1173C>T polymorphism in VKORC1 modulates the required warfarin dose.

The response to warfarin is highly variable among individuals and such variability is likely to have some genetic basis. We evaluted the effect of VKORC1 polymorphisms on warfarin response among Japanese, taking advantage of its unique population structure in which CYP2C9 *2 and *3 alleles are relatively rare. Thirty-one patients (12-34 years old; median, 22) on warfarin were recruited from a pediatric cardiology clinic. Genotyping of the C>T polymorphism at position 1173 in intron 1 of VKORC1 revealed that 26 patients (84%) were T/T homozygotes at nucleotide 1173, whereas 5 (16%) were C/T heterozygotes. Complete linkage disequilibrium was observed between the 1173C > T polymorphism and another polymorphism, the 3730G > A, in the 3' untranslated region. The C/T heterozyogtes at the 1173C > T polymorphism tended to require more warfarin than the T/T homozygotes, when adjusted for international normalized ratio (p = 0.003). Both the 1173C > T polymorphism and the 3730G > A polymorphism are likely to be inert from a functional standpoint. Rather, based on the complete linkage disequilibrium between 1173C > T and 3730G > A polymorphisms, we suspect that the actual change that defines the relative resistance to warfarin may be present in the proximity of these two polymorphisms.

Non-surgical closure of atrial septal defect.

BACKGROUND: Recently many devices for the transcatheter closure of atrial septal defect (ASD) were developed in the world. Several ASD closing devices, such as Clamshell device, buttoned device, ASD occluder system (ASDOS), Angel Wings, are not fully acceptable from a practical point of view. We reported the clinical trials of transcatheter closure of ASD for Clamshell double umbrella device and Amplatzer septal occluder (ASO) in Japan. METHODS: Clamshell devices were implanted in 11 patients. Clinical trials for ASO device were carried out in 34 patients in Japan. We reported the results of 17 patients in National Children's Hospital. RESULTS: Clamshell devices were implanted in all of the patients successfully. Minimal residual shunt was present in four patients (36%), 1 year after the procedure by Doppler color flow imaging. Nine of 11 umbrellas demonstrated fracture of the stainless steel arm. Arm fracture occurred between 1 week and 12 months after implantation. The implantations of ASO device were successful in all of the 17 patients. Sixteen out of 17 (94.1%) had complete closure in the average observation period of 5.5 months. Complications were minimal and transient. CONCLUSIONS: With respect to complete closure rate, easy manipulation, and complication rate, ASO is the best transcatheter ASD closure device among all the devices at the present time.

Isolation and molecular characterization of the first genomic clone of a major peanut allergen, Ara h 2.

BACKGROUND: Peanuts have been identified as potent food allergens responsible for life-threatening IgE reactions among hypersensitive individuals. With the current increase of peanut allergies, there is an urgent need to molecularly characterize the genes encoding the target proteins and to understand the nature of their regulation. OBJECTIVES: The objectives of this study were to isolate, sequence, and characterize at least one full-length genomic clone encoding the major peanut allergen Ara h 2. METHODS: A peanut genomic library, constructed in a Lambda Fix II vector, was screened with an 80-bp oligonucleotide probe constructed on the basis of the 5' end of a published Ara h 2 cDNA partial sequence. One putative positive lambda clone was isolated, digested with Bam HI to release its 16-kb insert, and confirmed by means of dot blot and Southern hybridization. The positive clone was subcloned in pBluescript SK+ vector, sequenced, and characterized. RESULTS: Sequence analysis revealed a full-length genomic clone with an open reading frame starting with an initiation codon (ATG) at position 1 and ending with a termination codon (TGA) at position 622. One putative polyadenylation signal (AATAAA) is identified at positions 951 in the 3' untranslated region, and 6 additional stop codons are located at positions 628, 769, 901, 946, 967, and 982 downstream from the start codon. In the 5' promoter region, a putative TATA box (TATTATTA) is located at position -72 upstream from the start codon. The deduced amino acid sequence has 207 residues and includes a putative signal peptide of 21 residues. CONCLUSIONS: The results reveal for the first time information on the structure of a major peanut allergen, Ara h 2. Comparison of the cDNA and genomic sequences revealed the absence of an intron but the presence of 2 isoforms of Ara h 2 or different members of the same gene family.

Heart transplantation in children in foreign countries with reference to medical, transportation, and financial issues.

Heart transplantation is increasingly becoming accepted worldwide as therapy for end-stage heart failure not only in adult patients but also in pediatric practice. The new law in Japan for organ transplantation from brain-dead patients was established on 16 October 1998, but there is no definite law or protocol for brain death in children under the age of 6 years and children less than 15 years of age cannot become donors. These facts make organ transplantation from the cadavers of neonates, infants and young children almost impossible in Japan, even though there are children who need heart or heart-lung transplantation. The present authors have to date transferred 8 patients to the USA or Germany for heart transplantation: 4 successfully underwent heart transplantation, but 4 died during the waiting period overseas. There are many things to consider; not only the medical problems involved in transportation, but also the financial issues when transferring patients to other countries. This report details the experience with the 8 cases that were transferred overseas for heart transplantation, and highlights the problems that need to be considered.

Intravenous and oral propafenone for treatment of tachycardia in infants and children: pharmacokinetics and clinical response.

To elucidate contribution of an active metabolite to overall clinical responses to propafenone, steady-state disposition of propafenone and its active metabolite and the clinical responses to treatment were examined in pediatric patients receiving intravenous or oral propafenone. There were more than ten-fold interindividual differences in apparent clearance, resulting in a wide range of the steady-state trough plasma concentrations of propafenone. The active metabolite, 5-hydroxypropafenone, was detected in four of the six patients receiving oral propafenone; however, two neonates receiving oral propafenone and all eight receiving intravenous propafenone had no detectable levels of 5-hydroxypropafenone in plasma. In nine patients for whom electrocardiographic (ECG) data were available, the PQ interval was significantly increased, whereas the QRS duration and the QTc interval were not. There was no close relationship between plasma concentrations of propafenone or 5-hydroxypropafenone and ECG parameters. Lack of good correlation between serum concentrations and clinical response precludes using a serum-concentration targeting strategy with propafenone therapy.

Are high-velocity tricuspid and pulmonary regurgitation endocarditis risk substrates?

BACKGROUND: A major predisposing cause of infective endocarditis is a susceptible cardiac substrate characterized by high-velocity turbulent flow. However, the risk incurred by high-pressure, high-velocity regurgitation across inherently normal pulmonary and tricuspid valves has not hitherto been examined. METHODS AND RESULTS: This study focused on 186 adult patients with congenital heart disease who had pulmonary vascular disease and inherently normal right-sided pulmonary and tricuspid valves. The observation period was approximately 1646 patient-years. Exclusion criteria were coexisting lesions that might have served as independent risk substrates for infective endocarditis. High-velocity turbulent pulmonary and tricuspid regurgitation were identified and quantified by color flow imaging and continuous wave Doppler echocardiography. Diagnoses of infective endocarditis were based on established clinical and laboratory criteria. Tricuspid regurgitation was moderate to severe in 80 patients and mild or absent in 106 patients. Pulmonary regurgitation was moderate to severe in 84 patients and mild or absent in 102 patients. With the exception of a single habitual intravenous drug abuser, no patient, irrespective of the degree of high-velocity turbulent pulmonary or tricuspid regurgitation, had infective endocarditis. CONCLUSIONS: High-velocity turbulent flow across inherently normal pulmonary and tricuspid valves rendered incompetent by pulmonary hypertension may represent a relatively low-risk or no-risk substrate for infective endocarditis.

Congenital heart disease in adults--collaboration between pediatric and medical cardiologists.

Congenital heart disease in adults has become a special area of cardiovascular interest, but remains a relatively unfamiliar discipline. Advances in diagnostic and surgical techniques have had a striking impact on longevity in infants and children with congenital heart disease. Nevertheless, since true cures are rare, long-term care is obligatory for most if not all patients. In parallel with diagnostic and surgical developments, advances in medical management have had a major impact on life span in both postoperative and unoperated patients. Who will assume responsibility for the long-term care of these adult patients? Relatively few medical cardiologists are equipped to do so and relatively few pediatric cardiologists are sufficiently well versed with the accrued problems of aging. Accordingly, the current approach involves collaboration between pediatric and medical cardiologists. The purpose of this report is to underscore the importance of this collaboration, and to focus on 2 particular issues-the management of cyanotic congenital heart disease and the management of congenital heart disease and pregnancy.

