Cor triatriatum with unroofed coronary sinus and persistent left superior vena cava associated with atrial tachycardia.

A 2-year-old girl with cor triatriatum with unroofed coronary sinus and persistent left superior vena cava underwent preoperative radiofrequency catheter ablation for atrial tachycardia attack that developed after admission to our hospital. The procedure was not successful. Cryoablation was successfully performed during corrective surgery. Cutting back from the coronary sinus orifice, resection of the fibrous tissue above the mitral valvular orifice, closure of the excised fossa ovalis and coronary sinus orifice with a Gore-Tex patch, and ligation of the persistent left superior vena cava resulted in an excellent hemodynamic outcome. At 2-year follow-up, the patient was free from tachycardia attack.

Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction.

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Angle-resolved photoemission study of insulating and metallic Cu-O chains in PrBa2Cu3O7 and PrBa2Cu4O8

We compare the angle-resolved photoemission spectra of the hole-doped Cu-O chains in PrBa2Cu3O7 (Pr123) and in PrBa2Cu4O8 (Pr124). While, in Pr123, a dispersive feature from the chain takes a band maximum at k(b) (momentum along the chain) approximately pi/4 and loses its spectral weight around the Fermi level, it reaches the Fermi level at k(b) approximately pi/4 in Pr124. Although the chains in Pr123 and Pr124 are approximately 1/4 filled, they show contrasting behaviors: While the chains in Pr123 have an instability to charge ordering, those in Pr124 avoid it and show an interesting spectral feature of a metallic coupled-chain system.

Interstitial cystitis and ileus in pediatric-onset systemic lupus erythematosus.

A girl aged 11 years presented with autoimmune hemolytic anemia with thrombocytopenia, and subsequently developed severe abdominal pain, vomiting, and pollakiuria. X-ray findings of her abdomen demonstrated paralytic ileus with intestinal wall thickening. Intravenous pyelography revealed bilateral hydroureter with mild hydronephrosis and contracted bladder. Pathological examination of her bladder revealed interstitial cystitis, with evidence of focal deposition of IgG and C3 in a granular pattern on small blood vessel walls. She was diagnosed as having systemic lupus erythematosus (SLE) associated with paralytic ileus and chronic interstitial cystitis. Although initiation of high-dose prednisolone therapy resulted in a gradual improvement in clinical symptoms, reducing the dosage of prednisolone caused a relapse. To our knowledge, the combination of paralytic ileus and chronic interstitial cystitis is quite uncommon in pediatric-onset SLE.

J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors.

A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M3 receptors over M2 receptors. Subsequent synthetic derivatizations resulted in highly potent M3 receptor antagonists with selectivity greater than two orders of magnitude for M3 over M2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hyd roxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for M3 receptors (Ki = 4.2 nM) over M2 receptors (Ki = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K(B) value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.

J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.

Farnesylation of the activated ras oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Because squalene synthase and FTase recruit farnesyl pyrophosphate as a common substrate, we modified squalene synthase (SS) inhibitors to develop FTase inhibitors. Among the compounds tested, a novel FTase inhibitor termed J-104,871 inhibited rat brain FTase with an IC50 of 3.9 nM in the presence of 0.6 microM farnesyl pyrophosphate (FPP), whereas it scarcely inhibited rat brain protein geranylgeranyltransferase-I or SS. The in vitro inhibition of rat brain FTase by J-104,871 depends on the FPP concentration but not on the concentration of Ras peptide. Thus, in vitro studies strongly suggest that J-series compounds have an FPP-competitive nature. J-104,871 also inhibited Ras processing in activated H-ras-transformed NIH3T3 cells with an IC50 value of 3.1 microM. We tested the effects of lovastatin and zaragozic acid A, which modify cellular FPP levels, on Ras processing of J-104,871. Lovastatin, a hepatic hydroxymenthyl coenzyme A reductase inhibitor that reduced the cellular FPP pool, increased the activity of J-104,871, whereas 3 microM zaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 microM. These results suggest that J-104,871 inhibits FTase in an FPP-competitive manner in whole cells as well as in the in vitro system. Furthermore, J-104,871 suppressed tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells.

Clinical and histopathological studies in children with supraventricular tachycardia.

