Yoichi Noda

ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles.

Rho-associated kinase (ROCK) I mediates signaling from Rho to the actin cytoskeleton. To investigate the in vivo functions of ROCK-I, we generated ROCK-I–deficient mice. Loss of ROCK-I resulted in failure of eyelid closure and closure of the ventral body wall, which gave rise to the eyes open at birth and omphalocele phenotypes in neonates. Most ROCK-I−/− mice died soon after birth as a result of cannibalization of the omphalocele by the mother. Actin cables that encircle the eye in the epithelial cells of the eyelid were disorganized and accumulation of filamentous actin at the umbilical ring was impaired, with loss of phosphorylation of the myosin regulatory light chain (MLC) at both sites, in ROCK-I−/− embryos. Stress fiber formation and MLC phosphorylation induced by EGF were also attenuated in primary keratinocytes from ROCK-I−/− mice. These results suggest that ROCK-I regulates closure of the eyelids and ventral body wall through organization of actomyosin bundles.

Successful intrauterine treatment with radiofrequency ablation in a case of acardiac twin pregnancy complicated with a hydropic pump twin

Twin reversed arterial perfusion sequence is a serious complication of monochorionic twin pregnancy, as the pump twin that perfuses blood to the acardiac twin may experience heart failure and fetal hydrops resulting in a poor perinatal outcome. A woman with an acardiac twin pregnancy complicated by a hydropic pump twin underwent intrauterine treatment with radiofrequency ablation (RFA) at 27 weeks of gestation. Obliteration of blood flow to the acardiac twin from the pump twin was successful. Fetal hydrops resolved by the time of delivery at 32 weeks of gestation, in spite of transient deterioration, and a good postnatal outcome was achieved for the pump twin. We found that RFA was an effective intrauterine treatment for acardiac twin pregnancy and suggest that it could be introduced in cases complicated by a hydropic pump twin. Copyright

In utero diagnosis of an aneurysm of the vein of Galen causing hydrocephalus and heart failure.

A prenatally diagnosed aneurysm of the vein of Galen was presented in the fetus of a patient referred to our hospital at 31u2003weeks of gestation. Ultrasonography demonstrated polyhydramnios, cardiomegaly, dilatation of the right atrium and superior vena cava, tricuspid valve regurgitation, hydrocephalus, and a large hypoechoic mass with blood flow in the suboccipital region. Skin edema was shown thereafter. A 3262‐g male was delivered by cesarean at 35u2003weeks of gestation. Computed tomography imaging demonstrated a large mass in the suboccipital region, after which thrombocytopenia appeared and the neonate died at 18u2003days of age.

Fetal hemolytic disease due to anti-Rh17 alloimmunization

Objective: To delineate clinical features of a case of fetal hemolytic disease due to anti-Rh17, along with a review of relevant studies published in English and Japanese. Methods: We present clinical features of a –D-/-D- phenotype woman with anti-Rh17 alloimmunization during pregnancy. Relevant English literature in the MEDLINE database was reviewed, while Japanese studies were searched in the Japana Centra Revuo Medicina database. Results: A Japanese –D-/-D- woman with anti-Rh17 (Hro) was treated during pregnancy. Serial ultrasonography, antibody titers, amniocenteses, and cordocenteses were conducted for perinatal management. Amniocentesis results demonstrated a high delta optical density level of 450 in the amniotic fluid, while cordocentesis revealed alloimmunization between the mother and the fetus as well as fetal hemolytic anemia. Blood flow velocity in the middle cerebral artery indicated a rapid development of fetal anemia. The newborn demonstrated severe anemia and hyperbilirubinemia, which were successfully treated with exchange transfusions. Two cases of prenatally diagnosed fetal hemolytic disease due to anti-Rh17 were found published in English and 5 in Japanese. Conclusion: A –D-/-D- phenotype patient with anti-Rh17 was successfully managed during pregnancy and a good outcome for the neonate was achieved. Our results and a review of related literature led to the following suggestions. The first pregnancy in a –D-/-D- woman may be affected, an anamnestic immune response can easily occur during pregnancy, the level of anti-Rh17 titer is indicative of the degree of fetal hemolysis, and appropriate intrauterine intervention is warranted for achievement of a good outcome.

Protein S gene mutation in a young woman with type III protein S deficiency and venous thrombosis during pregnancy.

