bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphogenetic process of dysraphic malformations induced by thalidomide in JW‐NIBS rabbits
Authors: MIKAMI Takashi , MATSUBARA Yoshio 
Published: May 2008

Abstract: Our previous study demonstrated thalidomide‐induced anencephaly and holoprocencephaly at a high frequency in JW‐NIBS rabbits. In order to know the early morphogenetic process of these two malformations, thalidomide was orally given to pregnant JW‐NIBS rabbits on day 7 or on days 6–9 of gestation, and the embryos were examined on days 9–13 in histological sections and scanning electronmicroscopic specimens.The preponderant site of thalidomide‐induced dysraphic change was the midfrontal portion of the prosencephalic vesicle. A widely opened cephalic neural tube at this portion and consequent eversion of the telencephalic wall observed in day‐9‐embryos (231 hours postcoitus) was the first change of most anencephaly in this experiment. Incomplete closure of the cephalic neural tube under the closed surface ectoderm observed at the midfrontal portion of day‐9‐embryos was divided into two types: One type showed a contact of the neural folds but no histological continuation, and the other type evidenced a degeneration of the neuroepithelial tissue at the closing site and hypoplasia of the surrounding mesenchymal tissue. The mesenchymal tissue over the neuroepithelial layer showed curled cellular processes and a loose interconnection in scanning electronmicroscopic specimens. The midfrontal encephalocele observed in day‐13‐embryos could be regarded as the consequence of the former type of incomplete closure. Defective formation of the longitudinal fissure of the telencephalon due to the midfrontal encephalocele was the cause of holoprosencephaly later. Not only unclosure of the neural tube but also the latter type of incomplete closure was considered to manifest anencephaly.
Effects of Pyrimethamine and Folic Acid on Plasma Level of 5‐Methyltetrahydrofolic Acid in Rats
Authors: TSUNEMATSU Kunitoshi , KUDO Gen , SHIMODA Minoru , KOKUE Eiichi , HAYAMA Toyoaki 
Published: May 2008

Abstract: The relationship between pyrimethamine (PYR) teratogenesis and the plasma level of 5‐methyltetrahydrofolic acid (5MF), known as an active form of folate in plasma, was studied in rats using an HPLC‐ECD method for 5MF determination. The rat received, for 5 days, in‐feed PYR with or without folic acid (FA), which was previously reported as a potentiator of PYR teratogenesis. PYR alone caused a dose‐dependent decrease in the plasma 5MF level after the 5 day dosings. A potentiated decrease in the 5MF level was observed after the concomitant dosing of PYR with FA. The concomitant dosing of PYR 1.6 mg/kgBW/day (subteratogenic dose of PYR alone) with FA 50 mg/kg/day, which was 100% teratogenic dose in our previous report, decreased the 5MF level more than that after the dosing of PYR 3.6 mg/kg/day alone (100% teratogenic dose of PYR alone).The sequential changes of the plasma 5MF level after the single oral dosing of PYR 3.6 mg/kg with or without oral FA 50 mg/kg also revealed a strong potentiative effect of oral FA on the 5MF‐level‐lowering effect of PYR. These results indicate that a decrease in the plasma 5MF level may be related to PYR teratogenesis.
Participation of Neural Crest Cells in Cardiovascular Morphogenesis of Chick Embryos
Authors: HAYAKAWA Kunio , OKISHIMA Takahiro , TAKAMURA Kazushi , OHDO Shozo 
Published: May 2008

AbstractNeural crest cells appear on top of the neural folds at closure of the neural tube. These cells are capable of migrating and differentiating into multiple tissues. In 1983, Kirby et al., using chimera methodology, reported that cranial neural crest cells participated in aorticopulmonary and truncal septation. Since that time, many experimental studies have been done in this field. In this paper, we report new experimental findings and review four areas of study on neural crest cells, i.e. their general characteristics, participation of neural crest cells in formation of the normal heart, cardiovascular anomalies due to ablation of the neural crest cells, and the relationship between neural crest cells and congenital malformation syndromes, especially the DiGeorge sequence.
Morphological Analysis of Neural Tube Defects in Non‐obese Diabetic (NOD) Mouse Embryos
Authors: ANDO Seiichi , OTANI Hiroki , TANAKA Osamu , MORITAKE Kouzo 
Published: May 2008