Infective endocarditis in congenital heart disease.

The average life expectancy of patients with congenital heart disease has dramatically improved over the past four decades because of advances in medical and surgical therapy, with patients with complex lesions surviving to adolescence and adulthood. Tetralogy of Fallot, transposition of the great arteries, ventricular septal defects, patent ductus, and bicuspid aortic valves in particular are susceptible to infective endocarditis. Most operated patients are left with some form of residua or sequelae, many of which predispose to infective endocarditis. Surgical palliation, such as systemic-to-pulmonary shunts, and reparative surgery, often requiring prosthetic valve or conduit replacement, are major predisposing conditions. Accordingly, recognition, prevention, and treatment strategies for infective endocarditis assume increasing importance in adolescents and adults with congenital heart disease, operated or not.

A symptomatic atypical mycobacterial infection masquerading as a vascular ring on chest x-ray.

Atypical mycobacterium is rare in children. There are few case reports of childhood pulmonary diseases caused by atypical mycobacterium. The case of a 20-month-old boy who had stridor and respiratory distress is presented. Chest x-ray showed right-sided narrowing of the trachea and left-sided aortic knob. Ziehl-Neelsen stain showed acid-fast bacilli. The culture showed Mycobacterium malmoense.

Cardiovascular abnormalities in Noonan syndrome: the clinical findings and treatments.

The clinical findings and treatment of cardiovascular abnormalities in 33 patients with Noonan syndrome are reviewed. Major cardiovascular abnormalities were pulmonary valvular stenosis in 17 patients (51.1%), hypertrophic cardiomyopathy (HCM) in 11 (33.3%), and atrial septal defect in 9 (27.3%). Dysplastic pulmonary valve was seen in 6 (35.3%). Balloon pulmonary valvuloplasty was performed for 4 patients with dysplastic pulmonary valves. Two patients were successfully treated. Surgical treatment was performed in 13 patients, 11 alive and 2 died. Two patients with HCM and arrhythmia died suddenly. In conclusion, balloon pulmonary valvuloplasty should be the initial palliation for dysplastic pulmonary valve in Noonan syndrome, and HCM is the risk factor for sudden death in Noonan syndrome.

Anomalous origin of the left main pulmonary artery from the ascending aorta associated with DiGeorge syndrome.

We place on record 2 infants with the DiGeorge syndrome and anomalous origin of the left pulmonary artery from the ascending aorta. We postulate that: (1) embryogenesis of anomalous origin of the left pulmonary artery from the ascending aorta might be due to the persistent fifth aortic arch connecting both arterial systems; (2) an anomalous pulmonary artery arising from the ascending aorta is part of the aortic arch abnormality accompanied by normal conotruncal septation; and (3) in the DiGeorge syndrome, cardiac anomalies that originate from the conotruncus or aortic arch, or both, may have the same embryologic mechanisms.

Chaotic atrial rhythm in children.

Chaotic atrial rhythm (CAR) usually occurs as a sequela of chronic obstructive lung disease in adults. We report the clinical manifestations and response to therapy in nine children with CAR treated predominantly with propafenone or amiodarone. Age at presentation ranged from 1 day to 30 months; six patients were < or = 2 weeks old. Six patients had tachycardia, and three had congestive heart failure. The atrial rate was 200 to 500 (mean 369 +/- 71) beats/min and the ventricular rate 150 to 300 (mean 251 +/- 37) beats/min. Eight patients had cardiac abnormalities. Intravenous drug therapy was not successful in converting CAR to sinus rhythm in any patient. A mean of four (range three to five) drugs was used in each patient; amiodarone and propafenone, alone or in combination, proved most successful. Seven patients were discharged from the hospital: full control was achieved in three (digoxin and amiodarone in two and digoxin, amiodarone, and procainamide in one), good control in three (digoxin, amiodarone, and propafenone in two and digoxin and propafenone in one), and ventricular rate control in one (digoxin, amiodarone, and propafenone). Two neonates with hypertrophic cardiomyopathy died. Long-term follow-up showed that CAR had resolved in five patients but persisted in two. We conclude that CAR remains difficult to control despite the use of newer antiarrhythmic agents but may resolve during long-term follow-up.

