bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastructure of the Adenohypophysis in a Case of Cyclopia
Authors: SUMIDA Hiroshi , AKIMOTO Naotaka , INOUE Naohiko , SATOW Yukio
Published: May 2008

The 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

On 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

Sodium 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.
Stage‐Specific Relationship between Plasma Total and Cerebellar Bilirubin Levels during Early Postnatal Period in Jaundiced Gunn Rats
Authors: OHSUGI Mami , TAKAGISHI Yoshiko , YAMAMURA Hideki
Published: May 2008

Abstract Relationships between plasma total or unbound bilirubin level and cerebellar bilirubin level were examined during the first 14 days after birth in homozygous Gunn rats with hyperbilirubinemia. Correlation coefficients between plasma total and cerebellar bilirubin levels were 0.63, 0.74, 0.48 and 0.60 at days 3, 7, 9 and 11, respectively, and were all significant, whereas the coefficient at day 14 (0.10) was not significant. The correlation coefficients between plasma unbound and cerebellar bilirubin levels were 0.40, 0.09, and 0.12 at days 7, 11 and 14, respectively, and were not significant. Thus, the cerebellar bilirubin level is suggested to depend on the plasma total bilirubin level from day 3 to 11.
Genetic Analysis and Histology of Hypoplastic Kidneys in the Male Hypogonadic Mutant (hgn/hgn) Rat
Authors: SUZUKI Katsushi , SUZUKI Hiroetsu , HAKAMATA Yoji , KAMEI Takayuki , KIKUKAWA Keiichiro
Published: May 2008

Abstract Bilateral hypoplastic kidneys have been found to associate with the male hypogonadism rat (hgn/hgn). The hypoplastic kidney was persistent to the male homozygote for hgn and it was also seen in some females with unknown genotype. The affected kidney was apparently smaller in size than phenotypically normal one. When females with hypoplastic kidney were mated to proven heterozygous males for hypogonadism (hgn/+), the ratio of the affected testis to phenotypically normal one was 32: 20 in the Fl generation. This segregation ratio did not deviate siginificantly from the 1: 1 ratio expected from the hypothesis that the genotype of females with hypoplastic kidney in parent generation for hypogonadism would consist of hgn/hgn alone. The ratio expected from the other hypotheses was denied statistically. The ratio of the affected kidney to phenotypically normal one in both sexs of the Fi was 53: 50, fitting to 1: 1 hypothesis for a single autosomal recessive trait. There was neither a case showing the phenotypically normal kidney with the affected testis, nor the hypoplastic kidney with the phenotypically normal testis. The results suggest that the gene responsible for the hypoplastic kidney and the gene for hypogonadism would be identical or both genes reside in the close vicinity in a chromosome. The results also suggest that the homozygotes for hgn can be selected by the presence of hypoplastic kidney.
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.
Ameliorative Effect of Folic Acid on Pyrimethamine Teratogenesis in Pigs
Authors: SATOH Keiichirou , KOJIMA Natsuki , FURUNO Masaru , KOKUE Eiichi , HAYAMA Toyoaki
Published: May 2008

Abstract The effects of oral dosing of folic acid (FA) on pyrimethamine (PYR) teratogenesis were examined in Goettingen minipigs. PYR (3.6 mg/kg/day) was orally administered in the feed to sows with or without FA (2.5, 10 or 50 mg/kg/day) for 12 days, (days 11 ‐ 22 of gestation). Major malformations, such as cleft palate, cleft lips, micrognathia and clubfoot, were observed in all treated groups. The incidence of malformed fetuses decreased dose‐dependently as the FA level was raised. This new finding suggests FA administration may prevent newborns from PYR induced malformations. This result contrasts in the observations in rats, in which PYR teratogenesis was potentiated by the concurrent oral dosing of FA. Neither PYR blood concentrations nor plasma protein binding was significantly affected by FA dosing in nonpregnant sows. These results suggest a mechanism other than pharmacokinetic modification was responsible for the protective effect of FA on PYR teratogenesis in minipigs.
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

