Electron temperature and density measurement by Thomson scattering with a high repetition rate laser of 20 kHz on LHD.

Thomson scattering measurements with a high-repetition-rate laser have commenced in the Large Helical Device. As an example of the fast phenomena captured by this diagnostic system, measurements at a 20 kHz repetition-rate in hydrogen pellet-injected plasmas are presented. Signal processing methods for this measurement have been developed and electron temperature profiles with almost 70 spatial points were evaluated at time intervals of 50 [Formula: see text]s. After Raman scattering calibration, electron density profiles were derived. Fast changes in the electron temperature and density profiles within 1 ms were observed.

Preceding propagation of turbulence pulses at avalanche events in a magnetically confined plasma.

The preceding propagation of turbulence pulses has been observed for the first time in heat avalanche events during the collapse of the electron internal transport barrier (e-ITB) in the Large Helical Device. The turbulence and heat pulses are generated near the foot of the e-ITB and propagate to the peripheral region within a much shorter time than the diffusion timescale. The propagation speed of the turbulence pulse is approximately 10 km/s, which is faster than that of the heat pulse propagating at a speed of 1.5 km/s. The heat pulse propagates at approximately the same speed as that in the theoretical prediction, whereas the turbulence pulse propagates one order of magnitude faster than that in the prediction, thereby providing important insights into the physics of non-local transport.

Enhanced Material Assimilation in a Toroidal Plasma Using Mixed H_{2}+Ne Pellet Injection and Implications to ITER.

The ablation and assimilation of cryogenic pure H_{2} and mixed H_{2}+Ne pellets, which are foreseen to be used by the ITER tokamak for mitigating thermal and electromagnetic loads of major disruptions, are observed by spatially and temporally resolved measurements. It is experimentally demonstrated that a small fraction (here ≈5%) of neon added to hydrogenic pellets enhances the core density assimilation with reduced outward transport for the low magnetic-field side injection. This is consistent with theoretical expectations that line radiation increased by doped neon in dense plasmoids suppresses the plasmoid pressure and reduces the E[over →]×B[over →] transport of the ablated material.

Electro-optically Q-switched operation of a high-peak-power Tb:LiYF4 green laser.

We report on an electro-optically Q-switched Tb:LiYF4 green laser pumped by a frequency-doubled optically pumped semiconductor blue laser. The electro-optically Q-switched characteristics were studied under a wide range of repetition rates from 200 Hz to 50 kHz using a KD2PO4 Q-switch. Up to 198 µJ of pulse energy was obtained with a pulse width of 248 ns at a repetition rate of 200 Hz, corresponding to a peak power of 797 W at 544 nm.

Efficient visible laser operation of Tb:LiYF4 and LiTbF4.

We report laser operation of two Tb3+-activated gain media, Tb:LiYF4 and LiTbF4, in yellow or/and green spectral region. A record-high slope efficiency of 63% among Tb3+-lasers and maximum output power of 1.17 W (incident power of 2.79 W) at around 544 nm were obtained with a c-cut 15%Tb:LiYF4 crystal. The yellow laser characteristics in σ-polarization were studied. A slope efficiency of 21% at 582 nm was achieved. More importantly, we succeeded in laser operation of LiTbF4 for the first time to the best of our knowledge. Laser oscillation at around 544 nm yielded a maximum slope efficiency of 45%. This points toward the possibility of producing high-energy pulsed lasers using LiTbF4, which features a high active-ion concentration as well as relatively long lifetime.

Graphene Q-switched Tb:LiYF4 green laser.

We report the Q-switched operation of a Tb3+-laser for the first time, to the best of our knowledge. The passiveQ-switching was realized by a 15% Tb:LiYF4 gain medium and a single-layer graphene saturable absorber. An average output power of 744 mW at 544 nm was achieved with slope efficiency of 41%, pulse width of 2.9 µs, and repetition rate of 38.7 kHz. The corresponding pulse energy and peak power were calculated to be 19.2 µJ and 6.6 W, respectively.

