2 and 1.1 km, respectively, and were given a diagnosis of MDS 44 and 46 years after the bombing, respectively. The male patient had refractory anemia(RA) and a bone marrow cell karyotype of 46, XY, del(1)(p22p32), t(8;11)(p11;p15). The female patient had RA with excess of blasts (RAEB) and a karyotype of 45, X, -X, t(1;11)(p32;q23), +del(1)(p32), inv(3) (p21q27), del(5)(q15), -6, -9, -19, +mar 1, +mar 2. Multi-separated nuclear megakaryocytes were observed in both patients. These findings suggested that they had been exposed to radiation near the atomic explosion despite the fact that their symptoms of MDS developed more than 40 years after the bombing. 1p32 is known to be the locus of the TAL1 gene. However, Southern blot analysis did not reveal rearrangement of the TAL1 gene in the male patient.

For most intracardiac tumors, operation is the only means of therapy. In our institute, we have aggressively performed operation for intracardiac tumors regardless of histological type because resection for tumor had a beneficial effect on the hemodynamics with congestive heart failure. Twenty-five cases of cardiac tumors were operated upon from 1980 through 1998. The follow-up period ranged from 2 months to 19 years. The histological diagnoses of the tumors were as follows: benign tumors 24 (myxoma 21, papillary fibroelastoma 1, fibroma 1, angiomyolipoma 1) and malignant tumor (angiosarcoma 1). There was one hospital death in this series. In the New York Heart Association classification, the cardiac performances of intracardiac benign tumors after operation were Class I or II. The results of surgical treatment of intracardiac benign tumors were satisfactory both in short-term and in long-term. On the other hand the long term result of malignant tumor was extremely poor. A patient with angiosarcoma died 8 months later due to bone metastasis.

We experienced a rare case of leptomeningeal melanomatosis. The proliferative activity and nuclear accumulation of p53 in this tumor were examined, since the relationship between this tumor type and growth has not yet been elucidated. A 33-year-old Japanese man was shown to have leptomeningeal melanomatosis with multiple cutaneous pigmented nevi. The autopsy findings showed the presence not only of benign diffuse melanosis of the leptomeninges but also of leptomeningeal melanomatosis in the subarachnoid space and brain parenchyma. In the brain parenchyma, the direct invasion of tumor cells from the subarachnoid space and Virchow-Robin spaces filled with melanoma cells were observed. Multiple hemorrhagic areas invaded by melanoma cells were also present. Immunohistochemical staining with a monoclonal antibody to melanoma cells showed positivity in the tumor cells. Proliferation analysis using the MIB-1 antibody demonstrated that the labeling index of tumor cells invading brain parenchyma (2.54%) was higher than that in other lesions of the inner (0.89%) and outer layer (0.76%) of the subarachnoid space. Nuclear accumulation of p53 protein was rarely seen in the tumor cells. We reported a case of leptomeningeal melanomatosis. Higher proliferative activity was found in invading cells of the brain parenchyma. Malignant transformation of the tumor did not appear to be associated with p53 gene mutation.

We recently conducted video-assisted thoracoscopic surgery (VATS) on an 8-day-old boy in whom a congenital mediastinal cyst had caused obstruction of the left main bronchus. After the surgery, the cyst recurred and caused reobstruction of the airway. When he was 51-day-old, we conducted VATS again. We could not perform cystectomy by VATS because the left lung was inflated, and we conducted cystectomy by thoracotomy.

Between January, 1996 and December, 1998, 29 patients were undergone emergency coronary artery bypass grafting (CABG) in our institute. Age ranged 34 to 85 years (mean 65 +/- 11 years, male:female = 25:4). Of 29 emergency cases, 3 were hospital death. Hospital mortality rate was 10.7%, which was significantly higher than the hospital mortality of elective CABG (1.4%) during the same period. The necessity of IABP before CABG was 72% in emergency cases (elective surgery: 0%). Thus the use rate of arterial grafts were 86.2% in emergency cases (elective surgery: 100%), the patency of the arterial grafts were 100%. It is important to make stable condition of the patients before the operation, and therefore it is important to make contact closely with the cardiologists for making stable condition and for lowering the operative mortality. And, we should use arterial grafts for the long term result as much as possible if it is an urgent operation.

