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Herein is described a case of breast fibroadenomas in a 16-year-old girl with Beckwith-Wiedemann syndrome (BWS) and uniparental disomy (UPD) of chromosome 11p15.5. She was clinically diagnosed with BWS and direct closure was performed for an omphalocele at birth. Subtotal and 90% pancreatectomy were performed for nesidioblastosis at the ages 2 months and 8 years, respectively. Bilateral multiple breast fibroadenomas were noted at the age of 16 and 17 years. In this case, paternal UPD of chromosome 11p15.5 was identified on microsatellite marker analysis. The relevant imprinted chromosomal region in BWS is 11p15.5, and UPD of chromosome 11p15 is a risk factor for BWS-associated tumorigenicity. Chromosome 11p15.5 consists of imprinting domains of IGF2, the expression of which is associated with the tumorigenesis of various breast cancers. This case suggests that fibroadenomas occurred in association with BWS.

In this study, we have investigated the specific binding proteins of Zinc-L-carnosine (Polaprezinc) using Polaprezinc-affinity column chromatography in vitro. A protein having a 70-kDa molecular mass was eluted by the linear gradient of 0-1.0 mM Polaprezinc from the affinity column and the protein was identified as the molecular chaperone HSP70 by immunoblotting. The chaperone activity of HSP70 was completely suppressed by Polaprezinc. The ATPase activity of HSP70 was affected to some extent by the reagent. In the circular dichroism (CD) spectrum, the secondary structure of HSP70 was changed in the presence of Polaprezinc, i.e. it decreased in the α-helix. We have determined the Polaprezinc-binding domain of HSP70 by using recombinant HSP70N- and C-domains. Although Polaprezinc could bind to both the N-terminal and the C-terminal of HSP70, the HSP70N-domain has a high affinity to the drug. Regarding the peptide cleavage of the HSP70N- and C-domains with proteinase K, the intact HSP70N still remained in the presence of Polaprezinc. On the other hand, the quantity of the intact C-domain slightly decreased under the same conditions along with the newly digested small peptides appeared. It has been suggested that Polaprezinc binds to HSP70 especially in the N-domains, suppresses the chaperone activity and delays an ATPase activities of HSP70.

加算平均心電図 (SAE) の心筋梗塞 (Ml) 後の致死性不整脈・突然死の予知に対する意義をprospectiveに検討した.1986年2月～1990年1月に急性心筋梗塞にて本院に入院した連続186例のうちSAEを記録, 分析可能であった130例について追跡調査した.平均追跡期間は4.7±2.4年間である.持続性心室頻拍・心室細動および突然死を不整脈事故と定義しその発生を調査したところ, 不整脈事故は発生は異常SAE群26例中6例 (23%) , また正常SAE群で104例中2例 (2%) と異常SAE群で有意に高率であった (P

We describe a 30-month-old boy with multiple anomalies and mental retardation with hereditary spherocytic anemia. His karyotype was 46,XY,del(8)(p11.23p21.1). Genes for ankyrin and glutathione reductase (GSR) were localized to chromosome areas 8p11.2 and 8p21.1, respectively. Six patients with spherocytic anemia and interstitial deletion of 8p– have been reported. In these patients, severe mental retardation and multiple anomalies are common findings. This is a new contiguous gene syndrome. Lux et al. [1990: Nature 345:736–739] established that ankyrin deficiency and associated deficiencies of spectrin and protein 4.2 were responsible for spherocytosis in this syndrome. We reviewed the manifestations of this syndrome. Patients with spherocytic anemia and multiple congenital anomalies should be investigated by high-resolution chromosomal means to differentiate this syndrome. © 1995 Wiley-Liss, Inc.

The effect of early reperfusion on the time course of signal-averaged ECG was examined in 90 patients with myocardial infarction. Abnormal signal-averaged ECG disappeared more frequently (p0.05) and earlier in cases with early reperfusion than in those without. Serious arrhythmic events in the late phase (7 days) occurred in patients with abnormal signal-averaged ECG, but not in cases with early reperfusion. These results indicate that dynamic changes in tissue structure and the physiological state of viable muscles after early reperfusion produce different time courses for signal-averaged ECG. The risk of arrhythmic events among patients with abnormal signal-averaged ECG seems to be lower in cases with early reperfusion than in those without.

To study the effect of nipradilol, a new antianginal agent with vasoactive property as well as β-blocking action, on exercise electrocardiogram, multi-stage treadmill tests were performed after the administration of nipradilol and propranolol in 10 patients with stable effort angina pectoris. The effect of nipradilol on conventional measures in exercise ECG (heart rate, systolic BP, ST segment deviation, exercise duration, pressure rate product) was not significantly different from that of propranolol. An analysis of heart rate-ST loop (HR-ST loop), ST segment deviation plotted as a function of heart rate, during exercise and recovery revealed that nipradilol shifted the HR-ST loop rightward, indicating less prominent ST segment depression relative to the increase in HR when compared with propranolol. Calculated ST segment depression relative to the change in HR was smaller with nipradilol than with propranolol during exercise (ΔST/ΔHR from rest to peak exercise: nipradilol 5.57±0.81 vs propranolol 6.71±1.07μV/bpm, p

