Diagnostic potential of antibody titres against Candida cell wall ß-glucan in Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis syndrome of unknown aetiology in children. The administration of Candida cell wall antigens induced KD-like coronary vasculitis in mice. However, the responses of KD patients to Candida cell wall antigen are unknown. In this study, we examined the response of KD patients to ß-glucan (BG), one of the major fungal cell wall antigens, by measuring the anti-BG titre. In KD patients, the anti-C. albicans cell wall BG titre was higher than that in normal children. The anti-BG titre was also higher in KD patients compared to children who served as control subjects. The efficacy of intravenous immunoglobulin (IVIG) therapy in KD is well established. We categorized the KD patients into three groups according to the therapeutic efficacy of intravenous immunoglobulin (IVIG) and compared the anti-BG titre among these groups. Anti-BG titres were similar in the control group and the non-responsive group. In the fully responsive group, the anti-BG titre showed higher values than those in the normal children. This study demonstrated clinically that KD patients have high antibody titres to Candida cell wall BG, and suggested the involvement of Candida cell wall BG in the pathogenesis of KD. The relationship between IVIG therapy and anti-BG titre was also shown. These results provide valuable insights into the therapy and diagnosis of KD.

[Clinical characteristics of congenital heart disease diagnosed during neonatal period].

We have analyzed 43 newborn babies with congenital heart disease (CHD) over the last two years. The occurrence rate of CHD was 7.5 per 1,000 live births in our maternity hospital, and 4.5% of all babies admitted to our NICU. Low birth weight (<2,500g), and prematurity (<37 weeks of gestation) led to occurrence rates of 34% and 26%, respectively. Cardiac symptoms (heart murmur and cyanosis) accounted for 47% of all cases in which CHD was discovered, and extracardiac symptoms accounted for 40%. Prenatal diagnosis was made in two patients. Twenty babies were transferred to the pediatric cardiac care unit in the general hospital from our maternity hospital during their neonatal period. Dividing them into two categories by hemodynamic state, acyanotic type made up 72% of all patients; VSDs (Ventricular Septal Defects) were the most frequent anomaly. Cyanotic type made up only 28%, but included all 4 cases of neonatal death. Twelve babies underwent surgery during the study period, and 7 of them reached final anatomical correction. Early detection of the cardiac anomaly, including prenatal diagnosis, plays an important role in improving the prognosis of patients, and comprehensive therapeutic strategies are essential for neonatal CHD.

Surgical treatment of coarctation complex in neonates and infants.

BACKGROUND: There remains controversy regarding the appropriate surgical treatment of coarctation of the aorta associated with intracardiac anomalies in neonates and infants. Furthermore, the relative benefits of one versus two-stage repair, and subclavian flap aortoplasty versus end-to-end anastomosis for some of these lesions, remain controversial. The purpose of this paper is to review our experience with two-stage repair using subclavian flap aortoplasty and to seek an appropriate procedure. METHODS AND RESULT: From June 1996 to November 1999, thirteen patients underwent subclavian flap aortoplasty in our department. The age range was 16 to 101 days (mean 52 days), and the body weight range was 1.9 to 4.5 kg (mean 3.0 kg). Anatomic diagnosis was coarctation with ventricular septal defect (six patients), double outlet right ventricle (two patients), atrioventricular canal defect (one patient), tricuspid atresia (two patients), mitral atresia (one patient), and single atrium and subaortic stenosis (one patient). There was one hospital death in our series due to the progression of pulmonary hypertension 3 months after the operation. The mean follow up for remaining twelve patients was 28 months (range 7 approximately 48 months). There was one reoperation for recurrent coarctation. Three patients underwent pulmonary artery plasty in a second operation because of right pulmonary artery stenosis. We performed the definitive operation for six patients with coarctation with ventricular septal defect and two patients with double outlet right ventricle, and we performed a bidirectional cavopulmonary shunt for four univentricular hearts who are candidates for the Fontan operation. Two patients required Damus-Kaye-Stansel procedure to release restrictive bulboventricular foramen. Three patients underwent a modified Fontan operation after these palliations. In our series, the intraoperative mortality rate for subclavian flap aortoplasty was 0% and the post operative mortality rate was 7.7% (1/13). Ten patients underwent the final operation successfully, and further two patients are considered good candidates for the final operation. The overall mortality was 7.7% (1/13). CONCLUSION: Two-stage repair appears to offer a good prognosis for neonates and infants with a coarctation complex. Subclavian flap aortoplasty showed the lowest rate of restenosis. However, late mortality may be associated with the progression of pulmonary vascular disease and the presence of associated severe cardiac anomalies. Although Fontan candidates need staged operations, if biventricular repair is feasible, one-stage repair would be a reasonable procedure considering the progression of the pulmonary vascular disease and the distortion of the pulmonary artery due to pulmonary artery banding. It would appear to improve the quality of life of those children if a one-stage operation can be performed with reasonable risk and good midterm outcome.

