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.

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.

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.

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.

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.

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.

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.

Enhancement of osteoclastogenic activity in osteolytic prostate cancer cells by physical contact with osteoblasts.

BACKGROUND: The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood. METHODS: Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay. RESULTS: When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA. CONCLUSION: Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.

Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice.

Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.

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.

IκB kinase ß inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.

BACKGROUND: Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) ß is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKß-NF-κB pathway may be an ideal strategy for the management of airway remodelling. OBJECTIVE: We examined the effects of a newly synthesized IKKß inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. METHODS: A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. RESULTS: NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-ß, via inhibition of IKKß. IMD-0354 inhibited IL-13 and IL-1ß production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. CONCLUSION: IKKß plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKß inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.

Total synthesis of ciguatoxin CTX3C.

More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered the isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. The large (3 nanometers long) and complicated molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. Our highly convergent strategic approach featuring the chemoselective ring-closing metathesis reaction as a key tactic has enabled the total synthesis of ciguatoxin CTX3C, which will provide a practical supply for further studies.

Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Synchronous occurrence of intraductal papillary mucinous neoplasm (IPMN) and ductal carcinoma of the pancreas has been reported. Branch duct IPMNs with lower likelihood of malignancy are not submitted to resection but are followed-up, so ductal carcinoma may develop during the follow-up. The development of ductal carcinoma of the pancreas during follow-up of branch duct IPMNs was investigated. METHODS: 60 patients with branch duct IPMN who had an intraductal tumour of <10 mm on imaging examinations and a negative result for malignancy on cytological examination of the pancreatic juice were investigated. They were followed-up mainly by ultrasonography (US), and additionally by endoscopic ultrasonography (EUS), CT, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) with cytological examination of the pancreatic juice for an average period of 87 months. RESULTS: Ductal carcinoma of the pancreas distinct from IPMN developed in 5 of 60 (8%) branch duct IPMNs during follow-up. The 5-year rate of development of ductal carcinoma was 6.9% (95% CI 0.4% to 13.4%), the incidence of ductal carcinoma was 1.1% (95% CI 0.1% to 2.2%) per year and the standardised incidence ratio of development of ductal carcinoma was 26 (95% CI 3 to 48). Patients >70 years old developed ductal carcinoma significantly more frequently than those under 69. Four of five ductal carcinomas identified during follow-up were resectable. Cancer developed in IPMN in 2 of 60 (3%) branch duct IPMNs during follow-up. CONCLUSIONS: During follow-up of branch duct IPMNs, ductal carcinoma of the pancreas not infrequently developed distinct from IPMN. In the follow-up of IPMN, special attention should be paid to the development of ductal carcinoma of the pancreas.

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.