Publications by authors named "Masanobu Fujimoto"

24 Publications

  • Page 1 of 1

Cord Blood from SGA Preterm Infants Exhibits Increased GLUT4 mRNA Expression.

Yonago Acta Med 2021 Feb 20;64(1):57-66. Epub 2021 Jan 20.

Division of Pediatrics and Perinatology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan and.

Background: Insulin and insulin-like growth factor (IGF) signaling plays an important role in prenatal and postnatal growth and glucose metabolism. Both small-for-gestational age (SGA) and preterm infants have abnormal growth and glucose metabolism. However, the underlying mechanism remains unknown. Recently, we showed that term SGA infants have abnormal insulin/IGF signaling in cord blood. In this study, we examined whether preterm infants show similar aberrations in cord blood insulin/IGF signaling.

Methods: A total of 41 preterm cord blood samples were collected. Blood glucose, insulin, IGF-1, and C-peptide concentrations were measured, and mRNA expression of , , , , and (, GLUT4) was analyzed by quantitative reverse-transcription PCR.

Results: This study included 34 appropriate-for-gestational age (AGA) and 7 SGA preterm neonates. No hyperinsulinemia or any differences in or mRNA expression were detected between the two groups. However, GLUT4 mRNA levels were increased in preterm SGA. Moreover, the expression level in hypoglycemic preterm SGA was significantly higher than that in hypoglycemic preterm AGA. mRNA expression did not show a statistically significant difference between preterm SGA and AGA neonates.

Conclusion: SGA preterm birth does not induce hyperinsulinemia; however, it modifies insulin/IGF signaling components such as GLUT4 in umbilical cord blood. Our study suggests that prematurity or adaptation to malnutrition alters the insulin/IGF signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.33160/yam.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902168PMC
February 2021

Independent predictors of discordance between the resting full-cycle ratio and fractional flow reserve.

Heart Vessels 2021 Jun 5;36(6):790-798. Epub 2021 Jan 5.

Department of Cardiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

The resting full-cycle ratio (RFR), a novel resting index, is well correlated with and shows good diagnostic accuracy to the fractional flow reserve (FFR). However, discordance results between the RFR and FFR have been observed to occur in about 20% of cases. This study aimed to clarify the prevalence and factors of discordant results between the RFR and FFR through a direct comparison of these values in daily clinical practice. A total of 220 intermediate coronary lesions of 156 consecutive patients with RFR and FFR measurements were allocated to four groups according to RFR and FFR cutoff values. We compared the angiographic, clinical, and hemodynamic variables among the groups. Discordant results between the RFR and FFR were observed in 19.6% of vessels, and the proportion of discordant results was significantly higher in the left main trunk and left anterior descending artery (LM + LAD) than in non-LAD vessels (25.2% vs. 12.3%, p = 0.006). In the multivariable regression analysis, LM + LAD location, hemodialysis, and peripheral artery disease were associated with a low RFR among patients with a high FFR. Conversely, the absence of diabetes mellitus and the presence of higher hemoglobin levels were associated with a higher RFR among patients with a low FFR. Specific angiographic and clinical characteristics such as LM + LAD location, hemodialysis, peripheral artery disease, and absence of diabetes mellitus and anemia can be independent predictors of physiologic discordance between the RFR and FFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-020-01763-1DOI Listing
June 2021

