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Glucocorticoids (GCs) are highly effective yet problematic agents against bronchopulmonary dysplasia (BPD). The dimeric trans-activation of GCs induces unfavorable effects, while monomeric trans-repression suppresses inflammation-related genes. Recently, non-steroidal-selective glucocorticoid-receptor agonists and modulators (SEGRAMs) with only the trans-repressive action have been designed.Using a bleomycin (Bleo)-induced alveolar simplification newborn rat model (recapitulating arrested alveolarization during BPD), we evaluated the therapeutic effects of compound-A (CpdA), a SEGRAM. Sprague-Dawley rats were administered Bleo from postnatal day (PD) 0 to 10 and treated with dexamethasone (Dex) or CpdA from PD 0 to 13. The morphological changes and mRNA expression of inflammatory mediators, including interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-C motif chemokine 2 (CCL2) were investigated.Similar to the effects of Dex, CpdA exerted protective effects on morphological derangements and inhibited macrophage infiltration and production of pro-inflammatory mediators in Bleo-treated animals. The effects of CpdA were probably mediated by GC receptor (GR)-dependent trans-repression, because unlike the Dex-treated group, anti-inflammatory genes specifically induced by GR-dependent trans-activation (such as "glucocorticoid-induced leucine zipper, GILZ") were not upregulated.CpdA improved lung inflammation, inhibited the arrest of alveolar maturation, and restored histological and biochemical changes in a Bleo-induced alveolar simplification model.SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs. Compound A, one of the SEGRAMs, improved lung morphometric changes and decreased lung inflammation in a bleomycin-induced arrested alveolarization, a newborn rat model representing one of the main features of BPD pathology. Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment. SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.

In evaluating vitamin E (VE) nutritional status of preterm infants, it is essential that any data should be compared with those of healthy term infants, and never with those of adults. Moreover, it should be evaluated in terms of gestational age (GA), not birth weight (BW), because placental transfer of most nutrients from mother to fetus is dependent on GA, not BW. Judging from the limited data during the last 75 years, there was no significant correlation between GA and VE concentrations in circulation or in the red blood cells (RBCs), leukocytes, and buccal mucosal cells. In addition, the oxidizability of polyunsaturated fatty acids (PUFAs) in plasma or RBCs, as targets for protection by VE chain-breaking ability, was lower in preterm infants. However, because of the minimal information available about hepatic VE levels, which is considered a key determinant of whole body VE status, the decision on whether VE status of preterm infants is comparable with that of term infants should be postponed. Clinical trials of VE supplementation in preterm infants were repeatedly undertaken to investigate whether VE reduces severity or inhibits development of several diseases specific to preterm infants, namely retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and germinal matrix hemorrhage - intraventricular hemorrhage (GMH-IVH). Most of these trials resulted in a misfire, with a few exceptions for IVH prevention. However, almost all these studies were performed from 1980s to early 1990s, in the pre-surfactant era, and the study populations were composed of mid-preterm infants with GAs of approximately 30 weeks (wks). There is considerable difference in 'preterm infants' between the pre- and post-surfactant eras; modern neonatal medicine mainly treats preterm infants of 28 wks GA or less. Therefore, these results are difficult to apply in modern neonatal care. Before considering new trials of VE supplementation, we should fully understand modern neonatal medicine, especially the recent method of oxygen supplementation. Additionally, a deeper understanding of recent progress in pathophysiology and therapies for possible target diseases is necessary to decide whether VE administration is still worth re-challenging in modern neonatal intensive care units (NICUs). In this review, we present recent concepts and therapeutic trends in ROP, BPD, and GMH-IVH for those unfamiliar with neonatal medicine. Numerous studies have reported the possible involvement of reactive oxygen species (ROS)-induced damage in relation to supplemental oxygen use, inflammation, and immature antioxidant defense in the development of both BPD and ROP. Various antioxidants effectively prevented the exacerbation of BPD and ROP in animal models. In the future, VE should be re-attempted as a complementary factor in combination with various therapies for BPD, ROP, and GMH-IVH. Because VE is a natural and safe supplement, we are certain that it will attract attention again in preterm medicine.

Purpose: To report a case of fundus oculi albinoticus diagnosed as Angelman syndrome (AS) via genetic testing. Case Report: This study reports on a 4-year-old boy. Since he had been having respiratory disturbance since birth, he underwent a complete physical examination to investigate the cause. The results indicated that he had various brain congenital abnormalities, such as a thin corpus callosum, as well as hydronephrosis, an atrial septal defect, and skin similar to patients with fundus oculi albinoticus. Examination revealed bilateral fundus oculi albinoticus, mild iridic hypopigmentation, optic atrophy, and poor visual tracking. Genetic testing revealed a deletion in the Prader-Willi syndrome/AS region on chromosome 15, and together with the results of methylation analysis, his condition was diagnosed as AS. Follow-up examinations revealed no change in the fundus oculi albinoticus and optic atrophy, nor did they indicate poor visual tracking. Conclusions: When fundus oculi albinoticus and optic atrophy are observed in patients with multiple malformations, AS should be considered as a differential diagnosis.

Purpose: We performed ophthalmic examinations, including optical coherence tomography (OCT), on a case diagnosed with hydranencephaly. Case Report: This case involved a female infant born at the gestational age of 35 weeks and 4 days, with the birth weight of 2,152 g, who was one of monochorionic diamniotic twins, and the identical twin died in utero at the gestational age of 24 weeks. After that, examination by fetal echo indicated that she had microcephaly and ventriculomegaly. Postnatal magnetic resonance imaging (MRI) of her head indicated microcephaly and significant enlargement of the lateral ventricle on both sides, with no obvious signs of elevated intracranial pressure. The brain parenchyma of both sides of the frontal lobe, parietal lobe, and occipital lobe had marked thinning, yet that of the temporal lobe, basal ganglia, thalamus, brain stem, and cerebellum had been maintained. Moreover, no obvious hematoma or neoplastic lesions were observed. Ophthalmic examinations indicated that both of her eyes had slight light reflex, attributed to optic nerve atrophy. Examination by use of a hand-held OCT system indicated a layered structure of the retina and thinning of the ganglion cell layer. Flicker electroretinogram (ERG) examination by use of a hand-held ERG system indicated an almost normal wave. However, no clear visual reaction was observed when she was 10 months old. Conclusion: Our findings in this case of hydranencephaly revealed that even though the outer layer functions of the patient’s retina were maintained, extensive damage to her cerebral cortex resulted in poor visual function.

Background Oxidative stress is a major factor responsible for minimal-change nephrotic syndrome (MCNS), which occurs most commonly in children. However, the influence of oxidative stress localized to mitochondria remains unclear. We examined the effect of a mitochondrion-targeting antioxidant, MitoTEMPO, in rats with puromycin aminonucleoside (PAN)-induced MCNS to clarify the degree to which mitochondrial oxidative stress affects MCNS. Materials and methods Thirty Wistar rats were divided into three groups: normal saline group (n = 7), PAN group (n = 12), and PAN + MitoTEMPO group (n = 11). Rats in the PAN and PAN + MitoTEMPO groups received PAN on day 1, and those in the PAN + MitoTEMPO group received MitoTEMPO on days 0 to 9. Whole-day urine samples were collected on days 3 and 9, and samples of glomeruli and blood were taken for measurement of lipid peroxidation products. We also estimated the mitochondrial damage score in podocytes in all 3 groups using electron microscopy. Results Urinary protein excretion on day 9 and the levels of lipid peroxidation products in urine, glomeruli, and blood were significantly lower in the PAN + MitoTEMPO group than in the PAN group (p = 0.0019, p = 0.011, p = 0.039, p = 0.030). The mitochondrial damage score in podocytes was significantly lower in the PAN + MitoTEMPO group than in the PAN group (p

Aim Methods to improve the mental development of extremely low birthweight (ELBW) children are currently lacking. We assessed the effects of long-term supplementation of alpha-tocopherol on the neurological development of 259 school-aged ELBW children. Methods Extremely low birthweight participants were divided into three groups: group A with no alpha-tocopherol supplementation (n = 121); group B with the supplementation for

The presence of microorganisms in gastric fluid in neonates at birth is postulated to reflect antenatal infection and also to be associated with the development of bronchopulmonary dysplasia (BPD).A logistic regression analysis, after controlling for other risk factors, indicated that Ureaplasma-positive infants were not at increased risk for moderate/severe BPD (adjusted odds ratio (OR): 2.58, 95% confidence interval (CI): 0.57-6.89, P = 0.12). However, the association between the presence of Ureaplasma species and the risk for moderate/severe BPD increased significantly in infants on mechanical ventilation (MV) ≥2 wk (adjusted OR: 4.17, 95% CI: 1.62-44.1, P = 0.009). An analysis using a lung injury marker indicated that Ureaplasma-positive infants with MV ≥2 wk, but not other infants, showed higher serum KL-6 levels in samples taken from cord blood, and that KL-6 levels increased time-dependently up to 4 wk of age.Antenatal exposure to Ureaplasma species induces lung injury prior to birth and synergistically contributes to the development of BPD in infants requiring prolonged MV (≥2 wk).We recovered gastric fluid specimens from 122 infants with gestational age (GA)29 wk or birth weight1,000 g to investigate whether these microorganisms influence respiratory outcome of BPD. A PCR analysis was used to detect urease and 16S ribosomal RNA (rRNA) genes to classify neonates into Ureaplasma-positive or Ureaplasma-negative infants.

Background: Persistent pulmonary hypertension of the newborn is often associated with meconium aspiration syndrome (MAS) or perinatal asphyxia. Objective: To determine the effect of meconium or asphyxia on pulmonary arterial pressure and circulating levels of vasoactive substances, we conducted a prospective study of 54 term infants, including infants with meconium-stained amniotic fluid with normal (MSAF) or abnormal (MAS) chest X-ray findings, infants with perinatal asphyxia, and controls. The purpose of this study was to determine the group most likely to have elevated pulmonary arterial pressure and a disturbed balance between vasoactive substances. Methods: To estimate the pulmonary arterial pressure by echocardiography, we used the ratio of the right to left systolic ventricular pressure (RVP/LVP ratio). We measured the plasma concentrations of endothelin-1 (ET-1), cyclic guanosine monophosphate (cGMP) as an indicator of nitric oxide (NO) production, and 6-keto-prostaglandin F1α (6-keto-PGF1α) for the estimation of prostacyclin concentration. We also measured KL-6 as a marker of lung injury. Results:The RVP/LVP ratio was significantly higher in the MAS group than the other groups on day 0. Although ET-1 and 6-keto-PGF1α levels were comparable among all groups, the cGMP level on days 3–5 and the KL-6 level throughout the first postnatal week were significantly higher in the MAS group. Conclusions: It is possible that meconium aspiration delays normal decline of pulmonary vascular resistance shortly after birth through lung parenchymal injury. The subsequent increase of cGMP in MAS may be an adaptive response to prevent further elevation of pulmonary arterial pressure by inducing NO.