AbstractBackground: We attempted to identify a gene defect in a young woman with type III protein S deficiency and venous thrombosis during pregnancy.nMethods: Measurements of total and free PS antigen levels in plasma were carried out using an enzyme-linked immunosorbent assay. Plasma PS cofactor activity was determined by a clotting assay using activated factor V as the substrate. Genomic DNA prepared from peripheral blood was amplified by polymerase chain reaction (PCR) with PROS1-specific oligonucleotide primers. PCR products were sequenced on both strands using specific oligonucleotide primers.nResults: Plasma PS cofactor activity was undetectable in every measurement at 36 weeks of gestation, as well as at 2 weeks and 4 months after delivery. Plasma total PS antigen levels were 70% and 67% at 2 weeks and 4 months after delivery, respectively. Free PS antigen level was 24% at 4 months after delivery. Of all exons analyzed, codon 295 of GGC in exon 10 was substituted for AGC. This missense mutation predicted an amino acid change of glycine to serine.nConclusions: Measurements of total and free PS antigen levels along with PS activity indicated that this was a case of type III PS deficiency. DNA analysis identified a heterozygous missense mutation of codon 295 in the PS gene, substituting glycine for serine.

Comparison of the Responses to Thrombin in Monkey Renal and Uterine Arteries

Objective: Thrombin is known to regulate vascular tone. We analyzed and compared mechanisms of thrombin action in primate renal and uterine arteries. Results: Renal arteries responded to thrombin with relaxation, which was inhibited by NG-nitro-L-arginine or indomethacin and resersed to contractions by the combination. The relxations were also resersed to contractions by endohelial denudation. Conversely, thrombin caused uterine arterial contradictions that were unaffected by endothelial denudation. Relations in both renal arteries and contractions in uterine arteries were suppressed by hirudin (a specific thrombin inhibitor). Relaxant response to A23187 (Ca2+ ionophore), nitroprusside sodium (nitric oxide donor), and beraprost sodium (prostacyclin analogue) did not differ between renal and uterine arteries. Conclusion: Thrombin-induced relaxation of renal artieries appears to be mediated by nitric oxide and vasodilaor prostaglandins liberated from the endothelium, whereas uterine arterial contraction is caused by an endothelium-independent mechanism.

Mutational analysis of the follistatin-related gene in women with premature ovarian failure and polycystic ovary syndrome

Follistatin-related gene (FLRG) protein, also called follistatin-like 3 (FSTL3), is a recently described member of the follistatin family and is widely expressed, including in human ovary (1) and endometrium. Like follistatin, FLRG protein binds activins that appear to play a crucial role in ovarian follicle development, however, follistatin and FLRG protein have distinct intracellular localization and differentially regulate activins (2). Urbanek et al. recently studied 37 possible candidate genes that may be involved in the inheritance of polycystic ovary syndrome (PCOS) and demonstrated that the strongest evidence for genetic linkage in PCOS patients was with the follistatin gene (3), however, the conclusion is still controversial. On the other hand, preliminary analysis of FLRG transgenic female mice showed that their ovaries contained fewer antral follicles and more apparent follicular atresia, suggesting that FLRG protein regulates follicular development and function through inhibition of the paracrine activity of activin and/or other related factors, such as bone morphogenetic proteins (BMPs) (4). Therefore we focused on this new follistatin member, FLRG , and speculated that impaired FLRG protein signaling might cause ovarian dysfunction in humans. The aim of this study was to search for mutations in the coding regions of the FLRG in Japanese women with 46,XX premature ovarian failure (POF) and PCOS. This study was approved by the Institutional Review Board of Shiga University of Medical Science. Informed consent was obtained from all patients and controls. Fifty-three unrelated women with a history of infertility were recruited for this study. The age at presentation ranged from 20 to 37 years. Of these 53 patients, 16 patients were diagnosed as idiopathic POF, defined as secondary amenorrhea before 40 years of age with elevated gonadotropins on at least two occasions (with follicle-stimulating hormone (FSH): 96.99/8.9 mIU/ml and LH: 38.99/15.3 mIU/ml; mean9/SD). The reference range for FSH is 2.0 14.8 mIU/ml, and values above 40 mIU/ml are indicative of ovarian failure. Each patient’s medical history was taken and each underwent a physical examination to rule out any identifiable cause of POF. Thirty-seven patients were diagnosed as PCOS according to the following criteria of the Japan Society of Obstetrics and Gynecology: 1. amenorrhea or oligomenorrhea without specific underlying diseases of the adrenal or pituitary glands; 2. a high basal LH level and a high LH:FSH ratio; and 3. bilaterally enlarged ovaries with multiple small