AbstractNeural tube defects (NTDs) were demonstrated to occur at a high rate (29.4%) in non‐obese diabetic (NOD) mouse embryos on day 13 of gestation. Macro‐scopically, three different forms of NTDs were observed: the combined form of exen‐cephaly and myeloschisis, the pure form of exencephaly, and that of myeloschisis. The neural walls of the open tube were everted bilaterally. It was microscopically demonstrated that NTDs were composed of not only the everted neural walls but also voluminous mesenchymal tissue adjacent to the everted neural walls. The everted neural wall had three‐layered structure made up of outer, intermediate, and inner zones. The morphological findings of the intermediate and inner zones were similar to those of mantle and marginal layers in the normally closed neural tube. However, the outer zone, which corresponded to the ependymal layer in the normal neural tube, had characteristic findings. Namely, the cells were small, round and uniform in shape. Almost no mitotic figures were observed in this zone, and electron microscopic investigation revealed few cytoplasmic organelles. Of 9 NOD mouse embryos with NTDs, 2 exhibited duplicated notochords. In one of these two embryos, an aberrant tubal structure was formed of neural tissue. The plausible causes of NTDs in NOD mouse embryos were discussed based on these findings.
Delayed Maturation of Fetal Lung in Yellow KK Mice
Authors: OOSHIMA Yojiro , SHIOTA Kohei , IHARA Toshio 
Published: May 2008

AbstractYellow KK mice have the Ay allele and spontaneously develop non‐insulin dependent diabetes mellitus (NIDDM). In the present study, female yellow KK mice were mated at 7 or 13 weeks of age (the average blood glucose levels were ca. 260 and 500 mg/dl, respectively), and their fetuses were examined on days 18 or 19 of gestation.The fetuses from 13‐wk‐old dams were smaller than those from 7‐wk‐old dams. The average lung weight on day 19 of gestation was slightly greater in the fetuses from 13‐wk‐old dams than in those from 7‐wk‐old dams (23.3 vs 21.2 mg). Histologically, alveolar spaces were smaller and alveolar walls were thicker in the fetuses from 13‐wk‐old dams than in those from 7‐wk‐old dams. Morphometric analysis revealed that the percentage area of the fetal lung occupied by alveolar spaces was significantly smaller in the former fetuses than in the latter.Day‐15 fetal lungs of KK mice, which do not have the Ay allele, were cultured in hyperglycemic media (glucose levels: 400 and 700 mg/dl) for 48 hr. The development of alveoli was inhibited in hyperglycemic media as compared to the development of the lungs grown in the control medium. The inhibitory effect was dependent on the glucose concentration in the media.Thus, it seems that maternal hyperglycemia itself is a major cause of the delayed maturation of the fetal lung in NIDDM mice.
Induction of Cardiovascular Malformations by Leupeptin in the Rat
Authors: MIYATA Koichiro , KODAMA Akihiko , CHEN Shen‐Fang , TACHIKURA Toshio , OKU Shozo , YAMASAKI Takatoshi , NAKAMURA Makoto 
Published: May 2008

AbstractThe teratogenic effects of leupeptin on the rat embryonic heart were examined. Wistar rats were injected with 30mg/kg of leupeptin, 50mg/kg of leupeptin, and 2.5ml/kg of normal saline (control group) on days 9 and 10 of gestation. Term fetal weight was significantly lower in the leupeptin groups than in controls. At leupeptin 30mg/kg, the resorption rate, incidence of malformation, and incidence of cardiovascular (CV) malformation were 13.2%, 34.8%, 16.7%, respectively. At leupeptin 50 mg/kg, the resorption rate, incidence of malformation, and incidence of CV malformation were 19.7%, 81.4%, 36.3%, respectively. The most common malformations were hydrocephaly, anophthalmia, microphthalmia, VSD, ASD, hydronephrosis, and diaphragmatic hernia. Multiple organ systems were affected. Malformation types were similar to those induced by anti‐kidney antiserum (AKS) and trypan blue (TB).
Ultrastructure of the Adenohypophysis in a Case of Cyclopia
Authors: SUMIDA Hiroshi , AKIMOTO Naotaka , INOUE Naohiko , SATOW Yukio 
Published: May 2008

