Intravenous immunoglobulin treatment for obstetric antiphospholipid syndrome refractory to conventional therapy: A single-arm, open-labelled multicentre clinical trial.

OBJECTIVES: The objective of the study was to compare the efficacy of intravenous immunoglobulin (IVIG) therapy for obstetric antiphospholipid syndrome (APS) refractory to conventional treatment. METHODS: We conducted a single-arm, open-label multicentre clinical intervention trial. The enrolled criteria were patients with refractory APS who had a history of still or premature birth before 30 weeks of gestational age, even though they had been treated with conventional treatment, i.e. heparin and low-dose aspirin. After confirming the foetal heartbeats, a single course of IVIG (0.4 g/kg body weight daily for 5 days) was added to conventional treatment. The primary outcome was a live birth ratio of >30 weeks of gestational period, and the secondary outcome included improving pregnancy outcomes compared to previous pregnancy. RESULTS: Twenty-five per cent of patients (2 of 8 cases) achieved a live birth after the 30th week of pregnancy by IVIG-only add-on treatment, which is the same prevalence as the historical control. However, by adding other second-line therapy to IVIG and conventional treatment, further three patients (37.5%) achieved improvements in pregnancy outcome compared to previous treatments. In total, five patients (62.5%) were able to achieve preferable pregnancy outcomes through combination treatment including IVIG. CONCLUSIONS: This clinical trial could not demonstrate the efficacy of IVIG-only add-on therapy at improving the pregnancy outcomes of patients with obstetric APS refractory to conventional treatment. However, the combination of IVIG with rituximab or statins adding to conventional treatment improved pregnancy outcomes and resulted in more live births. Further studies are needed to investigate the efficacy of multi-targeted therapy to treat obstetric refractory APS.

Supersonic jet noise from launch vehicles: 50 years since NASA SP-8072.

In 1971, the U.S. National Aeronautics and Space Administration (NASA) published a seminal report-NASA SP-8072-which compiled the results of the early supersonic jet noise studies and provided methods to calculate the noise produced from launch vehicles. Fifty years later and despite known limitations, SP-8072 remains the foundation for much of the launch vehicle noise modeling today. This article reviews what has been learned about the physics of noise generation and radiation from free and impinging rocket plumes since the completion of SP-8072. State-of-the-art methods for the mitigation of launch vehicle noise are also reviewed. A discussion of launch vehicle noise modeling, from empirical to numerical and including reduced-order models of supersonic jets, points to promising approaches that can describe rocket noise characteristics not captured by SP-8072.

Experimental study on effects of plate angle on acoustic waves from supersonic impinging jets.

This study experimentally investigates the generation mechanism of a higher-angle lobe which is an acoustic field feature of a supersonic jet impinging on an inclined flat plate. The overall sound pressure level distribution and spectra, the conditional averages of near field schlieren movies, and the time-averaged wall pressure distribution were obtained for three cases of Mach 1.8 ideally expanded impinging jets with plate angles of 45°, 22.5°, and 10° to the jet downstream axis. In the 45° and 22.5° cases, a higher-angle lobe appears. The dominant acoustic waves in the higher-angle lobe are radiated from the source region that contains shock waves and are suggested to be correlated with large-scale turbulent structures. These results suggest that the higher-angle lobe is dominated by acoustic waves generated by the interaction between the shock waves and large-scale turbulent structures. This inference is supported by the fact that the near-field acoustic wave patterns are qualitatively reproduced by the interference of monopoles located near the shock waves in the 45° and 22.5° cases and that neither the shock wave nor the higher-angle lobe is observed in the 10° case.

Conditional sampling analysis of high-speed schlieren movies of Mach wave radiation in a supersonic jet.

Acoustic-triggered conditional sampling analysis can extract the broadband-noise-related intermittent fluctuations from complicated schlieren visualization movies around the source region, which is difficult when using conventional methods. In this study, an analysis of the Mach wave radiation from a supersonic jet was performed. The extracted results properly captured the known features of the Mach waves and their sources (i.e., wavepacket at the jet boundary) and clearly showed the correlation between these near-field fluctuations and the far-field intermittent acoustic events. This analysis can potentially be applied to other broadband, intermittent turbulent noise and will provide a better understanding of their generation mechanisms.

Data-educed broadband equivalent acoustic source model for supersonic jet noise.

