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Biomedical subjects

Tohru Yorifuji

Publications and source records attributed to Tohru Yorifuji.

At least 19 recordsLinked to original sources
PubMed2007

Improvements of hypertriglyceridemia and hyperlacticemia in Japanese children with glycogen storage disease type Ia by medium-chain triglyceride milk.

BACKGROUND: Besides profound hypoglycemia with hyperlacticemia, glycogen storage disease type Ia (GSD Ia) presents hypertriglyceridemia that is often resistant to dietary treatment with cornstarch. The present study aimed to evaluate the effects of medium-chain triglycerides (MCT)--which are absorbed via the portal vein without being incorporated into chylomicrons--on hypertriglyceridemia and to explore otherwise metabolic changes in children with GSD Ia. PATIENTS AND METHODS: A 13-year-old boy with GSD Ia who received a dietary treatment with MCT milk after cornstarch administration and two infants also with GSD Ia, ages 6 and 7 months, who received MCT milk after carbohydrate-rich, lipid-poor milk were enrolled. In addition to serum glucose and lactate levels, serum levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were serially determined. Simultaneously, serum levels of total carnitine, free carnitine, acylcarnitine, and ketone bodies were determined to evaluate fatty acid beta-oxidation. RESULTS: Mean glucose level (mmol/l) of patient 1 remained stable, the value being around 4.5, while those of patients 2 and 3 increased to this level from 4.00 and 3.72, respectively. Lactate levels were significantly decreased in all patients. Mean triglyceride levels (mM) of patient 1 decreased from 3.00 to 2.05. Also, triglyceride levels of patients 2 and 3 decreased from 2.74 and 3.15 to 2.13 and 2.70, respectively. HDL cholesterol, acylcarnitine, and ketone body levels increased in all patients after MCT administration, while total and free carnitine levels decreased. CONCLUSION: We describe here the beneficial effects on lipid and carbohydrate metabolisms in three Japanese children with GSD Ia. In light of the unfavorable influence of lipid restriction on growth and development in infancy, dietary treatment with MCT milk may be a better treatment for infants with GSD Ia. Further investigation should be required to confirm the efficacy of MCT milk in GSD Ia.

Adolescent↗
PubMed2006

Fibrillin I gene polymorphism is associated with tall stature of normal individuals.

In order to test the hypothesis that polymorphisms of the Marfan syndrome gene (FBN1) might affect the stature (height) of normal individuals, we genotyped three exonic SNPs on 428 males, 219 with tall stature (>2 SD) and 209 with normal stature (within +/-1 SD). One of the SNPs, rs8033037, in exon 15 showed a significant correlation (P = 0.0061) with the adult height, suggesting that FBN1 is one of the 'stature genes' of normal individuals.

Body Height↗
PubMed2006

Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress.

The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper that generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic antioxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5), and fulminant hepatic failure (group III, n = 5) and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in group II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-dependent superoxide dismutase (CuZn-SOD), and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase (GPx) activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD, and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.

Adult↗
PubMed2006

Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency.

BACKGROUND: The aim of this study was to investigate the effects of arginine on nutrition, growth and urea cycle function in boys with late-onset ornithine transcarbamylase deficiency (OTCD). Seven Japanese boys with late-onset OTCD enrolled in this study resumed arginine treatment after the cessation of this therapy for a few years. Clinical presentations such as vomiting and unconsciousness, plasma amino acids and urinary orotate excretion were followed chronologically to evaluate urea cycle function and protein synthesis with and without this therapy. In addition to height and body weight, blood levels of proteins, lipids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein -3 (IGFBP-3) were monitored. RESULTS: The frequency of hyperammonemic attacks and urinary orotate excretion decreased significantly following the resumption of arginine treatment. Despite showing no marked change in body weight, height increased gradually. Extremely low plasma arginine increased to normal levels, while plasma glutamine and alanine levels decreased considerably. Except for a slight increase in high-density lipoprotein cholesterol level, blood levels of markers for nutrition did not change. In contrast, low serum IGF-I and IGFBP-3 levels increased to age-matched control levels, and normal urinary GH secretion became greater than the level observed in the controls. CONCLUSION: Arginine treatment is able to reduces attacks of hyperammonemia in boys with late-onset OTCD and to increase their growth.

Age of Onset↗
PubMed2005

The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.

CONTEXT: Known genes in maturity-onset diabetes of the young account for only a fraction of families with dominantly inherited diabetes in Japan. There should be as-yet-unidentified genes that account for the rest of the patients. OBJECTIVE: To identify and characterize the mutation responsible for a Japanese family with dominantly inherited diabetes mellitus. SUBJECTS: Members of a four-generation family with dominantly inherited diabetes mellitus observed in three generations. None of the patients in this family had permanent neonatal diabetes. One had transient neonatal diabetes, one had childhood diabetes, and the others had adult-onset diabetes without autoantibodies or insulin resistance. METHODS: Screening of the chromosomal location of the gene by a genome-wide linkage analysis followed by candidate gene sequencing. Confirmation of the functional significance of the identified mutation by the population survey and the physiological analysis. RESULTS: We identified a novel mutation (C42R) in the KCNJ11 gene coding for the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel. The patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of our patients. CONCLUSIONS: These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset.

Amino Acid Substitution↗
PubMed2005

Evaluation of risk for atherosclerosis in Alagille syndrome and progressive familial intrahepatic cholestasis: two congenital cholestatic diseases with different lipoprotein metabolisms.