AbstractThe adenohypophysis of a newborn with cyclopia was examined by electron microscopy. The hypophysis was normal in size and shape in the present case. Electron microscopy, however, showed degenerating cells in the adenohypophysis. These cells had small number of granules and cytoplasmic organelles, and the concentric membranous structure, but were not considered as necrotic cells. These findings may indicate overproduction of hormones by the damage of the negative feedback system. No remarkable change, however, was observed in the endocrine organs by light microscopy. Thus, the possible disorder of the hormone production might not be severe enough to cause abnormal formation of the endocrine system in the present case.
Spontaneous Intrauterine Repairment of Cleft Palate Induced by Amniocentesis in Rats
Authors: MOHANTY Chhandamayee , SINGH Gajendra , DAS Braja Kishore 
Published: May 2008

AbstractOn day 15 of gestation, 180 fetal sacs in 43 pregnant Charles Foster rats were subjected to amniocentesis producing a series of total or partial clefts in the hard and soft palate regions. Fetuses recovered on days 19, 20 or 21 showed a gradual decline in the incidence of total clefts with increasing gestational age, i.e. 34% on day 19, 29% on day 20 and 13% on day 21, suggesting spontaneous ‘repairment’ of the clefts induced by amniotic sac puncture. Prenatal ‘repairment’ at times leaving residual partial clefts in the hard palate, suggested delayed rotation of the palatine shelves following reaccumulation of lost quantity of amniotic fluid and withdrawal of tongue obstruction. The experiment suggested that the palatine shelves retain intrinsic ‘shelf force’ for a much longer period than thought earlier. However, a gradual increase in the incidence of residual partial cleft with increasing gestational age, i.e. 45% on day 19; 50% on day 20 and 67% on day 21, respectively, suggests only incomplete (partial) repair in most of the cases probably due to paucity of time.
Sodium Valproate‐lnduced Cardiovascular Abnormalities in the JchlCR Mouse Fetus
Authors: SONODA Tohru , OHDO Shozo , OHBA Ken‐ichi , OKISHIMA Takahiro , HAYAKAWA Kunio 
Published: May 2008

AbstractSodium valproate was administered to Jcl:ICR mice in order to evaluate teratogenicity in the cardiovascular system. A single dose of 600mg/kg of sodium valproate was injected intraperitoneally on gestational day 6, 7, 8 or 9. On day 18 of gestation, dams were laparotomized to observe incidence and type of cardiovascular abnormality in live fetuses. Cardiovascular abnormalities were found most frequently in the group treated on day 7, being recognized in 86% of litters (19/22) and in 29% of live fetuses (70/238). Among these, there were 28 cases of transposition of the great arteries, 13 of double outlet right ventricle, 11 of endocardial cushion defect, 9 of ventricular septal defect, 5 of tricuspid atresia, and 4 of hypoplastic left heart syndrome.
Pathogenesis of Experimental Lumbosacral Agenesis in Rats
Authors: Taniuchi Mikihiro , Nakata Katsuji , Onomura Toshinobu 
Published: May 2008

Abstract Pathogenesis of lumbosacral agenesis following trypan blue treatment was studied in rats. Pregnant rats (on day 8 of pregnancy) were intraperitoneally injected with 2% trypan blue (40 mg/kg), and the fetuses at various stages of gestation were submitted to morphological examination. Every fetuses were observed under a stereoscopic microscope, and serial sections of the lumbosacral region were made for light microscopy. Fetal growth was classified into 6 stages based on the fetal posture and the development of neutral tube. At Stage 2 (corresponding to gestational age of 237 ± 6 hours) and at later stages, a cystic change was found stereoscopically on the dorsal side of the tail end in 23–33% of the fetuses. The cyst was unilocular or multilocular and was seen on one side or both sides of neural groove. After Stage 3 (240 ± 6 hours), the cysts were enlarged. At Stage 5 (252 ± 6 hours), cysts were various in shape and size. The initial histological lesion induced by trypan blue was edematous splitting of the intercellular spaces in the mesoderm and resultant cyst formation. After Stage 3, cysts in the mesoderm pushed the neural epithelium towards the back and caused deformation of the neural groove. After day 13, characteristic changes of lumbosacral agenesis, such as tail defect, short tail, and hind leg deformation, were observed in 20–30% of the fetuses. At day 21, lumbosacral agenesis was recognized on soft X‐ray films. The site and incidence of lumbosacral agenesis corresponded with those of cyst formation in an early gestation period.The present experiment showed that the cystic change in the mesoderm is the early and primary histological lesion of trypan blue‐induced lumbosacral agenesis, and that alteration of the neural tube is secondary to the cystic change of the mesoderm.
Analysis of Cardiac Loop Formation in Avian Embryos with Spontaneous Heart Malformations
Authors: NAKAMURA Harukazu , ITASAKI Nobue 
Published: May 2008