A broadband equivalent acoustic source distribution can be used to model the sound field near a high-speed jet. Such models must account for the spatiospectral variation of the sound levels. This work presents a technique for obtaining such a model using a spectral decomposition method associated with large and fine-scale turbulent mixing noise to create broadband equivalent source distributions for each noise type. The large-scale turbulent mixing noise is represented by frequency-dependent wavepackets, while the fine-scale turbulent mixing noise is modeled as a frequency-dependent incoherent, extended source distribution. This technique is applied to acoustical measurements from an ideally expanded, unheated Mach 1.8 jet. The wavepackets model the sound field levels in the maximum radiation region, but the second incoherent source distribution is required to obtain the levels at the other locations. The combination of the incoherent source distribution and the wavepacket provides a broadband, equivalent acoustic source representation that adequately models the sound field for Strouhal numbers between 0.04 and 0.25. At higher Strouhal numbers, better agreement is obtained when accounting for a frequency-dependent shift in the apparent acoustic source region. This frequency-dependent source region is more important closer to the jet than in the far field.

Whole-exome sequencing confirmation of a novel heterozygous mutation in RUNX1 in a pregnant woman with platelet disorder.

We describe a successful pregnancy and delivery in a patient with platelet disorder. Prophylactic platelet transfusions ensured that there were no bleeding complications during and after cesarean section. Following delivery, we performed whole exome sequencing, using next generation sequencing, to analyze the DNA samples of the patient and her family, and to identify the disease-causing mutation or variant. To identify de-novo mutations systematically, we also analyzed DNA isolated from the parents of the patient and the neonate. We successfully identified a causative novel mutation c.419 G > A (p.S140N) in RUNX1 in the patient and the neonate. Mutations of RUNX1 have been reported to be associated with familial platelet disorder and with a predisposition for myelodysplasia and/or acute myeloid leukemia. The patient and the neonate require careful long-term hematological follow-up. Identification of mutations by a through whole-exome analysis using next-generation sequencing may be useful in the determination of a long-term follow-up schedule for the patient.

Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.

Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as ABD mutations demonstrated that with only one exception disease-associated substitutions, surrounding hinge 1 demonstrated no tendency to form actin-filamin foci. The exception, a substitution in filamin repeat 6, lies within a region previously implicated in filamin-actin binding. These data are consistent with mutations in the ABD conferring enhanced actin-binding activity but suggest that substitutions affecting repeats near the flexible hinge region of FLNB precipitate the same phenotypes through a different mechanism.

Estrogen induces neurite outgrowth via Rho family GTPases in neuroblastoma cells.

Estrogen (E2) has direct in vivo and in vitro effects, such as inducing neurite outgrowth, on neurons. We investigated the morphological changes and intracellular signaling pathway induced by E2 in neuroblastoma (SH-SY5Y) cells. The effect of medroxyprogesterone acetate (MPA) or progesterone (P4) on the E2-induced neurite outgrowth was also examined using SH-SY5Y cells. Neurite outgrowth was induced by E2 in association with the phosphorylation of Akt, and these effects of E2 were abolished by MPA but not by P4. Progesterone receptor antagonist RU486 blocked the inhibitory effects of MPA. Estrogen receptor antagonist ICI 182,780 and phosphatidylinositol 3-kinase inhibitor LY294002 inhibited the E2-induced neurite outgrowth. Because the Rho family of small GTPases has been shown to be involved in the regulation of neurite outgrowth, we examined the cross-talk among Rac1, Cdc42 and RhoA in the E2-induced neurite outgrowth. E2 immediately increased the Rac1 and Cdc42 activity and decreased the RhoA activity. E2-induced neurite outgrowth was attenuated in cells expressing dominant-negative mutants for Rac1 or Cdc42. These results suggest that regulation of Rho family GTPase activity by E2 is important for the neurite outgrowth in neuroblastoma cells, and that MPA may have an antagonistic effect against E2.

A case of boomerang dysplasia with a novel causative mutation in filamin B: identification of typical imaging findings on ultrasonography and 3D-CT imaging.

Boomerang dysplasia is a rare lethal osteochondrodysplasia characterized by disorganized mineralization of the skeleton, leading to complete nonossification of some limb bones and vertebral elements, and a boomerang-like aspect to some of the long tubular bones. Like many short-limbed skeletal dysplasias with accompanying thoracic hypoplasia, the potential lethality of the phenotype can be difficult to ascertain prenatally. We report a case of boomerang dysplasia prenatally diagnosed by use of ultrasonography and 3D-CT imaging, and identified a novel mutation in the gene encoding the cytoskeletal protein filamin B (FLNB) postmortem. Findings that aided the radiological diagnosis of this condition in utero included absent ossification of two out of three long bones in each limb and elements of the vertebrae and a boomerang-like shape to the ulnae. The identified mutation is the third described for this disorder and is predicted to lead to amino acid substitution in the actin-binding domain of the filamin B molecule.

