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Hypoxic-Ischemic Neonatal Encephalopathy: Animal Experiments for Neuroprotective Therapies
Hiroshi Sameshima,Tsuyomu Ikenoue
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/659374
Hypoxic-Ischemic Neonatal Encephalopathy: Animal Experiments for Neuroprotective Therapies
Hiroshi Sameshima,Tsuyomu Ikenoue
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/659374
Abstract: Hypoxic-ischemic neonatal encephalopathy and ensuing brain damage is still an important problem in modern perinatal medicine. In this paper, we would like to share some of the results of our recent studies on neuroprotective therapies in animal experiments, as well as some literature reviews. From the basic animal studies, we have now obtained some possible candidates for therapeutic measures against hypoxic-ischemic neonatal encephalopathy. For example, they are hypothermia, rehabilitation, free radical scavenger, neurotrophic factors and growth factors, steroid, calcium channel blocker, vagal stimulation, some anti apoptotic agents, pre- and post conditioning, antioxidants, cell therapy with stem cells, modulators of K(+)-ATP channels, and so on. Whether combination of these therapies may be more beneficial than any single therapy needs to be clarified. Hypoxia-ischemia is a complicated condition, in which the cause, severity, and time-course are different in each case. Likewise, each fetus has its own inherent potentials such as adaptation, preconditioning-tolerance, and intolerance. Therefore, further extensive studies are required to establish an individualized strategy for neuroprotection against perinatal hypoxic-ischemic insult. 1. Introduction Hypoxic-ischemic brain damage caused by intrapartum disastrous events is still an important problem in modern obstetrics even in developed countries. It accounts for 10% to 20% of infants with cerebral palsy [1, 2]. Since 1997, we have been performing a regional population-based study on intrauterine fetal deaths, neonatal deaths, and severely handicapped infants [1]. From a total of 140,000 deliveries in the last 13 years, we found a perinatal mortality rate of 4 per 1,000. This is the lowest rate in the world (perinatal mortality includes stillbirths ≥22 weeks of gestation and neonatal deaths ≤7 days of life). However, even where the most advanced perinatal services are available, the incidence of brain damage is 2/1,000, similar to rates around the world [2]. Among infants with brain damage, the most frequent cause is congenital abnormality (1/3), and hypoxic-ischemic encephalopathy constitutes 15%. Thus, it is important for us to study (1) how to predict fetal hypoxic-ischemic events early enough to prevent brain damage, (2) how to treat severely damaged neonates immediately after birth to prevent brain damage, and (3) how to individualize fetuses at high-risk of brain damage? We have been performing clinical and basic animal studies to elucidate the pathogenesis of hypoxic-ischemic brain damage of
Applying the Ecology Model to Perinatal Medicine: From a Regional Population-Based Study
Syuichi Tokunaga,Hiroshi Sameshima,Tsuyomu Ikenoue
Journal of Pregnancy , 2011, DOI: 10.1155/2011/587390
Abstract: Objective. Ecology model is useful to provide a framework for organizing medical care. We aimed to see if the ecology model is applicable to perinatal care in Japan. Methods. On a population-based approach, we had 53,461 deliveries in Miyazaki from 2001 to 2005. In comparison, we used all of the 106,613 deliveries in Tokyo in 2009. Women were divided into 4 grades by risk-allocation criteria and their proportion was expressed per 1,000 women to apply to the model and to delineate the ecology curve. The perinatal mortality was compared by Chi-square test. Results. We found remarkable similarity in ecology curves between the original ecology models and that representing Miyazaki perinatal data. However, the curve representing Tokyo was different from the original one. Besides, the perinatal mortality was significantly lower in Miyazaki (4.40/1,000) than in Tokyo (5.06/1,000). Conclusion. Applying the ecology model to perinatal care is useful with improvement of perinatal outcome and it would provide an appropriate framework for organizing perinatal care. 1. Introduction The ecology model of medical care was first introduced in 1961 [1]. In this original model concerning 1,000 adults at risk, 750 of these individuals feel sick, 250 consult a physician, 15 require specialized care, and 1 needs to be referred to a university medical center. A recent study to apply this model to modern medical care has shown some variation from the original one, but overall relationships are still stable for 40 years [2], suggesting that the original ecology model can be used as a standard framework for organizing health and medical care, medical education, and researches. Ecology is applicable to clinical medicine in which structure and dynamics among the medical personnel, disease prevalence, and health care system should be taken into consideration. For example, it will establish a balance between medical system providing all sites of care in a region and the portion of population who needs medical care according to the disease severity. Likewise, it also balances health care seeking behavior of people with the actual health service utilization. From the obstetric viewpoint, routine care for low-risk women belongs to primary care, some women with high-risk factors need specialized care requiring high-level perinatal centers, and some women need emergency transfer to tertiary centers due to severe complications of the mother and infant. However, application of the ecology model to obstetric care has not been performed using a population-based approach. Thus, we hypothesized
Magnesium Sulfate as a Second-Line Tocolytic Agent for Preterm Labor: A Randomized Controlled Trial in Kyushu Island
Yasuyuki Kawagoe,Hiroshi Sameshima,Tsuyomu Ikenoue,Ichiro Yasuhi,Tatsuhiko Kawarabayashi
Journal of Pregnancy , 2011, DOI: 10.1155/2011/965060
Abstract: Objectives. We evaluated the efficacy of magnesium sulfate as a second-line tocolysis for 48?hours. Materials and Methods. A multi-institutional, simple 2-arm randomized controlled trial was performed. Forty-five women at 22 to 34 weeks of gestation were eligible, whose ritodrine did not sufficiently inhibit uterine contractions. After excluding 12 women, 33 were randomly assigned to either magnesium alone or combination (ritodrine and magnesium). The treatment was determined as effective if the frequency of uterine contraction was reduced by 30% at 48?hours of the treatment. Results. After magnesium sulfate infusion, 90% prolonged their pregnancy for >48?hours. Combination therapy was effective in 95% (18/19), which was significantly higher than 50% (7/14) for magnesium alone. Conclusion. This randomized trial revealed that combination therapy significantly reduced uterine contractions, suggesting that adjuvant magnesium with ritodrine is recommended, rather than changing into magnesium alone, when uterine contractions are intractable with ritodrine infusion. 1. Introduction Acute tocolysis prevents preterm labor for 48 hours, which is the critical period for antenatal steroid administration or maternal transfer to perinatal centers to improve neonatal outcomes. Evidence supporting the effectiveness of magnesium sulfate for tocolysis is currently being questioned. Meta-analysis comparing magnesium sulfate and either placebo, no treatment, or alternative tocolytic agents showed that magnesium reduces the risk of birth within 48 hours by 15%, which is not statistically significant (relative risk (RR) 0.85, 95% confidence interval (CI) 0.58 to 1.25) [1]. A more recent report evaluating 19 randomized controlled trials reveals that magnesium fails to reduce delivery rate within 48 hours [2]. However, magnesium sulfate is currently the most commonly used tocolytic agent in America. In 2008, the Ministry of Health, Labor and Welfare of Japan finally approved magnesium sulfate as a tocolytic agent, but its use is restricted to the second-line tocolysis when the effect of a betamimetic agonist is not sufficient to reduce uterine contractions. Here, a question arises as to how we administer magnesium sulfate to these women, that is, to stop the betamimetic agonist and change into magnesium sulfate or add magnesium sulfate to the betamimetic agonist. The efficacy of tocolysis when using a combination of a betamimetic agonist and magnesium sulfate has been investigated, and some retrospective studies have shown that a combination therapy may be effective in
Is the Perinatal Outcome of Placental Abruption Modified by Clinical Presentation?
Seishi Furukawa,Hiroshi Sameshima,Tsuyomu Ikenoue,Masanao Ohashi,Yoshio Nagai
Journal of Pregnancy , 2011, DOI: 10.1155/2011/659615
Abstract: Objective. The purpose of this study was to elucidate the impact of the clinical presentation on perinatal outcome in placental abruption. Study Design. A retrospective study was performed in 97 placental abruptions. Placental abruptions were classified according to clinical presentation: pregnancy-induced hypertension (HT, =22), threatened premature labor and/or premature rupture of membranes (TPL/ROM, =35), clinically low risk (LR, =27), and others (=13). Perinatal outcomes were compared among the HT, TPL/ROM, and LR groups. Results. The HT had significantly higher incidence of IUGR, IFUD, and low fibrinogen. The TPL/ROM had less severe disease. However, the LR had significantly higher incidence of IUFD, low UA pH < 7.1, low Apgar score of <7 at 5 min, and low fibrinogen. Conclusion. Disease severity in placental abruption is likely to depend on the clinical presentation.
