Junji Takaya

Oxidative Metabolism and Phagocytosis of Polymorphonuclear Leukocytes in Patients with Chronic Renal Failure

The respiratory burst activity (generation of hydrogen peroxide) of peripheral polymorphonuclear leukocytes (PMN) in both phorbol myristate acetate (PMA)-stimulated and unstimulated states and phagocytosis were assessed using flow cytometry on 46 patients with chronic renal failure: 33 patients undergoing chronic hemodialysis (CHD), 8 patients who have never been on dialysis (nonhemodialysis; NHD), 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD); these patients were compared with 27 normal control subjects. In patients just before the initiation of dialysis, impaired hydrogen peroxide production by PMA-stimulated PMN and depressed phagocytosis were noted, which was restored to the control levels by hemodialysis. A mild but significant reduction of hydrogen peroxide production in a PMA-stimulated state was found in NHD patients, and an inverse correlation was noted between the impairment of this function and the degree of diminished renal function. There was no significant difference between CAPD patients and controls in hydrogen peroxide production by PMA-stimulated PMN. Decreased hydrogen peroxide production by unstimulated PMN was observed in both CHD and CAPD patients. These findings may explain, at least partly, the enhanced susceptibility to bacterial and fungal infections of these patients.

Magnesium deficiency in pregnant rats alters methylation of specific cytosines in the hepatic hydroxysteroid dehydrogenase-2 promoter of the offspring

Prenatal under-nutrition involves changes in the epigenetic regulation of specific genes. Maternal magnesium (Mg) deficiency affects maternal glucocorticoid metabolism, but the mechanisms underlying changes in glucocorticoid homeostasis of offspring are not well understood. In this study, we investigated the effects of feeding pregnant rats a Mg-deficient diet (0.003% magnesium) on the methylation of cytosine-guanine (CpG) dinucleotides in hepatic glucocorticoid genes of neonatal offspring, compared with controls (0.082% magnesium). Methylation of CpG dinucleotides in the peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1) and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters in the liver were measured by pyrosequencing. Quantitative real-time PCR was used to assess hepatic mRNA expression of each gene. Mean methylation of the Hsd11b2 promoter in the Mg-deficient offspring (33.2%) was higher than in controls (10.4%). This was due to a specific increase at CpG dinucleotides 1 (20.0% vs. control 10.1%), 2 (58.8% vs. 17.0%), 3 (29.7% vs. 6.2%) and 4 (38.7% vs. 8.8%) (p < 0.05). Ppara and Nr3c1 methylation status and expression did not differ between the groups. No significant difference was noted between male and female pups, which were equally represented. Therefore, a Mg-deficient diet alters glucocorticoid metabolism, predicting higher hepatic intracellular glucocorticoid concentrations, and is possibly a key mechanism that induces the metabolic complications of Mg deficiency.

Intracellular Magnesium and Adipokines in Umbilical Cord Plasma and Infant Birth Size

Many epidemiologic studies have disclosed that restricted fetal growth has been associated with an increased risk of insulin resistance in adulthood. We studied the relationship of intracellular magnesium ([Mg2+]i) in cord blood platelets to adipocytokine and birth size. The subjects were 20 infants with small for gestational age (SGA) and 45 infants with appropriate for gestational age (AGA). By using a fluorescent probe, we examined [Mg2+]i of platelets in the cord blood. Cord plasma insulin, IGF-I, ghrelin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), and leptin levels were determined with the use of ELISA. Mean [Mg2+]i was lower in the SGA than in the AGA groups (p < 0.001). Adiponectin and IGF-I were also lower in the SGA than in the AGA, whereas PAI-1 was higher in the SGA. [Mg2+]i was significantly correlated with birth weight, birth length, and adiponectin. Birth weight was also correlated with cord plasma IGF-I, adiponectin, and leptin. Quantitative insulin sensitivity check index (QUICKI) was lower in the SGA group than in the AGA group. [Mg2+]i and adiponectin were correlated with QUICKI in all subjects. [Mg2+]i, as well as leptin and IGF-I, reflect the extent of fetal growth. Decreased [Mg2+]i may be involved in the underlying processes to insulin resistance.

Transmesenteric hernia: report of two patients with diagnostic emphasis on plain abdominal X-ray findings

Transmesenteric hernia is a rare cause of small bowel obstruction and is seldom diagnosed preoperatively, partly because of unfamiliarity with this type of internal hernia. The clinical symptoms of internal hernia may be intermittent and nonspecific, making the diagnosis extremely difficult. We report two patients, 7- and 5-year-old girls, with mesenteric hernia of the ileum. Because of the difficulty of clinical diagnosis of internal hernia, imaging studies played a crucial role. We would like to stress the importance of plain radiological findings as diagnostic aids. Conclusion: a consistent intestinal gas imaging after some interval suggests the possibility of an internal hernia, especially accompanied with a circular or oval defect of the gas shadows in the middle of the abdomen. A serial abdominal X-ray study can be helpful in the diagnosis of internal hernia.