Recent clinical trials have demonstrated the efficacy and safety of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy (HIE). We previously reported that the levels of non-protein-bound iron and ascorbic acid (AA) are increased in the CSF of infants with HIE. In this study, we investigated the effect of hypothermia on the combined cytotoxicity of Fe and AA for differentiated PC12 cells. The optimal settings for hypothermic treatment were a temperature of 30-32 degrees C, rescue time window of less than 6 h, and minimum duration of at least 24 h. Hypothermia effectively prevented the loss of the mitochondrial transmembrane potential from 6 h to 72 h (end of the study period) and attenuated the release of apoptotic proteins (cytochrome c and apoptosis-inducing factor) at 6 h of exposure to Fe-AA. Activation of caspase-3 was also delayed until 24 h. Akt was transiently activated, although no influence of temperature was observed. Elevation of oxidative stress markers, including ortho-, meta-, and di-tyrosine (markers of protein oxidation) and 4-hydroxynonenal (lipid peroxidation) was significantly attenuated when the temperature was reduced by 5 degrees C. The half-cell reduction potential (Ehc) of GSSG/2GSH redox couple ranged from -220 to -180 mV in unstressed differentiated PC12 cells, and apoptosis was triggered when Ehc exceeded -180 mV. Hypothermia prevented Ehc from rising above -180 mV within 24 h of exposure to Fe-AA. In conclusion, hypothermia prevented cell death due to Fe-AA toxicity by inhibiting apoptotic pathways through maintenance of a reduced cellular environment, as well as by alleviating oxidative stress.

Objective: Gastric fluid microbes were examined in preterm infants at birth to assess their influence on the postnatal outcome. Study design: Prospective cohort study. Setting: Level III neonatal intensive care unit. Patients: A total of 103 premature neonates with a gestational age of less than 32 weeks. Main outcome measure: Gastric fluid microbes were identified by analysis of bacterial 16S ribosomal RNA gene. Additionally, the urease gene of Ureaplasma species was detected by polymerase chain reaction of gastric fluid obtained at birth and/or tracheal aspirate from ventilated preterm infants. The association between detection of microbes and bronchopulmonary dysplasia was investigated through assessment from clinical features and by a lung injury marker (KL-6). Results: Forty-two of 103 gastric fluid specimens were positive for microbes. Ureaplasma species were detected in 23 of the 42 (55%) gastric fluid specimens. All infants with Ureaplasma species in tracheal aspirate fluid also had positive gastric fluid specimens. Compared to infants negative for gastric fluid microbes, infants positive for microbes had higher rates of maternal chorioamnionitis (18% vs 78%), premature rupture of membranes (11% vs 55%), severe bronchopulmonary dysplasia (1.6% vs 14%) and showed higher plasma KL-6 levels during the initial 4 weeks of life. Conclusion: Detection of gastric fluid microbes was correlated well with antenatal infection and severe bronchopulmonary dysplasia. Detection of Ureaplasma species in gastric fluid was associated with subsequent respiratory colonisation. These results suggest that antenatal exposure of the immature fetus to microbes may cause lung injury and promote the onset of bronchopulmonary dysplasia.

Hyperoxia causes acute lung injury along with an increase of oxidative stress and inflammation. It was hypothesized that vitamin E deficiency might exacerbate acute hyperoxic lung injury. This study used alpha-tocopherol transfer protein knockout (alpha-TTP KO) mice fed a vitamin E-deficient diet (KO E(-) mice) as a model of severe vitamin E deficiency. Compared with wild-type (WT) mice, KO E(-) mice showed a significantly lower survival rate during hyperoxia. After 72 h of hyperoxia, KO E(-) mice had more severe histologic lung damage and higher values of the total cell count and the protein content of bronchoalveolar lavage fluid (BALF) than WT mice. IL-6 mRNA expression in lung tissue and the levels of 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) in both lungs and BALF were higher in KO E(-) mice than in WT mice. It was concluded that severe vitamin E deficiency exacerbates acute hyperoxic lung injury associated with increased oxidative stress or inflammation.

Involvement of cranial nerves is rare in plasma cell leukemia (PCL). Here, we report a case of PCL presenting with unilateral abducens paralysis. Cranial magnetic resonance imaging (MRI) disclosed a mass in the sphenoid sinus. Although the patient showed an initial response to chemotherapy, he died of disease progression 5 months later. Cytogenetic analysis showed translocation of chromosomes 11 and 14, t(11;14) (q13;q32), with additional complex abnormalities. This case implies an association between clinical manifestations and chromosomal abnormalities.

The analgesic effect of oral sucrose in newborn infants undergoing painful procedures is generally accepted. For blood sampling, some studies have shown that venepuncture (VP) is less painful than heel lance (HL).To determine the least painful and most effective method among blood sampling by VP or HL with or without sucrose.Randomised, double blind, placebo controlled trial.A total of 100 healthy, full term newborn infants being screened for inborn errors of metabolism were randomly allocated to one of four experimental groups (25 infants in each). Intervention andSeven specially trained nurses took turns to carry out blood sampling two minutes after administration of oral sucrose or water. Neonatal pain was assessed by the neonatal facial coding system (NFCS), as well as by crying.Without sucrose, the NFCS score was higher in the HL group than the VP group during blood sampling (median 58 v 23, p0.001). Oral sucrose significantly reduced the score of the HL group (58 v 47, p0.01) and also tended to reduce the score of the VP group (23 v 2, p0.1). However, the HL with sucrose group still had a higher score than the VP without sucrose group (47 v 23, p0.01). Crying and the total procedure time showed the same trends as the NFCS score.VP is less painful and more effective than HL for blood sampling in newborn infants. Although oral sucrose may have an additive analgesic effect, it is not necessarily required if VP is used for blood sampling.

