Design and simulation of an imaging neutral particle analyzer for the ASDEX Upgrade tokamak.

An Imaging Neutral Particle Analyzer (INPA) diagnostic has been designed for the ASDEX Upgrade (AUG) tokamak. The AUG INPA diagnostic will measure fast neutrals escaping the plasma after charge exchange reactions. The neutrals will be ionized by a 20 nm carbon foil and deflected toward a scintillator by the local magnetic field. The use of a neutral beam injector (NBI) as an active source of neutrals will provide radially resolved measurements, while the use of a scintillator as an active component will allow us to cover the whole plasma along the NBI line with unprecedented phase-space resolution (<12 keV and 8 cm) and a fast temporal response (up to 1 kHz with the high resolution acquisition system and above 100 kHz with the low resolution one), making it suitable to study localized fast-ion redistributions in phase space.

Inclusion of shear rate effects in the kinetics of a discretized population balance model: Application to struvite precipitation.

The effect of mixing in the modelling of processes based on mass transfer phenomena is commonly ignored in wastewater treatment industry. In this contribution, the effect of the average shear rate in the nucleation and growth rates of struvite is analyzed by combining experimental data with simulation results obtained with a previously presented mass-based discretized population balance model. According to the obtained results, the effect of the average shear rate is identifiable for the selected data and mechanisms. Therefore, it should be considered when a detailed modelling of the process is needed. Consequently, in this contribution, the average shear rate has been decoupled from the kinetic constants. In addition, kinetic rates where it is explicitly included as a power law function have been proposed. The exponents in these power law functions for the primary homogeneous nucleation and growth are 1.3 and 0.3, respectively. Considering shear rate effects allowed to see in the simulation outputs experimentally observed effects: a faster pH decay and smaller particle distribution for increasing mixing intensities.

Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.

Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 small interfering RNA (siRNA) or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.

A new compact solid-state neutral particle analyser at ASDEX Upgrade: Setup and physics modeling.

At ASDEX Upgrade (AUG), a new compact solid-state detector has been installed to measure the energy spectrum of fast neutrals based on the principle described by Shinohara et al. [Rev. Sci. Instrum. 75, 3640 (2004)]. The diagnostic relies on the usual charge exchange of supra-thermal fast-ions with neutrals in the plasma. Therefore, the measured energy spectra directly correspond to those of confined fast-ions with a pitch angle defined by the line of sight of the detector. Experiments in AUG showed the good signal to noise characteristics of the detector. It is energy calibrated and can measure energies of 40-200 keV with count rates of up to 140 kcps. The detector has an active view on one of the heating beams. The heating beam increases the neutral density locally; thereby, information about the central fast-ion velocity distribution is obtained. The measured fluxes are modeled with a newly developed module for the 3D Monte Carlo code F90FIDASIM [Geiger et al., Plasma Phys. Controlled Fusion 53, 65010 (2011)]. The modeling allows to distinguish between the active (beam) and passive contributions to the signal. Thereby, the birth profile of the measured fast neutrals can be reconstructed. This model reproduces the measured energy spectra with good accuracy when the passive contribution is taken into account.

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

[Management of massive hemoptysis]. / Prise en charge de l'hémoptysie massive.

Less than 5% of all cases of haemoptysis are considered to be massive, representing a life-threatening condition that warrants urgent investigations and treatment. Efforts should be concentrated on determining the origin of the haemoptysis and the presence of an underlying respiratory pathology, in order to ensure supportive measures and a rapid control of the bleeding. Bronchial artery embolization is considered to be the treatment of choice and thoracic surgery should only be considered in cases of localized lesions with a high risk of re-bleeding, pulmonary artery hemorrhage and failure or contraindications to embolization.

Model-driven experimental evaluation of struvite nucleation, growth and aggregation kinetics.

