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The aim of this study was to assess whether oxidative and inflammatory mediators in the cord blood of newborns with funisitis and chorioamnionitis can serve as indicators of their inflammatory status, and whether there is a positive association between higher mediator levels and an increased risk of admission to the neonatal intensive care unit (NICU). This study was conducted prospectively in a neonatology department of a university hospital. In total, 52 full-term newborns were evaluated, including 17 funisitis cases, 13 chorioamnionitis cases, and 22 control newborns without funisitis or chorioamnionitis. Cord blood samples were measured for oxidative stress and inflammatory status markers. The oxidative stress markers included the total nitric oxide (NO), total hydroperoxide (TH), biological antioxidant potential (BAP), and TH/BAP ratio, comprising the oxidative stress index (OSI). Inflammatory markers included interleukin (IL)-1b, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNFα), interferon γ (IFNγ), and complement component C5a. TH, OSI, IL-1b, IL-6, and IL-8 concentrations were higher in the funisitis group than in the chorioamnionitis and control groups. C5a was higher in the funisitis and chorioamnionitis groups than in the control group. Among all enrolled newborns, 14 were admitted to the NICU. Multiple logistic regression analysis showed that elevated umbilical cord blood levels of OSI and TH were associated with a higher risk of admission to the NICU (OSI: R = 2.3, 95% CI 1.26–4.29, p = 0.007 and TH: R = 1.02, 95%CI = 1.004–1.040, p = 0.015). In conclusion, OSI and TH in cord blood from full-term newborns can provide an index of inflammatory status, and higher levels are associated with the risk of admission to the NICU and, therefore, could serve as an early indicator of inflammatory conditions in newborns. [ABSTRACT FROM AUTHOR]

Objective: To analyze data from a registry of Japanese neonates with hypoxic respiratory failure associated with pulmonary hypertension (PH) to compare the effectiveness of inhaled nitric oxide (iNO) in neonates born <34 weeks vs. ≥34 weeks gestational age (GA). Materials and methods: iNO was administered according to approved Japanese product labeling. Study data were collected before iNO administration and at predefined intervals until discontinuation. Results: A total of 1,114 neonates were included (n=431, <34 weeks GA; n=675, ≥34 weeks GA; n=8, missing age data). Mean decrease from baseline oxygenation index (OI) was similar in both age groups. OI reduction was more pronounced in the <34 weeks subgroups with baseline OI ≥25. Survival rates were similar in the <34 weeks GA and ≥34 weeks GA groups stratified by baseline OI (OI<15, 89% vs. 93%; 15≤OI<25, 85% vs. 91%; 25≤OI≤40, 73% vs. 79%; OI>40, 64% vs. 66%). Conclusion: iNO improved oxygenation in preterm neonates as effectively as in late preterm and term neonates, without negative impact on survival. If clinically significant PH is present, as measured by pulse oximetry or echocardiography, a therapeutic trial of iNO might be indicated for preterm neonates. [ABSTRACT FROM AUTHOR]

Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury. S TEM C ells 2012;30:2234-2247 [ABSTRACT FROM AUTHOR]

