Shigeru Nishimaki

Yokohama City University, Yokohama, Kanagawa, Japan

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Publications (39)77.32 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: At birth, dynamic changes occur in serum components and haemodynamics, such as closure of the ductus arteriosus (DA). A previous study demonstrated that, in full-term human neonates, serum osmolality decreased transiently after birth, but recovered over the next few days. However, the significance of this transient decrease in osmolality has never been addressed. The objective of the present study was to examine the role of changes in serum osmolality after birth in DA closure. We found that rats exhibited a similar transient hypoosmolality after birth. Hypotonic stimulation induced constriction of DA rings and increased Ca2+ transient in DA smooth muscle cells, but not in the aorta. The hypoosmotic sensor transient receptor potential melastatin 3 (TRPM3) was highly expressed in the rat DA, and TRPM3 silencing abolished the Ca2+ response to hypoosmolality. Pregnenolone sulfate stimulation of TRPM3 induced rat DA constriction ex vivo and in vivo. Furthermore, hypertonic fluid injection impaired rat DA closure. In humans, neonatal serum hypoosmolality was observed in relatively mature preterm infants (a parts per thousand yen28 weeks). In extremely preterm infants (< 28 weeks), however, this hypoosmolality was absent. Instead, a rapid increase in osmolality occurred thereafter. Such an increase was greater, in particular, among patent DA (PDA) patients. A transient decrease in serum osmolality may promote DA closure during the first few days of life. Adjusting serum osmolality to proper levels might help to prevent the onset of PDA, improving the therapeutic outcome in extremely preterm infants.
    Cardiovascular Research 09/2014; 104(2). DOI:10.1093/cvr/cvu199 · 5.81 Impact Factor
  • Shigeru Nishimaki · Yoshio Shima · Miho Sato · Hiromi An · Keisuke Kadota · Shumpei Yokota
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    ABSTRACT: Abstract Objective: Fetal inflammatory response syndrome (FIRS), which induces hypercytokinemia, is important for the outcomes of premature infants. It is necessary to focus on the fetal inflammatory environments. Methods: A total of 37 premature infants (gestational age ≤ 32 weeks) were divided into 3 groups: (1) 15 without chorioamnionitis (CAM) or funisitis; C(-)F(-) group, (2) 15 with CAM but without funisitis; C(+)F(-) group, and (3) 7 with CAM and funisitis; C(+)F(+) group. Blood interleukin (IL)-1β, IL-6, and IL-8 levels were measured on day 0 (= in umbilical cord blood), 3, 7, 14, 21, and 28. Results: (1) day 0: Cord blood concentrations of IL-1β, IL-6, and IL-8 were significantly higher in the C(+)F(+) group than in the C(+)F(-) group and C(-)F(-) group. On the other hand, they were comparable between the C(+)F(-) group and C(-)F(-) group. (2) days 3 - 28: Elevated cytokines levels in the C(+)F(+) group with funisitis decreased on day 3 and later. Conclusions: We suggested that hypercytokinemia in the cord blood in premature infants were greatly related with funisitis. Diagnosis of funisitis would be important to find the premature infants who need to be managed their risk of FIRS. In addition, hypercytokinemia disappeared in a few days after birth, therefore cord blood data analysis of cytokines and/or inflammation-related proteins concentrations is necessary to evaluate the fetal inflammatory environments in premature infants after birth.
    The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 11/2013; 27(15). DOI:10.3109/14767058.2013.867321 · 1.21 Impact Factor
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    ABSTRACT: Haemophilus influenzae type b (Hib) vaccine became available for use in Japan in December 2008. The aim of the present study was to evaluate the immunogenicity of Hib vaccine in Japanese preterm infants. Serum samples were obtained from 54 preterm infants before the first vaccination and 1 month after the third. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using an enzyme-linked immunosorbent assay method. Antibody positivity was defined as levels >1 µg/mL. Of the 54 preterm infants, 46 (85.2%) achieved antibody levels >1 µg/mL. This compares with the 92.4% reported in full-term infants. The antibody seroconversion rate of infants starting vaccination at 2 months of age was close to being significantly lower than when vaccination was started at 3 months of age (P= 0.060). In addition, the percentage of infants achieving a positive response in the group with a history of antenatal steroid exposure was significantly higher than in those not exposed (P= 0.046). Thus, risk factors for lower Hib antibody concentrations after three doses of vaccine were age at first vaccination and lack of use of antenatal steroids. There is a possibility that perinatal factors and the environment unique to preterm infants are related to their lower antibody positivity rates compared to full-term infants. It may therefore be preferable to modify the proposed immunization schedule.
