Characteristics of pregnancy complicated with type 1 and type 2 diabetes.

OBJECTIVE: Diabetes in pregnancy is a major risk factor for adverse perinatal outcomes such as congenital anomalies, hypertensive disorders of pregnancy (HDP), and macrosomia. For the mechanism of onset of type 1 and type 2 diabetes are different, we focused on the difference in perinatal outcomes between the type 1 and type 2 diabetes groups. MATERIALS AND METHODS: We retrospectively reviewed 22 pregnancies with type 1 diabetes and 15 pregnancies with type 2 diabetes, who were managed in our single center, with regard to maternal diabetes conditions during pregnancy and neonatal birthweight and blood glucose level. Furthermore, we checked the effect of continuous glucose monitoring and continuous subcutaneous insulin injection in pregnancies with type 1 diabetes. RESULTS: Type 1 diabetes in pregnancy was less controllable and increased neonatal birth weight and neonatal hypoglycemia within 2 h after birth after neonatal care unit admission. Continuous glucose monitoring and continuous subcutaneous insulin injection that are convenient to use, had a similar effect in the management of type 1 diabetes during pregnancy, compared with conventional diabetes treatment. In contrast, maternal BMI and HDP were increased in women with type 2 diabetes. CONCLUSION: In the management of pregnancy with diabetes, we should pay attention to the difference in pregnancy prognosis between type 1 and type 2 diabetes.

The prognosis of neonatal respiratory status within three years after birth in chronic abruption-oligohydramnios sequence.

AIM: Chronic abruption-oligohydramnios sequence (CAOS), which is characterized by vaginal bleeding and oligohydramnios, adversely affects the lungs of fetuses due to bloody amniotic fluid and oligohydramnios. The criteria for termination of pregnancy remain controversial. This study aimed to examine respiratory function in infants within 3 years after birth and risk factors for respiratory prognosis, and to clarify the management of CAOS. METHODS: This study is a case series of patients with CAOS managed at our institution between 2010 and 2020. The clinical data of the patients and their infants within 3 years after birth were reviewed. The amniotic fluid volume was measured using the maximum vertical pocket (MVP). RESULTS: Six of 17 neonates (35.3%) used inhaled nitric oxide (iNO) to improve oxygenation. Women with longer periods of MVP <1 cm delivered more neonates using iNO; however, periods of MVP <2 cm were not associated with iNO use. Almost half of the infants required home oxygen therapy when discharged, regardless of amniotic fluid volume. At 18 months corrected age, only one child needed respiratory support, and the others discontinued. Two neonates, both born at 23 weeks of gestational age, died within 1 month after birth because of extremely preterm birth. CONCLUSIONS: The amniotic fluid volume could predict the use of iNO in neonates, but it did not affect the child's respiratory function after the newborn period. Almost all children born to women with CAOS can improve their respiratory function as they grow up.

A case of solitary lymph node recurrence 9 years after initial treatment for advanced premenopausal endometrioid endometrial cancer; clinical usefulness of hormonal replacement therapy.

There is no consensus on the use of hormone replacement therapy (HRT) after treatment of advanced corpus cancer. We report a case of advanced corpus cancer at a young age, in which HRT was initiated 7 years after surgery, and regional lymph node recurrence was later detected. The patient was 35 years old at the time of initial treatment in X year, when she was diagnosed with stageIIIC2 corpus cancer and underwent a hysterectomy with bilateral salpingo-oophorectomy and a retroperitoneal lymphadenectomy. HRT was started at X + 7 years, and at X + 9 years, a 25 × 12-mm-sized mass was found in the hilum of the right kidney. A laparoscopic resection revealed regional lymph node recurrence of the corpus cancer. A retrospective study further revealed that a tumor measuring 12 × 3 mm was found at X + 3 years and grew to 18 × 7 mm in X + 6 years, just before the start of the HRT. We hypothesize that HRT did not induce tumor recurrence; instead, it allowed for long-term follow-up and early diagnosis.

A Case of a Patient with Adhesive Small Bowel Obstruction in Pregnancy after Extensive Myomectomy for Diffuse Uterine Leiomyomatosis.

