Objective: Although there are a few reports on GH therapy in achondroplasia, these were based on a small sample and/or short-term observation. To clarify the effectiveness of GH treatment on short stature in achondroplasia and hypochondroplasia, a long-term treatment study in a larger number of patients was performed. Method: Forty-two children (16 males and 26 females, age 3±14 years) with achondroplasia were examined in this study. Initially, we evaluated hypothalamic±pituitary function and point mutation analysis as previously reported. After the evaluation, the children were treated with GH for more than 2 years; then post-treatment growth velocity and body proportion parameters were determined. Results: The 35 typical variants of our achondroplasia patients showed previously reported point mutation in the ®broblast growth factor receptor 3 gene. The annual height gain during GH therapy was signi®cantly greater than that before therapy (3:9 6 1:0 cm/year before treatment vs 6:5 6 1:8 cm/year for the ®rst year and 4:6 6 1:6 cm/year for the second year of treatment). The body disproportion had not been aggravated during the treatment period. Conclusion: We conclude that GH might be bene®cial in the treatment of short stature in children with achondroplasia in the ®rst 2 years of treatment. European Journal of Endocrinology 138 275±280
Fragmentation is a major factor limiting mass range and resolution in the analysis of DNA by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Protonation of the nucleobase leads to base loss and backbone cleavage by a mechanism similar to the depurination reactions employed in the chemical degradation method of DNA sequencing. In a previous study [Tang,W., Zhu,L. and Smith,L.M. (1997) Anal. Chem ., 69, 302-312], the stabilizing effect of substituting the 24 hydrogen with an electronegative group such as hydroxyl or fluorine was investigated. These 24 substitutions stabilized the N-glycosidic linkage, blocking base loss and subsequent backbone cleavage. For such chemical modifications to be of practical significance, it would be useful to be able to employ the corresponding 24-modified nucleoside triphosphates in the polymerase-directed synthesis of DNA. This would provide an avenue to the preparation of 24-modified PCR fragments and dideoxy sequencing ladders stabilized for MALDI analysis. In this paper methods are described for the polymerase-directed synthesis of 24-fluoro modified DNA, using commercially available 24-fluoronucleoside triphosphates. The ability of a number of DNA and RNA polymerases to incorporate the 24-fluoro analogs was tested. Four thermostable DNA polymerases [Pfu (exo-), Vent (exo-), Deep Vent (exo-) and UlTma] were found that were able to incorporate 24-fluoronucleotides with reasonable efficiency. In order to perform Sanger sequencing reactions, the enzymes' ability to incorporate dideoxy terminators in conjunction with the 24-fluoronucleotides was evaluated. UlTma DNA polymerase was found to be the best of the enzymes tested for this purpose. MALDI analysis of enzymatically produced 24-fluoro modified DNA using the matrix 2,5-dihydroxy benzoic acid showed no base loss or backbone fragmentation, in contrast to the extensive fragmentation evident with unmodified DNA of the same sequence.
A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based method has recently been reported for the typing of single nucleotide polymorphisms using single nucleotide primer extension. This method is limited in some cases by the resolution of the mass determination, as the mass difference between nucleotides can be as little as 9 Da (the difference between A and T). A variation of this method is described here in which a mass-tagged dideoxynucleotide is employed in the primer extension reactions in place of the unmodified dideoxynucleotide. The increased mass difference due to the presence of the mass-tags substantially improves the accuracy and versatility of the procedure.