Ménétrier’s disease evaluated serially by abdominal ultrasonography

We report the case of a 3-year-old boy with Ménétrier’s disease who presented with prominent anasarca associated with hypoproteinemia, but no proteinuria. An early sonogram of the stomach demonstrated thickening of the gastric wall which was found to resolve gradually on serial sonograms. Consequently, we considered that the submucosal layer of the gastric wall was particularly thickened as a result of Ménétrier’s disease. A gastric biopsy was performed 18 days after onset of the disease, and an electron-microscopic examination of the sample disclosed persistent widening of gastric tight junctions by more than 10 nm. The patient made a full recovery on supportive treatment in 3 weeks. Ultrasonography provided us with a potent tool not only in making the diagnosis, but also in following the course of the disease.

A case of Kawasaki Disease associated with syndrome of inappropriate secretion of antidiuretic hormone

Kawasaki disease (KD) is an acute vasculitis of unknown aetiology with varied clinical manifestations. Although coronary arteritis is common in the course of KD, central nervous system involvement is rare. We report a case of KD in an infant who developed convulsions and apnoea during his illness associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Increased intracellular calcium and altered phorbol dibutyrate binding to intact platelets in young subjects with insulin-dependent and non—insulin-dependent diabetes mellitus

Intracellular calcium ([Ca2+]i) and phorbol ester binding were studied in intact platelets of young patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Our objective was to evaluate disturbances in calcium regulation and signal transduction in platelets of diabetics. [Ca2+]i in platelets of the IDDM group (135 +/- 20 nmol/L) under basal conditions was significantly higher than that of the control group (81 +/- 8 nmol/L, P = .019), whereas at 60 seconds after stimulation with 0.1 National Institutes of Health (NIH) U/mL thrombin, [Ca2+]i in the NIDDM group (484 +/- 36 nmol/L) was significantly higher than that of the controls (347 +/- 22 nmol/L, P = .003) and IDDM group (360 +/- 45 nmol/L, P = .04), respectively. Phorbol 12,13-dibutyrate (PdBu) maximal binding capacity (Bmax) in the IDDM group was significantly lower than that in the control group either under basal conditions or after stimulation with thrombin (P = .0034 and P = .015, respectively). Bmax in the NIDDM group was significantly lower than that in the controls only after stimulation with thrombin (P = .047). The Kd for PdBu of the IDDM group was lower than that of the control group under basal conditions (P = .017). When analyzing the pooled data of all subjects, a significant correlation was observed between Bmax and Kd (under basal conditions, r = .544, P < .0001; after stimulation, r = .601, P < .0001). Our results support the idea that the increased affinity for PdBu may compensate for the decreased binding capacity. We interpret the data as indicating that the change in the binding of phorbol ester to protein kinase C (PKC) units may result in an altered PKC/calcium interaction in the pathogenesis of diabetes mellitus. Our study indicates that such metabolic derangements of [Ca2+]i have already been developing in young diabetic patients.

Altered intracellular calcium and phorbol 12,13-dibutyrate binding to intact platelets in young obese subjects

The study was designed to examine cytosolic free calcium ((Ca2+)i) and phorbol dibutyryl ester binding in intact platelets of young obese subjects as compared with the platelets of age-matched subjects with non-insulin-dependent diabetes mellitus (NIDDM) and those of healthy control subjects. The assay was studied in basal and thrombin-stimulated conditions. The binding parameter of phorbol ester is a criterion for active protein kinase C (PKC) units in the platelet plasma membrane. The resting (Ca2+)i correlated with body mass index (BMI)(r = 0.385, p = 0.0034) and plasma insulin level (r = 0.316, p = 0.0269), and the resting (Ca2+)i level was higher in the obesity group (160.6 +/- 15.8 nmol/L; n = 25) than controls (78.9 +/- 7.6 nmol/L; n = 24, p < 0.0001). Among the obesity and control groups, there was a correlation between BMI and fasting plasma insulin level (r = 0.399, p = 0.0237). Systolic blood pressure correlated with BMI(r = 0.504, p = 0.0005). The mean systolic blood pressure of the obesity group was higher than those of the other two groups. The mean Hill coefficient for thrombin-treated platelets of phorbol dibutyrate binding was higher in the obesity group when compared with healthy controls and the subjects with NIDDM (1.47 +/- 0.21 vs 1.06 +/- 0.16 and 0.99 +/- 0.09, respectively; p < 0.05). In conclusion, young subjects with simple obesity have already developed altered platelet Ca2+ regulation that is usually observed in adult patients with a number of metabolic diseases. These data are interpreted to indicate that a relationship exists between dysregulation of PKC and impaired glucose tolerance that precedes other complications of obesity.

Plasma Nitric Oxide Products Correlate with Cardiac Index of Congenital Heart Disease

Abstract. We wished to determine the relationship between circulating levels of nitric oxide (NO) and cardiac index (CI) in children with congenital heart diseases. We measured the plasma levels of nitrate/nitrite (NOx), the stable end products of NO production as well as tumor necrosis factor-α (TNF-α), atrial natriuretic peptide (ANP), and brain natriuretic peptide in relation to various parameters determined simultaneously.The plasma NOx levels correlated negatively with CI (r=−0.541, p < 0.05). No correlation was observed between NOx and cardiac output. TNF-α correlated with NOx levels (r= 0.593, p < 0.005) but not with either CI or cardiac output. Plasma levels of ANP and TNF-α were higher in atrial septal defect than those in the control group (p < 0.001 and p < 0.05, respectively). Elevated plasma NOx could explain the increased basal release of endothelial NO due to high pulmonary blood flow. Plasma NOx correlate negatively with CI in young patients with left-to-right shunt congenital heart diseases.

A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver

Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring.