Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Basal serum luteinizing hormone value as the screening biomarker in female central precocious puberty

PURPOSE: Precocious puberty refers to the development of secondary sex characteristics before ages 8 and 9 years in girls and boys, respectively. Central precocious puberty (CPP) is caused by premature activation of the hypothalamus-pituitary-gonadal (HPG) axis and causes thelarche in girls before the age of 8. A gonadotropin-releasing hormone (GnRH) stimulation test is the standard diagnostic modality for diagnosing CPP. However, the test cannot always be used for screening because it is expensive and time-consuming. This study aimed to find alternative reliable screening parameters to identify HPG axis activation in girls <8 years old (CPP) and for girls 8–9 years old (early puberty, EP). METHODS: From January 2013 to June 2015, medical records from 196 girls younger than 9 years old with onset of breast development were reviewed, including 126 girls who had a bone age (BA) 1 year above their chronological age. All patients underwent a GnRH stimulation test, and 117 underwent pelvic sonography. The girls were divided into 4 groups based on age and whether the GnRH stimulation test showed evidence of central puberty. Subanalyses were also conducted within each group based on peak luteinizing hormone (LH) level quartiles. RESULTS: Basal serum LH level was the most sensitive marker for screening CPP and EP. The cutoff values were 0.245 IU/L for CPP under 8 years old (P=0.049, area under the curve [AUC]=0.764, 88% sensitivity, 48% specificity) and 0.275 IU/L for EP between 8–9 years old (P=0.005, AUC=0.813, 79% sensitivity, 77% specificity). Peak LH level decreased as BMI z-score among subgroups increased when there was no difference in BA; however, higher BA eliminated this effect. CONCLUSION: Basal serum LH level is a useful screening parameter for diagnosing CPP and EP in girls. Peak LH levels were lower with increasing BMI z-score, although older BA eliminated this effect.

Congenital hypothyroidism due to thyroglobulin deficiency: a case report with a novel mutation in TG gene

Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates and infants with an incidence of one in 2,000 to one in 4,000 newborns. Primary CH can be caused by thyroid dysgenesis and thyroid dyshormonogenesis. CH due to a TG gene mutation is one cause of thyroid dyshormonogenesis and can be characterized by goitrous CH with absent or low levels of serum thyroglobulin (Tg). In the present case, a 15-day-old neonate was referred to us with elevated thyroid stimulating hormone detected during a neonatal screening test. At the age of 34 months, extensive genetic testing was performed, including targeted exome sequencing for hypothyroidism, and revealed compound heterozygous mutations in the TG gene. Sanger sequencing of both parents’ DNA samples revealed a c.3790T> C (p.Cys1264Arg) mutation located at exon 17 inherited from the mother, and a c.4057C> T (p.Gln1353*) mutation located at exon 19 was inherited from the father. The c.4057C> T (p.Gln1353*) mutation located at exon 19 has never been reported and, therefore, is a new discovery. We report a case of primary permanent CH with compound heterozygous mutations of the TG gene, including a novel mutation.

Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia. Under normoxia, the basal expressions of HIF1α and the glycolysis-associated genes, PDK1, PDK3, and GLUT1, were relatively low in U251 and GBM28, while their basal expressions were high in GBM37. Under hypoxia, the expressions of these genes were enhanced further in all three GBMs. Treatment with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), induced cell death in GBM28 and GBM37 maintained under normoxia, whereas DCA effects disappeared under hypoxia, suggesting that hypoxic adaptation dominated DCA effects in these GBMs. In contrast, the inhibition of HIF1α with chrysin suppressed the expression of PDK1, PDK3, and GLUT1 and markedly promoted cell death of all GBMs under both normoxia and hypoxia. Interestingly, however, GBMs treated with chrysin under hypoxia still sustained higher viability than those under normoxia, and chrysin and DCA co-treatment was unable to eliminate this hypoxia-dependent resistance. Together, these results suggest that hypoxic adaptation is critical for maintaining viability of GBMs, and targeting hypoxic adaptation can be an important treatment option for GBMs.

Fully Implantable Deep Brain Stimulation System with Wireless Power Transmission for Long-term Use in Rodent Models of Parkinson's Disease

OBJECTIVE: The purpose of this study to develop new deep-brain stimulation system for long-term use in animals, in order to develop a variety of neural prostheses. METHODS: Our system has two distinguished features, which are the fully implanted system having wearable wireless power transfer and ability to change the parameter of stimulus parameter. It is useful for obtaining a variety of data from a long-term experiment. RESULTS: To validate our system, we performed pre-clinical test in Parkinson's disease-rat models for 4 weeks. Through the in vivo test, we observed the possibility of not only long-term implantation and stability, but also free movement of animals. We confirmed that the electrical stimulation neither caused any side effect nor damaged the electrodes. CONCLUSION: We proved possibility of our system to conduct the long-term pre-clinical test in variety of parameter, which is available for development of neural prostheses.