To determine whether myocardial changes in patients with supraventricular tachycardia (SVT) are primary or secondary to persistent tachycardia, 11 patients with SVT were studied. These patients were divided into 2 groups with respect to the type of SVT. Group I consisted of 5 patients with incessant SVT and one with multifocal atrial tachycardia, while group II consisted of 4 patients with paroxysmal supraventricular tachycardia and one with short-run supraventricular premature contraction. All of the patients underwent electrophysiological study and endomyocardial biopsy from the right ventricle following routine cardiac catheterization. In group II, there were no significant abnormalities in the clinical and hemodynamic parameters. In group I, 3 patients had clinical features of dilated cardiomyopathy including abnormal ECG, chest X-ray and hypokinesis on left ventriculography. Induction and termination of SVT were possible in 2 patients in group I and in 4 of the 5 patients in group II. The only significant histologic difference between group I and group II was fibrosis. A high incidence of histopathological abnormalities, such as hypertrophy, degeneration, interstitial fibrosis and disarray was observed in both groups. The incidence of significant pathology was higher in group I than in group II. Almost all of the patients were given antiarrhythmic drugs. One patient underwent a successful surgical procedure and normal cardiac function returned after resection of the foci of the right atrium. Our present results suggest that patients with SVT who have incessant or recurrent SVT should undergo not only intracardiac electrophysiologic study but also endomyocardial biopsy for the evaluation of myocardial damage, since SVT might be the initial sign of cardiomyopathy.

Histopathological study on Kawasaki disease with special reference to the relation between the myocardial sequelae and regional wall motion abnormalities of the left ventricle.

Thirty-eight consecutive patients with Kawasaki disease (18 patients with normal coronary artery and 20 with coronary artery lesions) were studied in order to find the incidence of myocardial abnormalities and the influence of the myocardial damage on the regional wall motion of the left ventricle in patients with Kawasaki disease with or without coronary artery lesion. Abnormal regional wall motion of the left ventricle was found in 28% of the patients with normal coronary artery (NCA) and in 55% of those with coronary artery lesions (CAL). Hypertrophy of myocytes, degeneration of myocytes and disarray were found frequently in the patients with CAL. The histopathology of endomyocardial biopsy taken from patients more than 3 years after disease onset and less than 3 years after onset were compared. Histopathologic abnormalities were found even in the biopsies taken more than 3 years after onset, especially from patients with coronary artery lesions, although the incidence of abnormalities was less frequent. We consider that repeat endomyocardial biopsies may be necessary in the patients who have significant histopathologic changes in the first endomyocardial biopsy to clarify the natural course of myocardial abnormalities, regardless of whether or not they have CAL.

[Histopathological analysis of myocardial damages following Kawasaki disease with repeated endomyocardial biopsy].

Since Kawasaki disease was first reported 20 years ago, many investigations about cardiac complications and treatment have been carried out. However, etiology still remains unknown. Although many studies focused on coronary artery lesions (CAL) have been reported, there have been only a few reports of pathological studies on myocardial after-effects of Kawasaki disease using endomyocardial biopsy. In order to investigate the myocardial sequelae, repeated coronary arteriography and endomyocardial biopsy were performed in thirteen patients of Kawasaki disease with coronary artery lesions. Their ages ranged from 19 months to 12 years in the first study, 4 years to 15 years in the second study, and the male to female ratio was 8:5. In this study the interval between the first study and the second one was more than two years and six months. In the second study, progression of the CAL was noticed in 23% of the cases. It was unchanged in 54%, and regression was observed in 23%. Twenty-three percent of the patients were found to have an ejection fraction of less than 55%, and abnormal regional wall motion was found in 62% of the patients. Myocardial changes in the second endomyocardial biopsy were interstitial fibrosis in 62%, degeneration in 54%, disarray in 32% and inflammatory cell infiltration in 23%. One of the cases with Kawasaki disease, who had mild CAL, revealed massive inflammatory cell infiltration and myocytolysis in the second study performed seven years after onset, which suggested chronic myocarditis. Myocardial changes in the patients with advanced CAL were relatively mild, and low EF and abnormal regional wall motion were not always related to severity of CAL.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary arterial calcification in Kawasaki disease.

