Recombinant growth hormone therapy for prepubertal children with idiopathic short stature in Korea: a phase III randomized trial.

PURPOSE: Several studies have evaluated the effects of growth hormone (GH) on auxological and biochemical parameters in children with non-GH-deficient, idiopathic short stature (ISS). This study evaluated the efficacy and safety of Growtropin®-II (recombinant human GH) in Korean patients with ISS. METHODS: This was a 1-year, open-label, multicenter, phase III randomized trial of Growtropin®-II in Korean patients with ISS. In total, 70 prepubertal subjects (39 males, 31 females) between 4 and 12 years of age were included in the study. All patients were naive to GH treatment. RESULTS: Annual height velocity was significantly higher in the treatment group (10.68 ± 1.95 cm/year) than the control group (5.72 ± 1.72, p < 0.001). Increases in height and weight standard deviation scores (SDSs) at 26 weeks were 0.63 ± 0.16 and 0.64 ± 0.46, respectively, for the treatment group, and 0.06 ± 0.15 and 0.06 ± 0.28, respectively, for the control group (p < 0.001). Serum insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) increased significantly in the treatment group at week 26 compared to baseline. However, the SDS for body mass index (BMI) at 26 weeks did not change significantly in either group. Growtropin®-II was well tolerated and safe over 1 year of treatment. CONCLUSIONS: One-year GH treatment for prepubertal children with ISS demonstrated increased annualized velocity, height and weight SDSs, and IGF-1 and IGFBP-3 levels, with a favorable safety profile. Further evaluations are needed to determine the optimal dose, final adult height, and long-term effects of ISS treatment.

Effect of an obesity prevention program focused on motivating environments in childhood: a school-based prospective study.

BACKGROUND/OBJECTIVES: There has been an increasing global recognition of the need for effective strategies to prevent and control childhood obesity. In this study, we aimed to identify the effectiveness of an obesity prevention program focused on motivating environments in school. SUBJECTS/METHODS: In this school-based, prospective, quasi-experimental study, we enrolled three elementary (fourth graders) and two middle (seventh graders) schools located in Chungju, Korea. We assigned three of the schools to the intervention group and two schools to the control group. The intervention group received 1 year of environmental intervention. Diet- and exercise-related educational video content was provided by internet protocol television services during rest time, and various design materials were painted along the school staircase and hallway to encourage physical activities. Overweight and obese students were recommended to join the summer vacation obesity care program. RESULTS: The final number of total participants was 768 (control 350 and intervention 418). After 1 year of follow-up, there was no significant difference in the overweight/obesity incidence rates and remission rates between the two groups. However, the intervention group showed a greater decrease in the body mass index (BMI) z-score (-0.11 (95% confidence interval (CI) -0.16 to -0.06), P<0.001), increase in height (1.1 cm (95% CI 0.8 to 1.4), P<0.001), reduction of body fat, and increase in muscle mass compared with the control group. In addition, blood pressure (BP) was significantly reduced, and significant improvement in physical fitness followed. In subgroup analysis, students of normal weight, boys and younger participants showed the most beneficial results in weight-related outcomes. In addition, the BP reduction was more pronounced in the higher BMI group, boys and older children. CONCLUSIONS: A simple environmental intervention could effectively influence children. By adding to previously studied strategies, we can develop a more effective obesity prevention program for children.

Triglycerides/glucose index is a useful surrogate marker of insulin resistance among adolescents.