Operative Treatment of Trapezium Fractures

PURPOSE: Fractures of trapezium are uncommon carpal bone fractures and often unrecognized lesions. We investigated about operative treatment of trapezium fracture. MATERIALS AND METHODS: Seven patients with fractures of trapezium were evaluated after surgical treatment with a mean follow up time of 18 months (12 months~3 years). Functional assessment (pain, limitation in activities of daily living, satisfaction), physical examination (range of motion, grip strength), and radiographic evaluation were performed. Traumatic arthritis and carpometacarpal joint subluxation were confirmed by radiograph. RESULTS: During study period, 122 cases were carpal bone fractures, and seven of 122 cases were fractures of trapezium. All cases were intra-articular fractures of trapezium. 1st carpometacarpal joint dislocation at 4 patients, Bennett's fracture at 1 patient, hamate hook fracture at 1 patient, and base of 4th proximal phalanx fracture at 1 patient were associated with fracture of trapezium. Open reduction and internal fixation were performed at 6 cases and 1st carpometacarpal joint arthrodesis was performed at 1 case because of neglected fracture. One of 6 cases which were performed to open reduction and internal fixation was reoperated to external fixation due to reduction loss. Clinically 6 patients revealed good results. one of 7 patients experienced limitation of thumb opposition. CONCLUSION: Based on the good results obtained with surgical intervention, we advocated open reduction and internal fixation for fractures with intraarticular depressed more than 2 mm or combined with Bennett's fracture or carpometacarpal subluxation.

Clinical features of transient small bowel intussusception in children / 소아과

Purpose: We analyzed the clinical features, management and outcome of small bowel intussusception in children compared with ileocolic intussusception. Methods: We retrospectively reviewed the records of 210 children with documented intussusception, in whom intussusception was initially diagnosed by ultrasonography during the four-year period of 2002 to 2005. Results: A total of 191 children were diagnosed with ileocolic intussusception and 19 were diagnosed with small bowel intussusception. Children with small bowel intussusception were older than children with ileocolic intussusception (P<0.05). In comparison to patients with ileocolic intussusception the characteristic presenting symptoms-such as currant jelly stool and palpable mass-were rarely observed in patients with small bowel intussusception. In ileocolic intussusception, air reduction (92.2%), or surgical reduction (7.3%) was performed; however, in small bowel intussusception, spontaneous reduction (78.9%) was observed and no surgical reduction was required in our study. Conclusion: Conservative management with close observation and follow-up sonographic evaluation rather than an immediate operation is recommended for children with small bowel intussusception.

Two cases of central nervous system complications caused by Mycoplasma pneumoniae infection / 소아과

Mycoplasma pneumoniae (M. pneumoniae) infection causes a wide variety of clinical manifestations in children and young adults, the main one being pneumonia. M. pneumoniae is transmitted from person to person by infected respiratory droplets. Symptoms caused by M. pneumoniae infection can be divided into those involving the respiratory tract, and those caused by extrapulmonary disease. M. pneumoniae infections may cause central nervous system (CNS) complications-with encephalitis being the most frequent-and stroke being a rare complication. The pathogenesis of the CNS disease is unclear; possibilities include direct infection and an immune-mediated reaction. We present two cases of CNS complications subsequent to infection with M. pneumoniae; both cases had convincing evidence of preceding M. pneumoniae respiratory disease with no evidence of viable M. pneumoniae in the cerebrospinal fluid. We report cases of encephalitis and stroke following a recent M. pneumoniae infection.

Percutaneous Nephrostomy Combined with Antifungal Agent Therapy for Both Hydronephrosis and Obstructive Uropathy in VLBW Infant

With increasing survival of smaller, more immunocompromised preterm infants, the incidence of invasive fungal infection is increasing among NICU patients, with highly associated morbidity and mortality. The most common site of end organ dissemination in premature infants with fungemia is the renal system. Renal fungal infection is followed by acute pyelonephritis and renal cortical abscess, and leads to obstructive nephropathy and renal failure. We recently experienced a case of VLBW infant who was dignosed as both hydronephrosis and obstructive uropathy due to Candida albicans that was treated intravenous amphotericin B combined with direct daily irrigation into the renal pelvis via percutaneous nephrostomy catheter.