Risk-Based Screening for Thyroid Dysfunction during Pregnancy
Masanao Ohashi,Seishi Furukawa,Kaori Michikata,Katsuhide Kai,Hiroshi Sameshima,Tsuyomu Ikenoue
Journal of Pregnancy , 2013, DOI: 10.1155/2013/619718
Abstract: Objective. We conducted the study to see the incidence of thyroid dysfunction in women with obstetrical high-risk factors. Methods. We retrospectively reviewed medical charts of high-risk pregnant women who had examination for thyroid function during pregnancy. Women were divided according to clinical presentation, symptoms of thyroid disease and those with a personal history of thyroid disease (thyroid disease, ), intrauterine growth restriction (IUGR, ), diabetes mellitus (diabetes, ), hypertension ( ), intrauterine fetal death (IUFD, ), and placental abruption (abruption, ). The incidence of thyroid dysfunctions including hyperthyroidism or hypothyroidism was compared. Results. The overall prevalence of thyroid dysfunction was 24.7%. The incidence of thyroid dysfunction in each group was as follows: 31% in thyroid disease, 25% in IUGR, 30% in diabetes, 27% in hypertension, 12% in IUFD, and 7% in abruption. Except IUFD, the incidence was not statistically significant from the group of thyroid disease (thyroid disease versus IUFD, by test). Thyroid disease represented for only 10% of all thyroid dysfunctions. Conclusion. Testing of women with a personal history or current symptoms of thyroid disease during pregnancy may be insufficient to detect women with thyroid dysfunction, who will become at high-risk pregnancy. 1. Introduction Thyroid dysfunction is present in 2.3–3.8% in general [1], as well as during pregnancy [2]. However, nearly 10% of abnormal thyroid function was observed according to thyroid function survey using general health checkup system for the adult in Japan [3]. This implicates that pregnant women in Japan also have higher prevalence of thyroid dysfunction. Up to now, there are no large population studies regarding the prevalence of thyroid dysfunction in pregnant women in Japan. Thyroid dysfunctions are associated with neuropsychological complications on child. A well-known complication is low intelligence quotient in the infants born from mothers with overt hypothyroidism [4]. Subclinical hypothyroidism is also associated with impaired neuropsychological development of children [5]. Indeed, it remains unclear whether to treat subclinical hypothyroidism or not during pregnancy [6]. Thyroid dysfunctions are also associated with several obstetrical complications such as preeclampsia and placental abruption [7–10]. Consequently, there is a question whether the management of thyroid dysfunction could reduce these complications on both mother and child during pregnancy. Currently, no consensus has been reached on the universal screening
Chemotherapy (Gemcitabine plus Carboplatin versus Paclitaxel plus Carboplatin) in Elderly Patients with Non-Small Cell Lung Cancer  [PDF]
Takanori Ayabe, Masaki Tomita, Eiichi Chosa, Makoto Ikenoue, Yukie Shirasaki, Kunihide Nakamura
Journal of Cancer Therapy (JCT) , 2014, DOI: 10.4236/jct.2014.53035

Background: This retrospective study was to evaluate the efficacy and toxicity of gemcitabine plus carboplatin (GC regimen) and paclitaxel plus carboplatin (PC regimen) combination chemotherapy in elderly patients with non-small cell lung cancer. Methods: Seventy-four patients (GC regimen, n = 44; PC regimen, n= 30) received gemcitabine at a dose of 1000 mg/m2 on days 1 and 8, and carboplatin with the target dose of area under the curve (AUC) of 4 on day 8 every 28 days and paclitaxel at a dose of 70 mg/m2 on days 1, 8 and 15, and carboplatin with the target dose of AUC of 5 on day 1 every 28 days. Patients were divided in two groups (younger one: n = 42, <70 years old; elderly one: n= 32, ≥70 years old). Results: A total of 222 cycles of the treatment wasadministered. Seventy-one patients (95.9%) completed the scheduled cycles. Two patients in the elderly group were discontinued (6.3%) due to hematological toxicity and melena in

Identification of Two Wnt-Responsive Elements in the Intron of RING Finger Protein 43 (RNF43) Gene
Norihiko Takahashi, Kiyoshi Yamaguchi, Tsuneo Ikenoue, Tomoaki Fujii, Yoichi Furukawa