The influence of growth hormone (GH) on calcium-phosphorus metabolism and modulation of vitamin D metabolism has been demonstrated, but the mechanism remains unclear. We investigated the effect of a 6-month course of GH therapy on vitamin D and mineral metabolism in twelve GH-deficient children. Before GH therapy, levels of vitamin D metabolites and other biochemistry data were within normal ranges. All patients responded to GH therapy with increased growth velocity. 1,25-Dihydroxyvitamin D levels increased after 1 month of treatment and remained at these higher levels, with a significant increase found at 3 months (P < 0.05), whereas 24,25-dihydroxyvitamin D levels were decreased at 1 and 3 months, the latter being a significant decrease (P < 0.05), and then returned to the baseline levels at 6 months. 25-Hydroxyvitamin D levels did not change significantly. A significant increase in serum insulin-like growth factor-I (IGF-I) levels occurred during the 6 months of treatment (1 month, P < 0.01; 3 and 6 months, P < 0.001). Serum parathyroid hormone (PTH) levels decreased significantly at 3 and 6 months (3 months, P < 0.01; 6 months, P < 0.05). Serum calcium and phosphorus levels did not change significantly. Significant increases were found in the urinary calcium/urinary creatinine ratio (3 and 6 months, P < 0.05) and the percent tubular reabsorption of phosphorus levels (1 and 3 months, P < 0.05). The results of this study confirmed the actions of GH on renal tubules with increases in calcium excretion and phosphorus reabsorption, and indicate that the action of GH on modulating vitamin D metabolism may be IGF-I mediated, not PTH mediated.
Since the first H-mode discharges in 2010, the duration of the H-mode state has been extended and a significantly wider operational window of plasma parameters has been attained. Using a second neutral beam (NB) source and improved tuning of equilibrium configuration with real-time plasma control, a stored energy of W tot ∼ 450 kJ has been achieved with a corresponding energy confinement time of τ E ∼ 163 ms. Recent discharges, produced in the fall of 2012, have reached plasma β N up to 2.9 and surpassed the n = 1 ideal no-wall stability limit computed for H-mode pressure profiles, which is one of the key threshold parameters defining advanced tokamak operation. Typical H-mode discharges were operated with a plasma current of 600 kA at a toroidal magnetic field B T = 2 T. L-H transitions were obtained with 0.8-3.0 MW of NB injection power in both single-and double-null configurations, with H-mode durations up to ∼15 s at 600 kA of plasma current. The measured power threshold as a function of lineaveraged density showed a roll-over with a minimum value of ∼0.8 MW at ne ∼ 2×10 19 m −3 . Several edge-localized mode (ELM) control techniques during H-mode were examined with successful results including resonant magnetic perturbation, supersonic molecular beam injection (SMBI), vertical jogging and electron cyclotron current drive injection into the pedestal region. We observed various ELM responses, i.e. suppression or mitigation, depending on the relative phase of in-vessel control coil currents. In particular, with the 90 • phase of the n = 1 RMP as the most resonant configuration, a complete suppression of type-I ELMs was demonstrated. In addition, fast vertical jogging of the plasma column was also observed to be effective in ELM pace-making. SMBI-mitigated ELMs, a state of mitigated ELMs, were sustained for a few tens of ELM periods. A simple cellular automata ('sand-pile') model predicted that shallow deposition near the pedestal foot induced small-sized high-frequency ELMs, leading to the mitigation of large ELMs. In addition to the ELM control experiments, various physics topics were explored focusing on ITER-relevant physics issues such as the alteration of toroidal rotation caused by both electron cyclotron resonance heating (ECRH) and externally applied 3D fields, and the observed rotation drop by ECRH in NB-heated plasmas was investigated in terms of either a reversal of the turbulence-driven residual stress due to the transition of ion temperature gradient to trapped electron mode turbulence or neoclassical toroidal viscosity (NTV) torque by the internal kink mode. The suppression of runaway electrons using massive gas injection of deuterium showed that runaway electrons were avoided only below 3 T in KSTAR. Operation in 2013 is expected to routinely exceed the n = 1 ideal MHD no-wall stability boundary in the long-pulse H-mode ( 10 s) by applying real-time shaping control, enabling n = 1 resistive wall mode active control studies. In addition, intensive works for ELM mitigation, ELM dynamics, toroidal ro...
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