Impact of skeletal muscle mass on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Cardiovasc Interv Ther 2021 Oct 31;36(4):514-522. Epub 2020 Oct 31.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Low skeletal muscle mass is one of the components of sarcopenia. However, the prognostic impact of skeletal muscle mass on clinical outcomes in patients after transcatheter aortic valve replacement (TAVR) remains unclear. Therefore, we assessed the impact of skeletal muscle mass on future cardiovascular events in patients undergoing TAVR. We enrolled 71 consecutive patients who underwent TAVR for symptomatic severe aortic stenosis. We applied bilateral psoas muscles as an indicator of skeletal muscle mass. Psoas muscle volumes were measured from the origin of psoas at the level of the lumbar vertebrae to its insertion in the lesser trochanter on three-dimensional computed tomography datasets. Psoas muscle mass index (PMI) was calculated as psoas muscle volume/height (cm/m). According to the median value of PMIs (79.8 and 60.0 cm/m for men and women), the enrolled patients were divided into two groups. During the follow-up, 11 (31.4%) patients in low PMI group and 4 (11.1%) in high PMI group experienced major adverse cardiovascular events (MACE) defined as a composite of death from any cause, myocardial infarction, heart failure hospitalization, and stroke. The proportion of MACE-free survival was significantly lower in low PMI group (log-rank P = 0.033), mainly due to the difference of hospital readmission for congestive heart failure. On multivariate Cox proportional hazard analysis, PMI remained an independent negative predictor of MACE [hazard ratio 0.95 (95% confidence interval 0.92-0.98, P = 0.002)]. In conclusion, low skeletal muscle mass independently predicted MACE in patients undergoing TAVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12928-020-00725-8DOI Listing
October 2021

Genetic causes of growth hormone insensitivity beyond GHR.

Rev Endocr Metab Disord 2021 03 8;22(1):43-58. Epub 2020 Oct 8.

Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.

Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11154-020-09603-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979432PMC
March 2021

Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects.

Mol Cell Endocrinol 2020 12 30;518:110967. Epub 2020 Jul 30.

Division of Endocrinology, Children's National Hospital, Washington, DC, 20010, USA; Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, 20052, USA. Electronic address:

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), have long been recognized as central to human growth physiology. IGF-1 is known to complex with IGF binding proteins as well as with the acid labile subunit (ALS) in order to prolong its half-life in circulation. Factors regulating the bioavailability of IGF-1 (i.e. the balance between free and bound IGF-1) were less well understood. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) was discovered as a protease which specifically cleaves IGF-binding protein (IGFBP)-3 and -5. PAPP-A2 deficient patients present with characteristic findings including growth failure, elevated total IGF-1 and -2, IGFBPs, and ALS, but decreased percentage of free to total IGF-1. Additionally, patients with PAPP-A2 deficiency have impairments in glucose metabolism and bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) improved height SD scores, growth velocity, body composition, and dysglycemia. Mouse models recapitulate many of the human findings of PAPP-A2 deficiency. This review summarizes the function of PAPP-A2 and its contribution to the GH-IGF axis through an examination of PAPP-A2 deficient patients and mouse models, thereby emphasizing the importance of the regulation of IGF-1 bioavailability in human growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2020.110967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609568PMC
December 2020

Clinical feasibility of resting full-cycle ratio as a unique non-hyperemic index of invasive functional lesion assessment.

Heart Vessels 2020 Nov 6;35(11):1518-1526. Epub 2020 Jun 6.

Department of Cardiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

The resting full-cycle ratio (RFR) is a new physiologic index to assess myocardial ischemia. RFR and fractional flow reserve (FFR), the conventionally used index, have not been directly compared in evaluating the entire cardiac cycle. Accordingly, we aimed to compare the diagnostic performance of RFR directly with FFR and clarify the clinical feasibility of RFR as a unique non-hyperemic index in evaluating the cardiac cycle. The diagnostic performance of RFR was compared with FFR using an automated online calculation software. A total of 156 consecutive patients with 220 intermediate lesions were enrolled. RFR showed significant correlation with FFR (r = 0.774, p < 0.001). RFR systole and RFR diastole did also with FFR (r = 0.918, p < 0.001, and r = 0.733, p < 0.001, respectively). With FFR < 0.80 as a reference standard, RFR showed good diagnostic accuracy (DA: 80.5%), similar DA between RFR systole and RFR diastole (79.6% and 87.5%, p = 0.58, respectively), and good DA in any lesion locations, especially in non-left anterior descending coronary artery (LAD) lesions (73.7% and 87.6% for LAD vs. non-LAD, p < 0.05, respectively). RFR is a feasible and reliable non-hyperemic index regardless of the difference in cardiac cycle in evaluating physiological lesion severity in daily practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-020-01638-5DOI Listing
November 2020

Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology.