Background/Aims: To investigate the long-term efficacy and safety of two doses (33 and 67 μg/kg/day) of growth hormone (GH) in short Japanese children born small for gestational age (SGA). Methods: 96 children born SGA (age 3 to <8 years) were randomized to GH at 33 or 67 μg/kg/day for 104 weeks, or to an untreated control (UC) group for 52 weeks. After 52 weeks, the UC group was randomized to GH at a dose of 33 or 67 μg/kg/day for a 156-week extension study. Initial treatment groups continued unchanged for the extension phase. Efficacy was evaluated by change in height SDS for chronological age from baseline to 208/260 weeks. Results: After 208 weeks, change in height SDS from baseline (least square (LS) means (SE)) was 1.01 (0.47) and 1.99 (0.67) in the UC 33 and UC 67 μg/kg/day groups, respectively. After 260 weeks, change in height SDS from baseline was 1.22 (0.51) and 2.01 (0.64) in the 33 and 67 μg/kg/day groups, respectively. Insulin-like growth factor-1 levels were significantly higher in the groups receiving 67 μg/kg/day but largely remained within normal limits (-2 to +2 SDS). Conclusion: Long-term continuous GH treatment was well tolerated and effective in improving height SDS. Improvements were dose-dependent and significantly higher at 67 than 33 μg/kg/day. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival.Purpose: To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper.Materials and Methods: A clinical outpatient study measuring serum transforming growth factor (TGF)-β1, interferon (IFN)-γ, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients' regular follow-up visits.Results: There were no differences between the ABO-c and ABO-i groups in terms of recipient's age [mean 12.6 vs. 11.1 years (y)], post-LTx duration (mean 7.3 vs. 7.3 y), donor's age (mean 35.5 vs. 34.6 y), body weight (28.9 ± 2.9 vs. 27.9 ± 6.9 kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-β1, IFN-γ and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher γGTP levels in the ABO-i group, but this difference did not reach significance.Conclusion: ABO-incompatible LRLTx patients have higher serum TGF-β1, IFN-γ and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress has been suspected to influence graft survival and prognosis in pediatric recipients of living related liver transplantation (LRLT).Purpose: We determined the oxidative status of pediatric LRLT recipients during their regular outpatient follow-up visits, and looked for a relationship between oxidative status and post-liver transplantation (post-LTx) duration.Patients: The study included 43 patients (20 males and 23 females) between the ages of 1.6 and 25.1 years (median 10.7 years) who had undergone LRLT from 5 months to 17.5 years (median 7 years) prior to the study, between the ages of 1.2 and 14.4 years (median 3.5 years).Methods: Serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), gamma-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), direct bilirubin and choline-esterase were measured as part of the patients' regular follow-up visits. Serum total hydroperoxide (TH) and biological antioxidative potential (BAP) were measured using the free radical analytic system which requires 20 μl of serum and 10 min of processing time for each sample. Oxidative stress index (OSI) was calculated as the ratio of TH to BAP.Results: Serum OSI correlated positively with serum levels of GOT, GPT, LDH, ALP, γ-GTP and direct bilirubin. Serum OSI, TH, LDH, ALP and GOT correlated negatively with post-LTx duration. Serum BAP correlated positively with post-LTx duration. Serum TH correlated positively with serum GOT and γ-GTP, but negatively with serum BAP.Conclusions: (1) The OSI, which can be calculated based on data acquired through a simple outpatient procedure, can serve as an index of our patients' laboratory results and oxidative status. (2) The LRLT recipients in our study were at risk for oxidative stress early in the post-operative period, but this risk subsided with time. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. Method: Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-α, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. Results: Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-α, NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-α, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01). Conclusions: ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-α, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model. [ABSTRACT FROM AUTHOR]

Rotavirus, one of the major causes of severe gastroenteritis in children, occasionally causes central nervous system complications. Recently several patients with acute encephalitis/encephalopathy due to rotavirus associated with cerebellar signs and symptoms have been reported. The condition is characterized by disturbances of consciousness at onset and cerebellar signs and symptoms such as hypotonia, ataxia, dysmetria, and speech disorders, including mutism, slow speech, and dysarthria at convalescence. We report two patients (3-year-old girl, 2-year-old boy) who developed acute encephalitis due to rotavirus and showed cerebellar signs and symptoms. Both patients had characteristic history of consciousness disturbances subsequent to several days of diarrhea, vomiting and fever, and cerebellar symptoms such as hypotonia, ataxia, dysmetria, and speech disorders during the recovery period. Electroencephalography showed diffuse high-voltage delta wave activity in each patient. Brain magnetic resonance imaging showed cerebellar edema in the acute phase followed by cerebellar atrophy on follow-up images in both patients. In the first patient, diffusion-weighted images (DWI) revealed high signals at the left cerebellar peduncle region and apparent diffusion coefficient (ADC) maps showed decreased ADC values of the lesion in the acute phase. The first patient had dysmetria at 1-year follow-up. However, she had normal motor and cognitive functions and could lead her daily life without impairment. In the second patient, no further symptoms were apparent at 1-year follow-up. Acute encephalitis/encephalopathy due to rotavirus with cerebellar signs and symptoms might be diagnosed on DWI, by demonstrating decreased ADC values in acute phase. [ABSTRACT FROM AUTHOR]

