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Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

The elemental composition of a single yeast, green alga, or red blood cell (RBC) was precisely determined by using inductively coupled plasma-mass spectrometry (ICP-MS) operating in fast time-resolved analysis (TRA) mode. The technique is known as single-cell (SC)-ICP-MS. Phosphorus, sulfur, magnesium, zinc, and iron were detected in the three types of cell. The elemental composition of yeast and green alga obtained by SC-ICP-MS was consistent with results obtained from conventional ICP-MS measurements following acid digestion of the cells. Slight differences were found in the measured values between SC-ICP-MS and the conventional ICP-MS results for RBC. However, the SC-ICP-MS results for S and Fe in RBC were closer to the estimated values for these elements that were calculated from the level of hemoglobin in RBCs. The data suggest that SC-ICP-MS is suitable for the analysis of various cell types, namely, fungus, plant, and animal cells.

Background: A fast and sensitive method for the simultaneous analysis of iodine and bromine species in infant formula was developed using HPLC–inductively coupled plasma–MS (HPLC-ICP-MS). Method: To determine the four halogen species [iodide (I−), iodate (IO3−), bromide (Br−), and bromate (BrO3−)] in a milk-based Standard Reference Material and four commercially available infant formula products. Results: The four halogen species were baseline separated in less than 6.5 min using an anion exchange resin column and 5.0 mM NaH2PO4 / 15.0 mM Na2SO4 / 5.0 mM EDTA (pH 7.0) mobile phase. Following separation, the halogen species were detected by measuring m/z 79 for Br and m/z 127 for I using a triple quadrupole–ICP-MS. The instrument was operated in single quadrupole mode with helium cell gas. Excellent linearity (R = 0.9999 or better) was obtained for all four species with calibration standards ranging from 0 to 100 ppb. The LOD for I−, IO3−, Br−, and BrO3− were all less than 0.67 μg/kg. To test the suitability of the method for the accurate determination of low concentrations of the four species in infant formula samples, a spike recovery test was carried out at 20 and 40 μg/kg into the diluted infant formula samples. Conclusions: Total elemental determinations of iodine and bromine were also performed using the triple quadrupole–ICP-MS without HPLC.

To investigate the pregnancy outcome of the fetuses with trisomy 18, we studied 123 cases of trisomy 18 who were born at our hospital from 1993 to 2009. Among them, 95.9% were diagnosed with trisomy 18 prenatally. Prenatal ultrasound findings showed fetal growth restriction in 77.2%, polyhydramnios in 63.4% and congenital heart defects in 95.1%. For 18 cases, cesarean section (C-section) was chosen, and for 75 cases, transvaginal delivery was chosen. Premature delivery occurred in 35.5%. Stillbirths occurred in 50 cases (40.7%). Fetal demise before onset of labor occurred in 30 cases and fetal demise during labor occurred in 20 cases which was 26.7% of vaginal deliveries. Among the 73 live-born infants, the survival rate for 24 h, 1 week, 1 month and 1 year were 63%, 43%, 33% and 3%. The median survival time was 3.5 days. There was no significant difference between the survival time of C-section and that of vaginal delivery. However, for the births involving breech presentation, the survival time of C-section was significantly longer than that of vaginal delivery. When the fetus is diagnosed with trisomy 18, the parents have to make many choices. These findings constitute critical information in prenatal counseling to the couples whose fetuses have been found to have trisomy 18, especially when they choose palliative approaches in the perinatal management.

Background Delay of umbilical cord clamping by at least 1 min is recommended for newborns not requiring resuscitation in the International Liaison Committee On Resuscitation–Consensus on Science with Treatment Recommendations (ILCOR-CoSTR) 2010 guidelines. The delay in clamping improves iron status through early infancy but may increase the likelihood of jaundice requiring phototherapy. The present study investigated the relationship between umbilical cord hemoglobin and the rate of jaundice requiring phototherapy in healthy Japanese newborns. Methods Cord hemoglobin was measured in healthy newborns and the rate of infants receiving phototherapy for jaundice and other data were obtained from medical records. Results Jaundice requiring phototherapy mostly occurred in association with high cord blood hemoglobin, which is increased by delayed cord clamping. Conclusions Higher cord hemoglobin may increase neonatal jaundice in newborns in Japan, therefore the present results support the Japan Resuscitation Council guideline 2010, which does not recommend delay of umbilical cord clamping by at least 1 min, in contrast to the ILCOR guidelines.