Hum Mol Genet 2020 08;29(15):2625-2636

Division of Endocrinology, Children's National Hospital, Washington, DC 20010, USA.

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGF binding protein-3 (IGFBP-3), pregnancy-associated plasma protein A (PAPP-A2), IGF-II and IGFBP-5 in 838 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated single nucleotide polymorphisms near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger causal relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471503PMC
August 2020

Anthropometric and biochemical correlates of PAPP-A2, free IGF-I, and IGFBP-3 in childhood.

Eur J Endocrinol 2020 Mar;182(3):363-374

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Objective: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors.

Design: Cross-sectional study at a single center.

Methods: PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3-18 years old) and an evaluation of the relationship between these proteins and anthropometric factors.

Results: In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = -0.58, -0.65; P < 0.0001).

Conclusions: This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-19-0859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238294PMC
March 2020

Diagnostic Performance of High-Resolution Intravascular Ultrasound for the Detection of Plaque Rupture in Patients With Acute Coronary Syndrome.

Circ J 2019 11 12;83(12):2505-2511. Epub 2019 Oct 12.

Department of Cardiology, Aichi Medical University.

Background: The new 60-MHz high-resolution intravascular ultrasound (HR-IVUS) is the next-generation IVUS technology, providing higher image resolution than conventional IVUS. It gives clear images of plaque morphology and can discriminate the underlying mechanism of acute coronary syndrome (ACS). Our study aimed to evaluate the diagnostic performance of 60-MHz HR-IVUS in the detection of plaque rupture in patients with ACS.Methods and Results:Patients with ACS who underwent percutaneous coronary intervention for de novo native coronary artery lesions were enrolled. Both HR-IVUS and optical coherence tomography (OCT) were performed for the culprit lesions prior to interventions other than aspiration thrombectomy. Keeping plaque rupture detected by OCT as the gold standard, the diagnostic performance of HR-IVUS was evaluated. Overall, 70 patients underwent both HR-IVUS and OCT examinations. Of these, imaging assessments by HR-IVUS were available for all 70 patients (100%), and those by OCT were available for 54 patients (77.1%). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HR-IVUS for identifying a plaque rupture were 84.8%, 57.1%, 75.7%, 70.6%, and 74.1%, respectively.

Conclusions: HR-IVUS had high sensitivity, but modest specificity for identifying OCT-derived plaque rupture. Compared with results from previous conventional IVUS studies, HR-IVUS might have increased ability to detect OCT-derived plaque rupture, but there is still substantial scope for improvement, especially in the specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circj.CJ-19-0644DOI Listing
November 2019

Low IGF-I Bioavailability Impairs Growth and Glucose Metabolism in a Mouse Model of Human PAPPA2 p.Ala1033Val Mutation.

Endocrinology 2019 06;160(6):1363-1376

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Bioactive free IGF-I is critically important for growth. The bioavailability of IGF-I is modulated by the IGF-binding proteins (IGFBPs) and their proteases, such as pregnancy-associated plasma protein-A2 (PAPP-A2). We have created a mouse model with a specific mutation in PAPPA2 identified in a human with PAPP-A2 deficiency. The human mutation was introduced to the mouse genome via a knock-in strategy, creating knock-in mice with detectable protein levels of Papp-a2 but without protease activities. We found that the Pappa2 mutation led to significant reductions in body length (10%), body weight (10% and 20% in males and females, respectively), and relative lean mass in mice. Micro-CT analyses of Pappa2 knock-in femurs from adult mice showed inhibited periosteal bone expansion leading to more slender bones in both male and female mice. Furthermore, in the Pappa2 knock-in mice, insulin resistance correlated with decreased serum free IGF-I and increased intact IGFBP-3 concentrations. Interestingly, mice heterozygous for the knock-in mutation demonstrated a growth rate for body weight and length as well as a biochemical phenotype that was intermediate between wild-type and homozygous mice. This study models a human PAPPA2 mutation in mice. The mouse phenotype closely resembles that of the human patients, and it provides further evidence that the regulation of IGF-I bioavailability by PAPP-A2 is critical for human growth and for glucose and bone metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2018-00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507901PMC
June 2019

PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: and Evidence.

