Daigo Ochiai

Disruption of HIF-1α in hepatocytes impairs glucose metabolism in diet-induced obesity mice

The liver plays a central role in glucose homeostasis in the whole-body by responding to environmental factors including nutrients, hormones, and oxygen. In conditions of metabolic overload such as diabetes mellitus and obesity, coordinated regulation between oxygen supply and consumption has been reported to be disrupted and subsequently cause tissue hypoxia, although pathological significance of the disease-related hypoxia remains elusive. To investigate the role of tissue hypoxia in the liver on systemic glucose homeostasis, mice lacking HIF-1α gene, a critical component of a master regulator of hypoxic response, in hepatocytes were exposed to high fat/sucrose diet (HFSD). Exposure to HFSD for 5 weeks elicited liver hypoxia with a transient increase in HIF-1α protein expression in the liver of control mice. Glucose disposal was marginally impaired in control mice when challenged oral glucose tolerance test, but such impairment was enhanced in the mutant mice. This alteration was accompanied by a complete inhibition of glucokinase induction with a significant reduction of hepatic glucose uptake. Mice fed HFSD for 20 weeks exhibited fasting hyperglycemia and glucose intolerance, whereas these metabolic phenotypes deteriorated considerably with severe insulin resistance in skeletal muscles and adipose tissues in the mutant mice. These findings suggest that HIF-1 in hepatocytes plays protective roles against the progression of diabetes mellitus.

Pregnancy Outcomes After Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer: A 13-Year Experience in a Single Tertiary-Care Center.

Objective To investigate pregnancy outcomes in women after abdominal radical trachelectomy (RT) for early-stage cervical cancer. Methods The patients’ background, fertility, and pregnancy outcomes were reviewed in a total of 61 pregnancies in 48 of 172 women who underwent abdominal RT at Keio University Hospital between September 2002 and December 2013. Results There were 5 women with stage IA1, 2 with stage IA2, and 41 with stage IB1. Histological types were as follows: squamous cell carcinoma (n = 36), adenocarcinoma (n = 10), and adenosquamous cell carcinoma (n = 2). The pregnancy rate of women attempting to conceive after abdominal RT was 44% (48/109). The mean ± SD duration from abdominal RT to conception was 3.1 ± 1.9 years. Of 61 pregnancies, 42 pregnancies were achieved by fertility treatment (in vitro fertilization-embryo transfer, 39; intrauterine insemination, 3). After excluding one pregnancy without detailed clinical information, there were 42 live births (5 in 22–27 weeks, 11 in 28–33weeks, 20 in 34–36 weeks, and 6 in 37–38 weeks), 13 miscarriages, and 5 ongoing pregnancies. While there were 10 first trimester miscarriages, 3 pregnancies ended in the second trimester owing to chorioamnionitis. The mean gestational age at birth was 33 weeks of pregnancy. Thirty-seven neonates were appropriate-for-date, and one was small-for-date. Six pregnancies exhibited massive bleeding from the residual cervix in the late pregnancy. Preterm birth less than 34 weeks of pregnancy was related to premature rupture of the membrane (P < 0.05). Chorioamnionitis was evident in 9 of 11 pregnancies with preterm premature rupture of the membrane followed by birth at less than 34 weeks of pregnancy. No parturients exhibited lochiometra and endometritis postpartum. Conclusions Abdominal RT provided favorable pregnancy outcomes, and fertility treatment could be advantageous to conception. Massive bleeding from the residual cervix as well as ascending infection might be characteristic features during pregnancy after abdominal RT.

Simpson–Golabi–Behmel syndrome diagnosed by postmortem magnetic resonance imaging, restricted autopsy, and molecular genetics: a case report

Fig. 1. T2-weighted postmortem magnetic resonance imaging (MRI). Coronal view of the face demonstrates a small palatal fissure (A). Coronal view of the chest and abdomen shows a congenital diaphragmatic hernia (B). We used a two-dimensional T2-weighted fast-spin echo sequence with a 1.5 T scanner. MRI parameters were as follows: TR, 4800 ms; TE, 120 ms; field of view, 15 cm 15 cm; matrix, 192 256; slice, 2 mm; and scan time, 3 min. Dear Editor,

Prenatal diagnosis of cervical spinal cord compression in chondrodysplasia punctata brachytelephalangic type: A case report and literature review.

Chondrodysplasia punctata brachytelephalangic type is a common subset of a heterogeneous group of chondrodysplasia punctata. Most affected children generally do not have significant physical disabilities; however, a small number of patients are at risk of cervical canal stenosis with cervical cord compression leading to serious morbidity and early mortality. Very little is known about the in utero manifestation of severe complications. We report an affected child in whom the Binder phenotype was found on antenatal ultrasound and cervical spinal cord compression on fetal magnetic resonance imaging. Prenatal diagnosis of chondrodysplasia punctata brachytelephalangic type and its complications are beneficial for timely, prompt medical intervention.

Association of common polymorphisms with gestational diabetes mellitus in Japanese women: A case-control study

Gestational diabetes (GDM) and type 2 diabetes (T2DM) share part of pathomechanism and several T2DM susceptibility genes are demonstrated to be associated with GDM. No information on the genetics of GDM, however, was available in Japanese women. In this study, T2DM risk variants (45 single nucleotide polymorphisms [SNPs] from 36 genes) identified in previous studies were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in a cohort of 171 Japanese women with GDM and 128 normal glucose tolerance (NGT) diagnosed by the new International Association of Diabetes in Pregnancy Study Group criteria. Of 45 SNPs, three genetic variants were nominally associated with the development of GDM: rs266729 (p = 0.013, odds ratio [OR]: 1.56, 95% confidence interval [CI]: 1.10-2.23) in ADIPOQ, rs10811661 (p = 0.035, OR: 1.46, 95% CI: 1.03-2.08) in CDKN2A/2B, and rs9505118 (p = 0.046, OR: 1.41, 95% CI: 1.01-1.97) in SSR1-RREB1. There was a significant difference in the number of risk alleles of three variants between women with GDM and NGT (3.79 ± 1.33 vs. 3.05 ± 1.41, p = 6.0 × 10-6). In combined analysis of three genetic variants, women with five or more risk alleles had a 7.32-fold increased risk of GDM (p = 5.6 × 10-5, 95% CI: 4.54-11.96), compared with those having no more than one risk allele. Our results suggest several risk variants of T2DM had cumulative effects on the development of GDM in Japanese women.

Time-dependent changes in insulin requirement for maternal glycemic control during antenatal corticosteroid therapy in women with gestational diabetes: a retrospective study

Though recommended for pregnant women at risk of preterm birth to improve perinatal outcomes, antenatal corticosteroid (ACS) treatment can cause maternal hyperglycemia, especially in cases of glucose intolerance. A standardized protocol for preventing hyperglycemia during ACS treatment remains to be established. We herein retrospectively investigated the time-dependent changes in insulin dose required for maternal glycemic control during ACS treatment in gestational diabetes (GDM). Twelve singleton pregnant women with GDM who received 12 mg of betamethasone intramuscularly twice 24 hours apart were included in this analysis. Of those, eight also received ritodrine hydrochloride for preterm labor. The blood glucose levels were maintained at 70-120 mg/dL with continuous intravenous infusion of insulin and nothing by mouth for 48 hours after the first betamethasone administration. After the first dose of betamethasone, the insulin dosage needed for glycemic control gradually increased and reached a maximum (6.6 ± 5.8 units/hr) at 10 hours, then, decreased to 4.1 ± 1.5 units/hr at 24 hours. Similar changes in the insulin requirement were found after the second betamethasone dose (the maximum insulin dosage: 5.5 ± 1.6 units/hr at 9 hours following the second administration). Women treated with ritodrine hydrochloride needed more insulin, than those without ritodrine hydrochloride treatment (130.8 ± 15.0 vs. 76.8 ± 15.2 units/day, respectively, p < 0.05). Our data indicated that the requirement for insulin is highest 9-10 hours after each dose of betamethasone. When GDM is treated with ACS, levels of blood glucose should be carefully monitored, especially in patients treated with ritodrine hydrochloride.

Human Amniotic Fluid Stem Cells: Therapeutic Potential for Perinatal Patients with Intractable Neurological Disease

Mesenchymal stem cells (MSCs) have generated great interest in the fields of regenerative medicine and immunotherapy because of their unique biological properties. Among MSCs, amniotic fluid stem cells (AFS) have a number of characteristics that make them attractive candidates for tissue engineering and cell replacement strategies, particularly for perinatal medicine. If various neonatal conditions, including birth asphyxia, preterm birth, and congenital abnormalities, which result in long-lasting severe impairments, could be predicted during pregnancy, it would allow collection of small samples of amniotic fluid cells by amniocentesis. In vitro culture of these autologous AFS during pregnancy would make them available for use soon after birth. Hypoxic-ischemic encephalopathy (HIE) and myelomeningocele (MMC) are neonatal conditions that cause permanent neurological disability, for which the treatment options are extremely limited. Experiments using animal models of HIE and MMC and human clinical trials have demonstrated that MSCs, including AFS, have beneficial effects on the central nervous system through paracrine influences, indicating that autologous AFS treatment may be applicable for intractable neurological diseases, including HIE and MMC, during the perinatal period. In this review, we focus on recent research related to the therapeutic potential of AFS for perinatal neurological diseases such as HIE and MMC.