[Emphysematous cystitis and neuropathy; a report of the case with diabetes mellitus].

A study was made of a 55 years old male, who suffered from emphysematous cystitis with diabetes mellitus. He had multiple complications due to diabetic neuropathy such as foot ulceration, oculomotor nerve palsy, peroneal nerve palsy and a neurogenic bladder. Klebsiella pneumoniae and Pseudomonous aeruginosa were cultured from urine specimens. There have been only 19 reported cases of emphysematous cystitis since 1962. Fourteen of these cases had diabetes mellitus.

Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation.

Increased production of nitric oxide (NO) after induction of the cytokine-inducible isoform of nitric oxide synthase (iNOS or NOS2) in cardiac myocytes and other parenchymal cells within the heart may in addition to contributing to myocyte contractile dysfunction also contribute to the induction of programmed cell death (apoptosis). To investigate the mechanism(s) by which increased NO production leads to apoptosis, we examined the role of NO in primary cultures of neonatal rat ventricular myocytes (NRVMs) after induction by the cytokines interleukin-1beta (IL-1beta) and interferon gamma (IFNgamma) or exposure to the exogenous NO donor S-nitroso-N-acetylcysteine (SNAC) or peroxynitrite (ONOO(-)). Both SNAC (1 mmol/L) and ONOO(-) (100 micromol/L), but not their respective controls (ie, N-acetylcysteine and pH-inactivated ONOO(-)), induced apoptosis in confluent, serum-starved NRVMs at 48 hours. Similarly, incubation of NRVMs with IL-1beta and IFNgamma for 48 hours resulted in an increase in iNOS expression, nitrite production, and programmed cell death. Both the cytokine-induced nitrite accumulation and myocyte apoptosis could be completely prevented by the nonselective NOS inhibitor L-nitroarginine (3 mmol/L) or the specific iNOS inhibitor 2-amino-5, 6-dihydro-6-methyl-4H-1,3-thiazine (AMT, 100 micromol/L). NO-mediated myocyte apoptosis was not attenuated by the inhibition of soluble guanylyl cyclase with ODQ, nor could apoptosis be induced by the incubation of NRVMs with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analogue. However, NO-mediated apoptosis was significantly attenuated by the superoxide dismutase mimetic and ONOO(-) scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP, 100 micromol/L). NO/ONOO(-)-mediated apoptosis was associated with increased expression of Bax with no change in Bcl-2 mRNA abundance. Furthermore, apoptotic cell death was also confirmed in adult rat ventricular myocytes (ARVMs) when grown in heteroculture with IL-1beta- and IFNgamma-treated rat cardiac microvascular endothelial cells. Therefore, cytokine-induced apoptosis in NRVMs and ARVMs is mediated by iNOS induction, ONOO(-), and associated with an increase in Bax levels.

Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium.

Expression of innate immune response proteins, including IL-1beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappaB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.

Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane.

-The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis. In contrast, dexrazoxane (10 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to limit the toxicity of these drugs.

Silent myocardial ischemia in Kawasaki disease: evaluation of percutaneous transluminal coronary angioplasty by dobutamine stress testing.

BACKGROUND: Myocardial ischemia and myocardial infarction are the most serious complications of coronary artery lesions in children with Kawasaki disease (KD). Therefore, early detection and treatment of myocardial ischemia in patients with KD is essential. We studied the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) in patients with silent myocardial ischemia detected by dobutamine stress 99mTc myocardial scintigraphy (TMS), body surface mapping (BMS), and signal-averaged ECG late potentials (ELP). METHODS AND RESULTS: Eight of 76 asymptomatic patients with a coronary stenosis >25% and a positive dobutamine stress test were considered to have silent myocardial ischemia. All eight patients had >95% stenoses demonstrated by coronary angiography (CAG) just before PTCA. After PTCA, CAG showed that all of the coronary artery stenoses had been reduced to <50%. Additionally, intravascular ultrasonography (IVUS) performed in five patients before and after PTCA demonstrated adequate dilation of the coronary stenosis after PTCA. All eight patients underwent dobutamine stress TMS, BMS, and ELP 2 to 3 months after PTCA, which demonstrated no regions of myocardial ischemia. Approximately 6 months later, CAG was performed in all eight patients, and only one patient had developed restenosis. CONCLUSIONS: PTCA effectively dilates stenotic coronary arteries in children with KD. Moreover, dobutamine stress TMS, BMS, and ELP are useful for detecting silent myocardial ischemia and estimating the effectiveness of PTCA. Furthermore, IVUS is useful for evaluating the severity of coronary artery lesions before and after PTCA in patients with KD.