J Endocr Soc 2018 Jul 28;2(7):646-656. Epub 2018 May 28.

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Context: Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased free IGF-I.

Objective: To determine whether plasma transfusion or recombinant human (rh)PAPPA2 could increase free IGF-I in patients with PAPPA2 deficiency or idiopathic short stature (ISS).

Design: Single patient interventional study combined with experimentation.

Setting: Academic medical center.

Patients: Three siblings with PAPPA2 deficiency and four patients with ISS.

Interventions: An adult female with PAPPA2 deficiency received a 20 mL/kg plasma transfusion. PAPPA2, intact IGFBP-3, and free and total IGF-I levels were monitored during 2 weeks. rhPAPPA2 was added to serum from patients with PAPPA2 deficiency and ISS for 4 hours. Intact IGFBP-3 and free IGF-I levels were assayed via ELISA.

Main Outcome Measures: Free IGF-I concentrations.

Results: Plasma transfusion resulted in a 2.5-fold increase of free IGF-I levels on day 1 posttransfusion with a return to baseline during a 2-week period. studies demonstrated a dose-dependent increase in free IGF-I and decrease in intact IGFBP-3 after the addition of rhPAPPA2. The increase in free IGF-I was more pronounced in patients with PAPPA2 deficiency compared with those with ISS.

Conclusions: PAPPA2 plays a key role in regulation of IGF-I bioavailability. rhPAPPA2 is a promising therapy to increase free IGF-I levels both in patients with PAPPA2 deficiency as well as in patients with ISS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2018-00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009608PMC
July 2018

Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1.

Horm Res Paediatr 2018 22;89(3):205-210. Epub 2018 Mar 22.

Background/aims: Cholesterol side-chain cleavage enzyme (P450scc) deficiency is a rare genetic disorder causing primary adrenal insufficiency with or without a 46,XY disorder of sexual development (DSD). Herein, we report a case of the combination of primary adrenal insufficiency, a DSD (testes with female external genitalia in a setting of a 47,XXY karyotype), and Angelman syndrome.

Methods: Comprehensive genetic analyses were performed, including a single nucleotide polymorphism microarray and whole-exome sequencing. In vitro studies were performed to evaluate the pathogenicity of the novel mutation that was identified by whole-exome sequencing.

Results: The patient was found to have segmental uniparental disomy (UPD) of chromosome 15 explaining her diagnosis of Angelman syndrome. Whole-exome sequencing further revealed a novel homozygous intronic variant in CYP11A1, the gene encoding P450scc, found within the region of UPD. In vitro studies confirmed that this variant led to decreased efficiency of CYP11A1 splicing.

Conclusion: We report the first case of the combination of 2 rare genetic disorders, Angelman syndrome, and P450scc deficiency. After 20 years of diagnostic efforts, significant advances in genetic diagnostic technology allowed us to determine that these 2 disorders originate from a unified genetic etiology, segmental UPD unmasking a novel recessive mutation in CYP11A1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000487638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906135PMC
September 2018

Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2.

J Clin Res Pediatr Endocrinol 2017 Dec 27;9(Suppl 2):1-8. Epub 2017 Dec 27.

Cincinnati Children's Hospital Medical Center, Cincinnati Center for Growth Disorders, Clinic of Endocrinology, Cincinnati, Ohio, USA.

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4274/jcrpe.2017.S001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790331PMC
December 2017

Increased IRS2 mRNA Expression in SGA Neonates: PCR Analysis of Insulin/IGF Signaling in Cord Blood.

J Endocr Soc 2017 Dec 5;1(12):1408-1416. Epub 2017 Oct 5.

Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan 683-8504.

Context: Hypoglycemia is the most common metabolic problem among small-for-gestational-age (SGA) neonates. However, the pathological mechanism and insulin/ insulin-like growth factor (IGF) signaling axis in neonates remain unknown.

Objective: To determine the insulin/IGF axis in neonates, we analyzed the messenger RNA (mRNA) expression of insulin/IGF signaling in fetal umbilical cord blood.

Setting: The Perinatal Medical Center of Tottori University Hospital.

Participants: Fifty-two [42 appropriate-for-gestational-age (AGA) and 10 SGA] neonates.

Interventions: Immediately collected cord blood was placed into a PAXgene Blood RNA Tube. Total RNA from the blood was purified using reagents provided in the PAXgene Blood RNA Kit within 4 days, and reverse transcription polymerase chain reaction (PCR) was performed.

Main Outcome Measure: Quantitative real-time PCR analysis was applied to evaluate the mRNA expression of insulin receptor (), IGF-I receptor (), insulin receptor substrate 1 (), , and glucose transporters ( and ). was used as a control gene.

Results: Serum glucose and IGF-I levels in SGA neonates were significantly lower. The cord serum insulin levels were similar between AGA and SGA neonates. The mRNA expression was significantly higher in SGA than in AGA neonates ( < 0.05). The mRNA expression was significantly higher in hypoglycemic SGA neonates than in normoglycemic SGA neonates.

Conclusions: We determined that intrauterine growth restriction induces increased mRNA expression in cord blood, without hyperinsulinemia. The increased expression of mRNA might be associated with abnormal glucose metabolism in SGA neonates. Our findings might lead to the elucidation of abnormal glucose metabolism in SGA neonates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2017-00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695653PMC
December 2017

A novel frameshift mutation in NR3C2 leads to decreased expression of mineralocorticoid receptor: a family with renal pseudohypoaldosteronism type 1.

Endocr J 2017 Jan 5;64(1):83-90. Epub 2016 Oct 5.

Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by resistance to aldosterone, and the renal form of PHA1 is associated with heterozygous inactivating mutations in NR3C2, which encodes mineralocorticoid receptor (MR). Here we report a case of renal PHA1 due to a novel frameshift mutation in NR3C2. A 10-day-old Japanese male infant, born at 39 weeks gestation (birth weight, 2,946 g), was admitted to our hospital because of lethargy and vomiting, with a 6.7% weight loss since birth. Laboratory test results were: Na, 132 mEq/L; K, 6.6 mEq/L; Cl, 93 mEq/L. Both plasma aldosterone level and plasma renin activity were markedly elevated at diagnosis, 2,940 ng/dL (normal range: 26.9-75.8 ng/dL) and 560 ng/mL/h (normal range 3.66-12.05 ng/mL/h), respectively. Direct sequence analysis of NR3C2 revealed a novel heterozygous mutation (c.3252delC) in the patient and his father. The mutation causes a frameshift starting at amino acid I 963 within the C terminal ligand-binding domain of MR and results in a putative abnormal stop codon at amino acid 994, with an extension of 10 amino acids compared to normal MR. We performed cell culture experiments to determine the levels of mutant NR3C2 mRNA and MR, and evaluate the effects of the mutation on MR response to aldosterone. The mutation decreased the expression of MR, but not NR3C2 mRNA, and led to decreased MR function, with no dominant negative effect. These results provide important information about MR function and NR3C2 mutation in PHA1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ16-0280DOI Listing
January 2017

Influence of plaque characteristics on fractional flow reserve for coronary lesions with intermediate to obstructive stenosis: insights from integrated-backscatter intravascular ultrasound analysis.

Int J Cardiovasc Imaging 2015 Oct 1;31(7):1295-301. Epub 2015 Jul 1.

Department of Cardiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.