Objectives: To determine the serum ratio of holo-ceruloplasmin to total ceruloplasmin in patients with Wilson's disease (WD), we identified apo- and holo-forms of serum ceruloplasmin with native-PAGE electrophoresis. Design and methods: Serum obtained from nine patients with Wilson's disease was subjected to native-PAGE analysis. We also determined the ceruloplasmin level and ferroxidase activity in all of the samples. Results: Among the nine patients, three had both forms of ceruloplasmin and six had only apo-ceruloplasmin. In the patients who had only apo-ceruloplasmin, the serum ceruloplasmin level was significantly lower than in the patients with both forms. Conclusions: Differences in the ability to incorporate copper into ceruloplasmin may have a role in ceruloplasmin concentrations in patients with Wilson's disease.

Among various hypothetical mechanisms for the in vivo production of reactive oxygen species, transition metal-catalyzed reactions in cooperation with a biologic reducing agent like ascorbic acid or superoxide may be some of the most important. In the present study, we retrospectively examined the existence of non-protein-bound metal ions, an essentially hazardous pro-oxidant form of various transition metals, and the occurrence of metal-catalyzed reactive oxygen species production in cerebrospinal fluid (CSF) of 10 infants with hypoxic ischemic encephalopathy (HIE) subsequent to perinatal asphyxia and 12 control infants within 72 h of birth. Non-protein-bound iron was detected in eight out of 10 CSF samples from the HIE infants and its level was significantly correlated with Sarnat's clinical stage, whereas none of the control infants had detectable non-protein-bound iron levels. Non-protein-bound copper was below the detection limit in all CSF samples from both groups. Ascorbic acid was significantly increased in the CSF of HIE infants when compared with that of controls (means, 664.9 versus 449.4 microM, p = 0.008). ortho-Tyrosine and meta-tyrosine, which are highly specific and sensitive markers of protein oxidation induced by hydroxyl radicals, were significantly higher in HIE infants than in controls when evaluated by the ratio relative to their source amino acid, phenylalanine [means, 110.5 versus 75.4, p = 0.018 for ortho-tyrosine/phenylalanine; 104.6 versus 67.7 (nM/microM x 10(2)), p = 0.048 for meta-tyrosine/phenylalanine]. Both ratios were significantly correlated with non-protein-bound iron, but not with ascorbic acid. Our preliminary observations provide direct evidence that hydroxyl radicals are generated in the CNS during asphyxiation. Iron chelation therapy could be worth developing as a neuroprotective strategy for perinatal asphyxia.

Alpha-tocopherol (a form of vitamin E) is a fat-soluble vitamin that can prevent lipid peroxidation of cell membranes. This antioxidant activity of alpha-tocopherol can help to prevent cardiovascular disease, atherosclerosis and cancer. We investigated the alpha-tocopherol level and the expression of alpha-tocopherol transfer protein (alpha-TTP) in the leukocytes of children with leukemia. The plasma and erythrocyte alpha-tocopherol levels did not differ between children with leukemia and the control group. However, lymphocytes from children with leukemia had significantly lower alpha-tocopherol levels than lymphocytes from the controls (58.4 +/- 39.0 ng/mg protein versus 188.9 +/- 133.6, respectively; p < 0.05), despite the higher plasma alpha-tocopherol/cholesterol ratio in the leukemia group (5.83 +/- 1.64 micromol/mmol versus 4.34 +/- 0.96, respectively; p < 0.05). No significant differences in the plasma and leukocyte levels of isoprostanes (the oxidative metabolites of arachidonic acid) were seen between the leukemia patients and controls. The plasma level of acrolein, a marker of oxidative stress, was also similar in the two groups. Investigation of alpha-TTP expression by leukocytes using real-time PCR showed no difference between the two groups. These findings suggest that there may be comparable levels of lipid peroxidation in children with untreated leukemia and controls, despite the reduced alpha-tocopherol level in leukemic leukocytes.

We encountered two patients with abnormally low glycohemoglobin levels in spite of normal plasma glucose levels. Since the presence of an abnormal hemoglobin was suggested by high-performance liquid chromatography (HPLC), gene analysis of these two patients was conducted by single-strand conformation polymorphism (SSCP) analysis followed by direct sequencing, and Hb Kamakura with one base substitution (beta3 Leu --> Val) in the beta globin gene was detected in both patients. There was been only one report of Hb Kamakura in Kanagawa Prefecture, and our patients represent the second and third cases, respectively.

An autopsy case of an ACTH-producing pituitary carcinoma in a 59-year-old man who developed Cushing's disease is reported. The surgically removed pituitary tumor was diagnosed as chromophobe adenoma, however, pulmonary metastases appeared 2 years after the operation. Autopsy revealed a residual pituitary tumor in the sella turcica with systemic metastases to the lungs, liver, pulmonary lymph nodes, hypothalamus, dura mater, and the subarachnoid space of the midbrain and spinal cord. Immunohistochemistry revealed ACTH positivity in the tumor cells. Further immunohistochemical study showed positive high expression of Ki-67 in the tumor removed at surgery as well as in the autopsied tumor. Ki-67 labeling index provided valuable information about the invasive and proliferative potential compared to noninvasive benign pituitary adenoma.

