We determined the effects of dietary manipulations on messenger RNA of peroxisome proliferators activated receptor isoforms (i.e., PPAR alpha, beta/delta, gamma)in red vastus lateralis muscle of rats. Total 16 male Sprague-Dawley rats were used, and animals were divided into one of two dietary conditions :either chow diet group (CHOW ;n =8 )in which animals were fed with standard rodent chow (61.8% carbohydrate, 15.7% fat, 22.5% protein )or high fat diet group (FAT n =8 ) in which animals were fed 24.3% carbohydrate, 52.8% fat, 22.9% protein. At the end of the 8 weeks of experimental pe-riod, red vastus lateralis muscle was dissected out from all animals, and PPAR alpha, beta/delta, gamma mRNA expression was deter-mined. There was no significant difference in body mass (BM )between CHOW and FAT. As expected, blood glucose and free fatty acid (FFA )concentration was higher in FAT than CHOW (p <0.05 ), and lactate concentration was significan-tly lower in FAT compared to CHOW (p <0.05 ). Insulin concentration tended to higher in FAT than CHOW (67.2 +/- 21.9 vs. 27.0 +/-5.2 pmol/L ), but it did not reach to the statistical significance. Gene expression of PPAR alpha was not signifi-cantly different between CHOW and FAT. It was not also significantly different in PPAR beta/delta. Interestingly, expression of mRNA in PPAR gamma however, was markedly depressed in FAT compared to CHOW (approximately 3 fold higher in CHOW ; p <0.05 ). Results obtained from present study implies that PPAR gamma (as compensatory function of PPAR alpha is expressed ) possibly exerts another major tuning roles in fatty acid transport, utilization, as well as biosynthesis in skeletal muscle cells. The situations and conditions that can be postulated for this implication need to be further examined.
Animals ; Blood Glucose ; Diet ; Diet, High-Fat ; Gene Expression ; Humans ; Insulin ; Lactic Acid ; Male ; Muscle, Skeletal* ; Peroxisome Proliferator-Activated Receptors ; Peroxisome Proliferators ; Peroxisomes* ; PPAR alpha ; PPAR gamma ; Protein Isoforms* ; Quadriceps Muscle ; Rats* ; Rats, Sprague-Dawley ; RNA, Messenger* ; Rodentia

Alzheimer’s disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-β (Aβ) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing Aβ plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that Aβ serves biological roles, which include suppressing microbial infections, regulating synaptic plasticity, promoting recovery after brain injury, sealing leaks in the blood-brain barrier, and possibly inhibiting the proliferation of cancer cells. More importantly, these functions were found in in vitro and in vivo investigations in a hormetic manner, that is to be neuroprotective at low concentrations and pathological at high concentrations. We herein summarize the physiological roles of monomeric Aβ and current Aβ-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting Aβ should selectively target Aβ in neurotoxic forms such as oligomers while retaining monomeric Aβ in order to preserve the physiological functions of Aβ monomers.

Miller Fisher syndrome, first reported by Miller Fisher in 1956, is characterized by a triad of external ophthalmoplegia, areflexia, and ataxia. Many features shared with Guillain-Barre syndrome; CSF usually shows elevated proteins and the syndrome is often is preceded by an infectious disorder. It is believed that the level of anti-GQ1b IgG antibody is elevated during an acute phase, increases and decreases rapidly during clinical recovery, that the level of anti-GQ1b IgG can be used as a diagnostic tool for Miller Fisher syndrome during an acute phase. We report an 8 year-old boy who showed typical clinical manifestations of Miller Fisher syndrome, with respiratory tract illness, associated with the seroconversion of Mycoplasma pneumoniae titers during the development of neurological symptom, with positive anti- GQ1b IgG.
Ataxia ; Child* ; Guillain-Barre Syndrome ; Humans ; Immunoglobulin G ; Male ; Miller Fisher Syndrome* ; Mycoplasma pneumoniae* ; Mycoplasma* ; Ophthalmoplegia ; Pneumonia, Mycoplasma* ; Respiratory System

Background: Pheochromocytoma and paragangliomas (PPGL) are hereditary in approximately 30% to 40% cases. With the advancement of genetic analysis techniques, including next-generation sequencing (NGS), there were attempts to classify PPGL into molecular clusters. With NGS being applied to clinical settings recently, we aimed to review the results of genetic analysis, including NGS, and investigate the association with clinical characteristics in Korean PPGL patients. Methods: We reviewed the medical records of PPGL patients who visited Severance hospital from 2006 to 2019. We documented the clinical phenotype of those who underwent targeted NGS or had known germline mutations of related genes. Results: Among 57 PPGL patients, we found 28 pathogenic germline mutations of susceptibility genes. Before the targeted NGS was implemented, only obvious syndromic feature lead to the Sanger sequencing for the specific genes. Therefore, for the exact prevalence, only patients after the year 2017, when targeted NGS was added, were included (n=43). The positive germline mutations were found in 14 patients; thus, the incidence rate is 32.6%. Patients with germline mutations had a higher likelihood of family history. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate, presence of other tumors, and biochemical profile among three molecular clusters: pseudohypoxic tricarboxylic acid cycle-related, pseudohypoxic von Hippel-Lindau (VHL)/endothelial PAS domain-containing protein 1-related, and kinase-signaling group. Germline mutations were identified in seven PPGL-related genes (SDHB, RET, VHL, NF1, MAX, SDHA, and SDHD). Conclusion We report the expected prevalence of germline mutations in Korean PPGL patients. NGS is a useful and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification is needed for precise management.

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.

The purpose of this study was to investigate the distribution of eruption disturbance and to analyze its causes, treatment methods, and duration of orthodontic traction, based on 703 patients with eruption disturbance who were treated in the pediatric dental clinic of Seoul National University Dental Hospital between July 2011 and June 2016.Eruption disturbance in pediatric patients was most prevalent in the maxillary canine, followed by the maxillary central incisor and maxillary first molar. Eruption disorder of the maxillary canine was more common in females (p < 0.001), whereas the maxillary central incisor (p = 0.009), maxillary first molar (p < 0.001) and mandibular first molar (p = 0.028) were more common in males than females.The most common causes of eruption disturbance were abnormality of the eruption pathway and the presence of obstacles in the pathway. Orthodontic traction was the most prevalent treatment choice for eruption disorder, mostly done for the maxillary central incisors. The duration of orthodontic traction was shorter with younger age (p < 0.001) and lower crown position (p < 0.001).It is important for pediatric patients to detect eruption disorders early through regular checkup, and it is necessary to initiate treatment at an appropriate time with an accurate diagnosis and treatment plan.
Crowns ; Dental Clinics ; Diagnosis ; Female ; Humans ; Incisor ; Male ; Methods ; Molar ; Seoul ; Traction

PURPOSE: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. MATERIALS AND METHODS: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients. RESULTS: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01). CONCLUSION: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.
6-Mercaptopurine ; Alleles ; Computational Biology ; Cytochrome P-450 CYP1A1 ; Cytoprotection ; DNA Damage ; Genotype ; Humans ; Incidence ; Neutropenia* ; Pediatrics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma*

Background: Infants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors. Methods: Twenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy.Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered. Results: All 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5−15.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, eventfree, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable. Conclusion Our results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT.