Severe recurrent nocturnal hypoglycemia during chemotherapy with 6-mercaptopurine in a child with acute lymphoblastic leukemia.

Various endocrine dysfunctions occur during chemotherapy, including hypoglycemia. However, reports of hypoglycemia associated with 6-mercaptopurine (6-MP) are rare. Herein, we report an 8-year-old boy with severe symptomatic hypoglycemia likely due to 6-MP during chemotherapy. He had been diagnosed with acute lymphoblastic leukemia 3 years previously and was in the maintenance chemotherapy period. Treatment included oral dexamethasone, methotrexate, and 6-MP, of which only 6-MP was administered daily. Hypoglycemic symptoms appeared mainly at dawn, and his serum glucose dropped to a minimum of 37 mg/dL. Laboratory findings showed nothing specific other than increased serum cortisol, free fatty acids, ketone, alanine aminotransferase, and aspartate aminotransferase. Under the hypothesis of hypoglycemia due to chemotherapy drugs, we changed the time of 6-MP from evening to morning and recommended him to ingest carbohydrate-rich foods before bedtime. Hypoglycemia improved dramatically, and there was no further episode during the remaining maintenance chemotherapy period. To the best of our knowledge, this is the first report of this type of hypoglycemia occurring in an Asian child including Korean.

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.

AIMS: To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. METHODS: Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. RESULTS: Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. CONCLUSIONS: Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells.

Polyclonal gammopathy related to renal bleeding in a peritoneal dialysis patient.

Polyclonal gammopathy represents the diffuse activation of B cells and is usually related to inflammation or immune-related diseases. However, the mechanisms leading to polyclonal gammopathy are essentially speculative. Generally, infectious, inflammatory, or various other reactive processes may be indicated by the presence of a broad-based peak or band in the gamma region on serum protein electrophoresis results. A 15-year-old girl, who had been receiving peritoneal dialysis, presented with polyclonal gammopathy and massive gross hematuria. Renal artery embolization was performed, after which the continuous bleeding subsided and albumin-globulin dissociation resolved. This is a rare case of polyclonal gammopathy related to renal bleeding.

Changes of antithroglobulin antibody in children with congenital hypothyroidism.

PURPOSE: It has been reported that antithroglobulin (anti-TG) antibody is increased in the sera of both children with transient congenital hypothyroidism and their mothers. And transplacental transport of thyroid autoantibody was proposed as the pathogenesis of transient congenital hypothyroidism. However this is not known in nontransient congenital hypothyroidism. This study was done to see changes of anti-TG antibody in children with nontransient congenital hypothyroidism. METHODS: Study patients consisted of 60 patients diagnosed as congenital hypothyroidism in the Department of Pediatrics, Kyungpook National University Children's Hospital, Daegu, Republic of Korea between January 2010 and March 2013. Healthy control were 45 children showing normal thyroid function. Anti-TG antibody and various laboratory tests were analyzed retrospectively, and compared in both children with congenital hypothyroidism and controls. RESULTS: Anti-TG antibody was significantly higher in children with congenital hypothyroidism compared to healthy controls, 119.4±34.7 U/mL versus 80.6±19.6 U/mL, respectively (P<0.001). There was no significant difference of anti-TG antibody in gender and age. CONCLUSION: We observed a significant increase of anti-TG antibody in children with nontransient congenital hypothyroidism compared to healthy controls. Further study focusing pathogenetic role of anti-TG antibody in nontransient congenital hypothyroidism is necessary. Furthermore, the clinical significance in the course of congenital hypothyroidism need to be known.

Expression and characterization of recombinant kurtoxin, an inhibitor of T-type voltage-gated calcium channels.

Kurtoxin, a 63-amino acid peptide stabilized by four disulfide bonds, is the first reported peptide inhibitor of T-type voltage-gated calcium channels. Although T-type calcium channels have been implicated in a number of disease states, including epilepsy, chronic pain, hypertension and cancer, the lack of selective inhibitors has slowed progress in understanding their precise roles. Kurtoxin is a potentially valuable tool with which to study T-type calcium channels. However, because of the limited availability of the native protein, little is known about the structure and molecular mechanism of kurtoxin. Here we report the expression of kurtoxin in Escherichia coli and the structural and functional characterization of the recombinant protein. The disulfide bond pairings and secondary structure of recombinant kurtoxin were characterized through enzymatic cleavage, mass analysis and CD spectroscopy. Recombinant kurtoxin almost completely inhibited the T-type calcium channel in a manner identical to the native toxin. The availability of recombinant kurtoxin that is identical to the native toxin should help in the study of T-type calcium channels and enable development of new strategies for producing even more-selective T-type calcium channel inhibitors and for investigating the molecular basis of the toxin-channel interactions.