The purpose of this paper is to describe the clinical characteristics and significance of the coronary arterial calcification due to Kawasaki disease (KD), based on our five patients. The coronary arterial lesions (CAL) were in segments 1, 2, 5, 6 and 11 according to the classification of the American Heart Association. The interval from the onset to the first appearance of coronary calcification was 17 months to 61 months. Progression of CAL into coronary arterial stenosis or myocardial infarction occurred in all five patients. In the comparative study between the patients with calcified CAL and those with non-calcified CAL, the maximal size of CAL of the former was 8 mm or larger in contrast with that of the latter (less than 8 mm). It is concluded that coronary arterial calcification is one of the important signs which suggest the presence of the advanced CAL in the follow-up of children with a history of KD.

[Clinical investigation on the patients with tachyarrhythmic syncope with special reference to comparative study between long QT syndrome and ventricular tachycardia without long QT interval].

The long QT syndrome (LQTS) is one of the important diseases that may lead to sudden death mainly in childhood, however etiology and pathogenesis are still poorly understood. The group studied consisted of 6 patients with a history of ventricular tachyarrhythmic syncope, 3 with long QT syndrome (LQTS) and 3 without long QT interval, and of 4 patients with ventricular tachycardia without syncopal episode. Their ages ranged from 5 years to 17 years. Histopathology of endomyocardial biopsy was nonspecific and mild in two cases but in one patient with LQTS, who had several episodes of syncope and refractory ventricular arrhythmia, remarkable subendocardial fibrosis, interstitial fibrosis and hypertrophy of myocytes were demonstrated. As far as ventricular tachycardia without long QT interval was concerned, in the patients with VT with syncope, histopathological abnormalities were more remarkable than in those without syncope. Electrophysiological findings in the patients with LQTS showed no characteristic findings, but only mild abnormalities with functional atrioventricular conduction disturbance on programmed atrial pacing. No inducible VT was demonstrated. Although electrophysiologic study and endomyocardial biopsy are of limited value, such studies are considered to be worthwhile for treating ventricular arrhythmias, and making a prognosis of the patients with tachyarrhythmic syncope and LQTS.

[Clinical investigation on childhood HCM; long-term follow-up study with special reference to electrophysiology, histopathology by endomyocardial biopsy and ambulatory and exercise electrocardiography].

In order to determine the prognosis and risk factors of childhood HCM, we investigated clinical parameters, such as the age of onset, symptoms and signs related to HCM, dysrhythmias and ST-T and changes by Holter ECG and exercise ECG, electrophysiological study and histopathological study by endomyocardial biopsy. Heart murmur was the commonest sign although only one patient revealed a significant left ventricular outflow tract gradient of more than 20 mmHg. The peak age of patients diagnosed as having HCM was 10 to 15 years. The major ECG manifestations of our series showed specific findings and in some cases ECG changed remarkably during the follow-up period. The diagnosis of apical hypertrophy should be made with caution in childhood. Holter ECG seemed to be indispensable for the follow-up of childhood HCM because Holter ECG in our patients manifested such significant findings as ventricular premature contractions or couplets or ST depression. The degree of clinical severity did not always correlate with the histopathological severity obtained by endomyocardial biopsy. As HCM in childhood is heterogeneous and multifaceted, there is no one therapy, and prognosis and proper treatment with close observation should be carried out in each individual case.

Endomyocardial biopsy in children with Kawasaki disease.

To study the histopathology of the myocardium in Kawasaki Disease (KD) with various coronary angiographic findings, right endomyocardial biopsy specimens were evaluated on 20 boys and 16 girls with this disorder. KD with coronary artery lesions (CAL) showed various histopathological abnormalities, such as myocellular hypertrophy in 44%, degeneration in 61%, interstitial fibrosis in 44% and endomyocardial changes in 22%. KD without CAL revealed myocellular hypertrophy in 44%, degeneration in 50%, disarray in 28% and interstitial fibrosis in 6%. As in patients with long-standing KD, more than three years after onset, myocardial changes such as myocellular hypertrophy, disarray and interstitial fibrosis persisted, it is suggested that cardiomyopathy may develop in some patients with KD.

A new potential prodrug to improve the duration of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.

L-3-(3-Hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355) is a novel L-dopa prodrug. After oral administration with carbidopa in rats, 1 demonstrated 2.3 times longer duration (MRT) and 1.4 times larger bioavailability (AUC) on plasma L-dopa concentrations than those of L-dopa itself. Similar results were obtained in dogs. The prolonged profile of L-dopa was parallel to that of carbidopa, and the intact ester was undetectable in rat plasma. After intravenous administration in rats, 1 was converted quickly and completely to L-dopa in the systemic circulation. It was also noted that the oral LD50 value of 1 was greater than 6 g/kg in mice. These data suggest that 1 will offer long-lasting L-dopa therapy for the treatment of Parkinson's disease with little concern about toxicity.