The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific-enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE ( n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE ( n = 10, group 2) and another with HIE ( n = 5, group 3). CSF-NSE, totalhydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and Erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective. [ABSTRACT FROM AUTHOR]

Purpose: Sepsis and septic shock remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Our aim was to study the effects of polymyxin-B direct hemoperfusion (PMX-DHP) therapy on sepsis-induced respiratory impairment, liver dysfunction and leucopenia in a neonatal cecal ligation and perforation (CLP) model.Methods: Fourteen anesthetized and mechanically ventilated 3-day-old piglets underwent CLP and an arteriovenous extracorporeal circuit from 3 h until 6 h post-CLP, with a PMX column in the PMX-DHP treated group (7 piglets). Changes in oxygen saturation, PCO(2), base excess, white blood cell (WBC) count, platelet count, hematocrit (Hct%), serum glutamate pyruvate transaminase (SGPT), and serum glutamic oxaloacetic transaminase were measured before CLP and at 1, 3 and 6 h after.Results: At 6 h, the PMX-DHP group showed lower Hct%, and SGPT in comparison to the control group, but higher oxygen saturation and WBC count. No effects on the platelet count were found. The survival times of the PMX-DHP group were longer than in control.Conclusion: PMX-DHP therapy limited the respiratory impairment, liver dysfunction and leucopenia in a neonatal septic model, which resulted in an improvement of survival time. [ABSTRACT FROM AUTHOR]

Background and objective: The antiviral neuraminidase inhibitor oseltamivir (OSV) is used to treat influenza. The macrolide clarithromycin (CAM) is used to treat bacterial infections and has anti-inflammatory and immunomodulatory activities. This retrospective study investigated the immunomodulatory effects of CAM in children presenting with influenza A. Methods: The study recruited 40 children with acute influenza, and grouped them according to the treatment received: 5-day treatment with OSV ( n = 14), CAM ( n = 8), OSV + CAM ( n = 12) and untreated ( n = 6). The before and after treatment comparisons were made of the level of secretory IgA (sIgA) against influenza A virus (H3N2) and (H1N1), total sIgA, viral RNA copy numbers in nasopharyngeal aspirates and disease symptoms. Results: Infection induced anti-viral mucosal sIgA in the nasopharyngeal aspirates of most patients of all treatment groups. Particularly prominent increases in the levels were found in the CAM and OSV + CAM groups. Low induction of anti-viral sIgA was observed in the OSV group, but the addition of CAM to OSV augmented sIgA production and restored local mucosal sIgA levels. The frequency of residual cough in the OSV + CAM group was significantly lower than in the other groups including the group treated with OSV. Conclusions: CAM boosted the nasopharyngeal mucosal immune response in children presenting with influenza A, even in those treated with OSV who had low production of mucosal anti-viral sIgA, and alleviated the symptoms of influenza. [ABSTRACT FROM AUTHOR]

Easy screening and accurate diagnosis of congenital cytomegalovirus (CMV) infection are needed to predict and treat complications. We report the clinical course of two neonates with congenital CMV infection confirmed by real-time polymerase chain reaction (PCR) for CMV DNA in umbilical cord blood. A total of 1,010 neonates born at Yonaha Clinic from July 2005 to March 2007 were investigated. Umbilical cord blood was collected at birth, and DNA was extracted to screen for CMV DNA by real-time PCR. Head MRI and a developmental test were conducted for two cases (0.2%) in which CMV DNA was detected. Neither case showed clear abnormalities at birth, and head CT conducted at 1 month after birth revealed no abnormalities. Auditory brainstem responses were normal at both 1 and 12 months after birth in both cases. Head MRI at 12 months showed abnormalities in both cases. For both cases, development tests conducted at 12 months revealed mild developmental delays, particularly in posture and movement areas, which might have been caused by congenital CMV infection. J. Med. Virol. 81:1773-1776, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background/Aim: The R450H mutation of the TSH receptor (TSHR) gene has been frequently observed in Japanese patients with resistance to TSH. The purpose of this study was to clarify the phenotype of patients with a homozygous R450H mutation of the TSHR gene; the mutant receptor has previously demonstrated moderately impaired function in vitro. Methods: We performed a clinical investigation of 5 Japanese patients who had hyperthyrotropinemia as neonates, in whom a homozygous R450H mutation of the TSHR gene had been demonstrated by genetic sequencing analysis. Results: The thyroid hormone levels of the patients were normal in early infancy, although their serum levels of TSH were mildly elevated. After supplemental treatment with levothyroxine sodium (L-T4) was started, we had to increase the dose to maintain the level of TSH within the normal range in all patients. Thyroid dysfunction became obvious in one patient at reexamination during adolescence when L-T4 treatment was stopped for 1 month. Four patients were examined for intelligence quotient and their scores were normal. Conclusions: Thyroid hormone replacement therapy should be considered based on biological data in patients with hyperthyrotropinemia who have a homozygous R450H mutation of the TSHR gene even if they do not exhibit obvious hypothyroidism in infancy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:One of the pathological hallmarks of periventricular leukomalacia (PVL) is the selective vulnerability of late oligodendrocyte progenitors (preoligodendrocytes; preOLs) to hypoxia-ischemia (H-I). It is unknown whether recombinant human erythropoietin (rhEPO) protects preOLs in vivo. Objectives:To develop a rat PVL model in which preOLs are selectively damaged and exhibit similar pathological changes to diffuse-type human PVL, various conditions of H-I were compared in P2–P7 rats (P2 = postnatal day 2). To evaluate the effect of rhEPO on oligoprotection (preOLs), rhEPO was administered to P3 PVL rats. Methods:After counts of NG2-positive and O4-positive cells were performed in P2–P7 rats, right common carotid artery occlusion followed by 6 O2for 0–120 min was performed in P2–P4 rats. The mortality and histological alterations after hematoxylin/eosin staining and ED1 immunostaining were assessed 2 days after H-I. Various doses of rhEPO (1–30,000 U/kg i.p.) were administered to PVL rats 15 min before administration of 6 O2. Results:Double-positive cells for NG2 and O4 were detected from P2, and their number gradually increased until P7. Although right common carotid artery occlusion with 6 O2for 60 min resulted in a relatively high proportion of deaths in P2–P4 rats, typical histological changes in the PVL diffuse component were found in most surviving P3 animals. With 50–100 U/kg rhEPO, the histological damage was attenuated. Conclusions:Histological changes similar to those seen in the PVL diffuse component were induced by H-I in P3 rats, in which preOLs were gradually developing, and a low dose of rhEPO was effective in the treatment of brain damage induced by H-I.Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The sudden appearance of hypotension and oliguria without obvious cause following stable circulation and respiration in preterm infants is frequent in Japan. Such episodes are referred to as late-onset circulatory dysfunction of premature infants (LCD). Volume expanders and inotropic agents are often ineffective against this condition, whereas i.v. steroids are significantly effective. A major problem is that cystic periventricular leukomalacia (PVL) often develops a few weeks after an episode. The aim of the present study was to clarify the risk factors, including LCD, related to cystic PVL. Methods: A case–control study was performed for preterm infants who were delivered at <33 weeks of gestation and admitted to seven neonatal intensive care units in Japan. Cystic PVL infants were stratified into early-onset PVL diagnosed within 28 days of age and late-onset PVL diagnosed after more than 28 days of age. The reported and new risk factors for PVL, for each group of PVL infants, and for all PVL infants, were compared with controls. Results: Thirty-two infants were diagnosed with cystic PVL (17 early-onset and 15 late-onset). All PVL infants significantly differed from controls on Apgar score, number of abortions and pregnancies, intraventricular hemorrhage, and LCD. LCD was diagnosed in 28.1% of both PVL groups compared with 6.3% of controls ( P = 0.02). Multivariate analysis demonstrated significant association between late-onset PVL and LCD. Conclusion: LCD was significantly associated with cystic PVL, especially late-onset PVL. Elucidating the cause of LCD might reduce the incidence of PVL and improve the neurological prognosis of preterm infants. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the thyrotropin receptor (TSHR) gene were described as a syndrome characterized by thyroid hyposensivity to biologically active TSH, ranging from euthyroid to severe hypothyroidism. In Japanese, a common mutation in the TSHR gene is R450H, which demonstrated moderately impaired receptor function. We studied six subjects of Japanese origin whose major abnormality was persistent hyperthyrotropinemia by genetic sequence analysis of the TSHR gene. Three subjects were homozygous for the R450H mutation, whereas the three remaining subjects were single heterozygous. Homozygous subjects displayed mild hypothyroidism confirmed by moderately elevated basal TSH levels and excessive TSH response to TRH administration. Heterozygous subjects also demonstrated fully or partially compensated hypothyroidism, but less severe than that of homozygous subjects. More frequent involvement of the R450H mutation in the TSHR gene in Japanese was identified. In addition, a good correlation between phenotype and genotype was demonstrated in respect to biochemical analysis and drug dosage. Our observations showed clinical significance of heterozygosity associated with compensated hypothyroidism in spite of only mildly impaired receptor function. [ABSTRACT FROM AUTHOR]

