Yukiko Todoroki

Formation of Advanced Glycosylation End Products and Oxidative Stress in Young Patients with Type 1 Diabetes

Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type 1 diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type 1 diabetes at early clinical stages of the disease. Urine samples of 38 patients with type 1 diabetes [mean age (±SD), 12.8 ± 4.5 y; diabetes duration, 5.7 ± 4.3 y; HbA1c, 8.0 ± 1.6%; urinary albumin excretion, 12.6 ± 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria (≥15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type 1 diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.

Bone mineral status in ambulatory pediatric patients on long‐term anti‐epileptic drug therapy

Background : For ambulatory pediatric outpatients, reports of abnormalities of bone metabolism associated with anti‐epileptic drugs are inconsistent and may be difficult to interpret.

Oxidant and antioxidant activities in childhood meningitis

Animal studies have provided substantial evidence for a key role of reactive oxygen species, nitric oxide and its related compounds in the complex pathophysiology of bacterial meningitis. However, there is little information on changes in the redox status in human meningitis. In the present study, we evaluated the redox status and oxidative stress in the central nervous system of children with meningitis. Oxidant and antioxidant activities were assessed from cerebrospinal fluid levels of acrolein-lysine adducts (a marker of lipid peroxidation), nitrite (a marker of nitric oxide production) and bilirubin derivatives (a marker of antioxidant activity of bilirubin). All these markers were several times higher in children during the early phase of bacterial meningitis compared with those of children without meningitis and patients with aseptic meningitis. In the bacterial meningitis group, the levels of bilirubin derivatives correlated significantly with those of acrolein-lysine adducts and nitrite. Acrolein-lysine adducts and nitrite decreased significantly as the patients started to respond to treatment but bilirubin derivatives remained elevated. In conclusion, our data indicate the enhancement of both oxidant and antioxidant activities in the central nervous system of children with early bacterial meningitis, but not in those with aseptic meningitis. Clinical and laboratory improvement may be associated with a decrease in oxidant activities in the central nervous system.

Concentrations of thioredoxin, a redox-regulating protein, in umbilical cord blood and breast milk

Growing evidence indicates that oxidative stress occurs during the fetal-to-neonatal transition. Such stress plays an important role in the pathogenesis of many neonatal diseases. Thioredoxin (TRX), a redox-regulating protein with antioxidant activity, is induced in various cells against oxidative stress and is secreted extracellularly. This study was undertaken to examine the clinical and biological importance of TRX in the perinatal setting. We measured concentrations of TRX in umbilical cord blood and breast milk using a sandwich ELISA. Our study demonstrated that concentrations of TRX in umbilical cord blood were six to seven times higher than those in blood of healthy adults. This study also showed that umbilical concentrations of TRX were correlated significantly with the extent of prematurity of the newborn, and that they were elevated significantly in newborns of mothers with preeclampsia compared to those of mothers without preeclampsia. In contrast, concentrations of coenzyme Q10 and vitamin E in umbilical blood were lower than adult blood levels. Breast milk concentrations of TRX during the early postpartum period were seven to eight times higher than those in blood of lactating women. Those of the coenzyme Q10 were lower than adult blood levels, while those of vitamin E were comparable to adult blood levels. Our findings suggest that the systemic release of TRX is enhanced at birth, and that early breast milk is a rich source of this protein. Consequent high levels of TRX in newborns may provide a unique protective mechanism that allows the maintenance of redox balance during the fetal-to-neonatal transition.

Vasoactive and natriuretic mediators in umbilical cord blood: a report of our observation and review of the literature

BACKGROUND The relative potency and interrelationship among vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. However, little is known about their potential roles in the perinatal setting. AIM The aim of this study was to evaluate further the potential roles of vasoactive and natriuretic mediators in the perinatal setting. STUDY DESIGN We measured umbilical venous levels of arginine vasopressin, endothelin-1, adrenomedullin, natriuretic peptides and NO(2)(-)/NO(3)(-) in 24 vaginally delivered newborns and examined their possible functions. RESULTS Cord levels of vasopressin, endothelin-1 and adrenomedullin were considerably higher compared with normal adult values; the concentrations were more than 10-fold higher for vasopressin, and more than threefold higher for endothelin-1 and adrenomedullin. The levels of natriuretic peptides and NO(2)(-)/NO(3)(-) were almost comparable to those of normal adults. Among the mediators, there was a significant correlation between endothelin-1 and adrenomedullin. CONCLUSIONS It appears from other studies that the postnatal fall in vasopressin and endothelin-1 levels is associated with increased levels of natriuretic peptides and NO(2)(-)/NO(3)(-). Based on these observations, we consider that these mediators may play active roles in the initiation, maintenance or both of the transition from fetal to neonatal life.