OBJECTIVES: Our aim was to investigate the association between the triglycerides/glucose index (TyG index) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) in the prediction of insulin resistance (IR) among adolescents. METHODS: We conducted a cross-sectional study among 221 Korean adolescents (168 males and 53 females aged 9-13 years) from May to June 2014 in Chung-ju city. The TyG index was calculated as ln [triglycerides (mg dl-1) × fasting glucose (mg dl-1)/2]. IR was defined using HOMA-IR >95th percentile for age and sex. RESULTS: In the IR group, weight, body mass index (BMI), waist circumference, body fat, fasting insulin, fasting plasma glucose, triglyceride levels and triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) were significantly higher than that in the non-IR group. The TG index was significantly different between the IR group (n=22) and non-IR group (n=199), at 8.43±0.45 and 8.05±0.41, respectively (P<0.001). The TyG index was well correlated with HOMA-IR (r=0.41; P<0.001) and showed a strong positive association with TG/HDL-C (r=0.84; P<0.001). The cut-off of the TyG index for diagnosis of insulin resistance was 8.18. CONCLUSIONS: The TyG index is a simple, cost-effective surrogate marker of insulin resistance among adolescents compared with HOMA-IR.

Low albumin-to-globulin ratio associated with cancer incidence and mortality in generally healthy adults.

BACKGROUND: Chronic inflammation is known to be one of the main steps in carcinogenesis. Identification of those with chronic inflammation may help identify subjects at risk of cancer. Previous studies have reported low albumin-to-globulin ratio (AGR) to be associated with increased cancer mortality in cancer patients, but there has been no study based on healthy populations. PATIENTS AND METHODS: Our retrospective cohort study involved 26 974 generally healthy adults aged 30 or older who visited Seoul National University Hospital Health Promotion Center for self-referred health checkup. National medical service claims data were used to determine cancer incidence, and Korean death registry data was used to determine mortality. Median follow-up time for survival was 5.9 years (interquartile range 4.1 years). RESULTS: Compared with subjects with AGR ≥ 1.5, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR showed adjusted hazard ratio (aHR) 2.69 (95% confidence interval, CI, 1.54-4.72) and aHR 6.71 (95% CI 3.56-12.66) for all-cause mortality, aHR 2.95 (95% CI 1.42-6.11) and aHR 4.38 (95% CI 1.57-12.25) for cancer mortality, and aHR 2.07 (95% CI 1.28-3.36) and aHR 3.99 (95% CI 2.10-7.58) for cancer incidence, respectively. When cancer incidence events after 2 years from baseline were separately analyzed, subjects with 1.1 > AGR ≥ 1.0 and 1.0 > AGR were associated with aHR 1.88 (95% CI 1.01-3.48) and aHR 2.55 (95% CI 1.03-7.11) for cancer incidence, respectively. Cancer events were increased in all types of cancer, but especially in liver and hematologic malignancies. CONCLUSIONS: Low AGR is a risk factor for cancer incidence and mortality, both short- and long terms, in a generally healthy screened population. The results of this study need to be replicated in larger studies, along with the determination of the sensitivity and other diagnostic values of low AGR.

Impact of BMI on the incidence of metabolic abnormalities in metabolically healthy men.

OBJECTIVES: Although the existence of metabolically healthy obese (MHO) individuals has been recognized, little is known regarding metabolic health status in these subjects over time. Thus, we evaluated longitudinal changes in metabolic parameters among MHO subjects compared with metabolically healthy, normal-weight (MHNW) subjects. METHODS: A cohort study was performed on 2599 Korean men, 30-59 years of age, with no evidence of fatty liver disease on ultrasound and no traits of metabolic syndrome at baseline. BMI was categorized based on criteria for Asian population. Study participants were followed annually or biennially between 2002 and 2009. At each visit, the fatty liver on ultrasound was assessed and metabolic abnormalities were measured. Parametric Cox models and a pooled logistic regression models were used to evaluate the relationships of BMI with incident metabolic abnormalities. RESULTS: During 9647.1 person-years of follow-up, 1673 participants developed metabolic abnormalities. After adjusting for age, smoking, alcohol intake and exercise, higher baseline BMI categories predicted increased incidences of metabolic abnormalities in a dose-response manner. The hazard ratios (95% confidence intervals) for hypertriglyceridemia, prediabetes, pre-hypertension, low high-density lipoprotein-cholesterol, fatty liver, elevated high sensitivity-C reactive protein, elevated homeostasis model assessment of insulin resistance, any metabolic abnormality and metabolic syndrome among the MHO subjects compared with the MHNW subjects were 1.51 (1.23-1.85), 1.43 (1.19-1.72), 1.79 (1.45-2.22), 1.80 (1.30-2.49), 2.69 (2.19-3.31), 1.39 (1.16-1.67), 2.90 (2.31-3.62), 1.68 (1.45-1.93) and 1.84(1.02-3.30), respectively. CONCLUSION: In this study, MHO individuals showed higher incidences of metabolic abnormalities compared with MHNW individuals. This suggests that initially MHO individuals undergo adverse metabolic changes associated with obesity over time.