The Change of Oxidative Stress in Maternal Blood During Pregnancy.

Oxidative stress (OS) is a state in which the oxidative capacity exceeds the antioxidant capacity in vivo. OS is associated with various perinatal diseases. There have been few reports about OS during pregnancy, such as OS changes that occur during gestation, normal maternal OS dynamics, and OS levels in umbilical cord blood. We here examined the oxidative and antioxidant capacity in maternal blood as well as in umbilical cord vein blood during normal pregnancy. Pregnant women managed from early pregnancy to the postpartum period in our hospital, from April 2018 to March 2019, were included. We obtained maternal blood at 12, 24, and 36 weeks of gestation and obtained umbilical cord blood at delivery. The OS (derivatives of reactive oxygen metabolites [d-ROMs]) and antioxidant capacity (biological antioxidant potential [BAP]) of blood samples were measured. D-ROMs and BAP were compared across gestational weeks. Moreover, d-ROMs and BAP were compared between mothers with and without disease. We analyzed 100 pregnancies (651 specimens). Eleven patients developed hypertensive disorder of pregnancy (HDP)/preeclampsia (PE). The median maternal age was 35 years, and the median gestational age at delivery was 39 weeks. Thirty-one women had undergone fertility treatments. D-ROM values were significantly higher and BAP values were significantly lower in mid- and late pregnancy than in early pregnancy. D-ROM and BAP showed no significant differences between HDP/PE and non-hypertensive groups. During pregnancy, maternal OS increases, and antioxidant capacity decreases with advancing gestational age.

Infectious sacroiliitis due to group A streptococcus infection during pregnancy: a case report.

BACKGROUND: Group A streptococcus infection during pregnancy can be concerning. It may cause toxic shock syndrome, which can be fatal. Here, we report a rare case of a pregnant woman who developed infectious sacroiliitis due to group A streptococcus infection. To the best of our knowledge, this case is the first of its kind to be reported. CASE PRESENTATION: A 32-year-old multiparous Japanese woman presented with fever and right buttock pain at 28 weeks of gestation. Based on our clinical findings and investigations, she was diagnosed with group A streptococcus bacteremia and infectious sacroiliitis caused by group A streptococcus. A cardiotocography performed to assess the fetal status showed fetal tachycardia. To prevent the patient from progressing to toxic shock syndrome caused by group A streptococcus, we performed an emergency cesarean section. The patient and her infant had a good course after the cesarean section. CONCLUSION: A pregnant woman diagnosed with group A streptococcus infection needs to be monitored closely because a timely decision to deliver the fetus before rapid deterioration to toxic shock syndrome is crucial.

The safety of pranlukast and montelukast during the first trimester of pregnancy: A prospective, two-centered cohort study in Japan.

For leukotriene receptor antagonists (LTRAs), especially pranlukast, safety data during pregnancy is limited. Therefore, we conducted a prospective, two-centered cohort study using data from teratogen information services in Japan to clarify the effects of LTRA exposure during pregnancy on maternal and fetal outcomes. Pregnant women who being counseled on drug use during pregnancy at two facilities were enrolled. The primary outcome of this study was major congenital anomalies. The incidence of major congenital anomalies in women exposed to montelukast or pranlukast during the first trimester of pregnancy was compared with that of controls. Logistic regression analysis was performed to analyze the effects of maternal LTRA use during the first trimester of pregnancy on major congenital anomalies. The outcomes of 231 pregnant women exposed to LTRAs (montelukast n = 122; pranlukast n = 106; both n = 3) and 212 live births were compared with those of controls. The rate of major congenital anomalies in the LTRA group was 1.9%. Multivariable logistic regression analysis revealed that LTRA exposure was not a risk factor for major congenital anomalies (adjusted odds ratio, 0.78; 95% confidence interval, 0.23-2.05; p = 0.653). In addition, no significant difference was detected in stillbirth, spontaneous abortion, preterm birth, and low birth weight between the two groups. The present study revealed that montelukast and pranlukast were not associated with the risk of major congenital anomalies. Our findings suggest that LTRAs could be safely employed for asthma therapy during pregnancy.

Bezafibrate restores the inhibition of FSH-induced follicular development and steroidogenesis by tumor necrosis factor-alpha through peroxisome proliferator-activated receptor-gamma pathway in an in vitro mouse preantral follicle culture.