Neonatal suppurative parotitis possibly associated with congenital cytomegalovirus infection and maternal methyldopa administration.

Correspondence: Hirokazu Tsukahara, Department of Pediatrics, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan. Email: htsuka@fmsrsa.fukui-med.ac.jp Received 21 April 2004; accepted 28 February 2005. Suppurative parotitis is uncommon in neonates. 1,2 We have recently encountered a neonatal case of suppurative parotitis and speculate that its manifestation was associated with congenital cytomegalovirus (CMV) infection and maternal methyldopa administration. To our knowledge, no such cases have been documented in the previous literature.

Effects of antioxidant and nitric oxide on chemokine production in TNF-α-stimulated human dermal microvascular endothelial cells

Chemokines have been implicated convincingly in the driving of leukocyte emigration in different inflammatory reactions. Multiple signaling mechanisms are reported to be involved in intracellular activation of chemokine expression in vascular endothelial cells by various stimuli. Nevertheless, redox-regulated mechanisms of chemokine expression in human dermal microvascular endothelial cells (HDMEC) remain unclear. This study examined the effects of pyrrolidine dithiocarbamate (PDTC, 0.1 mM) and spermine NONOate (Sper-NO, 1 mM) on the secretion and gene expression of chemokines, interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), and eotaxin. This study also addresses PDTC and Sper-NO effects on activation of nuclear factor kappa B (NF-κB) induced by TNF-α (10 ng/ml). Treatment with TNF-α for 8 h significantly increased secretion of IL-8, MCP-1, and RANTES, but not of eotaxin, in cultured HDMEC. Up-regulation of these chemokines was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h, but not by 1 mM 8-bromo-cyclic GMP. The mRNA accumulation of IL-8, MCP-1, RANTES, and eotaxin, and activation of NF-κB were induced by TNF-α for 2 h; all were suppressed significantly by the above two pretreatments. These findings indicate that both secretion and mRNA accumulation of IL-8, MCP-1, and RANTES in HDMEC induced by TNF-α are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly via blocking redox-regulated NF-κB activation. These results suggest that restoration of the redox balance using antioxidant agents or nitric oxide pathway modulators may offer new opportunities for therapeutic interventions in inflammatory skin diseases.

Endothelial dysfunction in Kawasaki disease: focus on nitric oxide

Kawasaki disease (KD) is characterized by systemic panvasculitis accompanied by immunoregulatory abnormalities. In the acute stage, coronary aneurysm formation may occur, which may be associated with myocardial infarction and death. Although the etiology of KD remains a mystery, available data indicate that ‘endothelial dysfunction’ is a key event in the process of atherogenesis of this disease. 1

Methylenetetrahydrofolate Reductase Polymorphism in Childhood Primary Focal Segmental Glomerulosclerosis

Aim: The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population. Methods: Genotypes for MTHFR were determined in 15 primary FSGS patients (male/female, 6/9) and 238 control subjects (male/female, 110/128) by the polymerase chain reaction and restriction fragment length polymorphism method. Results: For the whole group, the genotype frequencies (CC/CT/TT) of MTHFR in FSGS and control subjects were almost comparable. The TT genotype was associated with early onset of the disease as compared with the CC genotype. Furthermore, all the patients with the TT genotype had steroid-resistant FSGS and developed into end-stage renal failure, while those carrying either CC or CT genotype did not. Conclusion: We speculate that the TT genotype may be associated with early development and progression of childhood FSGS. Confirmatory studies using larger and ethnically distinct populations are needed to reveal the role of homocysteine in FSGS with consideration of medical interventions.