Nd3+-activated CaF2 ceramic lasers.

Nd,Y:CaF2 and Nd,La:CaF2 ceramics featuring good optical quality have been fabricated by reactive sintering and a hot isostatic pressing method. The transmission spectra, emission spectra, and fluorescence decay curves were measured. Lasing at 1064 and 1065 nm was observed in Nd,Y:CaF2 and Nd,La:CaF2, respectively, upon quasi-continuous-wave pumping by a diode laser emitting at 791 nm. To the best of our knowledge, this is the first demonstration of Nd3+-activated CaF2 ceramic laser.

Effect of Systematic Conversion to Generic Mycophenolate Mofetil (MMF) in Kidney Transplantation: A Single-Center Clinical Experience from Japan.

INTRODUCTION: Recently, more and more generic drugs have been used for immunosuppressive drugs in the field of organ transplantation. Some reports have indicated that blood concentration of most generic drugs is difficult to maintain stability, and it may cause the difference in graft survival of transplanted organs between original drugs and generic drugs. In this article, we report the cases could not maintain blood concentration of generic drugs of mycophenolate mofetil (MMF). RESULTS: In 4 cases out of 5 cases that we had to change original MMF to generic MMF, there were cases that blood concentration level was not stabilized. There were possibility that the lowered blood concentration level of MMF caused a rejection, in two cases. Mean MMF trough level was decreased from 3.6 ± 1.9 µg/mL to 0.6 ± 0.4 µg/mL. Due to the early detection, it did not become severe or failure of graft function, however, we cannot deny the possibilities that side effects were increased and rejection rose. In these cases, we discontinued to use the generic drugs thereafter due to unstable plasma concentration of MMF. DISCUSSION: Some reports have indicated that failure to maintain plasma concentration of MMF leads to rejection. Therefore, maintenance of effective plasma concentration and prevention of rejection are essential to long-term graft survival in kidney transplant. CONCLUSION: Generic drug formulations may exhibit differences in effects and absorption compared to the brand-name drug. If the generic drug should be used, patients should be closely monitored.

Compact, highly efficient, 2.1-W continuous-wave mid-infrared Fe:ZnSe coherent source, pumped by an Er:ZBLAN fiber laser.

In this Letter, we report a compact and robust coherent source, operating in mid-infrared (IR) and based on the Fe:ZnSe chalcogenide gain medium, optically pumped by an Er:ZBLAN fiber laser. The output power of 2.1 W with a 59% slope efficiency with respect to the absorbed pump power at liquid nitrogen cooling is achieved. We show that strong re-absorption at a high pump power and iron ion doping concentrations leads to a continuous tuning of central wavelength from 4012 to 4198 nm. The robustness of a high-power Er:ZBLAN fiber laser combined with prominent spectroscopic properties of Fe:ZnSe media pave the way for the development of a reliable tunable continuous-wave mid-IR sources for scientific and industrial purposes.

Safety of Elderly Living Kidney Donors: 2 Cases of Donors Older Than 80 Years: A Case Report.

Much controversy exists over the performance of elderly living donor kidney transplantation. We report the safety of 2 cases of elderly living kidney donations in our hospital. CASE 1: An 82-year-old man was a living kidney donor for his 56-year-old son. The donor suffered from hypertension, but has successfully managed his blood pressure with only one medication. His serum creatinine was 0.7 mg/dL and inulin clearance was 122.5 mL/min, which met the usual criteria for living kidney donors. This was his son's secondary kidney transplantation, and no other donors existed. CASE 2: An 80-year-old woman was a living kidney donor for her 45-year-old son. Her serum creatinine was 0.61 mg/dL and inulin clearance was 71.7 mL/min, which met the marginal kidney donor criteria. In both cases, we determined that the donor kidney function was acceptable. Though we explained the risks of the transplantation thoroughly, the patients' strong will to offer a kidney to their family member did not change. We decided to carry out the transplantation. At the time of publication, nearly 2 years have passed since the transplantation, but both donors and recipients are doing well. In the future, it seems more likely that the number of elderly living donor kidney transplantation will rise. On one hand, there is no absolute contraindication for elderly donors, while on the other hand, the criteria for a living kidney donor must be strictly examined. Furthermore, careful observation of both donors and recipients after transplantation is required.