Evaluation of myocardial ischemia and infarction by signal-averaged electrocardiographic late potentials in children with Kawasaki disease.

We investigated myocardial ischemia and old myocardial infarction noninvasively using signal-averaged electrocardiographic late potentials (LPs) in patients with Kawasaki disease. Patients were divided into 4 groups: a noncoronary artery lesion group (n=136), a coronary artery lesion group (without myocardial ischemia and an old myocardial infarction; n=33), an ischemia group (n=16), and an old myocardial infarction group (n=13). Grouping was based on exercise thallium-201 myocardial scintigraphy, thallium-201 myocardial scintigraphy, exercise electrocardiography, coronary angiography, left ventriculography, and echocardiography. Signal-averaged electrocardiograms were recorded using a high-resolution system. Values of filtered QRS duration (f-QRSd), root-mean-square voltage, and duration of low-amplitude signal were judged using our own body surface area-related criteria (n=205) to determine positive rates of LPs and sensitivities and specificities to ischemia and infarction. These data were also interpreted using published criteria for adults and compared with those interpreted by our criteria. Positive rates by our criteria were 0% in the noncoronary artery lesion group, 9.1% in the coronary lesion group, 56.3% in the ischemia group, and 69.2% in the old myocardial infarction group. However, using the criteria for adults, these values were 0%, 3.0%, 25%, and 46.2%, respectively. Sensitivities to ischemia and infarction using our criteria were significantly higher (56.3% and 69.2%) than those using the criteria for adults (p < 0.05). Moreover, specificities to ischemia and infarction were very high (93.4% and 93.5%, respectively) using our criteria, and there were no significant differences from specificities using the criteria for adults. Also, we examined the reproducibility of values of LPs and LP parameters. The values of filtered QRS duration showed a high reproducibility in both LP-positive and -negative groups, followed by low-amplitude signal and then root-mean-square voltage. The results of LP presence or absence showed 100% reproducibility for both the LP-positive and -negative groups, supporting the utility of LPs for clinical applications. Thus, LPs provide useful information in a noninvasive manner for clarifying ischemia and infarction in patients with Kawasaki disease.

Treatment of benign prostatic hyperplasia with high intensity focused ultrasound: an initial clinical trial in Japan with magnetic resonance imaging of the treated area.

BACKGROUND: High intensity focused ultrasound (HIFU) is a method of delivering acoustic energy to a focal point and is expected to induce tissue thermal ablation. Transrectal HIFU was applied to symptomatic benign prostatic hyperplasia (BPH) for relief of intravesical obstruction without injury to surrounding tissue. The clinical effectiveness and safety of transrectal HIFU were investigated. METHODS: Thirty-seven Japanese men with symptomatic BPH were treated with HIFU. The treatment was minimally invasive; operating time was less than 40 minutes, and a posttreatment indwelling catheter was left in place for 3-4 days. RESULTS: The maximum urinary flow rate (ml. per second) increased from 7.6 +/- 0.6 to 9.3 +/- 0.6 at three months in 37 patients (P < 0.05). During the same period the International Prostatic Symptom Score and Quality of Life score (points) decreased from 23.6 +/- 1.4 to 10.5 +/- 0.3, 5.2 +/- 0.3 to 2.6 +/- 0.1 (P < 0.001), respectively. Overall response estimated by these three individual parameters were as follows; excellent 18.9%, good 48.6%, fair 10.8% and poor 21.6% at three months. Magnetic resonance imaging using an endorectal coil showed coagulative necrosis defined in the therapy zone at one month after treatment. Side effects were transient urinary retention in six patients (16.2%), gross hematuria in four patients (10.8%) and hematospermia in four patients (10.8%). There was almost no intraoperative blood loss. CONCLUSIONS: Transrectal HIFU treatment of symptomatic BPH is safe, reduces symptoms significantly, and leads to a slight increase in uroflow.

A Ro/SS-A auto-antibody positive mother's infant revealed congenital complete atrioventricular block, followed by insulin dependent diabetes mellitus and multiple organ failure.

We experienced a congenital complete atrioventricular block infant who was born from a Ro/SS-A antibody positive mother. Ro/SS-A antibody was also found in this baby which was presumed to be mediated by the maternal placenta. Temporary cardiac pacing was required at birth and pacemaker implantation was performed at 9 months. At 11 months of age, the baby fell into shock and experienced multiple organ failure because of diabetes mellitus-induced coma. The association between congenital complete heart block and the Ro/SS-A antibody is well known. However, the accompaniment of insulin-dependent diabetes mellitus has not been reported previously. As the Ro/SS-A antigen appears in the cytoplasm of many tissues, the possibility of an association between Ro/SS-A antibody and diabetes mellitus is difficult to deny. We report this rare case to draw attention to the possibility that babies who are born from an Ro/SS-A antibody positive mother may develop diabetes mellitus as well as congenital complete heart block.

Early detection of anthracycline cardiotoxicity in children with acute leukemia using exercise-based echocardiography and Doppler echocardiography.

We performed both supine bicycle ergometer (BEx) and hand-grip (HGx) exercise tests to evaluate cardiac function in 13 asymptomatic children with leukemia who had completed a general treatment protocol. We calculated fractional shortening (FS), end-systolic stress-volume index (ESS/ESVI), left ventricular diastolic filing velocity ratio (A/E) and normalized peak rate of diastolic increase in left ventricular internal dimension (dLVDt/dt/LVDt). Before the exercise, we found that dLVDt/dt/LVDt was decreased in the high-dose anthracycline group (anthracycline cumulative dose of 480-570 mg/m2), even though other cardiac function parameters were not different from those in the control. In BEx, the percent change in ESS/ESVI decreased in an anthracycline cumulative dose-dependent fashion. In HGx, ESS/ESVI showed a decreased response only in the high-dose anthracycline group. Therefore, we conclude that: 1) the diastolic function parameter dLVDt/dt/LVDt might show abnormalities prior to other systolic function parameters, 2) the percent change in ESS/ESVI in BEx is the most sensitive parameter studied, and could detect cardiac function abnormalities even in the small-dose anthracycline group (anthracycline cumulative dose of 175 mg/m2), and 3) BEx is more suitable for the early detection of anthracycline cardiotoxicity than HGx.

Increased plasma endothelin-1 concentration in Kawasaki disease.

We compared the variation in plasma endothelin-1 (ET-1) levels by the sandwich-enzyme RIA method during each of the clinical stages of Kawasaki disease, a systemic vasculitis occurring in children (30 cases, ages 4-62 months) and examined whether ET-1 could be a clinical parameter for predicting coronary artery dilatation. The results revealed that the ET-1 level in the acute stage was higher than that in the recovery stage, the chronic stage, or in healthy controls (3.46 +/- 1.22 versus 2.20 +/- 0.56, 1.55 +/- 0.52, and 1.57 +/- 0.45 pg/ml, respectively; p < 0.01). Furthermore, in the acute stage the ET-1 level in the group with coronary artery dilatation (positive group, five cases) increased more than that in the negative group (25 cases) (5.13 +/- 1.64 versus 3.09 +/- 0.70 pg/ml, respectively; p < 0.01). When the ET-1 value was more than 4.5 pg/ml in the acute stage, our prediction for coronary artery dilatation demonstrated a high value in indices of both sensitivity (100%) and specificity (96.1%). Thus, plasma concentration of ET-1 was increased in the acute stage of Kawasaki disease and was very high in patients with coronary artery dilatation. The plasma ET-1 level was considered to be an important factor in predicting the dilatational lesions of the coronary artery in the acute stage of Kawasaki disease.

Normal Y sequences in Smith-Lemli-Opitz syndrome with total failure of masculinization.

We report an infant with characteristics of Smith-Lemli-Opitz syndrome who had anteverted nostrils, apparently low-set ears, micrognathia, high-arched palate, cleft palate, growth and psychomotor retardation, hypotonia, poor suck, cerebral hypotrophy and double renal pelvis and ureter. An EEG showed spike waves in the right temporal area. The patient appeared to have normal internal and external genitalia of the female type. Both ovaries were dysplastic. The karyotype was 46,XY. All of 26 loci on the Y chromosome were positive including SRY, a candidate gene for TDF.