Nutrient stewardship is emerging as an issue of global importance, which will drive the development of nutrient recovery in the near to medium future. This will impact wastewater treatment practices, environmental protection, sustainable agriculture and global food security. A modelling framework for precipitation-based nutrient recovery systems has been developed, incorporating non-ideal solution thermodynamics, a dynamic mass balance and a dynamic population balance to track the development of the precipitating particles. The mechanisms of crystal nucleation and growth and, importantly, aggregation are considered. A novel approach to the population balance embeds the nucleation rate into the model, enabling direct regression of its kinetic parameters. The case study chosen for the modelling framework is that of struvite precipitation, given its wide interest and commercial promise as one possible nutrient recovery pathway. Power law kinetic parameters for nucleation, crystal growth and particle aggregation rates were regressed from an ensemble data set generated from 14 laboratory seeded batch experiments using synthetic solutions. These experiments were highly repeatable, giving confidence to the regressed parameter values. The model successfully describes the dynamic responses of solution pH, the evolving particle size distribution subject to nucleation, growth and aggregation effects and the aqueous magnesium concentration in the liquid phase. The proposed modelling framework could well be extended to other, more complex systems, leading to an improved understanding and commensurately greater confidence in the design, operation and optimisation of large-scale nutrient recovery processes from complex effluents.

Assessments of critical flux in a pilot-scale membrane bioreactor.

In this study, the influence of various parameters such as determination methods and step height and length of incremental flux on critical flux values were investigated. Experiments were carried out on a pilot-scale membrane bioreactor (MBR) treated municipal wastewater. Three of the five critical flux determination methods, such as flux linearity, 90% permeability and flux cycling conducted in this study, indicated a decline in critical flux values as the step height of incremental flux increased. However, the hysteresis method and the two-third (2/3) flux limitation method showed an increase and independence of critical flux to the step height of incremental flux, respectively. On the other hand, the step length of incremental flux had no obvious effect on critical flux values evaluated by all critical flux determination methods. Like critical flux, sustainable flux has negative relationship with the increase of step height but no influence of step length was found in this study.

How do I select cerebral protection devices today?

The establishment of cerebral protection has matured conceptually and clinically in recent years. We have accepted that some type of cerebral protection is desirable. We have some choices in whether to use filters, proximal occlusion, or proximal occlusion with reversed flow. There are anatomical and clinical factors that drive the choice of cerebral protection devices. Certain practical applications of cerebral protection technologies can be made based upon clinical experience. Making carotid artery stenting (CAS) safer is the key to a broader application of CAS as a treatment method and optimal selection of atherosclerosis new cerebral protection devices helps to achieve that goal.

2D electron cyclotron emission imaging at ASDEX Upgrade (invited).

The newly installed electron cyclotron emission imaging diagnostic on ASDEX Upgrade provides measurements of the 2D electron temperature dynamics with high spatial and temporal resolution. An overview of the technical and experimental properties of the system is presented. These properties are illustrated by the measurements of the edge localized mode and the reversed shear Alfvén eigenmode, showing both the advantage of having a two-dimensional (2D) measurement, as well as some of the limitations of electron cyclotron emission measurements. Furthermore, the application of singular value decomposition as a powerful tool for analyzing and filtering 2D data is presented.

Endovascular management of critical limb ischemia.

Endovascular management of critical limb ischemia has advanced significantly in the recent past, especially the ability to treat tibial artery lesions with reasonable results. The indications, results, and technical aspects or endovascular management of CLI is reviewed herein. An algorithm for clinical management of CLI in patients with tibial occlusive disease is also presented.

Pelvic haemophilic pseudotumour: management of a patient with high level of inhibitors.

Haemophilic pseudotumour (HP) is a rare but very serious complication of haemophilia. HP affects mainly patients with severe haemophilia and those who have developed antibodies to factor VIII or factor IX. We report on a 45-year-old man with haemophilia A and high titres of inhibitors who developed an extensive HP with progressive destruction of the right ilium over a period of 12 years. The different therapeutic options (conservative management by replacement therapy, surgical approach, radiotherapy, percutaneous evacuation with secondary refilled cavity and transcatheter arterial embolization) are reviewed.

Factors influencing ulcer healing in patients with combined arterial and venous insufficiency.