The molecular mechanisms by which hepatocyte nuclear factor (HNF)4α regulates fetal liver development have not been fully elucidated. We screened the downstream molecules of HNF4α during liver development and identified sodium-coupled neutral amino acid transporter (SNAT)4. The aim of this study is to investigate the regulation of SNAT4 by HNF4α and to clarify its roles in differentiating hepatocytes.HNF4α was overexpressed in cultured liver buds using adenovirus, and suppression subtractive hybridization screening was performed. Temporal and spatial expression of SNAT4 during liver development was investigated. Regulation of SNAT4 by HNF4α was examined by promoter analyses and electrophoretic mobility shift assays (EMSA). Metabolic labeling and western blotting were carried out using primary hepatoblasts with SNAT4 overexpression.The expression of Slc38a4 encoding SNAT4 showed a marked perinatal increase, and was predominant among system A amino acid transporters. It was first detected in embryonic day 18.5 liver, and found in most hepatocytes after birth. Three alternative first exons were found in the SNAT4 gene. Promoter analyses using approximately 3-kb fragments corresponding to each first exon (AP1, AP2, AP3) revealed that AP1 and AP2 exhibited strong promoter activity in mouse hepatoblasts with endogenous HNF4α. Transactivation of AP2 was upregulated by HNF4α in HeLa cells without endogenous HNF4α. EMSA has demonstrated that HNF4α directly binds to cis-elements in AP2. Overexpression of SNAT4 facilitated amino acid uptake and de novo protein synthesis in primary hepatoblasts.SNAT4 functions downstream of HNF4α and plays significant roles in liver development through mechanisms of amino acid uptake and protein synthesis.

Purpose We evaluated the clinicopathological characteristics of pediatric sacrococcygeal germ cell tumors (SGCTs) and yolk sac tumors (YSTs) developing after sacrococcygeal teratoma (SCT) resection, and discussed the pathogenesis of sacrococcygeal YST. Methods We retrospectively analyzed pediatric SGCT patients attending 10 Japanese institutions. Results A total of 289 patients were eligible, of which 74.6% were girls. The mean age at surgery was 7.1 months. There were 194 mature and 47 immature teratomas, and 48 YSTs. YST developed after SCT resection in 13 patients (5.4% of SCTs), and was detected between 5 and 30 months after resection. At initial surgery, 9 of these 13 patients were neonates, 12 underwent gross complete resection with coccygectomy, and 9 had histologically mature teratoma without microscopic YST foci. Postoperative serum alpha-fetoprotein (AFP) levels were regularly examined in 11 patients. Intervals of AFP measurement ≤ 4 months helped to detect subclinical localized YSTs for resection. Conclusions The characteristics of SGCT in Japanese children were similar with those reported in Europe or the United States. YST developed after SCT resection not only in patients with previously reported risk factors. We recommend that patients undergo serum AFP monitoring every 3 months for ≥ 3 years after SCT resection.

Recently, it was reported that ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes (ETANTR) show 19q13.42 amplification at a high frequency, suggesting that these tumors may constitute a single entity. As ependymoblastic rosettes are the most prominent features in both subtypes, embryonal tumor with multilayered rosettes (ETMR) was proposed, for which 19q13.42 amplification represents a specific molecular hallmark. However, ependymoblastic rosettes are not specific to ependymoblastoma and ETANTR, and are also found in a few other embryonal tumors as well as immature teratomas, and knowledge on 19q13.42 amplification in these tumors is limited. In this study, we performed fluorescence in situ hybridazation (FISH) analysis and differential polymerase chain reaction (PCR), and detected 19q13.42 amplification in three out of four ETANTR, one ependymoblastoma and one medulloepithelioma with ETANTR components, whereas none of the two atypical teratoid/rhabdoid tumors (AT/RT) with ependymoblastic rosettes nor two immature teratomas with developing neuroectodermal structures showed such amplification, suggesting that medulloepitheliomas would possibly be included in ETMR, and ependymoblastic rosettes in AT/RT do not signify that these tumors constitute ETMR. Also, we found C19MC rather than miR‐371‐373 was amplified in one ETANTR, suggesting that C19MC miRNA cluster seems to be more closely linked to the pathogenesis of ETMR.

Background Parenteral nutrition (PN)-associated liver dysfunction (PNALD) in term infants usually manifests as intrahepatic cholestasis, which recovers with enteral nutrition (EN) in most cases; however, as the number of extremely low-birthweight infants (ELBWI) has been increasing, and consequently intestinal diseases associated with ELBWI have been increasing, more intractable PNALD has been encountered after surgical treatment in ELBWI, which does not resolve or rather worsens with EN. Methods Three cases of ELBWI with intestinal perforation, which developed PNALD and eventually died of hepatic failure with intractable portal hypertension, were reviewed. Their gestational age and birthweight ranged from 23 to 26 weeks, and from 434 to 968 g, respectively. The intestinal diseases included necrotizing enteritis in two and meconium-related ileus with focal intestinal perforation in one. Results The duration of total PN without EN in the three cases was 17, 24 and 24 days, respectively. The interval between the introduction of PN and the onset of PNALD was 14, 4 and 18 days, respectively. A marked elevation of serum endotoxin level was detected in both cases of necrotizing enteritis. Histopathological study of the liver revealed marked cholestasis, significant hepatic necrosis with fibrosis, and proliferation of ductules in all these cases, which was responsible for portal hypertension. Conclusions PN after gastrointestinal disorders in ELBWI may cause refractory PNALD, which does not resolve, or rather worsens with the resumption of EN. Portal hypertension secondary to hepatic necrosis may be responsible for the exacerbation with the resumption of EN.

The present study aimed to clarify the protective effect of adenosine receptors against the excitotoxicity of cochlear afferent dendrites. The effects of 2-chloro-N6-cyclopentyladenosine (CCPA), an A1 adenosine receptor agonist, and 5'-N-cyclopropyl-carboxamidoadenosine (CPCA), an A2A adenosine receptor agonist, on cochlear excitotoxicity induced by kainic acid (KA) were examined using guinea pigs. KA was applied to the round window membrane at a concentration of 10mM for 30 min. CCPA or CPCA was given at the onset of KA application. KA morphologically induced the swelling of cochlear afferent dendrites and significantly elevated the threshold of the compound action potential (CAP) of the cochlea. CCPA inhibited the KA-induced CAP threshold shift and swelling of the cochlear afferent dendrites. However, CPCA did not affect cochlear excitotoxicity induced by KA. The results suggest that adenosine A1 receptor activation could prevent the excitotoxicity of cochlear afferent dendrites.