Effect of tubular orientation on the dentin bond strength of acidic self-etch adhesives.

OBJECTIVE: To determine the effect of varying the adhesive pH on the bond strength of an experimental self-etch adhesive system (BISCO, Inc) to dentin with the bonding surface perpendicular (occlusal direction) or parallel (axial direction) to dentin tubules. METHODS: An experimental self-etch adhesive was modified by adding base to increase the pH from 1.1 to 2.7. Shear bond strength (SBS) was measured using an Ultradent jig method with Aelite All-Purpose Body light-cured composite (BISCO, Inc). Human dentin was prepared by exposing the axial and occlusal surface. The self-etch adhesive was applied according to the manufacturer's instructions and cured for 10 seconds@ 500mW using a VIP (BISCO, Inc) halogen curing light. Scanning electron microscope (SEM) examination was used to view both the occlusal- and axial-oriented dentin surfaces that were etched using pH (1.2~3.0) adjusted phosphoric acid solutions. All bond strength data analysis was performed using ANOVA, followed by a Student-Newman-Keuls multiple range test. RESULTS: When the dentin-bonding surface was parallel to the tubule orientation (axial), the bond strength was independent of the pH of the self-etch adhesive (p>0.05). When the bonded surface was perpendicular to the tubule orientation (occlusal), the bond strength numbers were decreased as the pH decreased; the decrease became statistically significant when the pH was lower than 1.8. With a pH higher than 2.3, the bond strength had no difference (p>0.05) between the occlusal and axial positions. When the pH was lower than 1.8, SEM pictures confirmed that the smear layers and smear plugs were completely solubilized by the phosphoric acid solution. Higher pH values (2.0­2.8) showed smear layers partially solubilized and pH values of 3.0 fully retained the smear layer.

Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement.

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). A prospective brain MRI study was performed on 18 early-onset CMT patients with MFN2 mutations, and a high frequency (39%) of brain abnormalities was found. Early-onset patients showed multiple scattered or confluent brain lesions that involved gray matter as well as white matter. Patterns of brain involvement in early-onset patients differed from those of late-onset patients and other hereditary peripheral neuropathies. In addition, one CMT patient demonstrated a brain lesion before the development of peripheral neuropathy.

Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells.

After ovulation of an oocyte, granulosa cells of the ovarian follicle differentiate into luteal cells and become a major factor dedicated to the synthesis of the steroid hormone progesterone. We recently established granulosa cell lines by cotransfection of granulosa cells with SV-40 and Ha-ras oncogene. In these cells progesterone secretion can be induced by cAMP as in normal rat granulosa cells. The induction of progesterone secretion is observed only after approximately 24 h and closely follows the delayed but quantitatively dramatic induction of the mitochondrial cytochrome P450scc which catalyzes the first step in steroid hormone biosynthesis. The mitochondrial P450 system electron transport proteins, adrenodoxin and adrenodoxin reductase, are also induced but adrenodoxin shows a faster induction. Immunofluorescence studies show that the three enzymes are induced in all cells and incorporated into all mitochondria uniformly. Electron microscopic examination using immunogold technique further confirms this and reveals that adrenodoxin is predominantly located on the matrix side of the inner mitochondrial membrane. Thus, adrenodoxin, which is a small highly charged protein, shows a distribution similar to P450scc which is an integral membrane protein. The uniformity of the response of the cells provides further evidence for the homogeneity of the cell line and makes this new granulosa cell line a highly promising system for the study of the molecular mechanisms involved in changes in gene expression during the process of granulosa cell differentiation.