Background: In Japan, palivizumab was approved in 2002 for prophylaxis of severe respiratory syncytial virus disease in high-risk infants. In order to evaluate the efficacy and safety of this drug, a questionnaire survey was conducted. Methods: A questionnaire was sent to member institutions of the Japan Neonatologist Association. The subjects were premature infants who were considered possible candidates for treatment with palivizumab. Results: A total of 6302 case reports, including those of 2806 infants receiving palivizumab (group P) and 3496 infants not receiving palivizumab (group NP), respectively, were retrieved. Background characteristics revealed significant lower gestational age (GA) and birthweight for group P ( P < 0.0001). Sex ratio did not differ significantly, while use of oxygen and mechanical ventilation in the neonatal intensive care unit, and presence of chronic lung disease were significantly higher for infants in group P ( P < 0.0001). When comparison of hospitalization rate for respiratory symptoms was performed with stratification by eligibility criteria, in the group of infants born at 29–35 weeks GA the hospitalization rate was 4.0% and 5.7% in groups P and NP, respectively ( P < 0.05). Multivariate analysis also showed that prophylaxis with palivizumab was the only variable that significantly decreased rate of hospitalization (odds ratio 0.630, P= 0.0053). The incidence of adverse events associated with the administration of palivizumab was low. Conclusion: In this non-randomized questionnaire survey, multivariate analysis showed that palivizumab significantly decreased the rate of hospitalization due to respiratory symptoms for infants born prematurely at 29–35 weeks GA. These data confirmed the efficacy and safety of palivizumab. [ABSTRACT FROM AUTHOR]

Introduction: Hyperzincaemia and hypercalprotectinaemia with systemic inflammation, recurrent infections, hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive is an extremely rare disease and no therapy is reported. Aim: To evaluated the effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia in terms of serum cytokine level changes before and after treatment. Methods: A 10-year-old girl was admitted suffering from pyoderma gangrenosum, hepatosplenomegaly, anemia that was unresponsive to iron supplementation, persistent inflammation, arthritis, and increased serum zinc. The level of serum calprotectin was extremely high; therefore, we diagnosed hyperzincaemia and hypercalprotectinaemia and started cyclosporine A treatment. Twelve cytokines in serum were measured before and one year after treatment. Results: Cyclosporine A was very effective. Her skin lesion and joint pain were alleviated and quality of life was markedly improved. C-reactive protein had decreased and anemia had improved. While zinc levels had fallen, calprotectin remained at an extremely high level. Of the cytokines examined, interleukin -6 serum levels had fallen and interleukin -8 showed a marked reduction after treatment. Conclusion: Cyclosporine A is effective for hyperzincaemia and hypercalprotectinaemia. Serum interleukin -8 may be useful in assessing the therapeutic effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia. [ABSTRACT FROM AUTHOR]