Background: Diffuse uterine leiomyomatosis is a rare disease in which countless, poorly defined, and small nodules are present in most parts of the uterine myometrium. It frequently occurs in fertile women and causes infertility. A deep, median, longitudinal incision of the uterine corpus with the opening of the endometrial cavity, "extensive myomectomy," is required to restore fertility. However, myomectomy may also be a risk factor for perinatal complications. We present a rare case of adhesive small bowel obstruction after extensive myomectomy for diffuse uterine leiomyomatosis. Case: A 37-year-old primigravida presented with sharp epigastric pain and vomiting at 21-week gestation. The patient had a history of extensive myomectomy for diffuse uterine leiomyomatosis. Abdominal radiography revealed moderate air fluid levels in the small intestine, and the patient was diagnosed with adhesive small bowel obstruction. The patient was also diagnosed with placenta previa. Bowel rest with intestinal tube was continued until delivery. Cesarean section was performed at 32-week gestation due to (i) prolonged fasting and total parenteral nutrition for conservative treatment and (ii) fear of sudden massive bleeding from placenta previa. Because the ileum was strongly adherent to the uterine scar from the previous myomectomy, adhesiolysis and enterectomy were performed. The placenta was uncomplicatedly delivered and the hemorrhage was well-controlled. Conclusions: Pregnancy with a history with extensive myomectomy for diffuse uterine leiomyomatosis should be carefully monitored because of the occasional occurrence of adhesive small intestine obstruction during pregnancy.

Aplastic Anemia Treated with Eltrombopag during Pregnancy.

Aplastic anemia is a rare blood disorder characterized by pancytopenia and hypocellular bone marrow. In patients with aplastic anemia, pancytopenia sometimes worsens during pregnancy, and relapse of aplastic anemia in pregnancy is common. Nevertheless, only supportive care with blood products is the mainstay of treatment of aplastic anemia in pregnancy. Thus, the obstetric management and treatment of aplastic anemia in pregnancy is extremely challenging. We herein report the first case of a pregnant woman complicated with aplastic anemia who was successfully treated with eltrombopag, a thrombopoietin receptor agonist. A 27-year-old primigravida woman who had a history of aplastic anemia refractory to immunosuppressive therapy and was treated with eltrombopag became pregnant. Eltrombopag treatment was continued after weighing the benefits and potential risks. Throughout pregnancy, the woman's pancytopenia did not progress, and she delivered a 2336 g baby vaginally at 38 weeks of gestation. Her postpartum outcome was uneventful, and the neonate did not develop thrombocytosis. Since the efficacy and safety of eltrombopag in pregnancy has not yet been established, its routine use should be avoided. However, if limited to refractory cases and with adequate maternal and fetal monitoring, including neonatal blood examinations, the use of eltrombopag for patients with aplastic anemia during pregnancy may be acceptable and result in favorable maternal and fetal outcomes.

Laparoscopic hysterectomy for endometrial cancer after the Fontan procedure: The first case report.

The Fontan procedure is a palliative cardiac surgery performed for children with a single functional ventricle, and its aim is to divert central venous return to the pulmonary artery without passing through the right ventricle. We herein report the first case of endometrial cancer after the Fontan procedure that was successfully treated with laparoscopic hysterectomy. A 38-year-old female who underwent the Fontan procedure at the age of 23 presented with abnormal genital bleeding and was diagnosed with endometrial cancer. Computed tomography revealed distinctive venous vasculature in the pelvis: most of the venous return from the left lower extremity occurred via the extremely distended left ovarian vein. Laparoscopic total hysterectomy and bilateral salpingo-oophorectomy were performed. The pneumoperitoneum was maintained at 8-10 mmHg during the operation so that the high intra-abdominal pressure would not interfere with venous return. In addition, the left ovarian vein was first test clamped to ensure that circulation was maintained and was then resected. Although the volume of blood loss reached 358 ml due to high venous pressure, her postoperative course was favorable, and she had no signs of recurrence at the 12-month follow-up. Our case suggests that laparoscopic hysterectomy might be safe and feasible for patients with endometrial cancer after the Fontan procedure, as long as a preoperative study of pelvic vascularization and intraoperative monitoring of the circulation is carried out.

Recent advances in understanding adverse effects associated with drugs targeting the serotonin receptor, 5-HT GPCR.

It has been acknowledged that more women suffer from adverse effects of drugs than men globally. A group of drugs targeting serotonin [5-hydroxytryptamine] (5-HT) binding G-protein-coupled receptors (GPCRs) have been reported to preferentially affect women more than men, causing adverse effects such as breast cancer and infertility. 5-HT GPCR-targeted drugs in the central nervous system (CNS) manage psychiatric conditions, such as depression or bipolar and in the peripheral nervous system (PNS) treat migraines. Physiological characteristics such as specific types of hormones, higher body fat density and smaller body mass in women result in disparities in pharmacodynamics of drugs, thus explaining sex-related differences in the observed adverse effects. In this review, we discuss the side effects of drugs targeting 5-HT GPCRs based on serotonin's roles in the CNS and PNS. We have systematically reviewed adverse effects of drugs targeting 5-HT GPCR using information from the Food and Drug Administration and European Medicines Agency. Further information on drug side effects and receptor targets was acquired from the SIDER and DrugBank databases, respectively. These drugs bind to 5-HT GPCRs in the CNS, namely the brain, and PNS such as breasts, ovaries and testes, potentially causing side effects within these areas. Oestrogen affects both the biosynthesis of 5-HT and the densities of 5-HT GPCRs in given tissues and cells. 5-HT GPCR-targeting drugs perturb this process. This is likely a reason why women are experiencing more adverse effects than men due to their periodic increase and the relatively high concentrations of oestrogen in women and, thus a greater incidence of the oestrogen-mediated 5-HT system interference. In addition, women have a lower concentration of serotonin relative to men and also have a relatively faster rate of serotonin metabolism which might be contributing to the former. We discuss potential approaches that could mitigate at least some of the adverse effects experienced by women taking the 5-HT GPCR-targeting drugs.

V-ATPase Inhibition Decreases Mutant Androgen Receptor Activity in Castrate-resistant Prostate Cancer.

Prostate cancer is critically dependent on androgen receptor (AR) signaling. Despite initial responsiveness to androgen deprivation, most patients with advanced prostate cancer subsequently progress to a clinically aggressive castrate-resistant prostate cancer (CRPC) phenotype, typically associated with expression of splice-variant or mutant AR forms. Although current evidence suggests that the vacuolar-ATPase (V-ATPase), a multiprotein complex that catalyzes proton transport across intracellular and plasma membranes, influences wild-type AR function, the effect of V-ATPase inhibition on variant AR function is unknown.Inhibition of V-ATPase reduced AR function in wild-type and mutant AR luciferase reporter models. In hormone-sensitive prostate cancer cell lines (LNCaP, DuCaP) and mutant AR CRPC cell lines (22Rv1, LNCaP-F877L/T878A), V-ATPase inhibition using bafilomycin-A1 and concanamycin-A reduced AR expression, and expression of AR target genes, at mRNA and protein levels. Furthermore, combining chemical V-ATPase inhibition with the AR antagonist enzalutamide resulted in a greater reduction in AR downstream target expression than enzalutamide alone in LNCaP cells. To investigate the role of individual subunit isoforms, siRNA and CRISPR-Cas9 were used to target the V1C1 subunit in 22Rv1 cells. Whereas transfection with ATP6V1C1-targeted siRNA significantly reduced AR protein levels and function, CRISPR-Cas9-mediated V1C1 knockout showed no substantial change in AR expression, but a compensatory increase in protein levels of the alternate V1C2 isoform.Overall, these results indicate that V-ATPase dysregulation is directly linked to both hormone-responsive prostate cancer and CRPC via impact on AR function. In particular, V-ATPase inhibition can reduce AR signaling regardless of mutant AR expression.

Light Regulation of Chlorophyll and Glycoalkaloid Biosynthesis During Tuber Greening of Potato S. tuberosum.