Mid‐trimester residual cervical length and the risk of preterm birth in pregnancies after abdominal radical trachelectomy: a retrospective analysis

To investigate the association between mid‐trimester residual cervical length (CL) and the risk of preterm birth in pregnancies after abdominal radical trachelectomy (RT).

Intracranial sonographic features demonstrating in utero development of hemorrhagic brain damage leading to schizencephaly-associated COL4A1 mutation

A 34-year-old Japanese woman, gravida 3, para 3, was referred to our hospital at 21 weeks’ gestation for evaluation of unilateral ventriculomegaly. Detailed sonography showed an appropriate-for-date fetus with a ventricular width of 11 mm, suggesting mild unilateral ventriculomegaly (Fig. 1a). A follow-up sonography at 25 weeks’ gestation revealed bilateral ventriculomegaly with multiple hyperechogenic lesions (Fig. 1b), suggesting agenesis of corpus callosum with intracerebral lipomas. At 28 weeks’ gestation, hyperechogenic lesions disappeared and open clefts connecting with the lateral ventricles were noted in the bilateral parieto-temporal region (Fig. 1c). Serological screening for maternal infection with toxoplasma, rubella, herpes simplex, and cytomegalovirus were negative. No other structural abnormalities were found. Taken altogether, the fetus was diagnosed to have schizencephaly. On follow-up examinations, the open clefts became remarkable with severe cortical atrophy. At 37 weeks’ gestation, a female neonate weighing 2467 g was delivered by elective cesarean section, with Apgar scores of 9 and 9 at 1 and 5 min, respectively. Neonatal brain CT demonstrated bilateral open schizencephaly, cortical atrophy, and absence of corpus callosum (Fig. 1d). During the followup, the infant developed severe hemolytic anemia and the genetic examination revealed de novo COL4A1 mutation. Schizencephaly is a rare brain disorder characterized by cerebral clefts. Clinical presentations include microcephaly, seizures, mental retardation, and motor dysfunction. Although the etiology is poorly understood, recent reports have proposed the involvement of COL4A1 mutation in the pathogenesis of schizencephaly [1]. To date, several authors have shown prenatal sonographic and magnetic resonance images of schizencephaly [2]. However, there are no reports on prenatal features demonstrating the formation of schizencephaly. We herein describe the prenatal sonographic features in a case of ventriculomegaly progressing to schizencephaly, where a COL4A1 mutation appeared to be underlain. Mild ventriculomegaly is considered a normal variant, but it might be the only obvious sign of underlying abnormalities including congenital anomalies and infection. Therefore, serial scans should be performed, as many cases may develop. In our case, mild unilateral ventriculomegaly was found on the first examination, and thereafter, bilateral ventriculomegaly became remarkable with multiple hyperechogenic lesions. Since round-shaped lesions were sporadic in the cerebrum, a tentative diagnosis was lipomas. However, open clefts were noted in the corresponding lesions, indicating intracerebral hemorrhage (ICH) followed by cerebral disruptions. The pathogenesis of schizencephaly includes a neuronal migrational disorder and a vascular insult. COL4A1 is an important component of the Type IV collagen in the basement membranes and its mutation could underlie the development of schizencephaly. Likewise, COL4A1 mutation might be involved in the development of ICH leading to schizencephaly in our case.

Familial blue rubber bleb nevus syndrome in pregnancy with spinal epidural involvement.

Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder characterized by multiple venous malformations (VMs) of the skin, gastrointestinal tract, and other organs. To date, several cases of sporadic BRBNS involving various parts of the pregnant womans body have been reported; however, BRBNS in pregnancy with spinal epidural involvement has not been reported. Here, we describe the clinical features and management of familial BRBNS in pregnancy. The patient presented with multiple VMs on her head, neck, floor of the mouth, trunk, leg, foot, and vulva and spinal epidural lesions. The patients mother and sister also exhibited multiple VMs similar lesions, indicating a familial form of BRBNS. Cesarean section under general anesthesia was performed, and a healthy male neonate was delivered. The mothers postoperative course was uneventful and her VMs decreased in size after delivery. Physicians should consider the possibility of systemic diseases and familial inheritance in cases of VMs.