The 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

Transgenic 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

It 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

The 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

Recent 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.
Effect of Folic Acid on Pharmacokinetics of Pyrimethamine in Rats
Authors: TSUNEMATSU Kunitoshi , SHIMODA Minora , HAYAMA Toyoaki
Published: May 2008

The effect on pyrimethamine (PYR) pharmacokinetics of folic acid (FA) which potentiated the PYR teratogenesis was studied in rats. Gavage administration of PYR 1.6 mg/kgBW/day from day 11 to day 15 of gestation did not cause any malformation, but with concomitant dosing of FA 50 mg/kg/day in feed caused malformations in 75% of fetuses. Neither the plasma concentration‐time profile nor the plasma protein binding of the gavaged PYR was affected by the concomitant dosing of FA in the non‐pregnant rats. The pregnant rats which received the gavaged PYR with or without FA in feed for 5 days (from day 11 to day 15 of gestation) were killed at 4 or 12 hrs after the last dosing of PYR, and their plasma and fetuses were subjected to determination of PYR. The PYR concentration in the maternal plasma was comparable in both groups. The PYR concentration in fetuses of the PYR alone group was significantly higher than that of the PYR with FA group 4 hr after but not 12 hr after the last dosing. These results indicated that the pharmacokinetics of PYR was not affected by the concomitant dosing of FA, suggesting that FA potentiated the PYR teratogenesis by other mechanisms than pharmacokinetic modifications.
Effects of the Ay Gene on the Sensitive Periods of Hydrocortisone‐Induced Cleft Palate and Palatal Slit in Mice
Authors: HATAKENAKA Noriyuki , TERAMOTO Shoji
Published: May 2008

The effects of the Ay gene on the sensitive periods of hydrocortisone‐induced cleft palate and palatal slit were investigated in C57BL/6 (a/a) and its congenic strain of C57BL/6‐Ay (Ay/a) mice by using the single‐dose administration method. Matings were conducted as follows (femalex male): Group I, a/a × a/a; Group n, a/a ×Ay/a; and Group III, Ay/a × a/a. Pregnant females were subcutaneously given a single dose of 200 or 400 mg/kg of hydrocortisone on day 11, 12, 13 or 14 of pregnancy and killed on day 18 for examination of palatal defects of live fetuses. Cleft palate was produced in all groups by treatment on days 11–13 of pregnancy at a dose of 200 mg/kg without any increase in fetal mortality. In Group I, the maximum incidence was observed on day 11 and followed by a rapid decrease thereafter. In Group U, in which half of the fetuses were expected to carry the Ay gene, the incidence still remained high on day 12, although it was decreased to the level of Group I by day 13. In Group HI, in which maternal mice as well as half of their fetuses carried the Ay gene, significantly higher incidences were observed on days 12 and 13 with the maximum value on day 12 when compared with those in Groups I and/or II. Palatal slit was also induced in all groups on each of treatment days at a dose of 200 mg/kg. Although the incidences in both Groups I and II were high on days 11 and 12 and gradually decreased thereafter, the value on day 13 was significantly higher in Group II than in Group I. In Group IE, the maximum incidence was found on day 12 and the values on days 13 and 14 were still significantly higher than those in Groups I and/or II. These results indicate that the sensitive periods of hydrocortisone‐induced cleft palate and palatal slit are prolonged into the later stage of embryonic development as a result of the Ay‐gene effects.
Heterotopic Glial Nodule in the Lung of Anencephaly
Authors: SONG Sang Yong , CHI Je G.
Published: May 2008

Abstract Heterotopic glial nodule in the lung is a rare abnormality. Most reported cases are associated with major cranial malformations including anencephaly. The pathogenesis of this condition has not been established. The hypotheses are (1) embolization of glial tissue after head trauma during fetal development, (2) aspiration/implantation of fragments of brain tissue from the amniotic fluid, and (3) aberrant migration of neural crest elements to the lung. This report documents the presence of an intravascular embolus of a glial nodule, which offers support to the embolization theory for the pathogenesis of this peculiar abnormality.
Conducting Developmental Toxicity Studies Using the Ferret: Retinoic Acid as a Positive Control
Authors: HOAR Richard M. , CHRISTIAN Mildred S.
Published: May 2008