Potato, S. tuberosum, is one of the most important global crops, but has high levels of waste due to tuber greening under light, which is associated with the accumulation of neurotoxic glycoalkaloids. However, unlike the situation in de-etiolating seedlings, the mechanisms underlying tuber greening are not well understood. Here, we have investigated the effect of monochromatic blue, red, and far-red light on the regulation of chlorophyll and glycoalkaloid accumulation in potato tubers. Blue and red wavelengths were effective for induction and accumulation of chlorophyll, carotenoids and the two major potato glycoalkaloids, α-solanine and α-chaconine, whereas none of these accumulated in darkness or under far-red light. Key genes in chlorophyll biosynthesis (HEMA1, encoding the rate-limiting enzyme glutamyl-tRNA reductase, GSA, CHLH and GUN4) and six genes (HMG1, SQS, CAS1, SSR2, SGT1 and SGT2) required for glycoalkaloid synthesis were also induced under white, blue, and red light but not in darkness or under far-red light. These data suggest a role for both cryptochrome and phytochrome photoreceptors in chlorophyll and glycoalkaloid accumulation. The contribution of phytochrome was further supported by the observation that far-red light could inhibit white light-induced chlorophyll and glycoalkaloid accumulation and associated gene expression. Transcriptomic analysis of tubers exposed to white, blue, and red light showed that light induction of photosynthesis and tetrapyrrole-related genes grouped into three distinct groups with one group showing a generally progressive induction by light at both 6 h and 24 h, a second group showing induction at 6 h in all light treatments, but induction only by red and white light at 24 h and a third showing just a very moderate light induction at 6 h which was reduced to the dark control level at 24 h. All glycoalkaloid synthesis genes showed a group one profile consistent with what was seen for the most light regulated chlorophyll synthesis genes. Our data provide a molecular framework for developing new approaches to reducing waste due to potato greening.

The retrograde signaling protein GUN1 regulates tetrapyrrole biosynthesis.

The biogenesis of the photosynthetic apparatus in developing seedlings requires the assembly of proteins encoded on both nuclear and chloroplast genomes. To coordinate this process there needs to be communication between these organelles, but the retrograde signals by which the chloroplast communicates with the nucleus at this time are still essentially unknown. The Arabidopsis thaliana genomes uncoupled (gun) mutants, that show elevated nuclear gene expression after chloroplast damage, have formed the basis of our understanding of retrograde signaling. Of the 6 reported gun mutations, 5 are in tetrapyrrole biosynthesis proteins and this has led to the development of a model for chloroplast-to-nucleus retrograde signaling in which ferrochelatase 1 (FC1)-dependent heme synthesis generates a positive signal promoting expression of photosynthesis-related genes. However, the molecular consequences of the strongest of the gun mutants, gun1, are poorly understood, preventing the development of a unifying hypothesis for chloroplast-to-nucleus signaling. Here, we show that GUN1 directly binds to heme and other porphyrins, reduces flux through the tetrapyrrole biosynthesis pathway to limit heme and protochlorophyllide synthesis, and can increase the chelatase activity of FC1. These results raise the possibility that the signaling role of GUN1 may be manifested through changes in tetrapyrrole metabolism, supporting a role for tetrapyrroles as mediators of a single biogenic chloroplast-to-nucleus retrograde signaling pathway.

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer.

Vacuolar ATPase (V-ATPase) is an ATP-dependent H+ -transporter that pumps protons across intracellular and plasma membranes. It consists of a large multi-subunit protein complex and influences a wide range of cellular processes. This review focuses on emerging evidence for the roles for V-ATPase in cancer. This includes how V-ATPase dysregulation contributes to cancer growth, metastasis, invasion and proliferation, and the potential link between V-ATPase and the development of drug resistance.

A chloroplast-localized protein LESION AND LAMINA BENDING affects defence and growth responses in rice.

Understanding how plants allocate their resources to growth or defence is of long-term importance to the development of new and improved varieties of different crops. Using molecular genetics, plant physiology, hormone analysis and Next-Generation Sequencing (NGS)-based transcript profiling, we have isolated and characterized the rice (Oryza sativa) LESION AND LAMINA BENDING (LLB) gene that encodes a chloroplast-targeted putative leucine carboxyl methyltransferase. Loss of LLB function results in reduced growth and yield, hypersensitive response (HR)-like lesions, accumulation of the antimicrobial compounds momilactones and phytocassanes, and constitutive expression of pathogenesis-related genes. Consistent with these defence-associated responses, llb shows enhanced resistance to rice blast (Magnaporthe oryzae) and bacterial blight (Xanthomonas oryzae pv. oryzae). The lesion and resistance phenotypes are likely to be caused by the over-accumulation of jasmonates (JAs) in the llb mutant including the JA precursor 12-oxo-phytodienoic acid. Additionally, llb shows an increased lamina inclination and enhanced early seedling growth due to elevated brassinosteroid (BR) synthesis and/or signalling. These findings show that LLB functions in the chloroplast to either directly or indirectly repress both JA- and BR-mediated responses, revealing a possible mechanism for controlling how plants allocate resources for defence and growth.

Molecular interaction of jasmonate and phytochrome A signalling.

The phytochrome family of red (R) and far-red (FR) light receptors (phyA-phyE in Arabidopsis) play important roles throughout plant development and regulate elongation growth during de-etiolation and under light. Phytochromes regulate growth through interaction with the phytohormones gibberellin, auxin, and brassinosteroid. Recently it has been established that jasmonic acid (JA), a phytohormone for stress responses, namely wounding and defence, is also important in inhibition of hypocotyl growth regulated by phyA and phyB. This review focuses on recent advances in our understanding of the molecular basis of the interaction between JA and phytochrome signalling particularly during seedling development in Arabidopsis. Significantly, JA biosynthesis genes are induced by phyA. The protein abundance of JAR1/FIN219, an enzyme for the final synthesis step to give JA-Ile, an active form of JA, is also determined by phyA. In addition, JAR1/FIN219 directly interacts with an E3-ligase, COP1, a master regulator for transcription factors regulating hypocotyl growth, suggesting a more direct role in growth regulation. There are a number of points of interaction in the molecular signalling of JA and phytochrome during seedling development in Arabidopsis, and we propose a model for how they work together to regulate hypocotyl growth.

Rotational catalysis in proton pumping ATPases: from E. coli F-ATPase to mammalian V-ATPase.

We focus on the rotational catalysis of Escherichia coli F-ATPase (ATP synthase, F(O)F(1)). Using a probe with low viscous drag, we found stochastic fluctuation of the rotation rates, a flat energy pathway, and contribution of an inhibited state to the overall behavior of the enzyme. Mutational analyses revealed the importance of the interactions among ß and γ subunits and the ß subunit catalytic domain. We also discuss the V-ATPase, which has different physiological roles from the F-ATPase, but is structurally and mechanistically similar. We review the rotation, diversity of subunits, and the regulatory mechanism of reversible subunit dissociation/assembly of Saccharomyces cerevisiae and mammalian complexes. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).

Double rolling circle replication (DRCR) is recombinogenic.

Homologous recombination plays a critical role in maintaining genetic diversity as well as genome stability. Interesting examples implying hyper-recombination are found in nature. In chloroplast DNA (cpDNA) and the herpes simplex virus 1 (HSV-1) genome, DNA sequences flanked by inverted repeats undergo inversion very frequently, suggesting hyper-recombinational events. However, mechanisms responsible for these events remain unknown. We previously observed very frequent inversion in a designed amplification system based on double rolling circle replication (DRCR). Here, utilizing the yeast 2-µm plasmid and an amplification system, we show that DRCR is closely related to hyper-recombinational events. Inverted repeats or direct repeats inserted into these systems frequently caused inversion or deletion/duplication, respectively, in a DRCR-dependent manner. Based on these observations, we suggest that DRCR might be also involved in naturally occurring chromosome rearrangement associated with gene amplification and the replication of cpDNA and HSV genomes. We propose a model in which DRCR markedly stimulates homologous recombination.

Imaging of transgenic cricket embryos reveals cell movements consistent with a syncytial patterning mechanism.