Familial congenital diaphragmatic hernia (CDH) is extremely rare; it comprises about 2% of all CDH cases. The empirical risk is about 2%, increasing to 10% in a family with two affected children. This report describes severe CDH in two siblings who had been diagnosed prenatally. The female newborn diagnosed with left CDH prenatally was born at 38 weeks of gestation. Despite surgical repair and intensive treatment, she died 10 days after birth. Her younger brother was born at 39 weeks of gestation after being diagnosed with bilateral CDH prenatally, and died 75 min after birth. Both infants had neither other congenital anomaly nor chromosomal abnormalities. Their parents are healthy without consanguinity. Their first daughter and the fourth child have no congenital anomalies.

Although recent studies in patients with paternal uniparental disomy 14 [upd(14)pat] and other conditions affecting the chromosome 14q32.2 imprinted region have successfully identified underlying epigenetic factors involved in the development of upd(14)pat phenotype, several matters, including regulatory mechanism(s) for RTL1 expression, imprinting status of DIO3 and placental histological characteristics, remain to be elucidated. We therefore performed molecular studies using fresh placental samples from two patients with upd(14)pat. We observed that RTL1 expression level was about five times higher in the placental samples of the two patients than in control placental samples, whereas DIO3 expression level was similar between the placental samples of the two patients and the control placental samples. We next performed histological studies using the above fresh placental samples and formalin-fixed and paraffin-embedded placental samples obtained from a patient with a maternally derived microdeletion involving DLK1, the-IG-DMR, the MEG3-DMR and MEG3. Terminal villi were associated with swollen vascular endothelial cells and hypertrophic pericytes, together with narrowed capillary lumens. DLK1, RTL1 and DIO3 proteins were specifically identified in vascular endothelial cells and pericytes, and the degree of protein staining was well correlated with the expression dosage of corresponding genes. These results suggest that RTL1as-encoded microRNA functions as a repressor of RTL1 expression, and argue against DIO3 being a paternally expressed gene. Furthermore, it is inferred that DLK1, DIO3 and, specially, RTL1 proteins, play a pivotal role in the development of vascular endothelial cells and pericytes.

Down syndrome is an autosomal chromosome disorder, characterized by intellectual disability and muscle hypotonia. Muscle hypotonia is observed from neonates to adulthood in Down syndrome patients, but muscle hypertonicity is extremely unusual in this syndrome. During a study period of nine years, we found three patients with severe spastic quadriplegia among 20 cases with Down syndrome and congenital duodenal stenosis/atresia (3/20). However, we could find no patient with spastic quadriplegia among 644 cases with Down syndrome without congenital duodenal stenosis/atresia during the same period (0/644, P

We report a female fetus with sirenomelia with 46,X,t(X;16)(p11.23;p12.3) de novo. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes were employed for narrowing down the breakpoint regions. On chromosome 16, the breakpoint was mapped in the region of RP11-453F10 (19 920 640-20 118 153 bp from 16pter). On chromosome X, the breakpoint was mapped in the region of RP11-794A15 (47 333 744-47 524 066 bp from Xpter). This is the first case report of sirenomelia associated with translocations. The abnormal phenotype, associated with a balanced translocation, was caused by deletion or breakage of dosage-sensitive genes of the breakpoint, disruption of an imprinted gene, or uniparental disomy. Although the parental origin of normal 16 and der(16) remained undetermined, this case will provide insight into the pathogenetic mechanism of sirenomelia.