Abstract Embryos with heart tube malformations on the 2nd and 3rd day of incubation were selected to support the hypothesis that the heart tube rotates and bends to the right due to the stronger tension generated on the right side of the heart primordium than that on the left side.In 4 embryos, lateral endothelial heart tubes did not fuse at the midline, and each heart tube looped independently. It is suggested that each lateral heart tube generates tension, and can bend to its own side. In 8 conjoined twins in which 2 embryos shared a head and each embryo extended in opposite directions, lateral endothelial heart tubes did not fuse within the embryo on the ventral side, but fused between the sister embryos lateral to the embryos. Such heart tubes bent to the left. Since the heart tubes fused between the sister embryos, the heart primordium on the right side for each embryo occupied the left side of the fused heart tube. Thus in this case our hypothesis that the right‐side‐derived heart tube generates stronger tension for bending is valid. Heart tubes of 5 other parallel twins also supported our hypothesis.
A New in Vitro Screening Method for Teratogens Using Human Embryonic Palatal Mesenchymal Cells
Authors: NITO Shinji , ARIYUKI Fumio , NAKAYAMA Yoshio 
Published: May 2008

Abstract In order to establish an in vitro screening assay system for cleft palate‐inducing teratogens, we tested 31 teratogenic and 10 tionteratogenic compounds using human embryonic cultured cells. We examined whether cleft palate‐inducing ability can be detected by differential growth inhibition between human embryonic palatal mesenchymal (HEPM) cells and human embryonic fibroblasts (MRC‐5). Thirty one compounds with proven cleft palate‐inductive effects in vivo preferentially inhibited the proliferation of HEPM cells. The average of the relative resistant rates (rate of IC50 value for HEPM cells to MRC‐5 cells) of teratogens was 0.53. In contrast, almost all nonterato‐gens identically inhibited the proliferation of both cell lines and the average of the relative resistant rates was 1.01. These results show that teratogens which induce cleft palate in vivo preferentially inhibit the proliferation of embryonic palatal mesenchymal cells.The data indicated that in vitro screening using HEPM and MRC‐5 cells is useful for detecting the cleft palate‐inducing ability of chemicals.
Prenatal Diagnosis of Duchenne Muscular Dystrophy (DMD) by the Polymerase Chain Reaction (PCR)
Authors: HAYASHI Kazuhiko , NOSAKA Keisuke , TAKAHASHI Seiji , YONAMINE Kyoko , HAMADA Hiroshi , IMAIZUMI Kiyoshi , KUROKI Yoshikazu 
Published: May 2008

AbstractThe diagnosis of Duchenne muscular dystrophy (DMD) has been drastically improved by recent advances in DNA analysis. The Southern blot hybridization using the cDNA 8 probe and the restriction enzyme Hind III was conducted in a gravida and her family in blood samples. The diagnosis revealed partial gene deletions in both the gravida and the DMD‐affected second child. The prenatal diagnosis was performed by studying the PCR (polymerase chain reaction) for target DNAs of exons 48 and 51 that correspond with cDNA 8 probe. In the affected child, the 506 bp band at exon 48 was detected but 388 bp at exon 51 was missing. On the other hand, both the 506 bp band at exon 48 and the 388 bp band at exon 51 were detected in the cultured amniotic cells. Thus, the fetus was determined to be not affected.
Transgenic Mice in the Search for Development‐related Genes: Application for the Studies of Congenital Anomalies*
Authors: OTANI Hiroki , TANAKA Osamu 
Published: May 2008

AbstractTransgenic mice technology in conjunction with other molecular biological and embryo manipulation techniques has made it possible to manipulate the mouse genome to elucidate the molecular mechanisms of normal and abnormal embryonic development. This genetic technology also permits the isolation of novel genes involved in developmental events. It has and certainly will greatly contribute to the better understanding of the pathogenesis of congenital anomalies. However, the majority of congenital anomalies in humans occur from multifactorial causes including not only genetic but also various environmental factors. Thus, transgenic mice can be utilized as an excellent genetic tool on which all the available conventional teratological techniques and informations are concentrated to elucidate molecular mechanisms and the holistic picture of congenital anomaly formation.
Congenital Malformations in Newborns from Diabetic Mothers*
Authors: OMORI Yasue , SHIMIZU Meimi , MINEI Satomi , MORITA Yuko , TETSUO Tamaki , SUZUKI Natsuko , SANAKA Mayumi 
Published: May 2008