The search for a carnivore as an addition to a multilevel test system for determining developmental toxicity has been extended to include the ferret. The following discussion is an effort to simplify the procedures which should be used with this species when conducting a typical Segment II ‐ Teratology Study and to reduce the uncertainties which always accompany the introduction of a different animal model. It is recommended that developmental toxicity studies in ferrets include a positive control group. All‐trans retinoic acid (15 mg/kg on day 14 of gestation) had minimal effects on the dam and her pregnancy and maximal effects on the fetus. Administration of retinoic acid did not alter maternal weight or weight gain nor affect the average numbers of corpora lutea, implantations, resorptions or litter sizes. It did, however, reduce fetal body weight, produce gross external alterations in 90.6% of the fetuses and increase the skeletal alterations (particularly of the skull) in the exposed fetuses as compared with controls. Timed pregnant ferrets may be received from a supplier within a day or two after mating without interfering with implantation which occurs on day 12. Intubation with the test article is conducted throughout organogenesis from day 12 to day 30 with sacrifice on day 35 of gestation. Examination of the ferret fetuses is similar to that conducted with rat fetuses.
Campomelic Syndrome Associated with Potter's Syndrome and Car diosplenic Syndrome
Authors: Myong Na Hye , Chi Je G.
Published: May 2008

ABSTRACT Campomelic syndrome is a heterogeneous group of disorders characterized by short‐limbed dwarfism with congenital bowing or bending of the long bones particularly in the lower limbs and is frequently associated with a variety of non‐skeletal manifestations. Two distinct types are (1) long‐limbed campomelic dysplasia with bent bones of normal length and width: (2) short‐limbed campomelic dysplasia in which the bent bones are short and wide. We reported an autopsy case of this syndrome.

This male baby with gestational age of 32 weeks was born to a mother with placenta previa, showing abdominal distention and short‐limbed appearance. Postmortem examination revealed bilaterally enlarged Potter type 1 polycystic kidneys, a pancreatic cyst, and two spleens in the abdominal cavity. Both lungs were hypoplastic and the heart exhibited multiple congenital anomalies such as double outlet right ventricle, pulmonary artery hy‐poplasia, mitral atresia, absence of ductus arteriosus, and inferior vena cava draining into the left atrium. Characteristically both femur bones were curved at proximal two‐thirds with slightly shortened lengths. Both humeri also showed bending of distal one‐third. Other chondro‐osseous abnormalities such as small epiglottis, narrow thorax, dolichoce‐phaly, and bilateral equinovarus deformity were noted. These findings were compatible with campomelic dysplasia of long‐limbed type accompanying unusual sets of non‐skeletal manifestations of Potter's syndrome and cardiosplenic syndrome. Key words: campomelic syndrome, Potter's syndrome, cardiosplenic syndrome
Histological Analysis of Triphalangism Associated with Polydactyly of the Thumb
Authors: MAKINO Hitomi , MIURA Takayuki , NAKAMURA Ryogo , NOGAMI Hiroshi
Published: May 2008

ABSTRACT Wassel's classification of thumb polydactyly has some problems especially in categories IV and VII because it depends solely on X‐ray findings. In order to improve his thumb polydactyly classification, we examined histologically untreated 182 bifid thumbs from 171 patients at Branch Hospital, Nagoya University in the past eight years. Ninety‐five of these cases had proximal phalangeal separate type of polydactyly corresponding to Wassel's categories IV and VII. Forty‐five thumbs of these categories were excised from 44 patients and classified into type I (24 cases), type II (12). type III (4), and type IV (5) in accordance with Kanno's classification. In distal phalanges, normal cartilage development was observed in Kanno's type I, whereas proximally elongated cartilaginous tissue was formed in the type II. Three distal phalanges from types II and III showed depression at the ulnar side of elongated cartilage of the distal phalanx where immature chondrocytes transversely distributed. Three cases with incomplete and one case with complete joint formation were formed in elongated cartilage of the distal phalanx, and endochondral ossification developed in the central area of elongated cartilage of the distal phalanx in four cases from types III and IV. All of the cases showed only minimal mobility of their involved joints. Their tendon development did not correspond to their anatomical characteristics. Histological studies indicated that there was no distinct difference between Wassel's category IV and category VII. It was postulated that the triphalang‐
Overgrowth and Enlarged Heart in Mouse Fetuses with Maternally Inherited ThP and twLub2: An Example of Genomic Imprinting in Animals
Authors: MIYABARA Shinichi , BOGART Mark H. , WINKING Heinz , SUGIHARA Hajime
Published: May 2008