    Pediatrics International 11/2011; 54(1):64-7. DOI:10.1111/j.1442-200X.2011.03505.x · 0.73 Impact Factor
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    ABSTRACT: It is important to identify premature infants with prenatal inflammation as it contributes to short- and long-term complications. Our object was to study how prenatal inflammation affects the urinary β(2)-microglobulin (β(2)-MG) level. Preterm neonates were divided based on the presence of chorioamnionitis (CAM) into the CAM (n = 100) and non-CAM groups (n = 117). These were further subdivided into five groups each: 30 preterm neonates of 23-26; 42 neonates of 27-28; 54 neonates of 29-30; 51 neonates of 31-32; and 40 neonates of 33-34 weeks' gestation. The urinary β(2)-MG level within 48 h of birth was significantly higher in the CAM group than in the non-CAM group among the neonates of 23-26 weeks' gestation (18.3 ± 6.9 vs 10.0 ± 5.6 × 10(4) μg/gCr, p = 0.0018) and the neonates of 27-28 weeks' gestation (16.2 ± 10.8 vs 8.8 ± 3.3 × 10(4) μg/gCr, p = 0.0101). However, there was no difference in urinary β(2)-MG level between the CAM and the non-CAM group among the neonates ≥ 29 weeks 'gestation. Moreover, the elevated urinary β(2)-MG level in the neonates ≤ 28 weeks ' gestation with CAM had disappeared by 1 week after birth. The reasons for the increase in urinary β(2)-MG level within 48 h of birth in very preterm neonates (≤ 28 weeks' gestation) with CAM are believed to be not only prematurity, but also prenatal inflammation. It is suggested that the urinary β(2)-MG level during the early postnatal period can identify prenatal inflammation.
    Pediatric Nephrology 06/2011; 26(12):2185-91. DOI:10.1007/s00467-011-1924-8 · 2.88 Impact Factor
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    ABSTRACT: Aim:  The aim of this study is to elucidate whether the stage of chorioamnionitis is or is not associated with the development of neonatal diseases.Material & Methods:  We reviewed the neonatal intensive care unit discharge files and placental pathology reports of 302 preterm infants. The presence of various stages of chorioamnionitis as well as absence of an association with chorioamnionitis (non-chorioamnionitis) were compared among neonatal diseases.Results:  Preterm infants were grouped according to three stages of chorioamnionitis or the absence of an association with chorioamnionitis. Gestational age differed significantly between these groups. Before controlling for gestational age, the chorioamnionitis stage was significantly higher among infants with chronic lung disease, retinopathy of prematurity and intraventricular hemorrhage than in infants without these diseases. On the other hand, the chorioamnionitis stage was lower in infants with respiratory distress syndrome than without. After controlling for gestational age, the stage of chorioamnionitis was significantly lower in infants with respiratory distress syndrome than in infants without respiratory distress syndrome, whereas, significant differences were not detected between the presence and absence of chronic lung disease, retinopathy of prematurity and intraventricular hemorrhage. Furthermore, gestational age was a significant risk factor for chronic lung disease, respiratory distress syndrome, retinopathy of prematurity and intraventricular hemorrhage.Conclusions:  We found no significant differences in stages of chorioamnionitis between infants with and without neonatal diseases except for respiratory distress syndrome. A significant inverse relationship was observed between the stage of chorioamnionitis and development of respiratory distress syndrome.