In our institute, 1 ml of heparin is administered to the patients undergoing CABG before dissection and mobilization of the internal thoracic arteries (ITAs) and/or right gastroepiploic artery (GEA) to prevent possible thrombosis or coagulation tendency. Two patients with AT III deficiency underwent CABG and one of them died. The aim of this study is to know whether ACT check before and after administration of 1 ml of heparin is useful as a screening test of coagulation abnormalities including AT III deficiency. One hundred patients (84 males and 16 females) undergoing CABG were studied. Age ranged from 41 to 79 years (mean 64.8 +/- 8.0 years). One ml of heparin was administered to all the patients before ITAs and/or GEA were dissected and mobilized. ACT was doubly checked before (control ACT: c-ACT) and after (heparinized ACT: h-ACT) administration of heparin. ACT extension was defined as follows: ACT extension = (c-ACT)-(h-ACT). Mean c-ACT was 124 +/- 12 sec., h-ACT 188 +/- 26 sec. and ACT extension 64 +/- 24 sec. There were only 3 cases which ACT extension were less than 30 sec.: two of them were combined with AT III deficiency and the other was due to insufficient administration of heparin. In conclusion, examination of ACT after 1 ml administration of heparin is new, simple and convenient screening method for coagulation abnormalities including AT III deficiency during CABG.

Tacrolimus is a macrolide lactone with potent immunosuppressive properties. It has been shown in clinical studies to prevent allograft rejection. The pharmacokinetics of tacrolimus in healthy subjects and transplant patients has been described in earlier studies using immunoassay methods; however, detailed information on the absorption, distribution, metabolism, and excretion of tacrolimus using a radiolabeled drug is lacking. The objective of the present study was to characterize the disposition of tacrolimus after single i.v. (0.01 mg/kg) and oral (0.05 mg/kg) administration of 14C-labeled drug in six healthy subjects. Tacrolimus was absorbed rapidly after oral dosing with a mean Cmax and Tmax of 42 ng/ml and 1 h, respectively. The oral bioavailability was about 20%. After i.v. and oral dosing, most of the administered dose was recovered in feces, suggesting that bile is the principal route of elimination. Urinary excretion accounted for less than 3% of total administered dose. In systemic circulation, unchanged parent compound accounted for nearly all the radioactivity; however, less than 0.5% of unchanged drug was detectable in feces and urine. The excretion of the metabolites was formation-rate-limited. The mean total body clearance at 37.5 ml/min was equivalent to about 3% of the liver blood flow. Renal clearance was less than 1% of the total body clearance. The mean elimination half-life was 44 h.

To detect chromosomal abnormalities in prodromal phase of adult T-cell leukemia (ATL), we established a clonal culture method for human T-lymphotropic virus type I (HTLV-I) infected T-cells in methylcellulose containing recombinant human interleukin 2 (rhIL-2). We tried to analyze chromosomes of 187 colonies (4, 23, 69, 74, and 17, from HTLV-I-uninfected normal T-cells, HTLV-I-Infected normal T-cells, HTLV-I carriers, smoldering ATL, and chronic ATL, respectively), using chromosomal banding methods. In the prodromal group, 53% of colonies (84/160) (36/69, 37/74, 11/17 in HTLV-I carriers, smoldering ATLs, and chronic ATL, respectively) had chromosomal abnormal clones. In HTLV-I carriers, multiple clones with simple chromosomal abnormalities were observed. In more progressed chronic ATL, more complex chromosomal abnormalities were detected, and specific colonies were selected. Thus, colonies in the prodromal phase of ATL are characterized by cytogenetical clonal evolution and clonal changes.