Studies were designed to explore the role of vitamin E nutritional status in regulating the synthesis of alpha-tocopherol transfer protein (alphaTTP) in rat liver. In vitamin E-replete rats, expression of this protein and its specific messenger RNA (mRNA) was decreased by about 300% compared with rats with normal vitamin E levels. In vitamin E-depleted rats, the alphaTTP-specific mRNA level increased to about 150% of that in the normal vitamin E group. However, protein expression remained constant. These findings indicate that the synthesis of alphaTTP can be regulated by the vitamin E nutritional status.

We report a rare case of duplication for 7q22 7qter and deletion for 7p22 7pter, resulting from a meiotic recombination of a paternal pericentric inversion, inv(7)(p22q22). The newborn boy had the 7q trisomy syndrome. In addition, the diagnosis of chondrodysplasia punctata was made from lumbar and hand X-ray films taken soon after birth. Only two cases of rec(7)dup(7q), both in a single family, have been reported previously. We review 133 offspring with recombinations resulting from pericentric inversions on any chromosomes reported between 1981 and 1995. Of the 133 cases, 110 had a long-arm duplication and short-arm deletion, while only 23 had a short-arm duplication and long-arm deletion. In 85 of the 133 cases, the mother was an inversion carrier (five carriers had two affected offspring), and in 46, the carrier was a father (one carrier had three affected offspring). Kaiser [Hum Genet 1984;68:1–47] reviewed 63 offspring with recombinations derived from a parental pericentric inversion reported between 1972 and 1981. In both surveys, recombinations resulting from pericentric inversions of chromosomes 1, 12, 19, and Y were not found. Am. J. Med. Genet. 73:290–295, 1997. © 1997 Wiley-Liss, Inc.

Allantoin, the oxidation product of uric acid (UA), can be used as an in vivo marker of free radical generation. The aims of the present study were to evaluate the allantoin changes in plasma and bronchoalveolar lavage fluid (BALF) as well as to examine plasma levels of ascorbic acid (AA) and its oxidation product, dehydroascorbic acid (DHAA), in infants with or without chronic lung disease (CLD) during the first week of life. The study population was 20 infants of 24–30 weeks gestation, comprising 10 who subsequently developed CLD and 10 without CLD. In the CLD infants, the plasma allantoin/UA ratio showed a significant increase after day 1 and continued to increase gradually to reach a peak on day 6 (6.5 ± 4.1% for CLD and 2.1 ± 0.9% for non-CLD infants). The allantoin/UA ratio in BALF was also higher in CLD infants and the difference reached significance on days 4–6 (41.2 ± 15.8% for CLD and 11.7 ± 9.9% for non-CLD infants). In contrast to allantoin, the plasma DHAA/AA ratio did not differ between the 2 groups throughout the study period. Our findings that the allantoin/UA ratios were significantly higher in CLD than non-CLD infants not only in plasma but also in BALF, and that the intergroup differences of this ratio in both plasma and BALF was more prominent in the latter half of the first week of life further confirm our previous speculation that oxygen radicals are involved in the development of neonatal CLD.

It has been demonstrated that the level of serum copper unbound to ceruloplasmin (loosely bound copper) is increased in Wilson's disease, although the total serum copper concentration is usually low, reflecting a low ceruloplasmin level. To assess the contribution of free radical reactions catalyzed by nonceruloplasmin copper to the development of complications in this disease, we investigated copper and antioxidant status in four untreated patients who had hepatic dysfunction with or without hemolytic anemia and made a comparison with five patients controlled on penicillamine therapy and 19 age-matched healthy children. We found that loosely bound copper in plasma measured by the phenanthroline assay was detectable in three of four untreated patients with Wilson's disease, but was not detectable in the patients during therapy or in the healthy controls. Among the various antioxidants, the ascorbate and urate levels were markedly reduced before treatment (mean +/- SD, 23 +/- 16 microM for ascorbate and 90 +/- 59 microM for urate) compared with the values in the patients during treatment with penicillamine (67 +/- 19 and 302 +/- 78 microM, p < 0.05) and in control children (60 +/- 8 and 254 +/- 48 microM, p < 0.05). We also demonstrated that the plasma concentration of allantoin, an oxidation product of uric acid and a possible marker of radical generation in vivo, was markedly elevated in the untreated patients (11.0 +/- 1.8 versus 4.3 +/- 0.5 microM in patients on therapy and 6.5 +/- 0.8 microM in controls, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The vitamin E status of elderly Japanese individuals was investigated in the population of two institutions at Osaka and Kyoto. We determined α- and γ-tocopherol levels in red blood cells, platelets, mononuclear cells, polymorphonuclear cells, and buccal mucosal cells as well as plasma to assess the vitamin E status. Plasma α-tocopherol levels in the elderly were similar to those in young adult controls, while γ-tocopherol levels were significantlower in the elderly than in the young adults. Both α- and γ-tocopherol levels in the cells examined were significantly lower in the elederly than in the young adults. Analysis of the fatty acid composition of red cell ghost membranes revealed a higher peroxidizability index and a lower α-tocopherol to peroxidizability index ratio in the elderly as compared with the young adults, suggesting that the elderly had a higher susceptibility to oxidant stress. The daily intake of vitamin E was calculated from the menus of the two institutions, and was found to be lower than the Japanese recommended dietary allowance. These findings indicate that these institutionalized elderly in Japan have an inadequate vitamin E status.