    Journal of Obstetrics and Gynaecology Research 05/2011; 37(10):1313 - 1319. DOI:10.1111/j.1447-0756.2010.01519.x · 0.93 Impact Factor
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    ABSTRACT: Increasing admissions to neonatal intensive care units (NICUs) demand early discharge from the units. Our hospital aims to early discharge patients who meet the following requirements: they are able to regulate body temperature; neither apnea nor bradycardia is observed; and bodyweight increases with lactation. We studied the real state of this strategy. We looked at postmenstrual age, bodyweight, complication at the time of discharge and the readmission rate in 609 patients with gestational age of less than 34 weeks, who were discharged from our NICU between January 2000 and March 2008. The postmenstrual age and bodyweight at discharge decreased with the increase of gestational age. This tendency was stronger in cases with gestational age of less than 26 weeks. A comparison was made between two patient groups with a gestational age of less than 26 weeks and with the age of 26 weeks or longer. Many patients with a gestational age of less than 26 weeks suffered frequently from complications and were on home oxygen therapy. The readmission rates within 3 months and 1 year of NICU discharge were 10.4% and 26.9% in patients with gestational age between 22 and 25 weeks, respectively, while those rates were 2.8% and 7.4% in patients with gestational weeks of 26 to 34, respectively. The postmenstrual age and bodyweight at NICU discharge decreased in inverse proportion to gestational age, especially less than 26 weeks. Our requirements for early discharge were verified by the readmission rate in this investigation.
    Pediatrics International 02/2011; 53(1):7-12. DOI:10.1111/j.1442-200X.2010.03179.x · 0.73 Impact Factor
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    Y Shima · S Nishimaki · M Nakajima · S Kumasaka · M Migita
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    ABSTRACT: To evaluate the clinical utility of urinary β-2-microglobulin (B2M) at birth, an alternative to proinflammatory cytokines, as an indicative marker of fetal inflammatory response and subsequent higher risk of bronchopulmonary dysplasia (BPD) in premature infants. The relationship between urinary B2M at birth and the occurrence of BPD was examined in 96 premature infants with a description of perinatal backgrounds. Constructing a receiver-operating characteristic curve to determine the cutoff value of urinary B2M at birth for the development of BPD, a multivariate logistic regression analysis was performed to evaluate whether elevated urinary B2M at birth can be used as a predictor of BPD. BPD was diagnosed in 34% (33/96) of the infants. Neonates with BPD had a significantly higher occurrence rate of chorioamnionitis and greater levels of median urinary B2M at birth than did those without BPD. The selected cutoff value of urinary B2M at birth correlated with the development of BPD, even after adjusting for gestational age and other confounding factors. Elevated urinary B2M levels at birth can be used as an alternative marker of fetal inflammatory response and subsequent higher risk of BPD in premature infants.
    Journal of perinatology: official journal of the California Perinatal Association 12/2010; 31(5):330-4. DOI:10.1038/jp.2010.129 · 2.35 Impact Factor
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    ABSTRACT: Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 +/- 13.2 or 70.0 +/- 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 +/- 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.
    International journal of hematology 10/2009; 90(3):311-7. DOI:10.1007/s12185-009-0412-4 · 1.68 Impact Factor
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    ABSTRACT: The aim of the present study was to investigate the current conditions of psychological support for the families of children who died suddenly of disease or accident. A questionnaire survey was conducted in 2415 medical facilities across the country that have at least 100 beds and are staffed by pediatricians. Of these, 981 facilities (40.6%) responded to the questionnaire. There were 653 infant deaths soon after admission in 254 facilities (25.9%). For pronouncement of death, approximately 43% of the pediatricians made no attempt to provide psychological support for the family members affected. In contrast, some 53% of the pediatricians did offer psychological support. In self-assessments, approximately 53% of the pediatricians stated that the support was 'not very satisfactory' or 'unsatisfactory', while only 28% considered that they were 'fully satisfied with the help being given'. Reasons for this response were appropriate specialized knowledge, and enough time for such tasks. The proportion of institutions that employed staff specializing in psychological support for families was only 7%. Approximately 83% of institutions without such specialist staff, however, acknowledged the need for them. The number of medical facilities that gave information regarding family support associations to bereaved families was very low (11%). Psychological support for families of children who died shortly after entering hospital cannot be characterized as satisfactory. The provision of grief care by family associations is desirable, and the cooperation of the institutions and family associations is important.