Abstract Lung biopsies were taken at surgery from five patients (age 2–13, average 7.6 years) with tetralogy of Fallot and pulmonary atresia with major aortopulmonary collateral arteries. The biopsies were then processed for ultrastructural study, comparing paired samples taken, on the one hand, from a segment connected to central pulmonary arteries and, on the other hand, from a segment supplied directly by collateral arteries. Specimens from patients with isolated ventricular septal defect, and from those without cardiac disease, were used as controls. In the patients with tetralogy of Fallot and pulmonary atresia, all biopsies taken from segments supplied by the major collateral arteries showed marked deposition of collagen in the alveolar wall, with an increase in the thickness of the basement membrane (3.6±1.2 µm, mean±SD) greater than seen in those taken from segments connected to central pulmonary arteries (0.9±0.6, p

Retrospective examinations of 8,139 placentae were performed to clarify the relationship between placental disorders with massive intervillous fibrin deposition (MIFD) and intrauterine growth retardation (IUGR). Although the incidence of MIFD was low (0.4%), the small-for-date (SFD) birth rate in the MIFD group was significantly higher than that in the control group (62.9 vs. 8.3%; p0.001). Seventeen of 35 patients in the MIFD group had no clinical complications. MIFD itself was thought to be the main cause of IUGR in these patients. 78.4% of multiparae in the MIFD group have unsuccessful obstetrical histories such as intrauterine fetal death and fetal growth retardation. Four of 6 patients with a history of MIFD and SFD delivery in a previous pregnancy repeated the same episode. These data indicate that the MIFD recurrence rate in subsequent pregnancies must be high. Patients with a history of both SFD delivery and MIFD in previous pregnancies were defined as high-risk patients and they were given orally 30 mg of aspirin and 150 mg of dipyridamole daily and/or daily intravenous injection of 10,000 IU heparin during pregnancy. As a result, MIFD did not recur in all cases of the treated group and 87.5% (7/8) of the treated group could deliver approximate-for-date infants compared with 33.3% (2/6) of the untreated group (p0.05). These results indicate that anticoagulant and antiplatelet therapies are extremely effective for prevention of MIFD and IUGR due to MIFD.

The presence of several covalent DNA adducts in the human colon was demonstrated by 32P-postlabeling in a previous study. We demonstrated that DNA of all the colonic mucosa tested were selectively adducted by a single genotoxic agent and this modification was completely absent in the DNA of muscular layers. In this study, the DNA adducts of the small intestine are compared with those of the colon to understand the role of mucosa-specific DNA adduct (MSA) in intestinal carcinogenesis. The mucosal DNA of the small intestine from 19 adults undergoing surgery due to gastric carcinoma (seven cases), pancreatic carcinoma (four cases), colon carcinoma (four cases), small intestinal tumor (two cases), intestinal trauma (one case) and ectopic pancreas (one cases) were analyzed. The mucosa-adjacent muscular layer DNA of the corresponding samples was examined as a control. Several common DNA adducts were observed in both mucosal and muscular layers of all the adults. Besides these common background DNA adducts, two MSAs (Si1, Si2) were detected in most of the adults as in colon cases. Si1 was present in all adults examined (19/19 cases) at a level of 0.04-0.22 adducts/10(8) nucleotides (average 0.09) and Si2 was found in 13/19 patients at a level of 0.03-0.08 adducts/10(8) nucleotides (average 0.05). Si2 was the same adduct detected in the adult colonic mucosa. However, they were absent in the adjacent muscular layer as well as in the neonatal intestine tested as a control. The total level of the mucosa-specific DNA adducts of the small intestine was approximately 28-fold lower than that of the colon. Considering that the incidence of cancer in the small intestine is rather lower than that in the colon, these results may be relevant to the development of human intestinal cancer.

Expression of antioxidant enzymes is regulated by transcription factor NF-E2-related factor (Nrf2) and induced by oxidative stress. Reactive oxygen species contribute to the formation of several types of cochlear injuries, including age-related hearing loss and gentamicin ototoxicity. In this study, we examined the roles of Nrf2 in age-related hearing loss and gentamicin ototoxicity by measuring auditory brainstem response thresholds in Nrf2-knockout mice. Although Nrf2-knockout mice maintained normal auditory thresholds at 3 months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11 months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11 months of age. To examine the importance of Nrf2 in protecting against gentamicin-induced ototoxicity, 3-day-old mouse organ of Corti explants were cultured with gentamicin. Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. Furthermore, the expressions of some Nrf2-target genes were activated by gentamicin treatment in wild-type mice but not in Nrf2-knockout mice. The present findings indicate that Nrf2 protects the inner ear against age-related hearing injuries and gentamicin ototoxicity by up-regulating antioxidant enzymes and detoxifying proteins.

Nasopharyngeal carcinoma (NPC) is a unique disease with a clinical presentation, epidemiology, and histopathology differing from other squamous cell carcinomas of the head and neck. NPC is an Epstein-Barr virus-associated malignancy with a marked racial and geographic distribution. Specifically, it is highly prevalent in southern China, Southeast Asia, and the Middle East. To date, most NPC patients have been diagnosed in the advanced stage, but the treatment results for advanced NPC are not satisfactory. This paper provides a brief overview regarding NPC, with the focus on the early detection of initial and recurrent NPC lesions.