We describe a 27-year-old woman with disseminated intravascular coagulation and shock due to amniotic fluid embolism after Caesarean section who responded well to continuous hemodiafiltration (CHDF) therapy. The effectiveness of CHDF in treating amniotic fluid embolism is also discussed.

We report a neonatal infection with Streptococcus dysgalactiae subsp. equisimilis occurring through maternal transmission and presenting as streptococcal toxic shock syndrome 12 hours after birth. Pediatricians and obstetricians should be aware of the possibility of this infectious disease when examining newborns with fever. These observations suggest that antenatal maternal screening for S. dysgalactiae subsp. equisimilis should be considered.

We examined the distribution of beta-carotene in plasma lipoprotein fractions. In healthy children and adults, LDL contained more beta-carotene than did HDL, but in cord blood more beta-carotene was found in HDL than in LDL. After the oral administration of beta-carotene, its plasma level rose although its distribution in the individual lipoprotein fractions did not change. Among disease conditions associated with hyperlipidemia, the ratio of beta-carotene to plasma lipids was highest in anorexia nervosa, while nephrotic syndrome and diabetes mellitus had similar ratios to each other.

KL-6 is a mucinous glycoprotein that is preferentially expressed by alveolar type 2 cells. Plasma KL-6 was higher in infants with chronic lung disease (n = 12) than in infants without chronic lung disease (n = 14) on day 0-1, 10, and 30 (P =.04). KL-6 correlated with the alveolar-arterial oxygen tension difference on day 10 and day 30. Plasma KL-6 may be useful as an early marker of chronic lung disease and an indicator of severity.

We showed the increased susceptibility of neonatal biomembranes to oxidation by a kinetic analysis using an azo compound as a free-radical initiator and red blood cell (RBC) ghosts as a model membrane. When the RBC ghosts were oxidized, oxygen consumption was suppressed during the induction period in which membrane tocopherol was consumed at a constant rate, while increased oxygen uptake was observed after the tocopherol was exhausted. The total tocopherol content was similar in cord, maternal, and adult RBC ghosts, and there were no differences in the induction period (tinh) among the three types of ghosts. While the oxygen uptake rate during the induction period (Rinh) was similar in cord and adult ghosts, the rate in the subsequent phase (Rp) was considerably faster in the cord ghosts. Fatty acid analysis in the membrane lipids showed that the active bisallylic hydrogen (active H) content was greater in cord ghosts than in adult ghosts. The active H content closely correlated with the Rp, but did not with the Rinh. The kinetic chain length (KCL), i.e., the ratio of the rate of propagation to that of initiation, was calculated from Rp and tocopherol consumption rate and KCL values were higher in cord ghosts than in adult ghosts. The faster Rp and the higher KCL of the cord ghosts were attributable to a greater active H content rather than to the tocopherol content.

Intravascular large B-cell lymphoma (IVL) is a rare subtype of B-cell lymphoma presenting with neurological and dermatological lesions in addition to generalized symptoms such as fever and malaise. It may also be associated with variable manifestations of affected organs due to extranodal progression predominantly in the lumen of the small vessels. Here, we report a case of IVL with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as the sole manifestation at the initial presentation. The present case suggests that hormonal disturbances may progress in advance in IVL, before generalized symptoms develop.

There is growing evidence that free radical generation may play a key role in the neuronal damage induced by prolonged convulsions. Free radical scavengers are known to inhibit neuronal death induced by exposure to excitotoxins. However, this neuroprotective effect has not been demonstrated with treatment after seizures had been stopped. We investigated whether 3-methyl-1-phenyl-2-pyrazolin-5-one, edaravone (Ed), a newly developed free radical scavenger that has been used clinically to treat cerebral infarction, could prevent neuronal loss when administered after the occurrence of seizures in a kainic acid (KA)-induced seizure model. Compared with KA alone, cell loss was significantly reduced when animals received Ed (10 mg/kg i.v.) just after seizures, and when Ed was administered both 60 min before (30 mg/kg i.p.) and after KA injection. Combined before-and-after treatment with Ed significantly ameliorated the KA-induced decrease of glutathione and blocked the KA-induced increase of 4-hydroxy-2-nonenal (HNE). Because before-and-after treatment with Ed significantly lessened the KA-induced increase of HNE, Ed may exert its neuroprotective effect by inhibiting lipid peroxidation. However, post-treatment with Ed prevented neuronal cell loss, while HNE and glutathione levels did not differ from those in animals without Ed, so a mechanism other than free radical scavenging must be involved in the prevention of cell loss. Patients who develop status epilepticus are unlikely to receive adequate antioxidant therapy before the onset, so it is an advantage that Ed can prevent neuronal death even when administered after seizures.