    Pediatrics International 10/2009; 51(5):626-9. DOI:10.1111/j.1442-200X.2008.02802.x · 0.73 Impact Factor
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    ABSTRACT: It is clear that inflammation plays an important role in developing chronic lung disease in preterm infants. The purpose of the present study is to investigate changes of serum soluble tumor necrosis factor receptor-1 levels over time in infants with chronic lung disease. The serum levels of soluble tumor necrosis factor receptor-1 were measured after delivery, and at 7, 14, 21 and 28 days of age in 10 infants with chronic lung disease and in 18 infants without chronic lung disease. The serum level of soluble tumor necrosis factor receptor-1 was significantly higher in infants with chronic lung disease than in infants without chronic lung disease after delivery. The differences between these two groups remained up to 28 days of age. Prenatal inflammation with persistence into postnatal inflammation may be involved in the onset of chronic lung disease.
    Pediatrics International 10/2009; 52(2):268-72. DOI:10.1111/j.1442-200X.2009.02954.x · 0.73 Impact Factor
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    ABSTRACT: Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.
    Cytokine 07/2009; 47(2):91-7. DOI:10.1016/j.cyto.2009.05.002 · 2.87 Impact Factor
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    ABSTRACT: The ductus arteriosus (DA), an essential vascular shunt for fetal circulation, begins to close immediately after birth. Although Ca(2+) influx through several membrane Ca(2+) channels is known to regulate vasoconstriction of the DA, the role of the T-type voltage-dependent Ca(2+) channel (VDCC) in DA closure remains unclear. Here we found that the expression of alpha1G, a T-type isoform that is known to exhibit a tissue-restricted expression pattern in the rat neonatal DA, was significantly up-regulated in oxygenated rat DA tissues and smooth muscle cells (SMCs). Immunohistological analysis revealed that alpha1G was localized predominantly in the central core of neonatal DA at birth. DA SMC migration was significantly increased by alpha1G overexpression. Moreover, it was decreased by adding alpha1G-specific small interfering RNAs or using R(-)-efonidipine, a highly selective T-type VDCC blocker. Furthermore, an oxygenation-mediated increase in an intracellular Ca(2+) concentration of DA SMCs was significantly decreased by adding alpha1G-specific siRNAs or using R(-)-efonidipine. Although a prostaglandin E receptor EP4 agonist potently promoted intimal thickening of the DA explants, R(-)-efonidipine (10(-6) m) significantly inhibited EP4-promoted intimal thickening by 40% using DA tissues at preterm in organ culture. Moreover, R(-)-efonidipine (10(-6) m) significantly attenuated oxygenation-induced vasoconstriction by approximately 27% using a vascular ring of fetal DA at term. Finally, R(-)-efonidipine significantly delayed the closure of in vivo DA in neonatal rats. These results indicate that T-type VDCC, especially alpha1G, which is predominantly expressed in neonatal DA, plays a unique role in DA closure, implying that T-type VDCC is an alternative therapeutic target to regulate the patency of DA.
    Journal of Biological Chemistry 07/2009; 284(36):24025-34. DOI:10.1074/jbc.M109.017061 · 4.57 Impact Factor
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    ABSTRACT: Chronic lung disease (CLD) is a major component in the morbidity of premature infants suffering from fetal inflammatory response (FIRS). The aim of the present study was to compare the value of measuring neonatal urinary beta(2)-microglobulin (beta(2)-MG) levels with fetal blood interleukin (IL)-6 levels in premature infants at risk of developing CLD. Premature infants (gestational age <30 weeks) without CLD (n = 19) and with CLD (n = 10) were enrolled. We measured IL-6 levels in umbilical cord blood and beta(2)-MG levels in urine obtained within 48 h after birth. IL-6 and beta(2)-MG levels were significantly higher in infants who developed CLD than in those who did not (median IL-6, 54.7 vs 7.6 pg/mL; P < 0.005; beta(2)-MG 17.7 vs 9.3 x 10(4) microg/gCr; P < 0.05). The sensitivity and negative predictive value of beta(2)-MG at the cut-off value at 10.0 x 10(4) microg/gCr (0.90 and 0.92) were comparable to IL-6 at 16 pg/mL (0.90 and 0.94). We suggest that measuring urinary beta(2)-MG in premature infants soon after birth can monitor FIRS and may provide information on the risk of subsequent CLD development that is as clinically important as information derived from umbilical cord blood IL-6.