The mode of insect embryogenesis varies among species, reflecting adaptations to different life history strategies [1, 2]. In holometabolous insects, which include the model systems, such as the fruit fly and the red flour beetle, a large proportion of the blastoderm produces an embryo, whereas hemimetabolous embryos generally arise from a small region of the blastoderm [3]. Despite their importance in evolutionary studies, information of early developmental dynamics of hemimetabolous insects remains limited. Here, to clarify how maternal and gap gene products act in patterning the embryo of basal hemimetabolous insects, we analyzed the dynamic segmentation process in transgenic embryos of an intermediate-germ insect species, the cricket, Gryllus bimaculatus. Our data based on live imaging of fluorescently labeled embryonic cells and nuclei suggest that the positional specification of the cellular blastoderm may be established in the syncytium, where maternally derived gradients could act fundamentally in a way that is similar to that of Drosophila, namely throughout the egg. Then, the blastoderm cells move dynamically, retaining their positional information to form the posteriorly localized germ anlage. Furthermore, we find that the anterior head region of the cricket embryo is specified by orthodenticle in a cellular environment earlier than the gnathal and thoracic regions. Our findings imply that the syncytial mode of the early segmentation in long-germ insects evolved from a dynamic syncytial-to-cellular mode found in the present study, accompanied by a heterochronic shift of gap gene action.

Jasmonate and phytochrome A signaling in Arabidopsis wound and shade responses are integrated through JAZ1 stability.

Jasmonate (JA) activates plant defense, promotes pollen maturation, and suppresses plant growth. An emerging theme in JA biology is its involvement in light responses; here, we examine the interdependence of the JA- and light-signaling pathways in Arabidopsis thaliana. We demonstrate that mutants deficient in JA biosynthesis and signaling are deficient in a subset of high irradiance responses in far-red (FR) light. These mutants display exaggerated shade responses to low, but not high, R/FR ratio light, suggesting a role for JA in phytochrome A (phyA) signaling. Additionally, we demonstrate that the FR light-induced expression of transcription factor genes is dependent on CORONATINE INSENSITIVE1 (COI1), a central component of JA signaling, and is suppressed by JA. phyA mutants had reduced JA-regulated growth inhibition and VSP expression and increased content of cis-(+)-12-oxophytodienoic acid, an intermediate in JA biosynthesis. Significantly, COI1-mediated degradation of JASMONATE ZIM DOMAIN1-beta-glucuronidase (JAZ1-GUS) in response to mechanical wounding and JA treatment required phyA, and ectopic expression of JAZ1-GUS resulted in exaggerated shade responses. Together, these results indicate that JA and phyA signaling are integrated through degradation of the JAZ1 protein, and both are required for plant responses to light and stress.

The alpha-subunit of the heterotrimeric G-protein affects jasmonate responses in Arabidopsis thaliana.

Heterotrimeric G-proteins have been implicated in having a role in many plant signalling pathways. To understand further the role of G-proteins, a preliminary experiment was performed to assess the impact of the G alpha subunit loss-of-function mutation gpa1-1 on the Arabidopsis transcriptome. The analysis indicated that the G alpha subunit may play a role in response to jasmonic acid (JA). Consistent with this, G alpha mutants showed a reduced response to JA in inhibition of chlorophyll accumulation and root growth, whilst G alpha gain-of-function plants overexpressing G alpha showed the opposite phenotype. The levels of JA and related compounds were unaffected in the gpa1-1 mutant, as was autoregulation of the Allene Oxide Synthase (AOS) gene that encodes a key enzyme for JA biosynthesis. In contrast, further analyses using G alpha loss- and gain-of-function Arabidopsis lines indicated that G alpha positively modulates the expression of the Vegetative Storage Protein (VSP) gene. This indicates that the G alpha subunit regulates a subset of JA-regulated genes defining a branch point in this signalling pathway in Arabidopsis. Further analysis of the impact of G alpha loss of function upon the JA-regulated transcriptome using Arabidopsis full genome arrays indicated that up to 29% of genes that are >2-fold regulated by JA in the wild type are misregulated in the G alpha mutant. This supports the observation that a significant proportion of, but not all, JA-regulated gene expression is mediated by G alpha.