Primary cardiac angiosarcoma occurs rarely, and surgical resection is often required to relieve symptoms. A 66-year-old man whose presenting symptoms were palpitations and general fatigue is presented. Echocardiography revealed a large tumour occupying most of the right atrium. When superior vena caval (SVC) syndrome developed, surgical resection of the tumour was attempted. The tumour was found to have invaded the inflow of SVC, left atrium, right ventricle and ascending aorta. The bulk of the tumour was resected, requiring reconstruction of the right atrium and caval inflows. Histopathological diagnosis of the tumour was primary angiosarcoma. In the postoperative period, symptoms of SVC syndrome recurred, which were relieved temporarily by balloon angioplasty. After one month, recurrence of symptoms was again managed by catheter dilation. On this occasion a metallic stent was deployed, which prevented further symptoms of SVC syndrome during the eight months before the patient died with generalized metastases.

To support a long-lasting antihypertensive effect of transdermal clonidine (CAS 4205-90-7), changes in plasma norepinephrine (NE) levels and urinary NE excretion as indices of the sympathetic nervous activities were investigated following transdermal and oral clonidine in conscious spontaneously hypertensive rats. Plasma NE levels were significantly reduced for 24 h during transdermal application of clonidine patch at 1.5 and 4.5 mg/kg on the back of each rat. Oral clonidine at 100 microgram/kg also lowered plasma NE levels. However, significant falls in the levels lasted only for 4 h after oral dosing. Urinary NE excretion was significantly decreased during both 4-8 and 8-24 h periods, and during an 8-24 h period following transdermal clonidine at 1.5 and 4.5 mg/kg, respectively. Significant decrease in urinary NE excretion was also produced during a 4-8 h period following oral clonidine at 100 micrograms/kg. Total urinary NE excretion during a 0-24 h period was dose-dependently reduced following transdermal clonidine, but was not altered following oral dosing. These findings suggest that the sympathoinhibitory effect of transdermal clonidine is more persistent than that of oral clonidine. Therefore, long-lasting antihypertensive effect of transdermal clonidine is closely associated with the sustained suppression of the sympathetic nervous activity.

We report a 33-year-old man who manifested spastic paraplegia with congenital cataract, dementia, deformity of the foot (pes cavus, high arch and hammer toes), ataxia, and peripheral neuropathy. Magnetic resonance imaging showed mild deformity of the trunk of the corpus callosum and atrophy of superior cerebellar vermis. Metabolic diseases were ruled out by the clinical course and special examinations. Other patients, including 2 of ours, with spastic paraplegia and thin corpus callosum have been reported, but the present case is different because of congenital cataract and the form of the corpus callosum. We consider that there may be a variety of complicated forms of spastic paraplegia. To assess the etiology of complicated forms of spastic paraplegia, further case accumulation is very important.

Cytosolic sulfotransferases, which consist of at least three gene families, play a major role in activation and detoxification of both endogenous and exogenous chemicals. We recently purified a rabbit sulfotransferase, AST-RB2, showing high activities to both hydroxysteroids and amines. To characterize this enzyme, a rabbit cDNA library was screened using anti-AST-RB2 antibodies. The isolated cDNA was judged to encode AST-RB2 (ST2A8) based on the amino acid sequences of peptide fragments obtained from purified AST-RB2. The cDNA showed high similarity to other mammalian hydroxysteroid sulfotransferases (ST2) at the amino acid level (58-68%), but low similarity to aryl sulfotransferases (ST1) (less than 37%). The protein expressed in Escherichia coli catalyzed sulfation of typical ST2 substrates. Therefore, ST2A8 was judged to belong to the ST2 family from both its primary structure and substrate specificity. The ST2A8 protein expressed in E. coli clearly differed from rat ST2A1 and ST2A2 on its localization (cytosol/insoluble fraction ratio). ST2A8 had no activity to lithocholate, but showed the highest catalysis on dehydroepiandrosterone and testosterone among the four forms (ST2A1, ST2A2, ST2A3, and ST2A8), indicating a clear difference between ST2A forms in substrate specificity to endogenous chemicals.