Circulating KL-6 is a specific indicator of pulmonary injury affecting the alveolar epithelium and interstitium. Our preliminary study suggested the usefulness of plasma KL-6 as a marker of bronchopulmonary dysplasia (BPD). To confirm the diagnostic value of KL-6 for BPD as well as to determine the reference range, we conducted a larger prospective study in 135 preterm infants

We previously reported that the levels of non-protein-bound iron (NPBI) and ascorbic acid (AA) are markedly increased in the cerebrospinal fluid of infants with perinatal asphyxia. The present study showed that FeSO4 and AA synergistically induced apoptosis of PC12 cells, which was prevented by alpha-tocopherol and glutathione (GSH) ethyl ester. Markers of free radical damage, such as ortho-tyrosine, meta-tyrosine, and F(2alpha)-isoprostane, showed a gradual increase. AA and ferrous NPBI disappeared rapidly from the culture medium, but exposure for only a few hours was sufficient to trigger apoptosis. Intracellular GSH decreased progressively along with a concomitant increase of glutathione disulfide (GSSG). The baseline half-cell reduction potential (Ehc) for GSSG, 2H+/2GSH couple was -246 mV and an Ehc of -200 mV was the critical level to switch on apoptosis, although some cells escaped this fate by transient increase of intracellular GSH. Once Ehc reached around -165 mV (81 mV oxidation from the baseline), all cells lost the ability to maintain an adequate intracellular GSH level and subsequently underwent apoptosis. These findings at least partly explain the mechanism of Fe-AA cytotoxicity, in that ferrous iron catalyzes hydroxyl radical generation and induces lipid peroxidation, after which subsequent depletion of GSH raises Ehc to the critical level for triggering or potentiating the apoptotic cascade.

Alpha-tocopherol (a form of vitamin E) is a fat-soluble vitamin that can prevent lipid peroxidation of cell membranes. This antioxidant activity of alpha-tocopherol can help to prevent cardiovascular disease, atherosclerosis and cancer. We investigated the alpha-tocopherol level and the expression of alpha-tocopherol transfer protein (alpha-TTP) in the leukocytes of children with leukemia. The plasma and erythrocyte alpha-tocopherol levels did not differ between children with leukemia and the control group. However, lymphocytes from children with leukemia had significantly lower alpha-tocopherol levels than lymphocytes from the controls (58.4 +/- 39.0 ng/mg protein versus 188.9 +/- 133.6, respectively; p0.05), despite the higher plasma alpha-tocopherol/cholesterol ratio in the leukemia group (5.83 +/- 1.64 micromol/mmol versus 4.34 +/- 0.96, respectively; p0.05). No significant differences in the plasma and leukocyte levels of isoprostanes (the oxidative metabolites of arachidonic acid) were seen between the leukemia patients and controls. The plasma level of acrolein, a marker of oxidative stress, was also similar in the two groups. Investigation of alpha-TTP expression by leukocytes using real-time PCR showed no difference between the two groups. These findings suggest that there may be comparable levels of lipid peroxidation in children with untreated leukemia and controls, despite the reduced alpha-tocopherol level in leukemic leukocytes.

AIM To indicate the extent of lipid peroxidation induced by oxidative stress, by measuring aldehyde end products in biological samples. METHODS A highly specific gas chromatography and mass spectrometry (GC/MS) method was used to measure plasma concentrations of aliphatic aldehydes within the first week of life in 13 premature infants who subsequently developed chronic lung disease (CLD) and 11 infants without CLD (non-CLD). The oxime-tert-butyldimethylsilyl derivatives of aldehydes were analysed using 2,2,6,6-d4-cyclohexanone as the internal standard. RESULTS All of the aldehydes measured were raised in those infants with CLD compared with non-CLD infants. Plasma concentrations of heptanal, 2-nonenal, and 4-hydroxynonenal (HNE) were significantly increased in CLD infants on the day of birth, while the differences in all aldehydes between the two groups were not significant at 4–6 days of age. Logistic regression analysis showed that the increase in these three aldehydes within the first 24 hours of life independently showed significant associations with the development of CLD. In particular, an HNE concentration of ⩾ 200 nM on day 0 was the best predictor for the early detection of CLD (odds ratio = 32.0), followed by a 2-nonenal concentration of ⩾ 150 nM (odds ratio = 16.0). CONCLUSIONS These findings suggest that lipid peroxidation may have a role in the pathogenesis of neonatal CLD.

BACKGROUND An etiologically important role has been suggested for hepatitis C virus (HCV) infection in the development of B-cell non-Hodgkin's lymphoma (NHL). HCV has been recognized as the major cause of non-A, non-B chronic hepatitis throughout the world. Moreover, the occurrence of primary splenic malignant lymphoma (PSML) has been demonstrated in patients with chronic liver disease. METHODS In this study, the authors describe three patients with PSML. The clinical, histologic, and immunohistochemical features of the lymphomas were studied. Clonal immunoglobulin heavy chain gene rearrangement was investigated by polymerase chain reaction. RESULTS All three cases of PSML were detected by imaging studies performed in routine follow-up of cases of chronic liver disease associated with HCV infection. Macronodular lesions were found in the three spleens; two of them were of normal weight and another was moderately enlarged. The former two were the smallest PSMLs reported to date. The histology was B-cell NHL in all cases. All 3 patients were alive after splenectomy with an average follow-up of 51.7 months (range, 35-74 months). CONCLUSIONS HCV infection may play an etiologic role in the development of splenic B-cell lymphoma. The long survival of the patients in this study may have been due to early splenectomy. Cancer 1997; 80:1981-8. © 1997 American Cancer Society.

