Yoshinori Iitsuka

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

The Ncx/Hox11L.1 gene, a member of the Hox11 homeobox gene family, is mainly expressed in neural crest-derived tissues. To elucidate the role of Ncx/Hox11L.1, the gene has been inactivated in embryonic stem cells by homologous recombination. The homozygous mutant mice were viable. These mice developed megacolon with enteric ganglia by age 3-5 wk. Histochemical analysis of the ganglia revealed that the enteric neurons hyperinnervated in the narrow segment of megacolon. Some of these neuronal cells degenerated and neuronal cell death occurred in later stages. We propose that Ncx/Hox11L.1 is required for maintenance of proper functions of the enteric nervous system. These mutant mice can be used to elucidate a novel pathogenesis for human neuronal intestinal dysplasia.

Placental mesenchymal dysplasia initially diagnosed as partial mole.

Placental mesenchymal dysplasia is a rare condition of pregnancy that presents as macroscopic features of molar change in the placenta and normal karyotype fetus. These cases are often misdiagnosed as partial mole. We report a new case of mesenchymal dysplasia. A 27‐year‐old Japanese primigravida delivered an 820 g female baby (46XX karyotype) without congenital anomalies at 27 weeks gestation due to massive bleeding with placenta previa. The placenta had mimicking partial moles, grape‐like vesicles and normal villi that diffusely occupied the area on the maternal surface of the placenta. Pathologically, enlarged stem villi contained loose, moderately cellular connective tissue with focal cistern‐like formation, and peripherally located vessels. Abnormal trophoblastic proliferation and trophoblastic inclusions were not observed in any of the sections examined. Some villi contained chorioangiomatoid changes. The mother and child were followed up for more than 5 years and showed no sign of trophoblastic disease or Beckwith–Wiedemann syndrome features.

Application of Lung Volume Measurement by Three-dimensional Ultrasonography for Clinical Assessment of Fetal Lung Development

Objective. To prepare nomograms for normal fetal lung volume using three‐dimensional ultrasonography and to evaluate the possibility of clinical applications of this procedure. Methods. One hundred twenty‐five healthy neonates with birth weights within ±1.5 SD (group A), 9 neonates with intrauterine growth restriction (birth weight less than –1.5 SD) but no severe respiratory disturbance at birth (group B), and 10 neonates with severe respiratory disturbance but no intrauterine growth restriction (group C) were studied. With the use of a three‐dimensional ultrasonographic device, continuous B‐mode images centering on the fetal thorax were acquired as volume data. Analytical software was used to repeatedly trace the contours of bilateral fetal lungs on transverse slices to calculate the lung volume. Results. In group A, the total volume of normal fetal lungs can be expressed by the second‐degree regression equation: 0.08 × (gestational week – 30.1)2 + 3.28 × gestational week – 67.2 (R = 0.909; P < .001). The lung volumes of groups B and C were below the 25th and 2.5th percentiles, respectively, of this regression curve. For the same case, the lung volume increased with gestational week in group B but remained unchanged or even decreased in group C. The total volume of normal fetal lungs can also be expressed by the linear regression equation: 0.02 × estimated fetal weight + 0.29 (R = 0.902). The lung volumes of groups B and C were distributed below and above, respectively, the 2.5th percentile of the regression line. Conclusions. This analytical method may be applied to evaluate lung development.

Ncx, a Hox11 related gene, is expressed in a variety of tissues derived from neural crest cells

Abstract We have isolated the murine homeobox gene (Ncx) that belong to a Hox11 gene family. Expression of the Ncx gene was analyzed in total RNAs from embryos by reverse transcribed polymerase chain reaction (RT-PCR). The mRNA was detected in embryos after 9.5 days of embryogenesis (E9.5) and was maximal at E12.5. The RT-PCR also detected the message in total RNAs from adrenal glands and intestine in adult mice. The expression was further examined in various tissues from embryos by in situ hybridization. It was detected in dorsal root ganglia, cranial nerve ganglia (V, IX, X), enteric nerve ganglia and adrenal glands from embryos between E9.5 and E13.5. Since its expression is restricted to tissues derived from neural crest cells, Ncx may play a role in differentiation and proliferation of neural crest lineage cells.

Comparison of Chemotherapies with Methotrexate, VP-16 and Actinomycin-D in Low-Risk Gestational Trophoblastic Disease

Objective: To compare the efficiency and toxicity of four chemotherapeutic regimens in low-risk gestational trophoblastic disease. Methods: Since 1974, 247 patients with low-risk gestational trophoblastic disease have been treated with 5-day intramuscular methotrexate (MTX) (conventional MTX), 5-day intravenous drip infusion of VP-16, 5-day intravenous actinomycin-D (Act-D) or 8-day alternating intramuscular MTX-folic acid (MTX-CF) at Chiba University School of Medicine. We compared the primary remission rate, the response of human chorionic gonadotropin and the prevalence of drug toxicities in these 4 regimens. Results: The primary remission rate was 73.6% in the conventional MTX regimen, 90.1% in VP-16, 84.0% in Act-D, and 60.0% in MTX-CF. The primary remission rate was significantly higher in the VP-16 and Act-D regimens than in the conventional MTX and MTX-CF regimens. The response rate was significantly higher in the VP-16 regimen than in the other 3 regimens. The drug toxicity with VP-16 and Act-D was less than that with conventional MTX and MTX-CF regimens. Conclusions: The VP-16 regimen was highly effective and less toxic for gestational trophoblastic disease compared with other chemotherapeutic regimens.