Neonatal lupus erythematosus (NLE) is a rare disorder caused by the transplacental passage of maternal autoantibodies and manifests with characteristic skin eruption and/or congenital heart block. Anti-SSA 52-kDa and 60-kDa antibodies are important serology markers of the diagnosis of NLE. However, women who have these antibodies do not always give birth to children with NLE. Therefore, we investigated the avidity (quality of the antibody) using urea.The sera of 97 women and 3 umbilical cord blood specimens were measured using commercial ELISA kit (MESACUP 52K SS-A/Ro and 60K SS-A/Ro, MBL). Avidity index was obtained using 8M urea.The 21 mothers with infants demonstrating atrioventricular block (AB) showed higher antibody indexes for 52-kDa (p0.001) and 60-kDa (p=0.009) proteins than the 76 mothers of infants without AB. The 19 mothers with infants demonstrating AB had both anti-52-kDa and anti-60-kDa antibodies, and the 2 mothers had only anti-52-kDa antibody. They had higher avidity indexes to 60-kDa (p=0.026) than those without AB. A mother with infant demonstrating AB showed anti-52-kDa antibody isolated positive (96.0 Index), and showed low anti-52-kDa avidity antibody (6.3%). The case was a similar result in umbilical cord blood (75.8 Index, 6.0%).We conjecture that anti-52-kDa and anti-60-kDa avidity antibodies influence the development of AB. Two mothers with infant demonstrating AB showed anti-52-kDa antibody isolated positive. A fetus could develop AB in maternal low anti-52-kDa avidity antibody.

A nationwide survey on neonatal surgery conducted by the Japanese Society of Pediatric Surgeons has demonstrated that the mortality of neonatal intestinal perforation has risen over the past 15 years. The incidence of intestinal perforation in extremely low-birthweight (ELBW) neonates has been increasing as more ELBW neonates survive and as the live-birth rate of ELBW has increased. In contrast to necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP), the pathogenesis of meconium-related ileus, defined as functional bowel obstruction characterized by delayed meconium excretion and microcolon, remains unclarified.The histology of 13 ELBW neonates with intestinal perforation secondary to meconium-related ileus was reviewed, and the radiology of 33 cases of meconium-related ileus diagnosed on contrast enema was reviewed. Specimens obtained from 16 ELBW neonates without gastrointestinal disease served as age-matched controls for histological assessment.The size of the ganglion cell nucleus in meconium-related ileus and in control subjects was 47.3 ± 22.0 µm(2) and 37.8 ± 11.6 µm(2), respectively, which was not significantly different. In all cases of meconium-related ileus, contrast enema demonstrated a microcolon or small-sized colon, with a gradual caliber change in the ileum and filling defects due to meconium in the ileum or colon, showing not-identical locations of caliber changes and filling defects.Morphological immaturity of ganglia was not suggested to be the pathogenesis of meconium-related ileus. Impaction of inspissated meconium is not the cause of obstruction, but the result of excessive water absorption in the hypoperistaltic bowel before birth, although the underlying mechanism responsible for the fetal hypoperistalsis remains unclear.

Background: There are few reports describing the features of maternal anti-SSA antibody-associated congenital complete heart block (CCHB) patients developing endocardial fibroelastosis (EFE). The aim of this study was to describe the clinical features and the outcome of patients with CCHB, with or without EFE. Methods and Results: Over a 20-year period, 12 consecutive patients diagnosed with maternal anti-SSA antibody-associated CCHB were identified. The maternal anti-SSA antibody levels were measured and fetal echocardiographic findings were reviewed. The ratios of the thickness of the endocardium to that of the whole wall of the left ventricle (LE/W) and right ventricle (RE/W) were measured to investigate the degree of endocardial thickening. A total of 7 patients survived (living group) and were not diagnosed as having EFE. The remaining 5 patients died and were diagnosed with EFE during autopsy (dead group). Fetal echocardiography of the patients showed differences in the thickening and hyperintensity of the endocardium. The RE/W value was significantly higher in the dead group than in the living group. The titers of both maternal anti-52-kDa and anti-60-kDa SSA antibodies were high, but showed no significant differences between the 2 patient groups. Conclusions: EFE was the major negative prognostic factor for CCHB. Myocardial damage, predominantly in the right ventricle, was related to the outcome of CCHB associated with EFE. (Circ J 2011; 75: 1215-1221)

Twenty-two cases of delivery of twins following the antepartum death of one twin are presented. Serious complications were noted in 12 of the live-born twins. Nine live-born twins were delivered more than 1 week after the antepartum death of their counterpart. Two who were delivered 2 days and 5 days, respectively, thereafter showed fatal cerebral and/or renal necrosis caused by multiple infarction. In one case the course from the death of the counterpart to delivery was unclear. In all of these cases monochorionic placenta with superficial vascular anastomosis was noted. The remaining 10 twins had good outcomes. Monochronic placenta was noted in 7 cases and placental superficial vascular anastomosis in 4. In these cases, the surviving twin was delivered within 4 days of the antepartum death of the counterpart. In 3 cases in which the dichorionic placenta lacked vascular anastomoses, the surviving twin also showed excellent prognosis even though the duration after demise of the counterpart was prolonged. The incidence of venous anastomosis of the placental vessels and the type of anastomosis apparently is very important in determining the live-born twin survives. The autopsies revealed no definite evidence of intrauterine disseminated intravascular coagulation but intrauterine disseminated intravascular coagulation but intrauterine fetal embolism was considered to be the pathogenetic factor in multi-organ infarction.