Developmental changes in expression of alpha-tocopherol transfer protein (alpha-TTP) after birth were investigated using rats with respect to plasma changes of tocopherols. The expression of alpha-TTP in the neonatal rat liver, which was very low immediately after birth, increased steadily during the two weeks of life before weanling and reached the adult level at four weeks. During the suckling period, the plasma ratio of alpha-tocopherol to gamma-tocopherol linearly increased, because plasma alpha-tocopherol which was low immediately after birth, increased rapidly during the period, while gamma-tocopherol remained unchanged. The increase in the ratio seemed to correlate with the developmental expression of alpha-TTP in the liver during this period. The ratio also reached the adult level after four weeks. The expression of alpha-TTP was investigated using primary cultured rat hepatocytes. The expression of alpha-TTP was found to be extremely low after 20h of culture. The decrease in alpha-TTP expression was exacerbated by adding epidermal growth factor to the culture medium and was inhibited by adding dexamethasone. These observations suggest that expression of alpha-TTP may be affected by the state of hepatic differentiation.

Homocystinuria is an inborn error of methionine metabolism that is characterized by the premature development of arteriosclerosis. As one of the major factors in the pathogenesis of arteriosclerosis, modification of low-density lipoprotein (LDL) has received widespread attention by many investigators. In this study, to elucidate the relationship between elevated homocysteine levels and premature arteriosclerosis, we investigated the role of homocysteine in the iron-catalyzed oxidative modification of LDL. When LDL isolated from a healthy subject was incubated with homocysteine and ferric ion, a gradual decrease of polyunsaturated fatty acids (PUFA), formation of thiobarbituric acid-reactive substances (TBARS) and fluorescent substances, and the fragmentation of apoprotein B (apoB) were observed. The extent of oxidative modification was dependent on the concentration of homocysteine. Modification of LDL was suppressed until the remaining alpha-tocopherol concentration reached a critical level. When the alpha-tocopherol content of LDL was increased by 2.6-fold, both the formation of TBARS and the fragmentation of apoB were suppressed. These results suggest that homocysteine might promote iron-catalyzed oxidation of LDL and imply its role for the development of premature arteriosclerosis.

A 32-year-old man with primary embryonal carcinoma of the retro peritoneum, a very rare condition, is reported. The disease took an acute course with rapid enlargement of cervical and inguinal lymph nodes, and high serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) values were observed. His testes were, however, intact. Remarkable tumor regression was achieved by systemic combination chemotherapy with cisplatin, vin lastine, and bleomycin (PVB therapy). This chemotherapy is beneficial even in advanced cases. In the two years since therapy, no recurrence has been observed.(Internal Medicine 32: 295-297, 1993)

A 25-year-old Japanese woman experienced pulmonary edema, shock, encephalopathy and silent pancreatitis after hysterosalpingography using lipiodol ultra fluid, because the contrast media flowed directly into the blood stream from endometrium injured by several curettages for termination of pregnancy. Total iodine concentrations in plasma and urine decreased exponentially and their half-life was 16.12 and 13.04 days, respectively. Clear correlations were observed between the iodine concentration in plasma and the amelioration of both electroencephalogram and neuropsychic abnormalities. Adverse reactions of oil-soluble contrast media are also discussed.

We compared peroxidizability of neonatal and adult lipoproteins exposed to oxidative stress initiated by an azo-compound. Oxygen uptake showed a two-phase pattern, with slow oxygen uptake in the first phase and faster uptake in the second phase. During the first phase, tocopherol was consumed progressively, inhibiting lipid peroxidation by scavenging peroxy radicals. After the tocopherol concentration fell below a critical level, extensive propagation of chain oxidative reactions produced the rapid oxygen uptake in the second phase. In the first phase of neonatal lipoprotein oxidation, a faster oxygen uptake was observed and the length of this phase was shorter than in adults. The oxygen uptake rate in the second phase was smaller in the neonatal lipoproteins. In other words, neonatal lipoproteins were more susceptible to oxidative stress than were adult ones when tocopherol remained in lipoproteins, but after tocopherol depletion the reverse was true. These results were consistent with the finding that in neonatal lipoproteins the tocopherol/lipid ratio was significantly lower (length of the inhibitory phase was closely correlated to the lipoprotein tocopherol content). In addition, the average number of active bisallylic hydrogen atoms, which are considered to determine the relative susceptibility of polyunsaturated fatty acids to oxidation, was significantly smaller (oxygen uptake rate in the second phase was closely correlated to the active bisallylic hydrogen number) in neonatal lipoproteins, and the ratio of active bisallylic hydrogen to tocopherol content (which closely correlated to oxygen uptake rate in the first phase) was also significantly lower compared with the adult ratio. Under physiologic conditions, an intensive oxidation of lipoproteins sufficient to cause lipoprotein tocopherol to fall below critical levels is unlikely to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the renin-angiotensin system in polyuric patients was studied in 5 patients with pituitary diabetes insipidus, 1 patient with nephrogenic diabetes insipidus and 3 patients with psychogenic polydipsia by determining the plasma renin activity and infusing an angiotensin II analog, 1-Sar, 8-Ile angiotensin II. In all patients with diabetes insipidus, plasma renin activity was markedly increased and the blood pressure was reduced in 5 of 6 patients by the administration of the angiotensin II analog. In the other patient, the blood pressure remained unchanged. The plasma renin activity and response of blood pressure to the angiotensin II analog in a patient with nephrogenic diabetes insipidus were not significantly different from there of patients with pituitary diabetes insipidus. On the other hand, in all patients with psychogenic polydipsia, plasma renin activity was normal or low, and the blood pressure increased with the administration of the angiotensin II analog. These results suggest that evaluation of the renin-angiotensin system by determining plasma renin activity and infusing an angiotensin II analog is useful in differentiating between diabetes insipidus and psychogenic polydipsia.