[Histopathological studies of endomyocardial biopsy on the children with Kawasaki disease].

Since there has been many reports on the coronary artery lesions in the patients with Kawasaki disease, but only a few reports on histopathological investigation employing endomyocardial biopsy, histopathological study was performed in eighteen children of Kawasaki disease with coronary artery lesions and eighteen children of Kawasaki disease with intact coronary artery, aged from one year and ten months to fourteen years. There were twenty males and sixteen females. Comparing Kawasaki disease who had coronary artery lesions with those not, there was no striking difference in histologic findings. Kawasaki disease without coronary artery lesions revealed myocellular hypertrophy, degeneration of myocytes, disarray, interstitial fibrosis and endocardial changes in 44%, 61%, 11% and 44%, respectively. Among Kawasaki disease who had coronary artery lesions, children with coronary artery stenosis showed a higher incidence of histological abnormalities than those with coronary artery aneurysm. Some cases of Kawasaki disease were recognized to have significant myocardial abnormalities even in three to six years after onset, which seemed to persist whether or not they would have coronary artery lesions. Since Kawasaki disease who would have myocardial damages might have the potential for developing cardiomyopathy, careful attention should be payed to myocardial lesions as well as sequelae of coronary artery lesions.

[Electrophysiologic and histopathologic investigations in children with idiopathic ventricular arrhythmias].

Between April 1984 and December 1987, electrophysiological studies and endomyocardial biopsy were performed in 14 pediatric patients, aged from 7 to 15 years, with idiopathic ventricular arrhythmias in whom diagnostic evaluation had revealed no structural heart disease. They were 8 boys and 6 girls. Cardiac catheterization revealed regional wall motion abnormalities of the left ventricle in 3 patients, one of whom showed decreased ejection fraction (EF). Electrophysiologic examination showed sinus node dysfunction in 21%. AV nodal dysfunction in 14% and dual AV nodal pathway in 21%. Histopathologic examination by endomyocardial biopsy showed myocellular hypertrophy, degeneration of myocytes, interstitial fibrosis and endomyocardial thickness in 86%, 36%, 35% and 14%, respectively. Since idiopathic ventricular arrhythmias in pediatric age group included relatively high electrophysiologic and histopathologic abnormalities, which were suggestive of occult myocardial disease and might be the early stage of cardiomyopathy, careful follow-up should be required.

Two forms of hypertrophic cardiomyopathy distinguished by inheritance of HLA haplotypes and left ventricular outflow tract obstruction.

In this study we have performed human leukocyte antigen (HLA)-A and B typing on nine patients with hypertrophic cardiomyopathy (HCM) and their relatives. Four patients had relatives who also had the disease. HLA typing of the familial form of HCM revealed a very close association of a given HLA-A,B haplotype with the occurrence of the disease. All four patients who had affected relatives had obstruction of left ventricular outflow (LVOT), while four patients with unaffected relatives did not have obstruction. One additional patient with obstruction and without familial incidence was an only child and had few living relatives. Thus, HCM can be divided into two subtypes: a familial form linked to the HLA-A,B system, which may be related to obstructive type, and a sporadic form not linked to HLA antigens. These data confirm the existence of at least two separate forms of hypertrophic cardiomyopathy. The study also confirms their existence in the Japanese population, with a completely different gene pool than the population from the southeastern United States in whom the observation was initially described.

[High serum ferritin levels in malignant lymphoma of the ileum].

A 61-year-old woman was admitted to our hospital with lower abdominal distension, anemia and slight emaciation. Primary malignant lymphoma of the ileum was diagnosed after laparotomy and palliative surgery was performed. Pathological specimens demonstrated diffuse lymphoma, and histiocytic (Rappaport's classification) aneurysm-type macroscopic development. The preoperative serum ferritin level was high and increased postoperatively with a slight decrease during VEMP chemotherapy, suggesting it to be a marker of tumor activity. Although palliation was observed during chemotherapy, this patient died of pulmonary complications a little less than 3 months after the operation.