Introduction: Unlike gastroschisis, congenital omphalocele is often associated with other anomalies and is frequently complicated by polyhydramnios. We examined the relationships between polyhydramnios, pregnancy outcome and fetal prognosis.Patients and Methods: Clinical data from cases diagnosed antenatally with congenital omphalocele from 1993 to 2006 were analyzed retrospectively. Results: Fifty-two cases were diagnosed antenatally with congenital omphalocele, and 38 of these pregnancies resulted in delivered infants. Of these 38 pregnancies, 55.3% were preterm births before 37 weeks of gestation. The mean birth weight was 2,148 g (n = 38). Associated anomalies were recognized in 29 cases (76.3%), including 13 cases (34.2%) of chromosomal aberrations. There were 2 cases of trisomy 13, 10 cases of trisomy 18 and 1 case of trisomy 21. Polyhydramnios was detected in 14 cases (36.8%), and other anomalies were present in all of these cases. Discussion: For antenatal evaluation in cases of congenital omphalocele, it is important to examine the fetus for associated anomalies or underlying disease, especially when polyhydramnios is detected.

Aim: We examined birth-related malpractice civil litigation cases in Japan to clarify the actual status related to the implementation of an obstetrical no-fault compensation system in 2009. Material & Methods: In this retrospective review, we analyzed legal and medical information from 64 cases with a delivery date after 1987 and a judgment date between April 1997 and March 2007. Results: The malpractice claim was accepted in 44 cases and rejected in 20 cases. The period from the delivery to the judgment date was lengthy (90.1 months overall). The average amount of damages awarded was ¥97 810 000 for cases of cerebral palsy (CP). Preterm births and less than 2500 g infants represented a higher incidence rate in the rejected cases. There were 32 cases (50.0%) with CP, 18 (28.1%) with infant death, 10 (15.6%) with neonatal death, and 4 (6.3%) with fetal death. Twenty-three of 44 accepted cases (52.3%) and 11/20 rejected cases (55.0%) had a gestational age of more than 33 weeks at birth and weighed more than 2000 g. Forced deliveries were performed in 45/64 cases (70.3%), and augmentation/induction of labor was performed in 28/64 cases (43.8%). There were 13/16 (81.3%) accepted cases that underwent vacuum and/or forceps extraction after labor augmentation/induction. Conclusions: More than half of our cases could be sufficient for a no-fault compensation system in Japan. Though the system is considered to have some problems that need to be solved, this finding suggests that many children and their families may benefit from the new system without having to file.

To evaluate whether the routinely collected data in birth defect registries could be used to assess association between medications and risk for congenital anomalies an "exposed case-only" design was performed.Twelve registries provided 18,131 cases exposed to a medication during the first trimester of pregnancy and with at least one major malformation. Odds ratios for malformations associated with maternal use of selected medications were computed.Among seven most commonly used medications very few significant associations with malformations were identified. Among fourteen potentially teratogenic medications several strong associations were found, including valproic acid with spina bifida, and insulin (as proxy for diabetes) with several types of cardiac defects.Finding known associations provides assurance on the validity of this approach, whereas identifying new associations provides a signal to be followed by confirmatory studies. Through this activity, international networks of birth defect registries can contribute with limited resources to post-marketing surveillance of the teratogenicity of medications. (C) 2010 Elsevier Inc. All rights reserved.

Aim: This study of pregnant women was undertaken to clarify their immune status for rubella and to evaluate the efficacy of, and adverse reaction to, post-partum rubella vaccination. Methods: We determined the levels of both rubella antibody by hemagglutination inhibition test and IgM antibody by enzyme-linked immunosorbent assay in the first gestational trimester and surveyed the positive rates for rubella antibody in pregnant women at our perinatal center; we recommended post-partum vaccination for women with poor immune status. We also evaluated the effectiveness of the vaccine and any adverse reaction. Results: Among 2741 pregnant women, 185 cases (6.7%) were seronegative for rubella virus. This rate was especially high (12.4%) in the population who had opted out of the vaccination because of a change in Japanese government policy. A total of 30 cases (1.1%) were positive or false-positive for IgM antibody, but no congenital rubella syndrome (CRS) developed. The seropositive rate was 93.3% in total, but this figure includes those who required post-partum vaccination (558 cases or 20.3%) because their titers were 16× or lower. Among 145 cases who received post-partum rubella vaccine, no severe adverse reaction was detected, and in all 37 cases with hemagglutination inhibition antibody titers of 8× or lower, the efficacy rate was 100%. Conclusions: It is necessary to appropriately evaluate the CRS risk. Also, we need to emphasize the importance and safety of post-partum rubella vaccination in Japan.