The pharmacokinetic and pharmacodynamic behaviors of 4-[3-[3-[Bis(4-isobutylphenyl) methylamino] benzoyl]-1H-indol-1-yl]-butyric acid (FK143), a new nonsteroidal steroid 5 alpha-reductase inhibitor, in the ventral prostate were investigated after i.v. administration to rats. The relationship between blood concentrations at 24 hr and doses was linear in the range of 0.1 to 20 mg/kg. However, the levels of FK143 in the prostate were saturated over the dose of over 5 mg/kg. The dissociation constant (Kd) and maximum amount of binding substances (Bmax), calculated according to nonlinear kinetic analysis including a specific binding pool, was 0.0553 +/- 0.0117 microgram/ml (92 nM, estimated value +/- S.D.) and 0.908 +/- 0.092 microgram/g tissue, respectively. A combined pharmacokinetic/pharmacodynamic (PK/PD) model was constructed using change in dihydrotestosterone (DHT) levels in the prostate after i.v. administration of FK143 as an index for its pharmacological effect and blood concentration as an input function. The apparent reaction rate constant of drug and enzyme (K) was 39.7 +/- 25.1 g tissue/microgram/hr (estimated value +/- S.D.), the apparent turn-over rate constant of enzyme (k) was 0.140 +/- 0.107 hr-1, the elimination rate constant of DHT (kel, DHT) was 1.13 +/- 0.94 hr-1 and the fraction of FK143-insensitive DHT synthesis (F) was 0.461 +/- 0.037. The PK/PD analysis suggested that the duration of the effect of FK143 was related to its accumulation in the binding pool of the prostate. After i.v. administration of FK143 in the range of 0.1 to 20 mg/kg, the DHT levels in the prostate decreased to about 40% of control value, after which despite the rapid decline of blood FK143 concentration, slowly recovered according to the elimination rate of FK143 in the prostate. Moreover, the PK/PD profiles of FK143 after repeated i.v. administration were predictable by using the PK/PD parameters obtained after single administration of FK143.

To evaluate the clinical utility of 123I-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid (123I-BMIPP) for ischemic heart disease, we investigated the metabolic fate of 123I-BMIPP in canine models with mild and severe ischemia and evaluated the clinical utility of this tracer.Using open-chest dogs under anesthesia, we assembled a system that would release all the blood from the great cardiac vein without recirculation, if necessary. After injection of BMIPP into the left anterior descending coronary artery, blood samplings from cardiac vein and abdominal aorta were performed for 10-min ischemia (mild ischemia, five dogs) and 30-min ischemia (severe ischemia, six dogs), after reperfusion and for normal controls (six dogs). The catabolites of BMIPP, including backdiffusion of nonmetabolized BMIPP, were evaluated using high-performance liquid chromatography.Although the rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged among three groups, the early washout (at 8 min) of radioactivity significantly increased (from 50% +/- 13% to 61% +/- 8%; p0.05) in severe ischemia. The metabolites from the myocardium consisted of backdiffusion of nonmetabolized BMIPP and alpha-oxidation, intermediate-oxidation and full-oxidation metabolites. For mild ischemia, these values were not significantly changed from the normal control, although the respective proportions of metabolites showed some variation. Lactate production after reperfusion on mild ischemia, which indicates the severity of ischemia, was closely correlated with the level of backdiffusion of BMIPP (r = -0.92) and the full-oxidation metabolite (r = 0.78). On the other hand, for severe ischemia, the level of backdiffusion of nonmetabolized BMIPP increased (from 25.1% +/- 8.0% to 34.7% +/- 8.7%; p0.05), and the full-oxidation metabolites decreased (from 21.4% +/- 10.9% to 14.8% +/- 7.3%).The metabolism of BMIPP was closely associated with the severity of myocardial ischemia. Thus, 123I-BMIPP might be a promising and sensitive radiopharmaceutical for the evaluation of ischemic heart disease.