BACKGROUND: No epidemiological studies have examined risk factors for early spontaneous abortions among Japanese women. In this matched case-control study, we investigated the associations of reproductive, physical, and lifestyle characteristics of women and their husbands with early spontaneous abortion < 12 weeks of gestation. METHODS: Information was collected through medical records for 430 cases of early spontaneous abortion and 860 controls of term delivery. Two controls were individual-matched to one case according to maternal age (± 3 years) and calendar year of events (either early spontaneous abortion or delivery). Multivariable conditional odds ratios (ORs) and 95% confidence interval (CI) were calculated with conditional logistic-regression. RESULTS: The risk of early spontaneous abortions was higher for women with a past history of early spontaneous abortions; OR was 1.98 (95% CI: 1.35, 2.89) for one previous spontaneous abortion, 2.36 (95% CI: 1.47, 3.79) for two, and 8.73 (95% CI: 5.22, 14.62) for three or more. Other factors also influence risk; an OR of 2.39 (95% CI: 1.26, 4.25) was found for women who smoked, and 1.65 (95%CI: 1.17, 2.35) for women working outside the home. CONCLUSIONS: Our finding suggests that for Japanese women, smoking and working may be important public health issue targets for the prevention of early spontaneous abortions.

Endothelin-1 (ET-1), a potent vasoconstrictor, is considered to be implicated in failing Fontan circulation, however the expressions of ET-1 and endothelin receptor type A (ET(A)R) and type B (ET(B)R) in the pulmonary arteries of failed Fontan patients were not elucidated.Immunohistochemistry and quantitative real-time PCR were used to analyse the expression levels of ET-1 and its receptors in the pulmonary arteries of the autopsy lung tissues of the patients who died after the Fontan procedure (n=10). We divided these patients into 3 groups, failed Fontan (n=4), heart failure (n=3) and non-failed Fontan (n=3), and then compared those to the age-matched normal controls (n=4).The intra-acinar pulmonary arteries of failed Fontan patients showed significant medial hypertrophy. Computational optical density analyses of the immunostaining revealed that the expressions of ET-1, ET(A)R, and ET(B)R in the intra-acinar pulmonary arteries were significantly increased in the failed Fontan patients (P0.05 vs. normal controls), however no significant difference was observed between the non-failed Fontan patients and the normal controls. Quantitative real-time PCR analyses confirmed that the mRNA expressions of ET-1, ET(A)R, and ET(B)R were significantly increased in the failed Fontan patients (P0.05 vs. normal controls).The overexpression of ET-1 and its receptors in the pulmonary arteries can cause pulmonary vasoconstriction and vascular remodelling, leading to failed Fontan circulation. This study suggests a histopathological rationale for the potential benefits of endothelin receptor antagonists in patients with failing Fontan circulation.

2-Chlorodeoxyadenosine (2-CdA) has been successfully used in children to treat refractory Langerhans cell histiocytosis and juvenile xanthogranuloma (JXG) as salvage therapy. Although 2-CdA is generally well-tolerated, with temporary myelosuppression as the primary dose-limiting toxicity, prolonged myelosuppressive, and immunosuppressive effects have been reported. We describe an adolescent patient with refractory multiple central nervous system JXG, with the lesion size markedly reduced after treatment with 2-CdA. However, severe transfusion-dependent bone marrow failure developed after five courses of 2-CdA. He underwent successful bone marrow transplantation from his HLA compatible sister with reduced intensity conditioning.

Dysfunction of the cochlea causes sensorineural hearing loss. Glucocorticoids have been clinically applied for sensorineural hearing loss of sudden onset, including idiopathic sudden sensorineural hearing loss, acoustic injury, Meniere's disease, and immune-mediated hearing loss. However, clinical studies on sudden sensorineural hearing loss have revealed conflicting results regarding the efficacy of glucocorticoids. The findings obtained from animal experiments have demonstrated that glucocorticoids exhibited protective effects on some types of cochlear injury, but there were limitations regarding glucocorticoid therapy. Recently, the actions of neurosteroids in the cochlea have drawn much attention from auditory researchers. Clinical and experimental studies of the auditory system have indicated that estrogens affect auditory perception. Furthermore, estrogens and dehydroepiandrosterone (DHEA) exhibit protective effects on cochlear injury. This article was aimed to give an overview of steroid treatment for protection of the inner ear against various cochlear injuries. Findings obtained from animal studies are focused on.

Bacillus cereus is recognized as a major pathogenic bacterium that causes food poisoning and produces gastrointestinal diseases of 2 types: emetic and diarrheal. The emetic type, which is often linked to pasta and rice, arises from a preformed toxin, cereulide, in food. Rapid and accurate diagnostic methods for this emetic toxin are important but are limited. Here we describe 3 patients with B cereus food poisoning in which cereulide was detected and measured sequentially. Three family members began to vomit frequently 30 minutes after consuming reheated fried rice. After 6 hours, a 1-year-old brother died of acute encephalopathy. A 2-year-old sister who presented with unconsciousness recovered rapidly after plasma exchange and subsequent hemodialysis. Their mother recovered soon by fluid therapy. From leftover fried rice and the children's stomach contents, B cereus was isolated. Serum cereulide was detected in both children; it decreased to an undetected level in the sister. These cases highlight the importance of measuring the value of cereulide, which would reflect the severity of B cereus emetic food poisoning. The cases also suggest the possible role of blood-purification therapy in severe cases.

We report herein a case of Brachmann-de Lange syndrome complicated with congenital diaphragmatic hernia in which a NIPBL gene mutation was identified. A female infant born at 37 weeks of gestation died 134 min after delivery, even though endotracheal intubation and resuscitation were performed immediately after the scheduled caesarean operation. We diagnosed the infant with Brachmann-de Lange syndrome from her physical characteristics. An abnormal peak at the 29th exon in the translation area of the NIPBL gene was detected using denaturing high-performance liquid chromatography. In addition, a mutation of cytosine to thymine (nonsense mutation) at the 5524th base was identified using the direct sequence method. This variation was likely the cause of the syndrome.