CYP2C19 is a clinically important enzyme involved in the metabolism of therapeutic drugs such as (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2–5% of Caucasian populations, but at higher frequencies (18–23%) in Asians. CYP2C19*2 and CYP2C19*3, which are single-nucleotide polymorphisms of CYP2C19, are the main cause of PM phenotyping in homozygotes or compound heterozygotes. We report two novel mutations in the CYP2C19 gene identified by direct sequencing and subcloning procedures. One of these mutations was considered to be CYP2C19*3 by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). This result suggests that mutations classed as CYP2C19*3 might include other mutations. Further studies are needed to clarify the relationship between these novel mutations and enzyme activity. [ABSTRACT FROM AUTHOR]

Objective: Levels of nitric oxide (NO) and cytokines were assessed in amniotic fluid obtained from patients with severe chorioamnionitis (CAM) and appropriate controls. Methods: Amniotic fluid was obtained from 12 patients with CAM (17–24 weeks of gestation) and 89 patients undergoing diagnostic amniocentesis (16–18 weeks of gestation). The concentrations of NO, interleukin-6 (IL-6), and leukocyte elastase (LE) in amniotic fluid were then measured and compared. Results: The concentrations of NO, IL-6, and LE were all higher in CAM cases than in normal pregnant women. Furthermore, an inverse correlation between NO and LE was suggested in the CAM group. Conclusions: These results indicate that in severe CAM, the action of NO might be reduced, not only due to blockage of action but also by degradation, despite increased production. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Female patients with ornithine transcarbamylase deficiency (OTCD) show a wide range of clinical severity, from asymptomatic to lethal hyperammonemia. It is important to establish a simple method to distinguish symptomatic from asymptomatic patients.Methods: Uracil and orotic acid concentrations were analyzed in three female patients with OTCD at both the hyperammonemia-attack and interval stages. These concentrations were compared with those in asymptomatic female patients reported previously.Results: Uracil concentrations in symptomatic female patients were uniformly higher than those in asymptomatic female patients at both the hyperammonemia-attack and interval stages.Conclusion: Uracil may present a useful index for detecting OTCD female patients who are destined to suffer from hyperammonemia attack. Further data on uracil concentrations are necessary to establish the threshold for distinguishing symptomatic from asymptomatic subjects. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the cerebral blood flow of the posterior cerebral arteries (PCAs) in neonates in relation to the onset of periventricular leukomalacia (PVL). Methods: Among 57 low-birth-weight neonates studied, 7 were diagnosed with PVL with cyst formation on sonography and MRI. The mean cerebral blood flow velocity (CBFV) was measured in all the neonates by Doppler sonography through the posterior fontanel separately in the right and left PCA at days 0, 1, 2, 3, 4, 5, 7, 10, 14, 21, 28, 42, 56, and 70 following birth. Results: In the 7 neonates with PVL the mean CBFV in the right PCA was significantly lower than that in neonates without PVL at days 10, 14, 21, 28, 42, 56, and 70; the mean CBFV in the left PCA of neonates with PVL was significantly lower than that in those without PVL at days 7, 10, 14, 21, 28, 42, 56, and 70. CBFV measured in neonates without PVL exhibited a gradual increase postnatally. In contrast, CBFV values for neonates with PVL plateaued after day 5 or 7. Conclusions: The serial measurement of PCA CBFV postnatally may prove useful as a predictor of the development of PVL. [ABSTRACT FROM AUTHOR]