A 40-year-old man was diagnosed as having PDA with severe PH by cardiac catheterization. We decided that surgery was indicated on the basis of 100% oxygen inhalation test. After 100% oxygen inhalation, left to right shunt changed from 37.8% to 61.5%, Qp/Qs changed from 1.43 to 2.60, and PVR changed from 1,199 dyne/sec/cm5 to 237 dyne/sec/cm5. We decided to perform surgery. Under extracorporeal circulation, PDA was safely closed by triple ligation and was directly closed after pulmonary arteriotomy. The postoperative course was uneventful. Severe PH was greatly improved, pulmonary artery pressure recovering to the normal range, by administering PGE1, prostacyclin (PGI2), and nitroglycerin.

The disposition of a new nonsteroidal 5alpha-reductase inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyric acid (FK143), was investigated in rats. After intravenous administration of FK143 at 1 and 5 mg/kg, total body clearance, elimination half-life, and volume of distribution at steady-state were, respectively, 6.96 and 8.76 ml/min/kg, 10.31 and 9.83 hr, and 4.11 and 3.33 liters/kg. There were no essential differences between the two doses in any parameters. The serum protein binding in vitro was very high (99%). The unidirectional uptake clearance (CL1) to 13 tissues was determined by integration plot until 10 min after intravenous administration of 1 mg/kg. CL1 values were much smaller than blood flow rate in all tissues, including the prostate, the target organ, indicating that FK143 was transported from blood to tissues by a membrane-limited process. Since the elimination rates of FK143 from the liver, kidney, lung, epididymis, seminal vesicle, and prostate were slower than from the blood, the efflux rate constant (k2) and rate constants at a binding compartment (k3 and k4) were assumed in the pharmacokinetic model. A correlation was found between the binding potential of binding compartment (k3/k4) and V(max) of steroid 5alpha-reductase, the target enzyme, suggesting that the levels of 5alpha-reductase activity or that of associated substances are a primary determinant of the specific binding of FK143 in these tissues.

An episode of malignant hyperthermia occurring in a 42-year-old man undergoing hypothermic cardiopulmonary bypass is reported. Malignant hyperthermia is a syndrome initiated by a hypermetabolic state of skeletal muscle. A patient presented for correction of an acyanotic tetralogy of Fallot. The coincidental usage of hypothermic cardiopulmonary bypass obscured the classical presenting sings and symptoms of the malignant hyperthermia. And the disease of tetralogy of Fallot made the syndrome difficult to manage. Although the clinical diagnosis of malignant hyperthermia is difficult to be confirmed, when it is suspected, it is prudent for the case to be initially treated as malignant hyperthermia.

Coronary artery bypass grafting (CABG) has been performed for elderly patients with increasing frequency. Several studies have shown that the rate of complications and mortality in elderly patients are higher than in younger ones. This report presents results of CABG in patients over 75 years old. From January 1989 to February 1997, 604 patients underwent CABG, of whom 20 patients (3.3%) were 80-86 years old (group A) and 57 patients (9.4%) were 75-79 years old (group B). We compared these two groups with 100 younger patients (group C). Preoperative use of intraaortic balloon pumping and the emergency operation were more frequent in patients of group A (emergency 45%, IABP 20%). And the proportion of the no blood transfusion procedures was lower in elderly patients (group A 20%, group B 18%, group C 82%). The number of grafts per patient (group A 2.45 +/- 0.62, group B 2.2 +/- 0.6, group C 3.2 +/- 0.6) and the number of arterial grafts (group A 1.25 +/- 0.62, group B 1.25 +/- 0.66, group C 2.1 +/- 0.53) were different between the groups. But CABG in elderly patients was performed with low hospital mortality (group A 0%, group B 0.18%) and significant symptomatic benefit. We conclude that CABG can be performed in elderly patients with acceptable mortality and acceptable quality of life, so patients should not denied operation because of an advanced age.