PURPOSE: The purpose of this study was to determine the effectiveness of treatment of patients with combined arterial and venous insufficiency (CAVI), evaluate variables associated with successful ulcer healing, and better define criteria for interventional therapy. STUDY DESIGN: We retrospectively reviewed the records of patients treated at four institutions from 1995 to 2000 with lower extremity ulcers and CAVI. Arterial disease was defined as an ankle/brachial index less than 0.9, absent pedal pulse, and at least one in-line arterial stenosis > 50% by arteriography. Venous insufficiency was defined as characteristic clinical findings and duplex findings of either reflux or thrombus in the deep or superficial system. Clinical, demographic, and hemodynamic parameters were statistically analyzed with multiple regression analysis and correlated with ulcer healing and limb salvage. RESULTS: Fifty-nine patients with CAVI were treated for nonhealing ulcers that had been present from 1 to 39 months (mean, 6.4 months). All patients had edema. The mean ankle/brachial index was 0.55 (range, 0-0.86). Treatment included elastic compression and leg elevation in all patients and greater saphenous vein stripping in patients with superficial venous reflux. Fifty-two patients underwent arterial bypass grafting, three underwent an endarterectomy, one underwent superficial femoral artery percutaneous transluminal angioplasty, and three underwent primary below-knee amputation. For purposes of analysis, patients were divided into four groups according to the pattern of arterial and venous disease and the success of arterial reconstruction. Group 1 consisted of 22 patients with a patent arterial graft, superficial venous incompetence, and normal deep veins. Group 2 consisted of seven patients with a patent graft, superficial reflux, and deep venous reflux. Group 3 included 22 patients with a patent graft and deep venous thrombosis (DVT), and group 4 included eight patients with an occluded arterial graft. Follow-up ranged from 2 to 47 months (mean, 21.6 months). Forty-nine patients remained alive, and 10 died of unrelated causes. During follow-up, 48 of the 56 treated arteries remained patent and eight occluded. Thirty-four ulcers (58%) healed, 18 ulcers (31%) did not heal, and 7 patients (12%) required below-knee amputation for nonhealed ulcers and uncontrolled infection. No patient with graft occlusion was healed, and 12 ulcers persisted despite successful arterial reconstruction. Twenty-one (78%) of 27 patients undergoing greater saphenous vein stripping were healed, but none of these patients had DVT. The mean interval from bypass graft to healing was 7.9 months. Thirty-two (68%) of 46 patients without prior DVT were healed, whereas only two (15%) of 13 patients with prior DVT were healed, and this variable, in addition to graft patency, was the only factor statistically significant in predicting healing (P <.05). CONCLUSIONS: Ulcers may develop anywhere on the calf or foot in patients with CAVI, and healing requires correction of arterial insufficiency. Patients with prior DVT are unlikely to heal, even with a patent bypass graft. Ulcer healing is a lengthy process and requires aggressive treatment of edema and infection, and successful arterial reconstruction. Patients with a prior DVT are unlikely to benefit from aggressive arterial or venous reconstruction.

Intraoperative superficial femoral artery balloon angioplasty and popliteal to distal bypass graft: an option for combined open and endovascular treatment of diabetic gangrene.

PURPOSE: The purpose of this study was to evaluate the results of combining intraoperative balloon angioplasty (IBA) of the superficial femoral artery (SFA) with distal bypass graft originating from the popliteal artery as a method of lower extremity revascularization in diabetic patients with gangrene. METHODS: Among 380 infrainguinal bypass grafts performed over a 6-year period, there were 110 reversed saphenous vein bypass grafts to the tibial or pedal arteries to treat diabetic patients with gangrene. Diffuse infrainguinal disease was treated with femoral-distal bypass graft (long; n = 46). Popliteal-distal bypass graft was performed when the inflow femoral artery was not significantly diseased (short; n = 52). Focal SFA stenosis and severe infrageniculate disease were treated with combined IBA of the SFA and distal bypass graft originating from the popliteal artery (combined; n = 12). Follow-up was performed with duplex scan surveillance of both the bypass graft and IBA sites. Treatment groups were compared with life-table analysis. RESULTS: There were no perioperative graft failures or amputations. The perioperative mortality rate was 1% (1 of 110). The 2-year primary patency rates were similar in the three groups: 72% in the long bypass graft group, 82% in the short bypass graft group, and 76% in the combined group (P =.8, log-rank test). SFA IBA sites developed recurrent stenosis in two patients, at 7 and 48 months; both were detected with surveillance and treated with percutaneous transluminal balloon angioplasty. The overall 5-year rate of primary patency was 63%, secondary patency was 78%, limb salvage was 81%, and survival was 35%. There were no significant differences among the three treatment groups with respect to these outcomes. CONCLUSION: Results with the combined procedure were similar to those achieved with either femoral-distal bypass graft or popliteal-distal bypass graft without SFA IBA. These data suggest that IBA of the inflow SFA may be combined with popliteal to distal bypass graft and that this technique is a reasonable alternative to longer, femoral-origin bypass graft in selected diabetic patients with gangrene.