Introduction: Fetus-in-fetu is a rare congenital fetiform mass whose etiology is still controversial. We report two cases of fetus-in-fetu. Case 1: A fetal retroperitoneal cystic tumor including two masses was detected by ultrasonography at 26 gestational weeks. The masses showed distinctive structures resembling a vertebral axis and were prenatally diagnosed as fetus-in-fetu. A resected specimen revealed two fetiform masses. Case 2: An intracranial tumor with hydrocephalus was detected by ultrasonography at 19 gestational weeks. The pregnancy was terminated, and a postmortem examination revealed six fetiform masses with immature teratoma. Discussion: The tumors may possibly consist of parasitic monozygotic diamniotic twins or highly differentiated teratomas.

Objective: To evaluate the risk of recurrence of fetal chromosomal aberrations in women who had offspring with numeric chromosomal abnormalities. Subjects and Methods: This collaborative study consisted of 1,076 Japanese women with a history of offspring with trisomy-21, -18, -13, or 45,X. Second-trimester amniocenteses were performed, resulting in 1,248 fetal karyotypes that were analyzed with reference to prior offspring karyotypes and maternal age. Results: Of the 842 women with trisomy-21 offspring, 10 conceived another such fetus. In 2 women with 3 or more such offspring, parental mosaicism of trisomy-21 was suspected. The incidence of recurrence of trisomy-21 increased with age, and significantly exceeded the incidence of trisomy-21 fetuses in the general population. None of the 170 women with trisomy-18 offspring, and none of the 46 women with trisomy-13 offspring, had another such fetus. Of the 18 women with 45, X offspring, 1 with mos 45, X/46, XX had another such fetus. Conclusions: The risk of recurrence of trisomy-21 is affected by maternal age and parental germline mosaicism. The risk of recurrence of trisomy-18 or -13 appears to be much lower than that of trisomy-21. Women who give birth to more than 1 offspring with 45, X should be examined for mos 45, X/46, XX.

Trace metals in sea-water were determined by ion chromatography (IC)–inductively coupled plasma mass spectrometry (ICP-MS). A nitrilotriacetate (NTA)-type chelating resin was applied to the separation and enrichment of the analyte metal ions. Transition metals and rare earth elements except Mn were retained on the NTA resin column whereas alkali and alkaline earth metals were eluted from the column by elution with 0.5 mM nitric acid. The NTA resin can simplify the procedure for matrix elimination and enrichment of analyte metals since mineral acids can be used as eluents. A linear calibration and repeatability of the signal intensity of ICP-MS were obtained in the determination of trace metals at the

Familial congenital diaphragmatic hernia (CDH) is extremely rare; it comprises about 2% of all CDH cases. The empirical risk is about 2%, increasing to 10% in a family with two affected children. This report describes severe CDH in two siblings who had been diagnosed prenatally. The female newborn diagnosed with left CDH prenatally was born at 38 weeks of gestation. Despite surgical repair and intensive treatment, she died 10 days after birth. Her younger brother was born at 39 weeks of gestation after being diagnosed with bilateral CDH prenatally, and died 75 min after birth. Both infants had neither other congenital anomaly nor chromosomal abnormalities. Their parents are healthy without consanguinity. Their first daughter and the fourth child have no congenital anomalies.