The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin.

We showed previously a cause and effect relationship between increased activity of an endogenous vascular elastase (EVE) and experimentally induced pulmonary hypertension in rats. We now report the isolation and characterization of EVE. Degenerate oligonucleotides synthesized to homologous sequences in serine elastases were used in a PCR with rat pulmonary artery (PA) cDNA. The PCR product hybridized to a 1.2-kb mRNA and the intensity of hybridization was threefold increased in RNA from rat hypertensive PA at a timepoint when EVE activity was increased. The PCR product was used to screen a cDNA library and sequences obtained encoded rat adipsin. We then used immunoaffinity to purify EVE. An antibody to the elastin-binding protein was used to remove this competitor of elastase from the PA extract and the elastolytic activity increased 100-fold. The enzyme was purified using an antibody that recognizes NH2-terminal sequences of serine proteinases and the eluate was further purified using an antibody raised against recombinant adipsin. A single band at 20 kD immunoreactive with the adipsin antibody was resolved as an active enzyme on an elastin substrate gel. Immunogold labeling with an antibody to an adipsin peptide sequence localized EVE to PA smooth muscle cells. This is the first isolation of EVE; it appears to be a novel enzyme related to the serine proteinase adipsin originally found in adipose tissue.

Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease.

In a rat model of pulmonary hypertension induced by monocrotaline, medial hypertrophy of the pulmonary arteries is associated with enhanced production (synthesis) of insoluble elastin relative to accumulation and an increased number of elastin fragments, features suggestive of an elastolytic process. In the present study, we measured and characterized pulmonary artery (PA) elastolytic activity at time points before as well as coincident with the progression of medial hypertrophy in monocrotaline-injected adult male Sprague-Dawley rats. We also determined whether medial hypertrophy is preceded by ultrastructural changes in elastin. Since medial hypertrophy develops but fails to progress in rats injected with monocrotaline at 8 days of age, we assessed whether, compared with adult rats, there were also structural and biochemical differences in elastin and elastolytic activity. A twofold increase in elastolytic activity per milligram tissue was observed 2 days after monocrotaline injection in adult rats (p less than 0.01), and there was an increased number of breaks in the internal elastic lamina (IEL) at 4 days (p less than 0.05) (i.e., before the development of medial hypertrophy). Associated with the progression of medial hypertrophy between 16 and 28 days after monocrotaline injection, there was a further threefold increase in elastolytic activity per milligram tissue by 28 days (p less than 0.01). Susceptibility of the elastolytic activity to specific inhibitors suggested that one or more serine elastases is involved. In infant rats in which medial and right ventricular hypertrophy fail to progress in severity between 16 and 28 days after monocrotaline injection, we did not measure an increase in elastolytic activity, nor was there evidence of an increase in the number of breaks in the IEL at 4 days, suggesting a lack of increased elastolytic activity at an earlier time point. The total content of PA elastin in infant rats, although increased compared with control rats (p less than 0.01), was not associated with heightened production and appeared ultrastructurally as thicker laminae (p less than 0.05) rather than as fragments previously reported in adult rats.

Two-dimensional pulsed Doppler echocardiographic technique for estimating pulmonary to systemic blood flow ratio in children with atrial septal defect and patent ductus arteriosus.

A two-dimensional pulsed Doppler echocardiographic method was evaluated for quantifying the pulmonary (Qp) to systemic (Qs) blood flow ratio. Twenty six patients were studied, 15 with atrial septal defect (ASD) and 11 with patent ductus arteriosus (PDA). An apical four-chamber view was used to measure the maximal Doppler flow velocities in the right and left ventricular inflow regions (RVIR and LVIR) and the maximal diameters of the tricuspid and mitral anuli at diastole. The two-dimensional pulsed Doppler pulmonary to systemic blood flow ratio (Qp/Qs) estimation involved calculating the area of the Doppler flow velocity signal along the time scale multiplied by the diameter of either the tricuspid or mitral anulus as measured on the apical four-chamber view. In ASD patients, Qp was measured at RVIR and Qs at LVIR. In PDA patients, Qp was calculated at LVIR and Qs at RVIR. Twenty-six healthy children comprised the control group. The areas of the Doppler flow velocity signals along the time scales of RVIR and LVIR were also quantified and the diameters of the tricuspid and mitral anuli were measured. In the control group, the linear correlation of the trans-mitral M(d)*M(a) to trans-tricuspid T(d)*T(a) value was r = 0.909, n = 26. The correlations between Doppler Qp/Qs ratio estimates and those obtained at cardiac catheterization were r = 0.902, n = 15 in ASD and r = 0.967, n = 11 in PDA. These results suggest a clinical application of this Doppler echocardiographic method in the noninvasive estimation of the cardiac shunt in ASD and PDA.

Evaluation and comparison of the axis of the interventricular septum by two-dimensional echocardiography among the patients with congenital heart disease (ASD, VSD, PDA, PS, TOF) and the normal subjects.

A two-dimensional echocardiographic method was applied to determine the axis of interventricular septum (IVS) in the horizontal plane. This study comprised 19 subjects with ASD, 15 subjects with VSD(I), 20 subjects with VSD(II), 13 subjects with PDA, 16 subjects with PS, 15 subjects with TOF and 99 normal children. Parasternal left ventricular short axis view was taken, and the IVS was recorded by using the polaroid prints. The axis of the IVS in the horizontal plane was measured from the recorded polaroid prints. The value of the angularity of IVS (IVS-A) expressed as means +/- one standard deviation (mean +/- 1S.D.) is 52.0 +/- 13.7 degrees in ASD, 42.2 +/- 9.7 degrees in VSD(I), 43.7 +/- 9.1 degrees in VSD(II), 41.6 +/- 11.4 degrees in PDA, 38.6 +/- 10.9 degrees in PS, 61.0 +/- 8.5 degrees in TOF and 40.1 +/- 8.2 degrees in normal controls. There was no significant difference among VSD(I), VSD(II), PDA, PS and normal controls but a highly significant difference was noted in ASD and TOF as compared to other groups. The correlation coefficient of the IVS-A with (1) the Qp/Qs ratio, (2) the magnitude of shunt (%), (3) the right ventricular pressure and (4) the hematocrits were evaluated among the patient groups. The IVS-A of ASD and VSD(II) had a good correlation with the shunt flow (r = 0.921 and 0.88 respectively) and/or the Qp/Qs ratio (r = 0.782 and 0.955 respectively); while that of VSD(I), PDA, and PS had a good correlation with the right ventricular pressure (r = 0.956, 0.953, 0.842 respectively) and that of TOF was mostly concerned with the hematocrits (r = 0.911). Besides, the IVS-A in each severe CHD subgroup was significantly (p less than 0.005 or a better value) higher than the normal control group. Thus an alternative method was validated for evaluating the severity of congenital heart disease by using a noninvasive two-dimensional echocardiographic technique.

[A study of the state-trait anxiety inventory (STAI) and its application to noise stress].

By using the STAI developed by Spielberger et al. we have investigated the validity and reliability of two scales, that is, State Anxiety (A-State) and Trait Anxiety (A-Trait), and at the same time have examined them under various conditions. The results obtained are as follows: 1) As a result of factor analysis concerning 40 items of the STAI used in this research, we have confirmed that both A-State and A-Trait have independent factor structures of their own, and that the items of the scales also carry their own validity. 2) After due consideration of the test-retest reliability of the two scales, we have found that A-Trait has rather high stability. Moreover, we have noticed that Cronbach's alpha coefficients, which show the reliability of the two scales, are high. In consequence, we have confirmed the high reliability of the two scales. 3) In comparing the scores of A-State and A-Trait obtained from young healthy people with those from healthy aged people, we have noticed that the aged get low scores on each of the two scales, and that each score distribution shows an excellent fit to the normal one. 4) We have found that A-State scores go up significantly when people are in a condition of emotional stress, but that there is not any change of A-Trait scores. 5) We have observed a significant increase of A-State scores at each noise level over 75 dB(A).(ABSTRACT TRUNCATED AT 250 WORDS)