Two forms of Hox11, a T cell leukemia oncogene, are expressed in fetal spleen but not in primary lymphocytes

HOX11 is identified from the breakpoint of human T cell acute lymphoblastic leukemias with t(10;14). Since overexpression of HOX11 in T cells caused leukemias in transgenic mice, the endogenous HOX11 may play a role in proliferation and differentiation of T cells. In order to elucidate the role, we examined the expression of Hox11 in normal lymphocytes by a reverse transcriptase-polymerase chain reaction analysis. Two alternatively spliced Hox11 mRNAs were expressed in fetal spleens. However, lymphocytes did not express Hox11 mRNA during differentiation. Furthermore, it was not induced in primary lymphocytes after activation. These results suggest that ectopic expression of HOX11 in T cells is responsible for leukemogenesis.

Adjuvant hysterectomy in low-risk gestational trophoblastic disease.

Objective To evaluate the efficacy of adjuvant hysterectomy with chemotherapy for women with low-risk gestational trophoblastic disease. Methods One hundred fifteen consecutive Japanese women (16–52 years old) with low-risk gestational trophoblastic disease (46 with metastatic disease and 69 without) were treated initially with single-agent chemotherapy (etoposide in 85, methotrexate in 27, and actinomycin D in three) with or without adjuvant hysterectomy, and 97 patients (84.3%) achieved primary remission with those treatments. Eight women (9.4%) treated with etoposide required other regimens because of drug resistance or toxicities. The total dose of etoposide given to achieve primary remission was analyzed in 77 women who received etoposide alone or with adjuvant hysterectomy. Results In 34 women with metastatic disease, the mean (± standard deviation [SD]) total dose of etoposide was not significantly different with and without adjuvant hysterectomy (2857 ± 842 mg versus 2815 ± 815 mg; P = .957; Mann-Whitney U test). However, in 43 women without metastases, the total dose of etoposide was significantly less in those who had adjuvant hysterectomies than in those who did not (1750 ± 635 mg versus 2545 ± 938 mg; P < .05; Mann-Whitney U test). Conclusion Adjuvant hysterectomy decreased the total dose of etoposide given to achieve primary remission in women with nonmetastatic, low-risk gestational trophoblastic disease. If the lesions of gestational trophoblastic disease are confined to the uterus and the woman has no desire to preserve fertility, she should be informed of adjuvant hysterectomy as a treatment option.

Genetic differentiation of complete hydatidiform moles coexisting with normal fetuses by short tandem repeat–derived deoxyribonucleic acid polymorphism analysis

OBJECTIVE We applied deoxyribonucleic acid polymorphism analysis on the basis of differences in the number of short tandem repeat sequences to genetically differentiate dizygotic twins with complete hydatidiform moles and normal fetuses from partial moles presenting a similar appearance. STUDY DESIGN Six pregnant women exhibiting apparent moles and coexisting fetuses were the subjects of this study. Eight polymorphic loci including short tandem repeat sequences were amplified by polymerase chain reaction from deoxyribonucleic acid of peripheral leukocytes of parents, umbilical cord, grossly normal placenta-villi, and molar tissue. The segregation of alleles among samples were determined by comparing band patterns on polyacrylamide gels. RESULTS In all 6 cases amplifications of polymorphic loci provided sufficient information to determine the parental origin. At informative loci the alleles of cord and placenta-villi were transmitted from both patients and husbands whereas molar tissue had only paternal alleles. These allele segregations indicated 2 different genetic origins, namely, normal parental for a fetus and androgenetic for molar tissue, and thus the diagnosis of dizygotic twins with a complete hydatidiform mole and a normal fetus was made. Additionally, the molar component was defined as a heterozygous mole in 2 cases. CONCLUSION Short tandem repeat-derived deoxyribonucleic acid polymorphism analysis was demonstrated to be a useful and precise procedure for the differential diagnosis of a complete hydatidiform coexisting with a normal fetus and the determination of its zygosity as well.

Profile of neurokinin B concentrations in maternal and cord blood in normal pregnancy

objective Neurokinin B (NKB) is a neuropeptide with a vasopressor effect belonging to the tachykinin family. This neuropeptide has attracted attention since recent reports indicated that it is also secreted in the placenta and is probably a cause of pre‐eclampsia. To provide a basis for elucidation of the relationship between pre‐eclampsia and NKB, this study aimed to clarify the trend of changes in blood NKB levels during normal pregnancy by measuring NKB concentrations in maternal blood during various gestational periods and in umbilical blood.

Positive Association of Maternal G Protein β3 Subunit 825T Allele with Reduced Head Circumference at Birth

G protein β3 subunit C825T polymorphism, which has previously been studied in association with common disorders in adults such as hypertension and obesity, has been focused upon recently for a possible important role in fetal metabolism. Japanese are characterized by having equal allele frequencies for this polymorphism. In this study, we determined the maternal and infantile genotypes in 342 pairs of normal healthy mothers and their infants, and compared the genotype frequencies with various infantile somatoscopic characteristics converted into SD units according to sex, parity and gestational weeks. We observed an association of the maternal (but not infantile) G protein β3 subunit 825T allele with reduced head circumference but not with reduced birth weight of the neonate. No association was observed between G protein β3 subunit C825T polymorphism and various maternal somatoscopic characteristics. Although detailed mechanism of this association requires further research, our results suggest that expression of the β3 subunit 825T allele in the mother may exert influence on fetal metabolic environment, perhaps through changes in the maternal uterine environment, or on maternal metabolism.