The aim of this study was to determine the correlation between the fractional flow reserve (FFR) values and volumetric intravascular ultrasound (IVUS) parameters derived from classic gray-scale IVUS and integrated backscatter (IB)-IVUS, taking into account known confounding factors. Patients with unstable angina pectoris with the frequent development of vulnerable plaques often showed the discrepancy between the FFR value and the quantitative coronary angiography findings. Our target population was 107 consecutive subjects with 114 isolated lesions who were scheduled for elective coronary angiography. The FFR was calculated as the mean distal coronary pressure divided by the mean aortic pressure during maximal hyperemia. Various volumetric parameters such as lipid plaque volume (LPV) and percentage of LPV (%LPV) were measured using IB-IVUS. Simple and multivariate linear regression analysis was employed to evaluate the correlation between FFR values and various classic gray-scale IVUS and IB-IVUS parameters. The Akaike information criterion (AIC) was used to compare the goodness of fit in an each model. Both the %LPV (r = -0.24; p = 0.01) and LPV (r = -0.40; p < 0.01) were significantly correlated with the FFR value. Only the LPV (AIC = -147.0; p = 0.006) and %LPV (AIC = -152.9; p = 0.005) proved to be independent predictors for the FFR value even after the adjustment of known confounding factors. The volumetric assessment by IB-IVUS could provide better information in terms of the relationship between plaque morphology and the FFR values as compared to the classic IVUS 2-dimensional gray-scale analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-015-0699-6DOI Listing
October 2015

Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature.

Clin Endocrinol (Oxf) 2015 Dec 11;83(6):834-41. Epub 2015 May 11.

Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago, Japan.

Objective: The type I insulin-like growth factor I receptor (IGF1R) plays an important role in growth. We aimed to evaluate the detailed mechanism underlying the effect of IGF1R on human growth.

Patients And Methods: We have performed sequence analysis of IGF1R in 55 patients with SGA short stature in Japan, since 2004, and identified novel heterozygous nonsense mutations in 2 patients: an 8-year-old Japanese boy (case 1), with a birthweight of 2228 g (-3·3 SDS) and height of 46 cm (-2·1 SDS), and a 3-year-old Japanese girl (case 2), with a birthweight of 2110 g (-3·0 SDS) and height of 44·3 cm (-2·8 SDS). Both patients had a short stature (-3·2 SDS, -3·1 SDS). We determined the protein expression of mutated IGF1R, assessed the effect of the endoplasmic reticulum-associated degradation (ERAD) pathway on mutated IGF1R, assessed the dominant-negative effect of IGF1R and performed quantitative RT-PCR analysis of IGF1R mRNA expression in whole blood cells.

Results: Two novel heterozygous nonsense mutations (case 1: p.Q1250X and case 2: p.W1249X) were identified. Although these mutations did not affect blood IGF1R mRNA levels, they significantly decreased the expression of IGF1R protein in transiently transfected cells. Treatment with the proteasome inhibitor MG132 showed significantly increased IGF1R protein.

Conclusions: Heterozygous nonsense mutations affecting the C-terminal region (p.Q1250X, p.W1249X) of IGF1R decreased the expression of IGF1R through the ERAD pathway. Our study revealed the importance of the C-terminal region and the dosage of this receptor for growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.12791DOI Listing
December 2015

Epstein-Barr virus-associated posttransplant lymphoproliferative disorder involving the central nervous system following autologous hematopoietic stem cell transplantation for neuroblastoma.

Springerplus 2014 6;3:582. Epub 2014 Oct 6.

Division of Pediatrics and Perinatology, Faculty of Medicine, University of Tottori, 36-1 Nishi-cho, Yonago, 683-8504 Japan.

Introduction: Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following solid organ or hematopoietic stem cell transplantation (HSCT). Although extranodal involvement of PTLD is common, its isolated involvement in the central nervous system (CNS) is extremely rare. To date, primary CNS-PTLD has been reported in 13 patients who underwent allogeneic HSCT, but no cases have been reported in autologous HSCT recipients.