Management of ischemic heel ulceration and gangrene: An evaluation of factors associated with successful healing.

OBJECTIVE: The objective of this study was to determine the effectiveness of treatment of nonhealing heel ulcers and gangrene and to define those variables that are associated with success. METHODS: A multi-institutional review was undertaken at four university or university-affiliated hospitals of all patients with wounds of the heel and arterial insufficiency, which was defined as absent pedal pulses and a decreased ankle/brachial index (ABI). Risk factors, hemodynamic parameters, and arteriographic findings were statistically analyzed to determine their effect on wound healing. Life-table analysis was used to assess graft patency and wound healing. RESULTS: Ninety-one patients (57 men, 34 women) were treated for heel wounds that did not heal for 1 to 12 months (62% of nonhealing wounds, 3 months or longer). The mean preoperative ABI was 0.51, and 31% of wounds were infected. Of the patients, 55% had impaired renal function (Cr > 1.5), with 24% undergoing dialysis, 70% had diabetes, and 64% smoked cigarettes. Treatment was topical wound care for all patients and operative wound débridement in 50%. Infrainguinal bypass was performed for 81 patients, 4 had inflow procedures, 3 had superficial femoral artery percutaneous transluminal angioplasty, and 3 had primary below-knee amputation. Postoperatively, 85% of patients had in-line flow to the foot with at least a single patent vessel, 66% had a pedal pulse, and the mean ABI improved by 0.40, to 0.91. Follow-up ranged from 1 to 60 months (mean, 21 months), and 77 patients (85%) are currently alive. In 66 patients (73%), the wounds healed-all within 6 months (mean, 3 months). For 14 (16%) the wounds had not healed, and 11 patients (11%) underwent below-knee amputation. By life-table analysis, limb salvage was 86% at 3 years. During follow-up, 75 infrainguinal bypasses (91%) remained patent (3 secondarily) and 6 occluded, with primary assisted patency of 87% at 3 years. All wounds in patients with occluded grafts failed to heal. Variables found to be statistically significant in predicting healing included normal renal function (95% healed vs 55% nonhealed, P <.002), a palpable pedal pulse (85% healed vs 42%, P <.0015), a patent posterior tibial artery past the ankle (86% healed vs 57%, P <.02), and the number of patent tibial arteries after bypass to the ankle (P <.0001). Neither the ABI nor the presence of infection (defined as positive tissue cultures or the presence of osteomyelitis), diabetes, or other cardiovascular risk factors influenced the outcome. CONCLUSIONS: Complete wound healing of ischemic heel ulcers or gangrene may require up to 6 months, and short-term graft patency is of minimal benefit. Successful arterial reconstruction, especially a patent posterior tibial artery after bypass, is effective in treating most heel ulcers or gangrene. Patients with impaired renal function are at increased risk for failure of treatment, but their wounds may successfully heal and they should not be denied revascularization procedures.

cDNA cloning and characterization of a human sperm antigen (SPAG6) with homology to the product of the Chlamydomonas PF16 locus.

Serum from an infertile male with high-titer anti-sperm antibodies was used to identify a novel human sperm antigen by screening of a testis expression library. The clone, initially designated Repro-SA-1 (HUGO-approved symbol SPAG6), was found to encode a sequence highly enriched in testis. The deduced amino acid sequence of the full-length cDNA revealed striking homology to the product of the Chlamydomonas reinhardtii PF16 locus, which encodes a protein localized to the central pair of the flagellar axoneme. The human gene encodes 1.8- and 2.8-kb mRNAs highly expressed in testis but not in prostate, ovary, spleen, thymus, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, liver, muscle, kidney, and pancreas. The gene was mapped to chromosome 10p11.2-p12. Antibodies raised against SPAG6 sequences localized the protein to the tails of permeabilized human sperm. Both the Chlamydomonas protein and SPAG6 contain eight contiguous armadillo repeats, which place them in a family of proteins known to mediate protein-protein interactions. The cloning of the human homologue of the Chlamydomonas PF16 locus provides a new avenue to explore the role of the axoneme central pair in human sperm function.