Introduction of a gonadotropin receptor expression plasmid into immortalized granulosa cells leads to reconstitution of hormone-dependent steroidogenesis.

We have recently succeeded in immortalizing rat granulosa cells by co-transfection with SV-40 DNA and the Ha-ras oncogene. These cells lost their response to gonadotropins, but expressed the cytochrome P450scc mitochondrial system enzymes and produced progesterone and 20 alpha-hydroxy-4-pregnan-3-one (20 alpha-OH-P) upon cAMP stimulation (Suh, B. S., and A. Amsterdam. 1990. Endocrinology. 127:2489-2500; Hanukoglu, I., B. S. Suh, S. Himmelhoch, and A. Amsterdam. 1990. J. Cell Biol. 111:1973-1981). In an attempt to restore the steroidogenic response to gonadotropins in immortalized cells, lutropin/choriogonadotropin (LH/CG-R) receptor expression plasmid was prepared by introducing the complete coding region of LH receptor cDNA (McFarland, K. C., R. Sprengel, H. S. Phillips, M. Köhler, N. Rosemblit, K. Nikolics, D. L. Segaloff, and P. H. Seeburg. 1989. Science (Wash. DC). 245:494-499) into a SV-40 early promoter based eucaryotic expression vector. Granulosa cells from preovulatory follicles were transfected with this LH receptor expression plasmid, together with SV-40 DNA and the Ha-ras oncogene. Cell lines obtained after this triple transfection accumulated cAMP in a dose-dependent manner in response to hCG. Moreover, they produced progesterone and 20 alpha-OH-P upon hCG stimulation with an ED50 of 125 pM and 75 pM, respectively, which is within the physiological range. Concomitantly with hCG induced differentiation, inhibition of cell proliferation was evident following stimulation with hormone concentrations as low as 40 pM. The number of hCG receptor sites per cell after numerous passages and several freezing and thawing cycles was 1.9 x 10(4), they showed a Kd of 180 pM. Stimulation with hCG induced pronounced morphological and biochemical changes in these cells including formation of mitochondrial located adrenodoxin, a marker enzyme for enhanced steroidogenesis. These findings make possible the expression in immortalized granulosa cells, of selectively mutated receptor molecules which preserve their steroidogenic potential, thereby opening the way to analysis of structure-function relationships of the receptor molecule.

Different clinical and magnetic resonance imaging features between Charcot-Marie-Tooth disease type 1A and 2A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the more frequent cause of demyelinating CMT, and CMT2A is the most common cause of axonal CMT. We conducted a magnetic resonance imaging (MRI) study on 39 CMT1A and 21 CMT2A patients to compare their neuroimaging patterns and correlate with clinical features. CMT1A patients showed selective fatty infiltration with a preference for anterior and lateral compartment muscles, whereas CMT2A patients showed a preference for superficial posterior compartment muscles. Early-onset CMT2A patients showed more severe leg fatty atrophy than late-onset CMT2A patients. In late-onset CMT2A, soleus muscle was the earliest, and most severely affected than the other leg muscles. Selective involvement of intrinsic foot muscles is a characteristic pattern of minimal CMT1A and CMT2A. Our MRI study demonstrates different patterns of fatty infiltration involving superficial posterior compartment muscles in CMT2A (partial T-type), and peroneal nerve innervated muscles in CMT1A (P-type).

Broadband electron spin resonance at low frequency without resonant cavity.