OBJECTIVES: To evaluate the risk for atherosclerosis in Alagille syndrome (AGS) and progressive familial intrahepatic cholestasis (PFIC) on the basis of lipoprotein metabolism and by ultrasonography. STUDY DESIGN: Five patients with AGS and 5 with PFIC, ages 3 to 4 years, were enrolled. Intimal-medial thickness and wall stiffness of the common carotid artery were examined by ultrasonography. Serum levels of lipids and lipoproteins were determined. Further, the chemical composition of LDL and its ability to transform macrophages into foam cells were determined. RESULTS: Intimal-medial thickness and wall stiffness were increased in patients with PFIC but not in patients with AGS. Total cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein X were remarkably increased in patients with AGS, whereas in patients with PFIC, an increase in triglyceride and a decrease in HDL cholesterol were the prominent findings. However, despite the normal LDL cholesterol level, oxidized LDL level was strikingly high in patients with PFIC. LDLs from patients with PFIC had high TG contents and exhibited high abilities to transform macrophages into foam cells. CONCLUSIONS: These findings suggest that patients with PFIC are at high risk for cardiovascular disorders involving atherosclerosis.

Alagille Syndrome↗
PubMed2004

Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency.

Deficiency of citrin due to mutations of the SLC25A13 gene causes adult-onset type II citrullinemia (CTLN2) and one type of neonatal intrahepatic cholestasis (NICCD). About half of the NICCD patients are detected based on high galactose, phenylalanine, and/or methionine concentrations on newborn mass screening (NMS). To clarify the perinatal and neonatal effects and the inconsistent results on NMS, we examined aminograms, the levels of bile acids and galactose in dried blood spots for NMS from 20 patients with NICCD. Birth weight was low for gestational age (-1.4 +/- 0.7 SD). Affected fetuses may have suffered intrauterine citrin deficiency. The first abnormality detected after birth was citrullinemia, and 19 of 20 patients had citrulline levels higher than +2 SD of controls. Tyrosine, phenylalanine, methionine, galactose, and bile acids were less affected than citrulline on d 5 after birth. Galactose and bile acids levels were increased at 1 mo in comparison with d 5 after birth due to impairment of the cytosolic NADH reducing-equivalent supply into mitochondria of hepatocytes. Patients with negative findings on NMS had low levels of total 20 amino acids. Citrulline/serine, citrulline /leucine plus isoleucine, and citrulline/total amino acids ratios, controlled for the confounding effect of low amount of total amino acids, were higher in all patients than +2 SD, +2 SD, and +3 SD of controls, respectively. NMS for citrin deficiency (frequency of homozygote with SLC25A13 mutation: 1/10,000-1/38,000 in East Asia) will be useful for clarification of the clinical course, treatment, and prevention of this disease.

Amino Acids↗
PubMed2004

Nitric oxide synthesis in ornithine transcarbamylase deficiency: possible involvement of low no synthesis in clinical manifestations of urea cycle defect.

Nitric oxide (NO) levels in plasma and urine were determined in 5 girls with ornithine transcarbamylase deficiency (OTCD) of late-onset type, who often developed migraine-like headache or vomiting. The patients were found to have low NO synthesis, suggesting that the low NO synthesis contributes to the clinical manifestations of urea cycle defect.

Child, Preschool↗
PubMed2004

Earlier initiation of GH therapy does not influence adult height but enables earlier start of pubertal induction in children with multiple pituitary hormone deficiency.

OBJECTIVE: For patients with GH and gonadotrophin deficiency, adult height and sexual maturation are important not only for their physical but also psychological status. GH therapy is usually initiated soon after diagnosis but the differences in the age for initiation of therapy have not been previously examined. In this study, we assessed the influence of timing of initiation of GH therapy on adult height and the time of initiation of pubertal induction. DESIGN, PATIENTS AND MEASUREMENTS: Height-related data from 16 short children (13 boys and three girls) with GH and gonadotrophin deficiency who reached adult height after 10.9 +/- 2.3 years of GH therapy were analysed retrospectively. RESULTS: Adult height (0.00 +/- 0.69 SD) improved remarkably compared to height SDS at the start of GH therapy (-3.75 +/- 0.94 SD). The age at which GH therapy was started ranged from 3.2 to 12.0 years, but we found that such a difference in age did not affect adult height. However, an earlier start of GH therapy allowed earlier pubertal induction without loss of height potential. CONCLUSIONS: Earlier initiation of GH therapy is not required for normalization of adult height in patients with GH and gonadotrophin deficiency but it makes earlier pubertal induction possible, which is important for quality of life.

Age Factors↗
PubMed2004

Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism.

Mutations in the gene coding for hepatocyte nuclear factor-1beta (HNF-1beta) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1beta gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1beta, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1beta gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1beta mutations.

Child↗
PubMed2003

Three novel mutations in Japanese patients with 21-hydroxylase deficiency.

OBJECTIVE: This study analyzed the mutation of 21-hydroxylase deficiency (21-OHD) in 36 unrelated Japanese patients with congenital adrenal hyperplasia (CAH). METHODS: All the exons of the functional CYP21 gene (CYP21A2) were analyzed by polymerase chain reaction (PCR) and PCR direct sequencing. RESULTS: Apparent gene deletions and conversions were present in 23.6% of the 72 CAH alleles, in which the most frequent mutation was the IVS2-13 A/C>G (27.8%), followed by I172N (26.3%), consistent with the frequencies reported for other countries. Previously described mutations were not present in three unrelated cases. Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence. These three putative novel mutations are located in exon 1 (M1I), in exon 5 (1210-1211insT), and in exon 3 (R124H). CONCLUSIONS: In this study, we have identified three putative novel mutations. It remains to be determined whether these three mutations are responsible for the significant number of as yet uncharacterized CAH patients in Japan.

Adrenal Hyperplasia, Congenital↗
PubMed2003

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 (> or =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.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

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Journal Article↗