Objective: To clarify whether combination treatment with desmopressin (DDAVP) and thiazide was clinically effective in a patient with congenital nephrogenic diabetes insipidus (CNDI), we evaluated the treatment in a 7-year-old boy with CNDI who had demonstrated a partial response to DDAVP. Method: Both volume of urine and the presence of nocturia were determined during treatment. Result: Neither the usual therapy of a low-salt diet and a thiazide nor intranasal therapy with a large dose of DDAVP was effective. However, combination treatment resulted in a decrease in urinary volume and the disappearance of nocturia. Conclusion: DDAVP coupled with thiazide may be useful for CNDI in patients who have shown a partial response to DDAVP.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract Background : Persistent pulmonary hypertension of the newborn (PPHN) commonly appears as a complication of several pulmonary and non-pulmonary diseases. The hypoxia possibly inhibits Ca2+ ± dependent K+ channels, thus resulting in membrane depolarization of pulmonary smooth muscle cells, which leads to the opening of Ca2+ channels and Ca2+ entry, resulting in contraction of the vascular smooth muscle. However, magnesium (Mg2+ ) is an antagonist of Ca2+ . We studied the effect of magnesium sulfate on the treatment of hypoxia-induced pulmonary hypertension and compared to the site of action of nitric oxide (NO). Methods : Zero-day-old piglets were used in each experiment. The effects of Mg2+ were tested in each hypoxic, normoxic and hyperoxic states. Once the desired physical state was achieved, Mg2+ was administered at a dose of 100 mg/kg approximately every 10 min. In order to determine the exact mechanism of the Mg2+ , N w-nitro-l-arginine (LNNA), a NO synthase-inhibitor, was administered simultaneously with Mg2+ in some of the experiments. Results : There was a significant correlation between the percent reduction of the pulmonary arterial pressure (PAP) caused by magnesium and the level of oxygen (O2 ) present in the pulmonary artery. The greatest amount of reduction was seen in the hypoxic condition where the least amount of O2 is found. A further reduction in the PAP was seen when NO was given at the end of the Mg2+ trials. There was no significant reduction seen in the systemic arterial pressure. Conclusion : Inhaled NO further reduced the PAP in piglets already treated with Mg2+ . [ABSTRACT FROM AUTHOR]

Summary. Human leucocyte antigen (HLA)-Cw-reactive cytotoxic T lymphocytes (CTL) were generated from cord blood (CB) lymphocytes of two cases used for cord blood stem cell transplantation (CBSCT). In both cases, the CTL were cytotoxic against the patient's leukaemic cells, as well as the patient's Epstein–Barr virus (EBV)-lymphoblastoid cell line (EBV-LCL) and phytohaemagglutinin blasts, and the cytotoxicity was blocked by anti-HLA-class I monoclonal antibodies. In the first case, the CTL recognized Cw 3 (Cw 9 and Cw 10)-positive EBV-LCL, while in the second case, the CTL recognized Cw1 and/or Cw7. These cases suggest that CB T cells may be competent enough for generating CTL to induce a graft-versus-leukaemia effect and/or graft-versus-host disease in patients with CBSCT and that the mismatching of Cw antigens between patient and CB may be related to the outcome of CBSCT. [ABSTRACT FROM AUTHOR]