To investigate the kidney as a metabolic organ of recombinant human insulin-like growth factor-I (rhIGF-I), a single chain polypeptide consisting of 70 amino acids, the renal extraction and urinary excretion of rhIGF-I were examined in rats. The distribution of rhIGF-I after subcutaneous administration and the degradation in various tissue homogenates were also studied to evaluate the contributions of the other tissues to its metabolism. Although potent enzymes capable of degrading rhIGF-I exist in other tissues, no other organ except the kidney seemed to play a specific role in clearing rhIGF-I from the systemic circulation.

Mitral regurgitation (MR) due to rupture of the papillary muscle is one of the most serious complications of acute myocardial infarction (AMI) as well as ventricular septal perforation and ventricular free wall rupture. We experienced a case of complete rupture of the anterior papillary muscle. A 68-year-old man experienced an episode of dyspnea. Electrocardiographic findings were consistent with postero-lateral infarction. Massive MR is present on color Doppler imaging. He was transferred to our hospital for urgent operative indication because of papillary muscle rupture due to AMI. Six hours after the onset, the operation was performed with intra-aortic balloon pump in place. The anterior papillary muscle was ruptured completely in the mid portion. He underwent a mitral valve replacement with a SJM prosthetic valve. There is a few cases with successful urgent surgery for a complete rupture of anterior papillary muscle.

Iodine-123-MIBG imaging has been used to evaluate myocardial sympathetic function in various cardiac diseases. In patients with obstructive sleep apnea syndrome (OSAS), increased sympathetic activity has been widely recognized, as assessed by measuring the plasma concentration and urinary excretion of catecholamines and by measuring muscle sympathetic nerve activity. However, these measurements are not specific indices of cardiac sympathetic function. Therefore, this study was undertaken to assess cardiac sympathetic function in patients with OSAS using MIBG cardiac scintigraphy.This study consisted of 11 patients (10 men, 1 woman; mean age 43 +/- 16 yr) with a diagnosis of OSAS established by polysomnography, and 8 age-matched normal control subjects (7 men, 1 woman; mean age 45 +/- 18 yr). Early (15 min) and delayed (3 hr) planar images were taken after the injection of 111 MBq of [123I]MIBG. The mean counts of the whole heart and the mediastinum were obtained to calculate heart-to-mediastinum count ratios from the early images (H/Me) and from the delayed images (H/Md) and the myocardial washout rate (WR). Eight patients were restudied after 1 mo of nasal continuous positive airway pressure treatment.The H/Me and H/Md ratios were significantly lower in the patients than in the control subjects (H/Me, 2.49 +/- 0.32 versus 2.84 +/- 0.34, p = 0.0207; and H/Md, 2.33 +/- 0.30 versus 3.02 +/- 0.36, p = 0.0013). The WR was higher in the patients than in the control subjects (36.2 +/- 9.0% versus 23.6 +/- 4.9%, p = 0.0022). The H/Me and H/Md ratios in the patients were significantly correlated with the apnea-hypopnea index and the degree of hypoxemia during sleep. After treatment, H/Me and H/Md remained unchanged, but WR significantly recovered (from 34.9 +/- 10.4% to 26.3 +/- 7.7%, p = 0.0357).Cardiac sympathetic function and integrity are impaired in subjects with OSAS when compared with age-matched control subjects. MIBG cardiac imaging can be helpful in evaluating cardiac involvement and efficacy of therapy in OSAS.

From January 1980, through December 1995, 60 patients underwent surgical treatment of infective endocarditis (IE) at Sakakibara Hospital. Of 60 patients, 40 showed active endocarditis and 20 healed endocarditis at the time of operation. The over-all hospital mortality was 10% (6/60). The complication of cerebral accident (embolism and bleeding) was related to a higher incidence of operative mortality. The reconstructions of destruction and disruption of ventricular-aortic or mitral-aortic continity in the presence of acute infection of the annular tissue were in need of radical and complex surgical techniques. It is recommended to follow up these patients thoughtfully and to perform reoperation or re-reoperation before a patient develops severe heart failure or multiple organ failure.