ABSTRACT Thp/+ mouse is known to have differing phenotypes depending on gender of the ThP parent. In the present study, fetuses with maternally [Group A (until day 18 of pregnancy) and Group C (day 19)] and paternally [Group B] inherited ThP were examined with particular reference to the developmental abnormalities of hearts. In addition, a small number of fetuses with maternally inherited twLub2 on day 19 were compared with Thp. Group A ThP fetuses had greater body weight, possibly larger body size, generalized edema (100%), marked enlargement of the hearts (100%) and hypoplastic pulmonary trunk (73.7%). There were no such malformations in Group B ThP fetuses or in the controls (+/+) for both groups. The bilaterally thickened ventricular wall of fetal hearts in Group A and C ThP fetuses bulged into ventricular cavity. The pulmonary valve was also thickened. The labeling indices of the ventricular myocardial cells by BrdU were inclined to be higher in Group A ThP than in the control (+/+) fetuses. Fetuses of twLub2 had abnormalities of the cardiovascular system similar to Group C Thp. The results suggest that cardiac lesions in fetuses with maternally inherited ThP and twLub2 correspond to cardiomyopathy. Overgrowth and enlarged heart indicate the possibility of ThP as an animal model for Wiedemann‐Beckwith syndrome.
Effects of N‐acetyl‐L‐cysteine on Teratogenicity of 5‐Fluorouracil in Mice
Authors: NAYA Masato , DEGUCHI Takashi , YASUDA Mineo
Published: May 2008

ABSTRACT Embryotoxicity and teratogenicity of 5‐fluorouracil (5‐FU) and modulation of its effect by N‐acetyl‐L‐cysteine (NAC) andor phorone were evaluated in mice. Pregnant ICR mice were intraperitoneally injected with 25 mglkg of 5‐FU on day 11 of gestation (vaginal plug = day 0). Pregnant mice were pretreated with NAC at dose levels of 80, 160, and 320 mg/kg injected intravenously 2 hours before dosing with 5‐FU. Pregnant mice were killed on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with 160 mg/kg and 320 mg/ kg of NAC decreased the incidence and severity of oligodactyly induced by 5‐FU. There was little difference in maternal body weight gain, fetal mortality, and fetal weight between the 5‐FU group and the 5‐FU plus NAC groups. Pretreatment with phorone, a glutathione depleting agent, at dose levels of 160 and 320 mg/kg injected intraperitoneally, 4 hours before dosing with 5‐FU, increased the incidence and severity of oligodactyly induced by 5‐FU. Cotreatment with NAC at dose levels of 160 and 320 mg/kg decreased the incidence and severity of oligodactyly induced by 5‐FU and 80 mg/kg of phorone. Cotreatment with NAC 160 mg/kg could not suppress the augmentative effect of phorone on 5‐FU teratogenicity under the severe condition, that is, the excess amount of phorone such as 320 mg/kg. These results indicate that the teratogenicity of 5‐FU is mitigated with NAC pretreatment, and also the level of endogenous glutathione is one of the factors which significantly affects teratogenicity of 5‐FU.
Rib Defects and Pattern Formation of the Thoracic Wall Muscles
Authors: KINOSHITA Yuko , MURAKAMI Gen , KATAMACHI Ikuo , HOSHI Hajime
Published: May 2008

A fragment of quail notochord (20 somite stage) was implanted into a host chick embryo (25–30 somite stage) just lateral to the thoracic somites or into the intersomitic space. Around the implanted notochord, aggregates of rib‐forming sclerotomal cells formed a large irregular mass of cartilage, resulting in segmental rib defects without any adverse effect on body wall muscle formation. This contrasted sharply with previous experimental studies in which abnormalities of other somite derivatives, in particular body wall muscles, were always associated with rib defects created by teratogenic agents, surgidal treatment or by genetic means.