Abstract Background: This study was performed to determine whether a combined therapy of nitric oxide (NO) inhalation and nitric oxide synthase (NOS) inhibitor is effective in experimental animals with endotoxin-induced refractive hypotension accompanied by pulmonary hypertension. Methods: Escherichia coli lipopolysaccharide (1 mg/kg) was administered to 10 newborn piglets to induce endotoxemia. The experiment then began 60 min later, when the systemic arterial pressure dropped. The inhalation of 20 p.p.m. NO at 60 and 120 min of endotoxemia created a control group. Another group was also administered N w-nitro-L-arginine (L-NNA; 5 mg) after the first NO inhalation at 60 min of endotoxemia (the L-NNA group). Pulmonary arterial pressure, systemic arterial pressure and cardiac output were measured and compared among the groups. Results: Three of the 5 piglets in the control group died of hypotensive shock, while in the L-NNA group the systemic arterial pressure recovered to pre-endotoxin administration levels. The L-NNA group produced a further increase in pulmonary arterial pressure against which NO inhalation was effective. Conclusion: Nitric oxide inhalation alone carries a potential risk of further lowering systemic arterial pressure in a piglet with hypotension induced by endotoxin, whereas the combined therapy resulted in the recovery of the blood pressure to pre-endotoxin levels. The combined therapy was simultaneously effective against pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Abstract Background: This is the first report about a prospective clinical investigation to study the efficacy and safety of nitric oxide (NO) inhalation in infants with persistent pulmonary hypertension of the newborn (PPHN) in Japan. Methods: Patients in the present study had to meet the following entry criteria: (i) they had to be younger than 7 days of age; (ii) they had to have evidence of PPHN as defined by echocardiograph; (iii) they had to have severe systemic hypoxemia under mechanical ventilation at 100% oxygen supplementation; and (iv) they had to have a failure to respond to conventional therapies. Patients were excluded from this trial if they had any of the following: hypoplastic lung, structural cardiac lesions or severe multiple anomalies. Results: Nitric oxide inhalation therapy was performed in 68 infants who had severe PPHN at 18 hospitals between May 1995 and May 1997. At birth, 21 of 68 infants (31%) weighed less than 1500 g and 39 infants weighed more than 2500 g. The diagnoses associated with PPHN were as follows: 27 infants had meconium aspiration syndrome, 15 infants had dry lung syndrome, nine infants had congenital diaphragmatic hernia, six infants had respiratory distress syndrome, three infants had pneumonia and eight infants had other diagnoses. The mean oxygenation index (OI) before NO inhalation therapy in 68 infants was 43.2; 55 infants (81%) had good responses. Conclusions: These results may be valuable for further randomized controlled and double-blind trials in Japan to evaluate whether NO inhalation therapy is more effective than conventional therapy in infants with severe PPHN. [ABSTRACT FROM AUTHOR]

Abstract Background: In previous reports, the reference range for urinary pyrimidine was determined on the basis of a small number of samples, with data for only a few patients being reported. In the present study, we measured urinary pyrimidine compounds in 25 healthy newborns, 33 healthy infants, 130 healthy children and 166 healthy adults. In addition, we also analyzed urinary pyrimidine compounds in various patients with abnormal pyrimidine metabolism, such as congenital pyrimidine metabolism disorders and urea cycle disorders. Methods: We analyzed urines by high-performance liquid chromatography with column switching. Analyses were performed with both a reverse-phase column and an anion-exchange column. The columns were connected by a column switch, with all systems being controlled automatically by a computerized system controller. Results: The excretion of pyrimidine compounds in patients with abnormal pyrimidine metabolism (containing heterozygotes) was out of our reference ranges. Conclusions: These results suggest that urinary pyrimidine analysis is a useful index for the diagnosis of pyrimidine metabolism disorders, urea cycle disorders and these heterozygotes. Based on this large-group analysis of healthy individuals, we were able to determine the reference ranges of urinary orotic acid, dihydrouracil and uracil for each age group. [ABSTRACT FROM AUTHOR]

Abstract Background: The purpose of this study was to evaluate whether or not dopamine (DA) can penetrate to the central nervous system (CNS) from the blood in the infantile period in rats. Methods: In a preliminary experiment, we administered a 50 mg/kg dose of DA hydrochloride, intraperitoneally, to 7-day-old rats (DA 50 mg/kg group), obtaining cerebrospinal fluid (CSF) both before and at 5, 10, 20, 30, 60 and 120 min after administration. The CSF levels of DA and its main metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were then measured. Next, we investigated the DA transfer from blood to the CNS by administering doses of 1, 5, 10 and 30 mg/kg DA hydrochloride (DA 1, 5, 10 and 30 mg/kg groups). In these groups, CSF samples were obtained only at 10 and/or 60 min after DA administration, based on the results of the DA 50 mg/kg group. Results: The DA concentrations in CSF significantly increased compared with values before DA administration in the DA 50 mg/kg group. The DA concentrations in the DA 30 mg/kg group, DOPAC concentrations in the DA 5, 10 and 30 mg/kg groups, and HVA concentrations in all groups were significantly higher than in the control (saline injection) group. Conclusions: These findings suggest easy DA transfer from blood to the CNS and immaturity of the blood–brain barrier for DA in the infantile period in rats. [ABSTRACT FROM AUTHOR]