Interleukin-8 (IL-8) exerts chemotactic activity on neutrophils at inflammatory sites to eliminate invading bacteria. To investigate whether the preterm fetus with chorioamnionitis produces IL-8, the titers of IL-8 were examined in sera of babies with (n = 38) and without chorioamnionitis (n = 34) using an EIA kit specific for IL-8. The infected babies had a significantly higher IL-8 titer than those not infected at 22-36 gestational weeks. The IL-8 titer was increased even in the mild histologic stage of chorioamnionitis and became much higher in the more severe stage. The IL-8 elevation, however, was remarkably suppressed by infusion of a steroid into the mother to promote fetal lung maturation. This retrospective study demonstrated that titration of IL-8 in cord serum is a more useful marker for the early detection of chorioamnionitis, because of its higher sensitivity and specificity, than conventional markers such as C-reactive protein.

Septic thrombophlebitis caused by head and neck infection has become a rare disorder due to the development of antibiotics. We report herein two cases of septic thrombophlebitis of the head and neck. Case 1 was a 7-year-old girl, who presented with fever, otalgia, and headache. Acute otitis media was diagnosed in another hospital. A computed tomography (CT) scan and magnetic resonance imaging (MRI) demonstrated mastoiditis with thrombophlebitis of the right lateral and sigmoid sinuses. Case 2 was a 39-year-old woman, who presented with left neck pain, fever chills and severe pharyngalacia. Peritonsillar abscess was diagnosed. A CT scan demonstrated a left internal jugular vein thrombus in addition to multiple pulmonary nodules with emboli. A diagnosis of Lemierre's syndrome was made based on these findings. Both cases were successfully treated by intravenous antibiotics. A lack of awareness of these conditions and a delayed diagnosis may lead to potentially fatal consequences. A clinical suspicion of septic thrombophlebitis seems to be essential to make an accurate diagnosis during the early stage of the disease and archive a successful outcome.

Neonatal lupus erythematosus (NLE) is a rare disorder caused by the transplacental passage of maternal autoantibodies and manifests with characteristic skin eruption and/or congenital heart block. Anti-SS-A 52-kDa and 60-kDa antibodies are important serology markers for the diagnosis of NLE. However, women who have these antibodies do not always give birth to children with NLE. Therefore, we investigated the avidity (quality of the antibody) using urea derivative.The sera of 54 women and 19 umbilical cord blood specimens were measured using a commercial ELISA kit (MESACUP 52K SS-A/Ro and 60K SS-A/Ro, MBL). Avidity index (AI) was obtained using a reagent prepared according to the method described in the European patent EP 0875761 as well as in the Japanese patent application No. 10-121896.Mothers with infants demonstrating atrioventricular block (AB) showed higher antibody indices for 52-kDa protein than mothers of infants without AB (p=0.0145). Mothers with cutaneous NLE had higher antibody indices for 60-kDa protein than mothers without cutaneous NLE (p=0.0058). Mothers had higher antibody indices and AIs than fetuses. There was a positive correlation between the antibody index and AI. The level of AI was increased in patients demonstrating low platelet counts in umbilical cord blood, but high antibody indices did not always increase in relation to the low platelet counts in umbilical cord blood.Mothers with high antibody indices do not always give birth to children with NLE, even if the AIs of the mother are high. The fetus side, that is, the factor on the antigen side would be more important. However, we conjecture that anti-60-kDa antibody influences the development of cutaneous NLE, and that anti-52-kDa antibody influences the development of NLE with AB. The high AI may be related to more severe symptoms of NLE.

The etiology and pathogenesis of endometriosis is largely unknown. It has been reported that advanced glycation end products-receptor for advanced glycation end products regulation relates to oxidative stress, inflammatory reaction, apoptosis, and angiogenesis through vascular endothelial growth factor activation. The purpose of this study was to examine whether advanced glycation end products-receptor for advanced glycation end products regulation contributes to the pathogenesis of endometriosis. Plasma, follicular, and peritoneal fluid samples were collected from women with or without endometriosis, and soluble receptor for advanced glycation end products, vascular endothelial growth factor and carboxymethyl lysine levels were measured by enzyme-linked immunosorbent assay. Vascular endothelial growth factor and soluble receptor for advanced glycation end products concentrations were similar in plasma; however, their concentrations in follicular fluid were significantly increased in endometriosis patients (soluble receptor for advanced glycation end products was 132 + 31 pg/mg of protein vs. 105 + 27 pg/mg; vascular endothelial growth factor was 70 + 3 pg/mg vs. 49 + 18 pg/mg, expressed as the mean + standard deviation). Increased soluble receptor for advanced glycation end products and vascular endothelial growth factor levels in a local environment suggest that the advanced glycation end products-receptor for advanced glycation end products may contribute to the pathogenesis of endometriosis.

Protein S is an antithrombotic cofactor for protein C that also has multifunctional anti-inflammatory, cellular protective, apoptotic and mitogenic properties. Protein S levels are thought to decrease during pregnancy, but the underlying mechanism remains unknown. We compared protein S concentrations throughout normal pregnancy with those of nonpregnant women and measured plasma C4b-binding protein levels in nonpregnant women and in pregnant women at the 40th gestational week. We also examined protein S and C4b-binding protein in the placenta by immunohistochemical staining at early (20th gestational week) and late (40th gestational week) stages of pregnancy. Plasma protein S activity and free protein S-antigen levels significantly decreased from the 10th gestational week and total protein S antigen decreased from the 20th. C4b-binding protein levels between pregnant and nonpregnant women did not significantly differ. The stainable portion of protein S was located at the fetomaternal interface, particularly at degenerative villi. C4b-binding protein was weakly stained at the same areas as protein S. Neither protein S nor C4b-binding protein were stained at normal villi. These results indicated that protein S can protect or restore damaged villi via a physiological effect in addition to its anticoagulation properties.