Case Description: Herein, we report the first report of a patient with neuroblastoma that progressed to CNS-PTLD after autologous peripheral blood stem cell transplantation (auto-PBSCT). A 27-month-old boy with stage IV neuroblastoma of the left adrenal gland received auto-PBSCT after intensive chemotherapy, tumor resection, and radiation of tumor bed and regional lymph node. An intracranial tumor in his left parietal lobe was detected by magnetic resonance imaging 99 days posttransplantation, and the tumor was completely resected. The histological diagnosis of the intracranial tumor was diffuse large B-cell lymphoma with latency type III Epstein-Barr virus infection. The patient has maintained tumor free status 3 years after auto-PBSCT.

Discussion And Evaluation: Given the rarity of CNS-PTLD, there is no consensus on the optimal treatment. Historically, the outcome of CNS-PTLD has been very poor. However, our patient remains free from PTLD after only total resection. The prognosis for PTLD following auto-HSCT may depend upon the underlying malignancy, immune state, EBV immune status, and treatments.

Conclusions: The outcome of PTLD following auto-HSCT is not necessarily poor prognosis. Further research is required to establish the optimal treatment strategy for CNS-PTLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/2193-1801-3-582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194306PMC
October 2014

Clinical overview of nephrogenic diabetes insipidus based on a nationwide survey in Japan.

Yonago Acta Med 2014 Jun 30;57(2):85-91. Epub 2014 Jul 30.

Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.

Background: Nephrogenic diabetes insipidus (NDI) is a rare disease whose complications include polyuria, renal dysfunction, growth disorder and mental retardation. The details of NDI's clinical course have been unclear. To address this uncertainty, we performed a large investigation of the clinical course of NDI in Japan.

Methods: Between December 2009 and March 2011, we provided a primary questionnaire to 26,282 members of the Japan Endocrine Society, the Japanese Urological Association, the Japanese Society for Pediatric Endocrinology, the Japanese Society for Pediatric Nephrology, the Japanese Society of Nephrology, the Japanese Society of Neurology and the Japanese Society of Pediatric Urology. In addition, we provided a secondary questionnaire to 121 members who reported experience with cases of NDI. We asked about patient's age at onset, diagnosis, complications, effect of treatment and patient's genotype.

Results: We enrolled 173 patients with NDI in our study. Of these NDI patients, 143 were congenital and 30 were acquired. Of the 173, 73 patients (42%) experienced urologic complications. Among the 143 with congenital NDI, 20 patients (14%) had mental retardation. Patients with NDI mainly received thiazide diuretics, and some patients responded to treatment with desmopressin acetate (DDAVP). Gene analyses were performed in 87 patients (61%) with congenital NDI, revealing that 65 patients had an arginine vasopressin receptor type 2 (AVPR2) gene mutation and that 8 patients (9.2%) had an aquaporin 2 (AQP2) gene mutation. Patients with the AVPR2 mutation (D85N) generally showed a mild phenotype, and we found that DDAVP was generally an effective treatment for NDI among these patients.

Conclusion: We suggest that adequate diagnosis and treatment are the most important factors for improving prognoses. We further suggest that gene analysis should be performed for optimal treatment selection and the early detection of NDI among siblings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198574PMC
June 2014

A rare CYP 21 mutation (p.E431K) induced deactivation of CYP 21A2 and resulted in congenital adrenal hyperplasia.

Endocr J 2015 15;62(1):101-6. Epub 2014 Oct 15.

Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene. The residual enzyme activity is strongly associated with the phenotype. We describe a rare case of CAH with a rare CYP21A2 mutation. The patient was a one-year-old Japanese boy. At 16 days old, he was referred to our hospital because of elevated serum 17-OH-progesterone (17-OHP) levels in neonatal screening. The compound heterozygous mutations (IVS2-13 A/C>G, and p.E431K) in CYP21A2 were identified at 2 months old, and we diagnosed non-classical CAH, since he did not have significant physical signs (pigmentation and salt-wasting). However, his body weight decreased, and his serum 17-OHP level (99.5 ng/mL) was elevated at 3 months old. Steroid replacement therapy was started at 3 months old. Our patient's clinical course resembled simple virilizing (SV) CAH, but classification was difficult because the patient showed increased renin activity indicating an aldosterone deficiency, and late onset of symptoms. While the IVS 2-13 A/C>G mutation is common in the classical form of CAH, p.E431K is a rare point mutation. Functional analysis revealed that the residual enzyme activity of p.E431L was 5.08±2.55% for 17-OHP and 4.12±2.37% for progesterone, which is consistent with SV CAH. p.E431 is localized in the L-helix near the heme-binding site. The mutation might interfere with heme binding, leading to deactivation of CYP21A2. This report showed that CYP21A2 p.E431 has an important effect on enzyme activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ14-0437DOI Listing
December 2015

Feasibility and safety of intracoronary nicorandil infusion as a novel hyperemic agent for fractional flow reserve measurements.

Heart Vessels 2015 Jul 19;30(4):477-83. Epub 2014 Apr 19.

Department of Cardiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.

Fractional flow reserve (FFR) is a useful modality to assess the functional significance of coronary stenoses. Although adenosine triphosphate (ATP) is generally used as the hyperemic stimulus, we sometimes encounter adverse events like hypotension during FFR measurement. Nicorandil, an ATP-sensitive potassium channel opener, recognized as an epicardial and resistance vessel dilator, has not been fully evaluated as a possible alternative hyperemic agent. The aim of this study was to evaluate the feasibility and safety of intracoronary nicorandil infusion compared to intravenous ATP for FFR measurement in patients with coronary artery disease. A total of 102 patients with 124 intermediate lesions (diameter stenosis >40 and <70% by visual assessment) were enrolled. All vessels underwent FFR measurements with both ATP (150 μg/kg/min) and nicorandil (2.0 mg) stimulus. FFR, hemodynamic values, and periprocedural adverse events between the two groups were evaluated. A strong correlation was observed between FFR with ATP and FFR with nicorandil (r = 0.954, p < 0.001). The agreement between the two sets of measurements was also high, with a mean difference of 0.01 ± 0.03. The mean aortic pressure drop during pharmacological stimulus was significantly larger with ATP compared to nicorandil (9.6 ± 9.6 vs. 5.5 ± 5.8 mmHg, p < 0.001). During FFR measurement, transient atrioventricular block was frequently observed with ATP compared to nicorandil (4.0 vs. 0%, p = 0.024). This study suggests that intracoronary nicorandil infusion is associated with clinical utility and safety compared to ATP as an alternative hyperemic agent for FFR measurement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-014-0508-5DOI Listing
July 2015

Castleman disease in a child with short stature.

Pediatr Int 2012 Oct;54(5):720-4

Department of Multidisciplinary Internal Medicine, Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan.

We report a 14-year-old boy with Castleman disease in this article. He complained of short stature, and his body height was 133.8 cm (<3rd percentile; z score -4.5). There was marked delay in the appearance of secondary sexual characteristics. He was found to have a remittent fever and a lower mid-abdominal tumor. Blood test revealed microcytic hypochromic anemia, thrombocytosis, polyclonal hypergammaglobulinemia, hyperfibrinogenemia, and elevated erythrocyte sedimentation rate. The serum IL-6 and C-reactive protein levels were increased. The mass was found to be mixed hyaline vascular and plasma cell type of Castleman disease through a pathological examination. Lymph nodes affected by Castleman disease cause overproduction of IL-6. It decreases IGF-1, IGFBP-3 and serum testosterone levels. As a result of tumorectomy, his short stature and delay in the development of secondary sexual characteristics were improved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1442-200X.2012.03589.xDOI Listing
October 2012

Leprechaunism (Donohue syndrome): a case bearing novel compound heterozygous mutations in the insulin receptor gene.

Endocr J 2013 9;60(1):107-12. Epub 2012 Oct 9.

Division of Pediatrics & Perinatology, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.

Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.ej12-0289DOI Listing
July 2013
-->