    Journal of Obstetrics and Gynaecology Research 07/2009; 35(3):472-6. DOI:10.1111/j.1447-0756.2008.00988.x · 0.93 Impact Factor
  • S Nishimaki · T Yukawa · Y Makita · H Honda · N Kikuchi · S Minamisawa · S Yokota
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    ABSTRACT: The present report concerns transient neonatal diabetes mellitus in an extremely preterm infant (gestational age 27 weeks, birth weight 718 g). The patient had intrauterine growth retardation and developed hyperglycaemia on the first day of life. Insulin administration was discontinued on the 89th day of life, which was 1 day before the original due date. This case suggests that (a) insufficient insulin secretion started at least from the second trimester of the pregnancy, and (b) the duration needed for recovery of insulin secretion was not dependent on the maturity.
    Case Reports 05/2009; 2009. DOI:10.1136/bcr.11.2008.1185
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    ABSTRACT: The aim of our study was (i) to determine whether chorioamnionitis (CAM) is associated with an elevated soluble tumor necrosis factor receptor I (sTNFR-I) level and (ii) to examine the time course of the concentration of sTNFR-I in preterm infants after birth. We measured sTNFR-I levels in the cord blood of 112 preterm infants (gestational age < or =34 weeks), and those in peripheral blood of 30 preterm infants on days 7, 14, 21 and 28. The median value for the sTNFR-I was significantly elevated in 33 infants with CAM at stage 3 (4618 pg/mL) compared with the 52 infants without CAM (2866 pg/mL), or the 13 infants with CAM at stage 1 (3638 pg/mL) and the 14 infants at stage 2 (3242 pg/mL). The severity of CAM is an independent factor for the elevation of cord blood sTNFR-I. The sTNFR-I level on day 0 was significantly higher in eight infants with CAM at stage 3 than in the 22 infants without CAM or with CAM at stage 1 and 2; however there were no significant differences on days 7, 14, 21 and 28. The serum level of sTNFR-I showed a significant gradual decline with time. We suggest that there is an association between elevated sTNFR-I levels in cord blood and maternal CAM, and this elevation may reflect the fetal inflammation. However the elevation of sTNFR-I could not persist postnatally for a long time.
    Journal of Obstetrics and Gynaecology Research 05/2009; 35(2):252-7. DOI:10.1111/j.1447-0756.2008.00949.x · 0.93 Impact Factor
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    ABSTRACT: Whole blood interferon-gamma assay QuantiFERON-TB2G (QFT-2G), which is a new specific method for diagnosing tuberculosis (TB), has been developed and used in the clinical field. The aim of the present study was to assess the usefulness of QFT-2G as an indicator, both for diagnosing childhood TB and for assessing therapeutic effectiveness. The subjects were 61 children introduced to the TB outpatient department for the first time between June 2004 and March 2006. QFT-2G, the tuberculin test and chest computed tomography (CT) were performed for all patients. Ten patients having typical characteristics of primary tuberculosis (PTB) on chest CT, and diagnosed as having tubercle bacillus infections, all had positive reaction on QFT-2G. Of seven patients who had no abnormalities on diagnostic imaging but who reacted positively on QFT-2G, one developed TB later, and no TB was detected over the period of observation in 44 patients with negative QFT-2G at their first consultation. Moreover, four patients with non-tuberculous acid-fast bacilli in which Mycobacterium avium or Mycobacterium gordonae was detected had negative reaction on QFT-2G. In addition, all 10 patients with positive reactions on QFT-2G in whom the subsequent course of the disease was observed had decrease on QFT after treatment. QFT-2G is a powerful tool with a wide application both in diagnosis and in assessment of treatment effectiveness in PTB.