The purpose of this study was to investigate the effects of different methods of brushing on plaque removal, using O'Leary's plaque Control Record during initial preparation. The results were as follows: 1. There were many 40-50 year-old patients and they showed a 63.0 percent first visit Plaque Control Record average. 2. Many of the patients entering the clinic had periodontal disease in mild stages. 3. In most cases the toothbrushing methods were the Rolling method and the Modified Stillman's method. Of the patients, 73.5% achieved Plaque Control scores at the 20 percent level. 4. Of the patients who had achieved a Plaque Control Record at the 20 percent level, half of the patients instructed to brush using the Rolling method had developed moderate forms of periodontal diseases, and half of the patients instructed to use the Modified Stillman's method had developed mild forms of periodontal disease. There is a close relationship between toothbrushing methods and the progression of diseases, and this shows that Plaque removal methods should be controlled.

歯肉の形態に影響を及ぼす因子としての主要な臨床所見の症状に着目し, それぞれの所見との関連性を検索した。その結果, 様々な歯肉形態め出現率に, 臨床所見の症状である歯周ポケット, 歯槽骨の吸収, プラーク, 歯石, 不良修復物等が影響し, 歯周疾患と歯肉形態には密接な関係があることが示唆された。各検査項目間の相関性の検討においてもcleft form以外で有為な相関性が認められた。これらの関連性を把握することは, 治療計画, 治療方法, 予後の推測等において重要な役割を果たすものと考えられる。

本研究の目的は歯周病患者の臨床症状として, 欠かすことの出来ないX線写真による骨吸収に重点をおいて診査し, 同部位のポケットの状態, 炎症の程度, 歯の動揺度との関係と特徴をとらえるために統計的に検討した。その結果, (1) 上下顎中切歯部において骨吸収が多く見られるが, ポケットの深さは平均2.6mm前後であった。 (2) 上下顎第一大臼歯部では骨吸収量は中切歯部に比べ少ないが, ポケットは平均約3.0mmであった。 (3) 骨吸収量の増加に伴い, 動揺度の値も大きくなる傾向が見られた。 (4) 骨吸収量の大きい中切歯部において歯肉炎症指数 (GI) も高い結果であった。 (5) 骨吸収パターンは約8割が水平型で遠心側に, 約2割が垂直型で近心側に多く見られた。

Background: The histological changes in uterine blood vessels during pregnancy have been well investigated, but there have been few reports focusing on the changes in blood vessels during the involution process, especially within the first 24 h. We observed the process of uterine involution, focusing on the vessels of the resected uterus. Methods: Paraffin-embedded uterine samples from 15 patients who underwent hysterectomy because of severe cervical laceration and uterine rupture were examined. The time between delivery and hysterectomy ranged from 15 min to 456 h. The specimens were stained with hematoxylin-eosin, elastica-van Gieson and an antioxytocin receptor antibody. Results: Changes in the uterine vessels varied substantially based on their location. The intima in arteries of the endometrial side thickened within 5 h after delivery. On the serosal side, phlebosclerosis was demonstrated 6 weeks postpartum. Immunoreactivity for the oxytocin receptor (OTR) appeared in the muscular medias of arteries 5 h after delivery although it was not expressed before this period. Conclusion: Remodeling of uterine vessels involved thickening of the arterial intima and OTR expression in vessel walls during the first 5 h postpartum; the parameters normalized within 6 weeks. However, phlebosclerosis persisted for a long time on the serosal side.

Prostaglandin D2(PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP1or DP2receptors. We investigated the role of PGD2in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD2production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed inL-PGDSorDP2knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased inHPGDS–L-PGDSdouble knock-out orDP1knock-out mice. The PGD2level inL-PGDS,HPGDS, andHPGDS–L-PGDSknock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD2production. DP1receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation inHPGDS–L-PGDSknock-out mice. Endothelial cells were severely damaged inHPGDS–L-PGDSandDP1knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD2protected the neonatal brain from hypoxic-ischemic injury mainly via DP1receptors by preventing endothelial cell degeneration.

We report on a fetal autopsy case in which a congenital cervical immature teratoma was diagnosed. A 24-year-old Japanese woman had carried a male fetus that was aborted because of a cervical tumor at 20 weeks 5 days of gestation. The cervical tumor weighed 93 g and measured 7.5x5.5x5 cm. The soft tumor was encapsulated by a fibrous layer, was solid with small cysts on the cut surface, and showed a brain-like appearance. The tumor was composed of neoplastic cells derived from the three germ cell layers: ectoderm, mesoderm, and endoderm. The cells showed both immature and mature features. Small areas of thyroid tissue were detected in the cervical tumor. The left lobe of the thyroid gland was not observed, but the right lobe of the thyroid gland was present laterally between the trachea and the esophagus. Therefore, we concluded that the cervical tumor had arisen in the left lobe of the thyroid gland rather than from the soft tissue of the neck.

We describe a diastrophic dysplasia (DTDST) gene mutation in a Japanese male fetus with achondrogenesis type 1B and his relatives. Diagnosis in the fetus was based on roentgenographic data and pathological findings of bones and cartilage. Nucleotide sequencing of the DTDST gene demonstrated that the fetus was homozygous for both delVal340 and Thr689Ser and his parents and a healthy brother were heterozygous for the mutations. The former mutation was reported previously in patients with achondrogenesis type 1B, and the latter was detected in 5 alleles of 26 healthy Japanese individuals. These data suggest that delVal340 is associated with achondrogenesis type 1B in the Japanese, whereas a serine to threonine substitution is most likely polymorphic.