We have developed a nonconventional broadband electron spin resonance (ESR) spectrometer operating continuously in the frequency range from 0.5 to 9 GHz. Dual antenna structure and the microwave absorbing environment differentiate the setup from the conventional one and enable broadband operation with any combination of frequency or magnetic field modulation and frequency or magnetic field sweeping. Its performance has been tested with the measurements on a 1,1-diphenyl-2-picrylhydrazyl (DPPH) sample and with the measurements on the single molecular magnet, V6, in solid state at low temperature.

Designing a magnesium alloy with high strength and high formability.

Although magnesium alloys, as the lightest structural alloys, offer significant potential for automotive applications, their applications remain limited due to their poor formability at room temperature. Since the strategies used for improving formability usually result in a degradation of strength, there are no high strength magnesium alloys showing good formability. Here we report an alloy design concept that can simultaneously provide high strength and good formability. Such designed alloy when subjected to an appropriate processing technique shows a combination of strength and formability that surpasses those of the existing magnesium alloys reported so far. The alloy design concept used in the present study is based on the utilization of alloying elements that can induce precipitation, as well as maximize the segregation of other texture-controlling alloying elements. Such developed alloy is expected to broaden the application of Mg alloy sheets, which are now starting to gain acceptance by automotive industries.

Demonstration of 2-hydroxybenzoylglycine as a drug binding inhibitor in newborn infants.

Newborn infants have drug binding defects that share similarities to those of uremic subjects. Since 2-hydroxybenzoylglycine has been chemically defined to be a major drug binding inhibitor in uremia, a search for the presence of a similar compound in the sera of newborn infants was made. An organic substance that has the characteristics of 2-hydroxybenzoylglycine as supported by the retardation factor values on thin-layer chromatograms, retention times of high performance liquid chromatograms, fluorescence emission spectra, and mass spectrum has been demonstrated to be present in the majority of the neonatal sera studied. A strong positive correlation between the levels of the binding inhibitor and the extent of binding defects for nafcillin has been observed. The substance could effectively reduce the total bilirubin concentration when added to the cord sera specimens. It is concluded that 2-hydroxybenzoylglycine plays an important role in drug binding defects observed in the newborn, and the inhibitor may also play a part in the precipitation of bilirubin-induced neurotoxicity in neonates when the substance is abnormally elevated.

Isolation and chemical characterization of 2-hydroxybenzoylglycine as a drug binding inhibitor in uremia.

An organic compound that inhibits drug binding in uremia has been isolated from the sera of chronic renal failure patients, and its chemical structure has been determined. Addition of the compound to normal human sera in vitro resulted in drug binding defects similar to those seen in uremia. The purification of this substance was accomplished by n-butyl chloride extraction of acidified (pH 3.0) uremic sera followed by column chromatography, thin-layer chromatography, and paper electrophoresis. From analytical studies including ultraviolet and fluorescence spectroscopy, gas chromatography, chemical ionization and electron impact mass spectrometry, and proton nuclear magnetic resonance spectroscopy, the chemical structure of the uremic binding inhibitor was deduced to be 2-hydroxybenzoylglycine. This confirms the hypothesis that the drug binding defect in uremia is due to the accumulation of endogenous metabolic products rather than an intrinsic structural defect in albumin.

The effect of curing modes on polymerization contraction stress of a dual cured composite.

Although a lower curing rate is often cited as the reason why a chemical cured (CC) dental composite produces lower polymerization contraction stress (PCS) than a light cured (LC) composite, the exact mechanism is still unclear. In addition, the comparison is often made by using different brands of composites. The comparison's fairness is questionable because the two composites have different compositions and preparation procedures. The goal of the present work was to determine if the curing mode alone can produce different PCS. We formulated a dual cured composite and prepared it the same way for both CC and LC modes. We measured PCS by a strain gauge method, shrinkage by a video-imagining technique, degree of conversion (DC) by infrared spectroscopy, and flexural modulus by the three-point bending test. The CC specimens showed lower PCS and lower flexural modulus than the LC specimens, although both possessed an identical chemical composition and physical texture before cure. This finding indicates that the curing mode alone can affect PCS. Because the CC and LC specimens produced a similar shrinkage and DC, the lower modulus is considered to be one of the reasons for the lower stress. Using a structural inhomogeneity model, we explained how a resin composite with an identical DC can have different physical properties such as the modulus.

A mechanism on why slower polymerization of a dental composite produces lower contraction stress.

It has been well documented that the rate of polymerization of a dental composite often affects its polymerization contraction stress. In most cases, a slower cure produces a lower stress. To investigate the mechanism behind this, we prepared an unfilled dimethacrylate resin sample and photocured it using two light irradiances, both with the same total irradiation energy. We measured the polymerization-induced shrinkage from the unbonded surface of a class I restoration, contraction stress, extent of polymerization, and flexural modulus. The resin specimens cured under the two irradiances achieved the same extent of polymerization and developed an identical amount of shrinkage from the unbonded surface. But those cured under the lower irradiance possessed a lower contraction stress and a lower flexural modulus than those cured under the higher irradiance. We demonstrated that the stress level did not respond to the extent of viscous flow of the curing resin because the slower polymerization did not produce more shrinkage from the unbonded surface. Instead, the lower stress is likely due to a lower modulus of the cured resin. To explain why the cured resin with an identical extent of polymerization can have different moduli, we proposed that slower polymerization produces a higher level of structural inhomogeneity, which reduces the rigidity of the cured resin.

Large linear magnetoresistance in heavily-doped Nb:SrTiO3 epitaxial thin films.

Interaction between electrons has long been a focused topic in condensed-matter physics since it has led to the discoveries of astonishing phenomena, for example, high-Tc superconductivity and colossal magnetoresistance (CMR) in strongly-correlated materials. In the study of strongly-correlated perovskite oxides, Nb-doped SrTiO3 (Nb:SrTiO3) has been a workhorse not only as a conducting substrate, but also as a host possessing high carrier mobility. In this work, we report the observations of large linear magnetoresistance (LMR) and the metal-to-insulator transition (MIT) induced by magnetic field in heavily-doped Nb:STO (SrNb0.2Ti0.8O3) epitaxial thin films. These phenomena are associated with the interplay between the large classical MR due to high carrier mobility and the electronic localization effect due to strong spin-orbit coupling, implying that heavily Nb-doped Sr(Nb0.2Ti0.8)O3 is promising for the application in spintronic devices.

Who may benefit from robotic gastrectomy?: A subgroup analysis of multicenter prospective comparative study data on robotic versus laparoscopic gastrectomy.

AIMS: Robotic gastrectomy for gastric cancer has been proven to be a feasible and safe minimally invasive procedure. However, our previous multicenter prospective study indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. This study aimed to identify which subgroups of patients would benefit from robotic gastrectomy rather than from conventional laparoscopic gastrectomy. METHODS: A prospective multicenter comparative study comparing laparoscopic and robotic gastrectomy was previously conducted. We divided the patients into subgroups according to obesity, type of gastrectomy performed, and extent of lymph node dissection. Surgical outcomes were compared between the robotic and laparoscopic groups in each subgroup. RESULTS: A total of 434 patients were enrolled into the robotic (n = 223) and laparoscopic (n = 211) surgery groups. According to obesity and gastrectomy type, there was no difference in the estimated blood loss (EBL), number of retrieved lymph nodes, complication rate, open conversion rate, and the length of hospital stay between the robotic and laparoscopic groups. According to the extent of lymph node dissection, the robotic group showed a significantly lower EBL than did the laparoscopic group after D2 dissection (P = 0.021), while there was no difference in EBL in patients that did not undergo D2 dissection (P = 0.365). CONCLUSION: Patients with gastric cancer undergoing D2 lymph node dissection can benefit from less blood loss when a robotic surgery system is used.