Fluoride-fiber-based side-pump coupler for high-power fiber lasers at 2.8 µm.

A side-pump coupler made of fluoride fibers was fabricated and tested. The tested device had a coupling efficiency of 83% and was driven with an incident pump power of up to 83.5 W, demonstrating high-power operation. Stable laser output of 15 W at a wavelength of around 2.8 µm was achieved over 1 h when using an erbium-doped double-clad fiber as the active medium. To the best of our knowledge, this is the first time a fluoride-glass-fiber-based side-pump coupler has been developed. A test with two devices demonstrated further power scalability.

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

BACKGROUND: Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I-R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS: Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS: Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS: Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

Implications of Clinical Mycophenolate Mofetil Dose According to Individual Body Weight in Japanese Renal Transplant Recipients.

BACKGROUND: Mycophenolate mofetil (MMF) is generally administered at a fixed dose of 0.5-1.5 g/d without considering individual body weight (BW) in Japanese renal transplant outpatients receiving maintenance therapy. We aimed to investigate the implications of the area under the curve of mycophenolic acid (MPA AUC):MMF dose ratio by individual BW and suggest the index of MMF dose according to individual BW. METHODS: Forty-three Japanese patients who received a renal transplant ≥6 months before the study were enrolled. Blood samples were collected at 4 time points: at predose, 20 minutes, 1 hour, and 3 hours after MMF administration. RESULTS: The mean ± standard deviation MMF dose, MPA AUC, and BW of all patients were 581 ± 207 mg/d, 36.2 ± 18.7 µg·h/mL, and 56.3 ± 11.1 kg, respectively. Patients with a lower BW tended to have a higher MPA AUC:MMF dose ratio than patients with a higher BW. There was a significant correlation between the MMF dose:BW ratios and MPA AUC (r(2) = 0.330; P < .01). The rate of MPA AUC between 30 and 60 µg·h/mL with the MMF dose:BW ratio of 10-16 mg/kg was 73.7%. CONCLUSION: Individual BW seems to affect the MPA AUC:MMF dose ratio; therefore, we need to consider individual BW when deciding on a MMF dose. The MMF dose:BW ratio of 10-16 mg/kg could predict MPA AUC between 30 and 60 µg·h/mL with a probability of approximately 75%. Therefore, it could be a useful index for outpatients, because it is difficult to draw blood frequently from such patients.

Multiple inductive effects of carbamazepine on combined therapy with paliperidone and amlodipine.

WHAT IS KNOWN AND OBJECTIVE: Carbamazepine is a potent inducer of cytochrome P450 3A and P-glycoprotein. However, there are no reports of the effects of carbamazepine on more than one co-administered drug. CASE SUMMARY: A 53-year-old female patient with schizophrenia and hypertension was on paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine was added to this prescription, the plasma concentrations of both drugs decreased dramatically in a dose-dependent manner. Although the patient's psychotic symptoms did not change, as a result, her mean blood pressure increased to 160·1/103·6 mmHg from 138·4/91·4 mmHg at a carbamazepine dose of 600 mg/day. WHAT IS NEW AND CONCLUSION: Theses cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together.

Receptor-type protein tyrosine phosphatase κ directly dephosphorylates CD133 and regulates downstream AKT activation.

Although CD133 has been considered to be a molecular marker for cancer stem cells, its functional roles in tumorigenesis remain unclear. We here examined the molecular basis behind CD133-mediated signaling. Knockdown of CD133 resulted in the retardation of xenograft tumor growth of colon cancer-derived HT-29 and LoVo cells accompanied by hypophosphorylation of AKT, which diminished ß-catenin/T-cell factor-mediated CD44 expression. As tyrosine residues of CD133 at positions 828 and 852 were phosphorylated in HT-29 and SW480 cells, we further addressed the significance of this phosphorylation in the tumorigenesis of SW480 cells expressing mutant CD133, with substitution of these tyrosine residues by glutamate (CD133-EE) or phenylalanine (CD133-FF). Forced expression of CD133-EE promoted much more aggressive xenograft tumor growth relative to wild-type CD133-expressing cells accompanied by hyperphosphorylation of AKT; however, CD133-FF expression had negligible effects on AKT phosphorylation and xenograft tumor formation. Intriguingly, the tyrosine phosphorylation status of CD133 was closely linked to the growth of SW480-derived spheroids. Using yeast two-hybrid screening, we finally identified receptor-type protein tyrosine phosphatase κ (PTPRK) as a binding partner of CD133. In vitro studies demonstrated that PTPRK associates with the carboxyl-terminal region of CD133 through its intracellular phosphatase domains and also catalyzes dephosphorylation of CD133 at tyrosine-828/tyrosine-852. Silencing of PTPRK elevated the tyrosine phosphorylation of CD133, whereas forced expression of PTPRK reduced its phosphorylation level markedly and abrogated CD133-mediated AKT phosphorylation. Endogenous CD133 expression was also closely associated with higher AKT phosphorylation in primary colon cancer cells, and ectopic expression of CD133 enhanced AKT phosphorylation. Furthermore, lower PTPRK expression significantly correlated with the poor prognosis of colon cancer patients with high expression of CD133. Thus, our present findings strongly indicate that the tyrosine phosphorylation of CD133, which is dephosphorylated by PTPRK, regulates AKT signaling and has a critical role in colon cancer progression.

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations.

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

Nerve growth factor derived from bronchial epithelium after chronic mite antigen exposure contributes to airway hyperresponsiveness by inducing hyperinnervation, and is inhibited by in vivo siRNA.

BACKGROUND: Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain. OBJECTIVE: In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation. METHODS: We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined. RESULTS: NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis. CONCLUSION AND CLINICAL RELEVANCE: These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.

Modulation of CD4⁺ T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis.

Dysfunction of T cells is a common feature in chronic persistent viral infections, including hepatitis C virus (HCV), and although hepatic and peripheral T cells have been studied extensively in chronic HCV hepatitis, the role of splenic T cell responses in such patients is poorly defined. This is an important issue, as thrombocytopenia is a complication of HCV-related liver cirrhosis (LC), due to splenic platelet sequestration and bone marrow suppression; splenectomy has been proposed to treat such patients. Herein, we studied peripheral blood mononuclear cells (PBMC) and splenic lymphoid subpopulations from a total of 22 patients, including 15 with HCV-related LC with marked thrombocytopenia treated with splenectomy, and seven controls. CD4(+) T cells from peripheral blood and spleen were isolated and phenotype and function evaluated. Splenic CD4(+) T cells in patients with LC expressed molecules associated with inhibitory signalling, including increased frequency of negative markers such as cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) and decreased production of cytokines. Patients with LC manifest higher levels of splenic CD4(+) regulatory T cells and PD-L1- and PD-L2-expressing cells than controls. Blocking of PD-1/PD-1 ligand interaction reconstituted proliferative and cytokine responses of splenic mononuclear cells (SMC) from patients with LC. Splenectomy was followed by an increase in the ratio of interferon (IFN)-γ to interleukin (IL)-10 and a reduction of PD-1-expressing CD4(+) T cells in peripheral blood. Our data suggest that peripheral tolerance is promoted by the spleen in LC via the up-regulated expression of PD-1 ligands.