These results suggest that migration of myogenic cells into the thoracic wall does not require the guidance of rib‐forming sclerotomal cells or their products. Moreover, those myogenic cells can develop into three layers of thoracic wall muscles, independent of skeletal pattern formation.
A Case Report of Lethal Multiple Pterygium Syndrome
Authors: SHIMADA Masami , TAUCHI Moriyuki , SAWADA Kouji , MINATO Michiyoshi , TAKADA Masaaki , TAKAHASHI Shigeru , OKUNI Masahiko , SHEIKH Aleemuzzaman , YAMADA Tsutomu
Published: May 2008

We report a patient with a lethal multiple pterygium syndrome. The patient was the first child born to a 28‐year old mother. The family history was unremarkable; no consanguinity was reported. The patient was the product of a 37‐week gestation by cesarian section, and admitted to our intensive care unit after resuscitation. He weighed 2,158 g, and measured 33cm (CHL). The patient had hydrops, cystic hygroma on the back of the neck, hypertelorism, a flat upturned nose, a highly arched cleft palate, micrognathia, low set ears and multiple pterygia. In addition, the finger showed slender and hypoplastic ridges and creases. The feet showed rocker‐bottom deformities. Furthermore, the genitalia was normally formed male with bilateral cryptorchism. The spine showed scoliosis and lordosis with vertebral bony fusions, separations and reduced intervertebral spaces. The ribs were 11 pairs and gracile. The lung was hypoplastic, and the heart was small but normal in structure. Chromosomal examination revealed a normal male karyotype (46, XY). The infant died within two hours after birth.

Gillin and Pryse‐Davis (1976) described three female siblings with this early lethal disorder. This disorder was separated from other conditions associated with pterygia by Hall et al. (1982). At least 30 cases have been reported. However, this type of case seems to have not been reported in Japan. This disorder is considered autosomal‐recessive, but in other report, X‐linked recessive inheritance is proposed. Therefore, further studies are necessary in order to make a more precise etiology of this disorder.
Lack of Constrictive Effects of Cocaine on the Fetal Ductus Arteriosus in the Rat
Authors: UKITA Katsuo , AREHIMA Kazuyoshi , TAKIZAWA Tatsuya , SHIRAI Mitsuyuki , YAMAMOTO Masako , FUKUI Yuko , SHIOTA Kohei
Published: May 2008

Cocaine (12.5 or 25 mg/kg) was administered intraperitoneally to pregnant rats 15 min to 12 hr prior to Caesarean section on day 20 of gestation. The fetuses were immediately frozen and serially sectioned, and the diameter of their ductus arteriosus (DA) was calibrated. The DA was patent in all the fetuses examined and the DA caliber was not significantly different between the control and the cocaine‐treated groups at any time interval after the cocaine dosing. It was concluded that cocaine has no constrictive effects on the fetal DA in the rat.
Clinical and Experimental Studies on Teratogenic Mechanisms of Congenital Absence of Digits in Longitudinal Deficiencies*
Authors: OGINO Toshihiko , KATO Hiroyuki
Published: May 2008