Effect of Betula platyphylla var. japonica on proteoglycan release, type II collagen degradation, and matrix metalloproteinase expression in rabbit articular cartilage explants.

Articular cartilage is a potential target for drugs designed to inhibit the activity of matrix metalloproteinases (MMPs) to stop or slow the destruction of proteoglycan and collagen in the cartilage extracellular matrix. The purpose of this study was to investigate the effects of Betula platyphylla var. japonica on inhibiting the release of glycosaminoglycan (GAG), the degradation of collagen, and MMP expression and activity in rabbit articular cartilage explants. Interleukin-1alpha (IL-1alpha) rapidly induced GAG, but collagen was much less readily released from cartilage explants. Betula platyphylla var. japonica significantly inhibited GAG and collagen release in a concentration-dependent manner. Betula platyphylla var. japonica dose-dependently inhibited MMP-3 and MMP-13 expression and activities from IL-1alpha-treated cartilage explant culture when tested at concentrations ranging from 0.02 to 0.2 mg/ml. Betula platyphylla var. japonica had no harmful effect on chondrocyte viability or cartilage morphology in cartilage explants. Histological analysis indicated that Betula platyphylla var. japonica reduced the degradation of the cartilage matrix compared with that of IL-1alpha-treated cartilage explants. These results indicate that Betula platyphylla var. japonica inhibits the degradation of proteoglycan and collagen through the down regulation of MMP-3 and MMP-13 expression and activities without affecting the viability or morphology of IL-1alpha-stimulated rabbit articular cartilage explants.

Puerariae radix promotes differentiation and mineralization in human osteoblast-like SaOS-2 cells.

Puerariae radix (PR) is a traditional medicine herb used for enhancing body resistance against various diseases. The aim of this study was to identify whether Puerariae radix extract induces osteogenic activity in human osteoblast-like SaOS-2 cells. Puerariae radix had no effect on the viability of osteoblastic cells, and dose-dependently increased alkaline phosphatase (ALP) activity. Puerariae radix markedly increased mRNA expression for vascular endothelial growth factor (VEGF), osteocalcin (OCN), osteopontin (OPN), and type I collagen (Col I) in SaOS-2 cells. Extracellular accumulation of proteins such as VEGF and Col I was increased in a dose-dependent manner. Also, Puerariae radix significantly induced mineralization in the culture of SaOS-2 cells. In conclusion, this study showed that Puerariae radix had no effect on viability, but enhanced ALP activity, VEGF, bone matrix proteins such as OCN, OPN, and Col I, and mineralization in SaOS-2 cells. These results propose that Puerariae radix can play an important role in osteoblastic bone formation, and may possibly lead to the development of bone-forming drugs.

Uncaria rhynchophylla induces angiogenesis in vitro and in vivo.

Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine the angiogenic properties of Uncaria rhynchophylla. Uncaria rhynchophylla significantly enhanced human umbilical vein endothelial cells (HUVECs) proliferation in a dose-dependent manner. Neutralization of vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) by monoclonal antibody suppressed the Uncaria rhynchophylla stimulatory effect on proliferation. In addition, Uncaria rhynchophylla significantly increased chemotactic-migration on gelatin and tubular structures on Matrigel of HUVECs in a dose-dependent manner. Interestingly, Uncaria rhynchophylla dose-dependently increased VEGF, and bFGF gene expression and protein secretion of HUVEC. The angiogenic activity of Uncaria rhynchophylla was confirmed using an in vivo Matrigel angiogenesis model, showing promotion of blood vessel formation. These results suggest that Uncaria rhynchophylla could potentially used to accelerate vascular wound healing or to promote the growth of collateral blood vessel in ischemic tissues.

Proteome analysis by bio-active ceramic water in rat liver: contribution to antioxidant enzyme expression, SOD I.

The purpose of this study was to investigate the protective effect of bio-active ceramic water on rat liver. Male Wistar rats were divided into 4 groups of 15 animals each. Groups 1 and 2 were fed bio-active ceramic water and tap water for 4 months, respectively. Groups 3 and 4 were treated with the same condition for 12 months. The changes of protein expression of these four groups were investigated using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Eleven proteins were significantly up-regulated in bio-active ceramic water treated rat liver including aldehyde dehydrogenase I and II, albumin, fructose-1,6-bisphosphatase, and superoxide dismutase I (SOD I). The most highly expressed protein, SOD I with up-regulated enzyme activity, was confirmed by immunoblots as a major antioxidant capable of detoxifying normally generated reactive oxygen species. These data suggest that modified protein expression of the liver contributes to enhance liver function.