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086582
Abstract: RING finger protein 43 (RNF43), an E3-type ubiquitin ligase, is frequently up-regulated in human colorectal cancer. It has been shown that expression of RNF43 is regulated by the Wnt-signaling pathway. However the regulatory region(s) for its transcriptional activation has not been clarified. In this study, we have shown for the first time that RNF43 is a direct target of TCF4/β-catenin complex, and that its expression is regulated by a regulatory region containing two Wnt-responsive elements (WREs) in intron2. A reporter gene assay revealed that nucleotide substitutions in the WREs decreased the reporter activity in colon cancer cells, suggesting that both WREs are involved in the transcriptional activation. Knockdown of β-catenin by siRNA suppressed the reporter activity. In addition, ChIP assay showed that both elements associate with TCF4/β-catenin complex in colon cancer cells. These data indicate that expression of RNF43 is regulated by the canonical Wnt/β-catenin pathway through binding of the WREs with TCF4/β-catenin complex. These findings should be useful for the understanding of the regulatory mechanism of RNF43 and may contribute to the clarification of signaling pathways regulated by RNF43.
Overexpression of Cohesion Establishment Factor DSCC1 through E2F in Colorectal Cancer
Kiyoshi Yamaguchi, Rui Yamaguchi, Norihiko Takahashi, Tsuneo Ikenoue, Tomoaki Fujii, Masaru Shinozaki, Giichiro Tsurita, Keisuke Hata, Atsushi Niida, Seiya Imoto, Satoru Miyano, Yusuke Nakamura, Yoichi Furukawa
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085750
Abstract: Ctf18-replication factor C complex including Dscc1 (DNA replication and sister chromatid cohesion 1) is implicated in sister chromatid cohesion, DNA replication, and genome stability in S. cerevisiae and C. elegans. We previously performed gene expression profiling in primary colorectal cancer cells in order to identify novel molecular targets for the treatment of colorectal cancer. A feature of the cancer-associated transcriptional signature revealed from this effort is the elevated expression of the proto-oncogene DSCC1. Here, we have interrogated the molecular basis for deviant expression of human DSCC1 in colorectal cancer and its ability to promote survival of cancer cells. Quantitative PCR and immunohistochemical analyses corroborated that the expression level of DSCC1 is elevated in 60–70% of colorectal tumors compared to their matched noncancerous colonic mucosa. An in silico evaluation of the presumptive DSCC1 promoter region for consensus DNA transcriptional regulatory elements revealed a potential role for the E2F family of DNA-binding proteins in controlling DSCC1 expression. RNAi-mediated reduction of E2F1 reduced expression of DSCC1 in colorectal cancer cells. Gain- and loss-of-function experiments demonstrated that DSCC1 is involved in the viability of cancer cells in response to genotoxic stimuli. We reveal that E2F-dependent expression of DSCC1 confers anti-apoptotic properties in colorectal cancer cells, and that its suppression may be a useful option for the treatment of colorectal cancer.
Atacama Compact Array Antennas
Masao Saito,Junji Inatani,Kouichiro Nakanishi,Takahiro Naoi,Masumi Yamada,Hiro Saito,Bungo Ikenoue,Yoshihiro Kato,Kou-ichiro Morita,Norikazu Mizuno,Satoru Iguchi
Physics , 2011, DOI: 10.1117/12.926987
Abstract: We report major performance test results of the Atacama Compact Array (ACA) 7-m and 12-m antennas of ALMA (Atacama Large Millimeter/submillimeter Array). The four major performances of the ACA antennas are all-sky pointing (to be not more than 2.0 arcsec), offset pointing (to be < 0.6 arcsec) surface accuracy (< 25(20) micrometer for 12(7)m-antenna), stability of path-length (15 micrometer over 3 min), and high servo capability (6 degrees/s for Azimuth and 3 degrees/s for Elevation). The high performance of the ACA antenna has been extensively evaluated at the Site Erection Facility area at an altitude of about 2900 meters. Test results of pointing performance, surface performance, and fast motion capability are demonstrated.
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