ABSTRACT: In order to clarify teratogenic mechanisms of congenital absence of the digits in longitudinal deficiencies, ulnar deficiency, radial deficiency, central polydactyly, osseous syndactyly and cleft hand (central deficiency) were analyzed. Then, the same anomalies induced in rat fetuses with myleran were analyzed. In ulnar and radial deficiencies, the more severe was the degree of finger deficit, the more severe was the arrest of the forearm bone. The critical periods of these anomalies were earlier than those of other anomalies. Ulnar deficiencies were induced only in Gun: Wistar rats and radial deficiencies only in WKAH/Hkm rats. A genetic factor may influence the teratogenesis of ulnar and radial deficiencies. From histological analysis of tibial deficiency, it may be suggested that the cause of absence of digits in longitudinal deficiency is closely related to a deficit of mesenchymal cells. The analysis of skeletal changes of central polydactylies, osseous syndactylies and cleft hands suggested that there seemed to be the cleft hand formation process from osseous syndactylies and central polydactylies. These anomalies were often observed in both hands in various combinations. They could be induced by the same treatment at the same developmental stage in rats. The teratogenic mechanism of cleft hand seemed to be failure of induction of digital rays in the hand plate.
Neural Crest and Central Nervous System Malformation*
Authors: TAKASHIMA Sachio , KATO Mitsuhiro , MATSUDA Fumiko
Published: May 2008

ABSTRACT The normal development of some neural crest derivatives and the spinal cord, and the neuropathology of the neurocutaneous syndrome were studied. In developing human embryos and fetuses, HNK‐1 was expresed in the intermediate zone of the neural tube and somites in 3–4 week embryos and weakly remained in the white matter until 20 weeks’gestation, and remained positive in peripheral nerves from embryo to adult. High signal intensity was observed in the basal ganglia, brainstem and cerebellum on T2‐weighted MRI. Neuropathological examination revealed proliferation of astroglial fibers in the leptomeninges and the perivascular area in the cerebellum and basal ganglia. In tuberous sclerosis, immunohistochemistry revealed GFAP‐positive structure in the dermis of adenoma sebaceum. Giant astrocytes in tubers and tumors were positive for GFAP and NSE. Thus, the tumor cells have the characteristics of both astrocytes and neurons. HNK‐1 immunoreactivity reappeared in tissue surrounding giant astrocytoma. The nuropathology of hemimegalencephaly comprised abnormal gyration, LGH, disturbed lamination, large neurons and increased neuronal heterotopia in the subcortical and deep white matter. Fenitin‐positive oligodendroglia were increased on affected side. The dysplasia may have arisen from neural crest cells.
Clinical Aspects of Cleft Lip and Cleft Palate Patients Treated at Kanazawa Medical University Hospital from 1974 to 1993*
Authors: TSUKADA Sadao , TANIGUCHI Wakae
Published: May 2008

ABSTRACT Currently, clefts of the lip, alveolus, and palate are thought to be the most common congenital malformations. In this study, we examined 1,565 cases of clefts we treated over the last 18 years, in order to summarize the clinical features and to evaluate the treatment outcomes.

This study involved 589 cleft lip (CL) cases, 576 cleft lip and palate (CLP) cases, 286 cases of cleft palate (CP), 81 cases of submucous CP and 33 cases of CL and submucous CP. The familial incidence was 11.1% (174 cases). Overall, the average incidence of associated congenital abnormalities was 27.9%. Approximately half of the patients with CP alone or with submucous CP were found to have additional congenital malformations. Standeard surgical techniques for unilateral and bilateral CL cases were the Skoog's and Millard's methods, respecively, which resulted in satisfactory outcomes. As a primary operation for CP, pushback procedure was performed using a partial mucosal flap from the palate. Using this procedure 96.5% of 455 cases achieved satisfactory nasopharyngeal closure. The main objective in the treatment of CL patients is not only the repair of growing tissues but also appropriate morphological, functional and psychological reconstruction for the purpose of correcting growth inhibitory problems caused by anatomical malposition.