A 29-year-old primigravida developed polyhydramnios at 24 weeks of gestation, requiring six serial amnioreductions. In addition, prenatal ultrasound examinations revealed a fetus with small stomach pouch, small thorax, slightly shortened limbs, and skin edema; paternal uniparental disomy 14(upd(14)pat) phenotype was suspected. At 37 weeks, the patient delivered a 2558 g female infant with characteristic facial features, webbed neck, thoracic deformity, abdominal wall defect, skin edema, overlapping fingers, placentomegaly, and small thorax with 'coat-hanger' appearance of the ribs on chest X-ray. A phenotype consistent with upd(14)pat was confirmed by DNA analysis. Although the infant's condition was initially stable, hepatoblastoma was subsequently detected and right hepatectomy was performed on day 224. On day 382, the infant was discharged with in-home respiratory management.

We report a female fetus with sirenomelia with 46,X,t(X;16)(p11.23;p12.3) de novo. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes were employed for narrowing down the breakpoint regions. On chromosome 16, the breakpoint was mapped in the region of RP11-453F10 (19 920 640-20 118 153 bp from 16pter). On chromosome X, the breakpoint was mapped in the region of RP11-794A15 (47 333 744-47 524 066 bp from Xpter). This is the first case report of sirenomelia associated with translocations. The abnormal phenotype, associated with a balanced translocation, was caused by deletion or breakage of dosage-sensitive genes of the breakpoint, disruption of an imprinted gene, or uniparental disomy. Although the parental origin of normal 16 and der(16) remained undetermined, this case will provide insight into the pathogenetic mechanism of sirenomelia.

Down syndrome is an autosomal chromosome disorder, characterized by intellectual disability and muscle hypotonia. Muscle hypotonia is observed from neonates to adulthood in Down syndrome patients, but muscle hypertonicity is extremely unusual in this syndrome. During a study period of nine years, we found three patients with severe spastic quadriplegia among 20 cases with Down syndrome and congenital duodenal stenosis/atresia (3/20). However, we could find no patient with spastic quadriplegia among 644 cases with Down syndrome without congenital duodenal stenosis/atresia during the same period (0/644, P 0.05). Further, we did not find any cases with spastic quadriplegia among 17 patients with congenital duodenal stenosis/atresia without Down syndrome admitted during the same period to use as a control group (0/17, P 0.05). Our results suggest that congenital duodenal stenosis/atresia is a potential risk factor for spastic quadriplegia in patients with Down syndrome. Long-term survival is improving, and the large majority of people with Down syndrome are expected to live well into adult life. Management and further study for the various problems, representing a low prevalence but serious and specific to patients with Down syndrome, are required to improve their quality of life.

We examined birth-related malpractice civil litigation cases in Japan to clarify the actual status related to the implementation of an obstetrical no-fault compensation system in 2009.In this retrospective review, we analyzed legal and medical information from 64 cases with a delivery date after 1987 and a judgment date between April 1997 and March 2007.The malpractice claim was accepted in 44 cases and rejected in 20 cases. The period from the delivery to the judgment date was lengthy (90.1 months overall). The average amount of damages awarded was yen97 810,000 for cases of cerebral palsy (CP). Preterm births and less than 2500 g infants represented a higher incidence rate in the rejected cases. There were 32 cases (50.0%) with CP, 18 (28.1%) with infant death, 10 (15.6%) with neonatal death, and 4 (6.3%) with fetal death. Twenty-three of 44 accepted cases (52.3%) and 11/20 rejected cases (55.0%) had a gestational age of more than 33 weeks at birth and weighed more than 2000 g. Forced deliveries were performed in 45/64 cases (70.3%), and augmentation/induction of labor was performed in 28/64 cases (43.8%). There were 13/16 (81.3%) accepted cases that underwent vacuum and/or forceps extraction after labor augmentation/induction.More than half of our cases could be sufficient for a no-fault compensation system in Japan. Though the system is considered to have some problems that need to be solved, this finding suggests that many children and their families may benefit from the new system without having to file.