We recently reported that bezafibrate, a lipid-lowering drug of the fibrate class, administered in addition to clomiphene citrate (CC) successfully induced ovulation in CC-resistant polycystic ovary syndrome (PCOS) patients. We hypothesized that bezafibrate may directly affect ovarian follicle development. Insulin resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS. In this study, we first examined the effects of tumor necrosis factor-alpha (TNF), which plays a role in insulin resistance, on follicle development by using the follicle culture system. TNF significantly inhibited follicle-stimulating hormone (FSH)-induced follicle development, 17beta-estradiol (E2) secretion, and ovulation rate in a dose-dependent manner. We then examined whether bezafibrate treatment could rescue the inhibition of FSH-induced follicle development and steroidogenesis by TNF. Bezafibrate treatment rescued inhibition of follicle development, secretion of E2, and ovulation rate by TNF. We examined the expression of peroxisome proliferator-activated receptor (PPAR) subtypes in mouse preantral follicles. As the protein expression of only PPARG was observed in mouse preantral follicles, we examined whether bezafibrate could affect follicle development and steroidogenesis through PPARG pathways. Treatment with GW1929, a selective PPARG agonist, restored inhibition of FSH-induced follicle development and steroidogenesis by TNF, whereas treatment with GW9662, a selective PPARG antagonist, canceled the restorative effects of bezafibrate. Collectively, the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by TNF through the PPARG pathway.

Correction: Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel.

[This corrects the article DOI: 10.18632/oncotarget.25868.].

Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells.

Hypoxic response of endothelial cells (EC) is an important component of tumor angiogenesis. Especially, hypoxia-inducible factor-1 (HIF-1)-dependent EC-specific mechanism is an essential component of tumor angiogenesis. Recently, the Rho/Rho-associated kinase (ROCK) signaling has been shown to play a key role in HIF-1alpha induction in renal cell carcinoma and trophoblast. The present study was designed to investigate whether low oxygen conditions might modulate HIF-1alpha expression through the Rho/ROCK signaling in human umbilical vascular ECs (HUVEC). Pull-down assay showed that hypoxia stimulated RhoA activity. Under hypoxic conditions, HUVECs transfected with small interfering RNA of RhoA and ROCK2 exhibited decreased levels of HIF-1alpha protein compared with nontargeted small interfering RNA transfectants, whereas HIF-1alpha mRNA levels were not altered. One of ROCK inhibitors, fasudil, inhibited hypoxia-induced HIF-1alpha expression without altering HIF-1alpha mRNA expression. Furthermore, proteasome inhibitor prevented the effect of fasudil on HIF-1alpha expression, and polyubiquitination was enhanced by fasudil. These results suggested that hypoxia-induced HIF-1alpha expression is through preventing HIF-1alpha degradation by activating the Rho/ROCK signaling in ECs. Furthermore, hypoxia induced both vascular endothelial growth factor (VEGF) and VEGF receptor-2 expression through the Rho/ROCK/HIF-1alpha signaling in HUVECs. Thus, augmented VEGF/VEGF receptor-2 autocrine mechanism stimulated HUVEC migration under hypoxic conditions. In summary, the Rho/ROCK/HIF-1alpha signaling is an essential mechanism for hypoxia-driven, VEGF-mediated autocrine loop in ECs. Therefore, fasudil might have the antimigratory effect against ECs in tumor angiogenesis.

Successful management of cutaneous lymphangitis carcinomatosa arising from cervical cancer with paclitaxel-cisplatin and bevacizumab combination therapy: a case report and review of the literature.

BACKGROUND: Globally, cervical cancer is the fourth most common cancer in women. Here, we report a case of cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant condition. CASE PRESENTATION: A 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2 years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral and pubic area. Slight 18F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron emission tomography with computed tomography. A histopathological examination was performed on a biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/m2), cisplatin (50 mg/m2), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days. Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free interval after the last chemotherapy session. CONCLUSION: Our findings suggest that combination chemotherapy plus bevacizumab is an effective therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.

Prenatal diagnosis of thanatophoric dysplasia by 3-D helical computed tomography and genetic analysis.

OBJECTIVE: We report the first case of thanatophoric dysplasia (TD) successfully diagnosed in utero by a combination of 2-D ultrasound, computed tomography (CT) 3-D imaging and genetic analysis at 26 weeks' gestation. METHODS: Prenatal sonographic examinations performed at 23 weeks' gestation revealed micromelic shortening of the limbs, reduced thoracic cavity and a presence of cloverleaf skull deformity. Based on these findings, a lethal form of skeletal dysplasia was suspected and a helical CT imaging with 3-D reconstruction depicted skeletal abnormalities which suggested TD. The prenatal diagnosis was affirmed on amniotic fluid cells by DNA mutation analysis of the fibroblast growth factor receptor 3 gene. RESULTS: A missense mutation (tyrosine 373 to cysteine) was detected, and was diagnosed as TD type I. CONCLUSION: Helical CT imaging with 3-D reconstruction and molecular testing are useful adjuncts to 2-D ultrasonography in the diagnosis of lethal skeletal dysplasias, allowing for appropriate perinatal support including genetic counseling.

Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.

Vascular endothelial growth factor (VEGF)-induced endothelial cell migration is an important component of tumor angiogenesis. Rho and Rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber formation, and thus cell motility. Inhibitors of this pathway have been shown to inhibit endothelial cell motility and angiogenesis. In this study, we investigated the antiangiogenic effect of fasudil, one of the ROCK inhibitors. Fasudil inhibited VEGF-induced endothelial cell migration, viability, and tube formation in vitro in human umbilical vein endothelial cells. VEGF-induced endothelial cell migration was reduced by fasudil associated with loss of stress fiber formation, focal adhesion assembly, and with the suppression of tyrosine phosphorylation of focal adhesion proteins. Furthermore, fasudil inhibited VEGF-induced phosphorylation of myosin light chain, which is one of the main substrates of ROCK. Therefore, the effect of fasudil was suggested to be ROCK dependent. Fasudil not only inhibited VEGF-induced cell proliferation but also reversed the protective effect of VEGF on apoptosis, which resulted in the decrease of cell viability. Moreover, fasudil inhibited VEGF-induced angiogenesis in a directed in vivo angiogenesis assay. These data are the first demonstration that fasudil has antiangiogenic properties. Therefore, fasudil might be useful for the treatment of angiogenesis-related diseases, especially cancer.

Longitudinal serum and urine steroid metabolite profiling in a 46,XY infant with prenatally identified POR deficiency.

Although POR deficiency (PORD) is assumed to be accompanied by excessive placental androgen accumulation and enhanced adrenal and testicular androgen production via the backdoor pathway as well as compromised testicular androgen production via the frontdoor pathway, there is no direct evidence for the flux of excessive placental androgens into the fetal circulation and for the production of dihydrotestosterone (DHT) via the backdoor pathway. We examined longitudinal serum and urine steroid metabolite profiles in a 46,XY infant with PORD who was prenatally identified because of the progressive fetal masculinization and maternal virilization from the mid-gestation and the presence of fetal radio-humeral synostosis and was confirmed to have compound heterozygous mutations of POR (p.Q201X and p.R457H). The results showed (1) markedly and inappropriately elevated serum androstenedione and testosterone (T) values at birth, (2) a markedly increased serum DHT value with a normal DHT/T ratio at birth, (3) transient elevation of serum T and DHT values accompanied by a normal DHT/T ratio and concomitant elevations of intermediate steroid metabolites on both the frontdoor and backdoor pathways at 30 days of age, and (4) persistent PORD-compatible urine steroid profiles. Although the data obtained from a single infantile patient are too premature to be generalized, they imply: (1) the transfer of excessive placental androgens into the fetal as well as the maternal circulations from the mid-gestation, (2) lack of a clinically discernible amount of DHT production via the adrenal backdoor pathway around birth, and (3) the activation of both the frontdoor and backdoor pathways in the testis around the mini-puberty, with no production of a clinically discernible amount of DHT via the testicular backdoor pathway.

Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel.

INTRODUCTION: Uterine serous carcinoma (USC) is more aggressive than other subtypes of endometrial carcinoma and is associated with a poor prognosis. We analyzed the metabolomic profile of USC with acquired resistance to paclitaxel. RESULTS: Glutathione (GSH) concentration in PTX-1 cells was higher than in USPC-1 cells. In addition, GSH concentration in the USPC-1 cells increased after treatment with paclitaxel but was unchanged in PTX-1 cells. Glucose-6-phosphate (G6P) and ribose-5-phosphate (R5P) concentrations in PTX-1 cells were higher than those in USPC-1 cells. G6P concentration in the USPC-1 cells was unchanged after treatment with paclitaxel, while it decreased in PTX-1 cells. CONCLUSION: Our results indicate that increased GSH and glucose metabolism may be related to acquiring resistance to paclitaxel in USC and thus may be targets for anti-USC therapy. MATERIALS AND METHODS: We compared metabolic profiles and reactions to paclitaxel in both a wild type USC cell line (USPC-1) and PTX-1, a cell line derived from USPC-1 which acquired paclitaxel resistance, using a capillary electrophoresis CE-MS/MS system.