Surgical procedures for CP patients are designed to meet several needs: correction of anatomical abnormalities of the palate and pharynx, achievement of proper nasopharyngeal closure necessary for normal phonation, prevention of growth disturbances of the maxilla, improvements in hearing and auditory tube function, and normalization of occlusion.
A Rare Case of Unilateral Brachymetatarsia of the 2nd Toe
Authors: KOSAKA Masaaki , SUGIMOTO Hajime , KAMIISHI Hiroshi
Published: May 2008

ABSTRACT A rare case of 2nd toe brachymetatarsia is presented. A satisfactory result was achieved with step‐osteotomy and bone grafting from the adjacent 3rd metatarsal shaft to the bony defects of the lengthened 2nd metatarsal, and rigid fixation with miniplate. This method of surgical correction is presented in detail with consideration of the surgical indications.
Effects of Food Restriction on the Fetal Development during Major Organogenesis in Rats
Authors: IKEMI Naoki , IMADA Junji , GOTO Takeshi , SHIMAZU Hiroshi , YASUDA Mineo
Published: May 2008

ABSTRACT This study was designed to determine the effects of food restriction and fasting on fetal development during major organogenesis in Sprague‐Dawley rats. The maternal body weight gain markedly decreased during the 60%‐ and 90%‐restricted feeding and fasting periods with a concomitant decrease in the plasma glucose levels. The number of resorptions slightly increased in the 90%‐restricted feeding and fasting groups with lower fetal viability. The mean fetal body weight of the restricted feeding and fasting groups and the mean placental weight of male fetuses of the 60%‐restricted feeding group were significantly lower than those of the control groups. Ossification of the metacarpi and metatarsi was slightly but significantly retarded by 60%‐restricted feeding. The incidence of cardiovascular malformations (mainly ventricular septal defect and abnormal origin of the right subclavian artery) and visceral variations apparently increased in the restricted feeding and fasting groups. Abnormal fetuses tended to be lighter than normal fetuses. In conclusion, maternal food restriction and fasting during major organogenesis caused the fetal growth retardation with slightly delayed ossification and a high incidence of cardiovascular abnormalities in rats. This possibility must be taken into consideration when teratology data with a reduction in maternal food consumption are evaluated.
A Thoracic Expansion Technique as a Life‐Saving Procedure for Jeune Syndrome (Asphyxiating Thoracic Dysplasia)
Authors: HASHIMOTO Ryozo , ESAKI Masakazu , UMEDA Takashi , SUGITOU Tetsuyuki , HATTORI Tatsuo
Published: May 2008

ABSTRACT We examined and treated two infants with Jeune syndrome. Their respiratory status had progressively deteriorated despite mechanical ventilation. Expansion of the thoracic cage by splitting the sternum and fixation with an artificial prosthesis was performed. A pneumotachograph was quite useful in determining the width of the prosthesis. The technique proved to be a life‐saving procedure in babies with Jeune syndrome.
Chromosomally Abnormal Gametes as a Cause of Developmental and Congenital Anomalies in Humans*
Authors: KAMIGUCHI Yujiroh , TATENO Hiroyuki , MIKAMO Kazuya
Published: May 2008

ABSTRACT Human gamete chromosome studies using 702 oocytes and 15,864 spermatozoa were reviewed. These studies were chosen because they were carried out with our improved chromosomal technique, the gradual fixation‐air drying method, which has been proven to be very reliable.

The incidence of aneuploidy was about eight times as high in the oocytes (11.0%) as in the spermatozoa (1.4%), whereas that of structural chromosome aberrations was three times as high in the spermatozoa (14.1%) as in the oocytes (4.7%). In the spermatozoa, segregation errors leading to aneuploidy were found randomly among eight chromosome groups (A‐G and sex chromosome). In contrast, they did not occur randomly in the oocytes. The observed frequency was significantly higher in group G and significantly lower in group A, as compared with the theoretical frequencies which were calculated according to the assumption that the segregation errors had taken place with an equal chance in each of 23 chromosomes. About 60% of the segregation errors were found to be due to so‐called nondisjunction (loss or gain of dyads) and about 40% were due to so‐called predivision (loss or gain of monads). The incidence of aneuploid oocytes increased slightly with the increase of donor age, although showing no statistical significance. The incidence of spermatozoa with structural chromosome aberrations vaned considerably from donor to donor (3.6–24.8%). However, there was no positive correlation between the occurrence of these spermatozoa and the age of donors or the habit of smoking.