AbstractIt has been well known that there is a high incidence of congenital malformations in newborns from diabetic mothers when the mothers' diabetes control before and during pregnancy is poor. We treated 438 pregnant diabetics who bore 443 children between February 1964 and June 1992. Among these children, there were 51 cases (11.5%) with congenital malformations, 21 cases with major anomalies (4.7%) and 30 cases with minor anomalies (6.8%).The type of malformations are not related to special organs; heart malformations and cleft lips are relatively frequent compared to other types of malformations. The mechanism of the congenital malformations in newborns from diabetic mothers remains unclear. However, clinically and experimentally it has been found to be due to fuel‐mediated teratogenesis. Since October 1978, HbAi has been used as an index of diabetic control and the relationship between congenital malformations and the mother's diabetes control has been observed. 1) There is no difference in the incidence of malformations in children from IDDM and NIDDM mothers. However, there are more severe malformations in the children from IDDM mothers compared to those from NIDDM mothers. 2) Mothers who bore children with major malformations had all made their first visit to our hospital after pregnancy. HbAi in the IDDM mothers who had children with malformations at the first visit was 11%. 3) In the NIDDM mothers, even if HbAi levels are near normal, children with major malformations were born and there was little relationship between congenital malformations and the mothers' diabetes control.These data suggest that there are two kinds of congenital malformations in children from diabetic mothers, fuel‐mediated teratogenesis, and malformations as seen in children from non‐diabetic mothers.
Congenital Anomalies in the Offspring of Epileptic Mothers*
Authors: NAKANE Yoshibumi , KANEKO Sunao 
Published: May 2008

AbstractThe incidences of various complications during pregnancy are not significantly different between epileptic and nonepileptic mothers in the majority of papers so far reported. More than 70 to 80% of women with epilepsy will have no change in seizure frequency, while 5% will have fewer seizures than before and the remaining patients will have more seizures during pregnancy provided that their drug compliance is good. Intrauterine growth, in particular, of head circumference of fetus is delayed. However, this retardation disappears within few years after birth. The risk of congenital malformations of the offspring born to treated epileptic mothers is greater than in the general population. Among risk factors for teratogenesis that had been considered to date, only antiepileptic drug (AED)‐related factors had proved to be significantly related to the occurrence of malformations. Among AEDs, methylphenobarbital, valproate, primidone, carbamazepine and phenytoin are teratogenic, particularly when they are used in combination. Follow up EEG of children born to epileptic mothers revealed that the incidence of abnormal EEG was 44%, and 28 to 38% showed epileptiform patterns. Only 7% of offspring had epileptic seizures. In the offspring without clinical seizures revealed that most of the epileptiform patterns disappear after the age 10. Recommendations concerning AED therapy during pregnancy are also discussed.
Immunohistochemical Examination of Developmental Brain Defects*
Authors: FUNAHASHI Atsushi 
Published: May 2008

AbstractRecent advances in immunohistochemistry have revealed the precise distribution of various neurotransmitter systems, their projections and ultrastructure in the brain. Based on these data, the structure and function of specific neurons or a group of neurons in the brain can be understood in terms of the dynamics of the neurotransmitters they utilize. This strategy of neuroscience may be utilized to explore higher brain functions such as learning, memory, cognition and sleep. Prenatal exposure of pregnant rats to methylazoxymethanol acetate (MAM) on day 15 of gestation produces offspring with severe microcephaly (MAM‐rats). These MAM‐rats show various behavioral abnormalities in learning, memory and cognition as well as hyperactivity and reduction of paradoxical sleep. Developmental abnormalities of serotonin (5HT) fibers in the cerebral cortex and 5HT neurons in raphe nuclei are examined. The cell deficits of cortical target neurons and irregularly arranged cortical layers were observed. Developmental abnormalities of 5HT neurons are discussed in terms of target dependent secondary degeneration. Vasoactive intestinal polypeptide (VIP) has an important role in behavioral modification. VIP is suggested to have a functional correlation with 5HT in the brain. The reduction of VIP neurons and hypo‐aggregation of their axonal boutons were observed in the cerebral cortex and hippocampus of infant MAM‐rats. However, in adult MAM‐rats, VIP axonal boutons showed layer‐dependent hyper‐ or hypo‐aggregation compared with the age‐matched control. The difference in the number of VIP neurons became small between the controls and MAM‐rats. These immunohistochemical observations of brain defects have an important implication for understanding the abnormal behavior of MAM‐rats.