Background Pediatric surgeons often encounter neonates who present with Hirschsprung's disease (HD)–like symptoms and plain x-ray findings, but respond well to conservative treatment. During our investigation of the etiology of this condition, which we named “benign transient nonorganic ileus of neonates” (BTNIN), we noticed that BTNIN included cases of cow's milk allergy (CMA). Therefore, a prospective study of the identity of BTNIN and CMA was conducted. Methods Cow's milk allergy was diagnosed when a baby showed HD-like symptoms after oral feeding, and a drug-induced lymphocyte stimulation test was positive for cow's milk with a titer of more than 300%. Materials Of 38 neonates with suspected HD, a surgical disorder was excluded by plain x-ray in 9, intestinal atresia was diagnosed in 3, and the remaining 26 were enrolled in this study. Results Of 26 cases, 9 were diagnosed as HD by manometric studies and 17 as CMA. Thirteen of 17 CMA cases had been fed with breast milk and 4 with formula milk. Conclusion The proportion of CMA in the cases presenting with HD-like symptoms in the neonatal period is much higher than what we expected, and most cases of BTNIN are caused by CMA. If HD is ruled out, CMA should be considered.

To evaluate the efficacy of dexamethasone for reducing postoperative nausea and vomiting (PONV) and analgesic requirements after thyroidectomy.In a prospective, randomized, double-blind, placebo-controlled study, 75 patients, 20 men and 55 women, received intravenously placebo or dexamethasone at 2 different doses (4 and 8 mg) (n=25 of each) at the end of surgery. A standard general anesthetic technique was used. PONV and analgesic requirements were evaluated.The rate of patients experiencing PONV during the first 24 hours after anesthesia was 64% with dexamethasone 4 mg (P=0.269) and 28% with dexamethasone 8 mg (P=0.001), compared with placebo (76%). The need of indomethacin for intolerable pain was less in patients who had received dexamethasone 8 mg than in those who had received placebo (P=0.009).Dexamethasone 8 mg effectively decreases PONV and analgesic requirements after thyroidectomy.

Neonatal myocardial infarction is rare and its prognosis is poor. We describe the clinical course and autopsy findings of a newborn female with myocardial infarction. Her clinical course was rapidly progressive, becoming fatal before we could detect the cause. Autopsy demonstrated significant occlusion of the left coronary artery as well as evidence of new infarction, suggesting that the event occurred at birth. This case illustrates myocardial infarction as a possible cause of early neonatal death.

We describe the clinical course and autopsy findings of a female fetus with hydrops fetalis due to a huge pericardial rhabdomyoma. Fetal echocardiography at 21 weeks gestation demonstrated a huge tumor in the left ventricle. The fetus died of hydrops fetalis due to cardiac dysfunction at 24 weeks gestation. Autopsy demonstrated that the tumor protruded from the epicardial region of the apex into the pericardial cavity and induced a hypoplastic left ventricle and lung. Microscopically, the cardiac tumor showed characteristics of rhabdomyoma. This localization of cardiac rhabdomyoma is rare, but we remain aware of the possibility of an unusual and rapid progression of cardiac rhabdomyoma.

Beckwith-Wiedemann syndrome (BWS) is characterized by numerous growth abnormalities and an increased risk of childhood tumors. The gene for BWS is localized in the 11p15.5 region, as determined by linkage analysis of autosomal dominant pedigrees. The increased maternal transmission pattern seen in the autosomal dominant-type pedigrees and the findings of paternal uniparental disomy reported for a subgroup of patients indicate that the gene for BWS is imprinted. Previously, we found p57KIP2, which is a Cdk-kinase inhibitor located at 11p15, is mutated in two BWS patients. Here, we screened for the mutation of the gene in 15 BWS patients.

We report on a fetus with a congenital pulmonary myofibroblastic tumor, the prenatal detection of which with imaging modalities has not been reported up until now. A 32-year-old woman was referred to our hospital at 29 weeks' gestation because of severe fetal hydrops. Sonograms and magnetic resonance imaging showed a large solid tumor in the left thorax. The fetus died in utero the next day. Autopsy confirmed that the tumor was confined to the lower lobe of the left lung, and circulatory insufficiency from compression by the tumor was considered to be the cause of fetal hydrops and demise. Histologic examination revealed that the tumor was composed of uniform short spindle cells with no atypia and a large number of vessels. In addition, with immunohistochemical studies, the tumor cells were stained for calponin but not for cluster differentiation (CD)-31, CD-34, alpha-smooth muscle actin or S-100.

The authors present a neonatal case of allergic colitis, which manifested the difficulty of spontaneous defecation and irregular narrowing of distal rectum in contrast enema. Rectal suction biopsy showed positive acetylcholinesterase activity. These clinical, radiological and histological findings were indistinguishable from Hirschsprung’s disease. Gastrointestinal symptoms were improved by the cessation of cow’s milk formula. The present findings may impact on the less recognizable gastrointestinal manifestation of allergic colitis.

Injection pain is a well-known adverse effect of propofol which distresses patients. Lidocaine pretreatment is the most popular method for reducing this pain but this drug cannot entirely eliminate the problem. The purpose of this study was to examine the analgesic effect of lidocaine/metoclopramide combination, compared with lidocaine alone, during propofol injection.In a randomized, double-blind, placebo-controlled trial, 90 patients, 40 males and 50 females, scheduled for elective plastic surgery received either lidocaine 20 mg plus metoclopramide 10 mg iv, lidocaine 20 mg iv, or placebo (saline); (n = 30 in each), with venous occlusion for one minute, followed by administration of propofol 0.5 mg.kg(-1) into a dorsal hand vein. Pain was assessed on a four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) during propofol injection.25 patients (83%) complained of pain in the placebo group, compared with 12 (40%) in the lidocaine group (P0.05) and three (10%) in the combination group (P0.05). Pain score (median) was less in the lidocaine (0) and combination (0) groups than in the placebo group (2); (P0.05). The difference in the incidence of pain between the combination and lidocaine groups was significant (P0.05).A lidocaine/metoclopramide combination is more effective than lidocaine alone for reducing pain on injection of propofol in a peripheral vein.