    Pediatrics International 03/2009; 51(1):97-102. DOI:10.1111/j.1442-200X.2008.02681.x · 0.73 Impact Factor
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    S Nishimaki · S Iwasaki · T Miyamae · M Mori · S Yokota
    Ultrasound in Obstetrics and Gynecology 12/2008; 32(7):956-8. DOI:10.1002/uog.6232 · 3.14 Impact Factor
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    ABSTRACT: We report a case of a neonate who was diagnosed as having congenital leukemia after presenting with an intracranial hemorrhage. The chief symptom was early-onset jaundice due to the hemorrhage. The intracranial hemorrhage and post-hemorrhage hydrocephalus advanced. In addition, the leukemia worsened leading to death at 14 days old. The possibility of leukemia, although rare, should be considered as a cause of intracranial hemorrhage in term babies.
    Archives of Gynecology 10/2008; 279(4):599-601. DOI:10.1007/s00404-008-0784-3 · 1.28 Impact Factor
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    ABSTRACT: In this study, we determined serum cartilage oligomeric matrix protein (COMP) levels in systemic juvenile idiopathic arthritis (sJIA) patients during both the active and the remission phases to investigate how the growth cartilage turnover changed under tocilizumab treatment. Specimens were collected from 201 healthy children under 16 years of age with no growth impairment, and paired sera were collected from 11 sJIA patients treated with tocilizumab. Disease activity was assessed from white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and ferritin, and the COMP concentration was determined by sandwich enzyme-linked immunosorbent assay. Serum COMP concentrations were found independent of age, and the mean value in healthy children was 17.74+/-5.6 U/L. The mean serum COMP in sJIA patients during the active phase was 10.75+/-3.9 U/L, lower than that of healthy children. The mean serum COMP in the remission phase (14.89+/-3.9 U/L) was significantly higher than that in the active period (P<0.05). These results suggested that in sJIA patients, a reduced serum COMP concentration is a useful marker of active disease and growth impairment, and that the growth cartilage turnover suppressed during the active phase is improved in the remission phase under tocilizumab treatment.
    Modern Rheumatology 09/2008; 19(1):42-6. DOI:10.1007/s10165-008-0115-3 · 2.21 Impact Factor
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    ABSTRACT: We have demonstrated that chronic stimulation of the prostaglandin E2-cAMP-dependent protein kinase A (PKA) signal pathway plays a critical role in intimal cushion formation in perinatal ductus arteriosus (DA) through promoting synthesis of hyaluronan. We hypothesized that Epac, a newly identified effector of cAMP, may play a role in intimal cushion formation (ICF) in the DA distinct from that of PKA. In the present study, we found that the levels of Epac1 and Epac2 mRNAs were significantly up-regulated in the rat DA during the perinatal period. A specific EP4 agonist, ONO-AE1-329, increased Rap1 activity in the presence of a PKA inhibitor, PKI-(14-22)-amide, in DA smooth muscle cells. 8-pCPT-2'-O-Me-cAMP (O-Me-cAMP), a cAMP analog selective to Epac activator, promoted migration of DA smooth muscle cells (SMC) in a dose-dependent manner. Adenovirus-mediated Epac1 or Epac2 gene transfer further enhanced O-Me-cAMP-induced cell migration, although the effect of Epac1 overexpression on cell migration was stronger than that of Epac2. In addition, transfection of small interfering RNAs for Epac1, but not Epac2, significantly inhibited serum-mediated migration of DA SMCs. In the presence of O-Me-cAMP, actin stress fibers were well organized with enhanced focal adhesion, and cell shape was widely expanded. Adenovirus-mediated Epac1, but not Epac2 gene transfer, induced prominent ICF in the rat DA explants when compared with those with green fluorescent protein gene transfer. The thickness of intimal cushion became significantly greater (1.98-fold) in Epac1-overexpressed DA. O-Me-cAMP did not change hyaluronan production, although it decreased proliferation of DA SMCs. The present study demonstrated that Epac, especially Epac1, plays an important role in promoting SMC migration and thereby ICF in the rat DA.
    Journal of Biological Chemistry 09/2008; 283(42):28702-9. DOI:10.1074/jbc.M804223200 · 4.57 Impact Factor