Incidences of chromosome aberrations in the human gametes (22.8% in oocytes and 15.5% in spermatozoa) were far higher than those in experimental animals. These seem to be associated closely with the characteristics of human reproduction and are responsible for a great part of human embryonic loss and developmental anomalies.
Symbrachydactyly of the Foot Associated with Absence of the Contralateral Pectoralis Major Muscle
Authors: UCHIDA Takashi , KOJIMA Tadao , KONNO Midori
Published: May 2008

Abstract A two‐year‐old girl who presented with Symbrachydactyly of the left foot associated with the absence of the right pectoralis major muscle was treated with phalangization of the toes. No other abnormalities were noted. The operative procedure was performed in two stages, separated by eight months. Excellent cosmetic and functional results were obtained. The combination of Symbrachydactyly of the foot and congenital absence of the contralateral pectoralis major muscle is extremely rare.
Susceptibility of Day‐12.5 and Day‐13.5 Fetal Mouse Palates Cultured in Vitro to 5‐Fluorouracil and Hydroxyurea
Authors: KOSAZUMA Tsuneo , KAWAUCHI Saju , CHOU Ming‐Jen , SHIOTA Kohei
Published: May 2008

Abstract The maxillary regions of day‐12.5 and day‐13.5 ICR mouse fetuses were cultivated in a chemically‐defined serumless medium by a suspension culture technique to examine the toxic effects of 5‐fluorouracil (5‐FU) and hydroxyurea (HU) on cultured palates and to compare the sensitivity of fetal mouse palates at different stages of development. The palates of day‐12.5 and day‐13.5 fetal mice were explanted and exposed in vitro for 72 hr to 0.1–50 μg 5‐FU/ml or to 5–76 μg HU/ml. 5‐FU inhibited the growth and fusion of day‐12.5 palatal shelves in vitro dependently on its concentrations. Day‐13.5 palates were significantly less sensitive to 5‐FU than day‐12.5 palates, and the minimal toxic concentrations (MTCs) of 5‐FU were 0.1 and 10 μg/ml for day‐12.5 and day‐13.5 fetal palates, respectively. HU inhibited the in vitro growth and fusion of day‐12.5 fetal palatal shelves in a concentration dependent manner, but only slightly suppressed the growth of day‐13.5 fetal palates. The MTCs of HU were 19 and 76 μg/ml for day‐12.5 and day‐13.5 fetal palates, respectively. Therefore, day‐12.5 fetal mouse palates (at stage‐1 or earlier stages of palatogenesis) seemed significantly more susceptible to these teratogenic chemicals than day‐13.5 fetal palates (at stages 2–3 of palatogenesis). The palates of day‐12.5 ICR fetal mice may be more suitable than day‐13.5 palates for in vitro teratogen screening and for the study of mechanisms of normal and abnormal palatogenesis.
Congenital Humero‐radio‐ulnar Synostosis with Constriction Ring and Flexion Contracture of the Fingers: A Case Report
Authors: KURIMOTO Sarina , KOJIMA Tadao , HIRAKAWA Masahiko , KONNO Midori
Published: May 2008

ABSTRACTCongenital humero‐radio‐ulnar synostosis (HRUS) is a rare malformation. Some cases are hereditary in origin and some are sporadic. We report on a sporadic case of HRUS.

A patient with HRUS is described who had constriction ring on the left upper limb and flexion contracture of the wrist joint and fingers. There was no range of motion nor crease at the elbow joint. Hypoesthesia was noted at the distal part of the ring of the upperarm as she did not respond to pin‐prick. But circulatory failure like cyanosis or congestion was not seen on the extremity. No operation was performed to release the constrictive ring because it was not so deep. Only splint was applied to correct flexion contracture of the thumb, middle finger and ring finger. Three months later, examination of the thumb and fingers showed full extention. The sense to pain by pin‐prick has been improved as the ring on the upperarm shallowed. A minor ischemic change may have been caused by the ring and followed by the contracture and the sensory disturbance. Synostosis also may have been related with the ring.