Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Histamine treatment induces rearrangements of orthogonal arrays of particles (OAPs) in human AQP4-expressing gastric cells.

To test the involvement of the water channel aquaporin (AQP)-4 in gastric acid physiology, the human gastric cell line (HGT)-1 was stably transfected with rat AQP4. AQP4 was immunolocalized to the basolateral membrane of transfected HGT-1 cells, like in native parietal cells. Expression of AQP4 in transfected cells increased the osmotic water permeability coefficient (Pf) from 2.02 +/- 0.3 x 10-4 to 16.37 +/- 0.5 x 10-4 cm/s at 20 degrees C. Freeze-fracture EM showed distinct orthogonal arrays of particles (OAPs), the morphological signature of AQP4, on the plasma membrane of AQP4-expressing cells. Quantitative morphometry showed that the density of OAPs was 2.5 +/- 0.3% under basal condition and decreased by 50% to 1.2 +/- 0.3% after 20 min of histamine stimulation, mainly due to a significant decrease of the OAPs number. Concomitantly, Pf decreased by approximately 35% in 20-min histamine-stimulated cells. Both Pf and OAPs density were not modified after 10 min of histamine exposure, time at which the maximal hormonal response is observed. Cell surface biotinylation experiments confirmed that AQP4 is internalized after 20 min of histamine exposure, which may account for the downregulation of water transport. This is the first evidence for short term rearrangement of OAPs in an established AQP4-expressing cell line.

Electron cyclotron resonance 140 mA D(+) beam extraction optimization for IFMIF EVEDA accelerator.

Based on the experience of the SILHI electron cyclotron resonance (ECR) ion source for the IPHI accelerator, which produces routinely 100-120 mA H(+) beam, the CEA-Saclay is in charge of the design and realization of the 140 mA cw deuteron source for the IFMIF project (International Fusion Materials Irradiation Facility). IFMIF is an accelerator-based neutron irradiation facility consisting of two accelerators of 125 mA D(+) beam at 40 MeV that hit in parallel a lithium target. IFMIF utilizes the deuteron-lithium (d-Li) neutron, producing a reaction to simulate the 14 MeV neutron environment in deuterium-tritium (D-T) fusion reactors. In the framework of the IFMIF EVEDA phase (Engineering Validation and Engineering Design Activities), we are studying a cw ECR ion source with a new extraction system to allow high current extraction while keeping a low divergence as well as a small emittance. Starting from SILHI five-electrode system with H(+) ions, the extracted beam characteristics as well as electric field conditions are compared with the cases of four- and three-electrode extraction systems. Experimental results made on the SILHI source with H(+) ions are briefly discussed. Extensive experimental results on the new source test bench BETSI are expected as soon as the design and fabrication of a dedicated extraction system with a new set of electrodes will be finished.

A 140 mA cw deuteron electron cyclotron resonance source for the IFMIF-EVEDA project.

In the framework of the IFMIF-EVEDA phase (International Fusion Materials Irradiation Facility-Engineering Validation and Engineering Design Activities), the CEA-Saclay is in charged of the design and realization of the 140 mA cw deuteron source. The IFMIF EVEDA demonstrator will be installed in Japan in the next six years and will have to accelerate the deuteron beam up to 9 MeV. CEA will build the source and the low energy beam line (LEBT) and will test the cw high intensity deuteron production at Saclay. The SILHI source is an electron cyclotron resonance (ECR) source, operating at 2.45 GHz. In 2001, it produced more than 130 mA of deuteron beam in pulsed mode to minimize neutron production. Such a result pushes to develop a new ECR source based on the SILHI design and equipped with a specific extraction system. Several options of the accelerator column will be implemented in order to improve the reliability and the efficiency of the source. The IFMIF source and LEBT design will be reported.

BETSI, a new test bench for ion sources optimization at CEA SACLAY.

In the framework of several International HPPA projects (such as IFMIF, IPHI, and Spiral2) the CEA handles the design and the developments of several electron cyclotron resonance (ECR) ion sources. For the IFMIF EVEDA demonstrator, a 140 mA cw extracted deuteron beam will be required for high yield of neutron production. For radioactive ion production in the Spiral2 project, several milliamperes of deuterons will be delivered with a permanent magnet source. The optimization of the beam quality at the entrance of the radio frequency quadropole (RFQ) accelerator system triggered the need of a new test bench for ion source optimization and beam qualification. The BETSI ion source test bench will operate up to 50 kV and ignite cw or pulsed hydrogen plasma with a 2.45 GHz magnetron. Great care has already been taken to design electrostatic optics of the extraction system to minimize the emittance growth. Plasma diagnostics will be inserted in the source chamber and several beam diagnostics (emittance and current measurements, beam species analysis) will also be implemented on the low energy beam line transport (LEBT). These diagnostics allow the simultaneous analysis of the beam quality with the plasma parameters of the source. Regional funding request will also be needed to improve the LEBT for space charge compensation measurements. The design of the present and upgraded test bench will be reported as well as the first extracted beam analysis.

Measurement of ion species in high current ECR H⁺/D⁺ ion source for IFMIF (International Fusion Materials Irradiation Facility).

Ion species ratio of high current positive hydrogen/deuterium ion beams extracted from an electron-cyclotron-resonance ion source for International Fusion Materials Irradiation Facility accelerator was measured by the Doppler shift Balmer-α line spectroscopy. The proton (H(+)) ratio at the middle of the low energy beam transport reached 80% at the hydrogen ion beam extraction of 100 keV/160 mA and the deuteron (D(+)) ratio reached 75% at the deuterium ion beam extraction of 100 keV/113 mA. It is found that the H(+) ratio measured by the spectroscopy gives lower than that derived from the phase-space diagram measured by an Allison scanner type emittance monitor. The H(+)/D(+) ratio estimated by the emittance monitor was more than 90% at those extraction currents.

Operation and commissioning of IFMIF (International Fusion Materials Irradiation Facility) LIPAc injector.

The objective of linear IFMIF prototype accelerator is to demonstrate 125 mA/CW deuterium ion beam acceleration up to 9 MeV. The injector has been developed in CEA Saclay and already demonstrated 140 mA/100 keV deuterium beam [R. Gobin et al., Rev. Sci. Instrum. 85, 02A918 (2014)]. The injector was disassembled and delivered to the International Fusion Energy Research Center in Rokkasho, Japan. After reassembling the injector, commissioning has started in 2014. Up to now, 100 keV/120 mA/CW hydrogen and 100 keV/90 mA/CW deuterium ion beams have been produced stably from a 10 mm diameter extraction aperture with a low beam emittance of 0.21 π mm mrad (rms, normalized). Neutron production by D-D reaction up to 2.4 × 10(9) n/s has been observed in the deuterium operation.

Localization of the FA-CHIP water channel in frog urinary bladder.

Like mammalian kidney collecting duct, the water permeability of frog urinary bladder epithelial cells is antidiuretic hormone (ADH)-sensitive. In kidney, this permeability is mediated by water channels named aquaporins. We recently reported the cloning of the frog aquaporin CHIP (FA-CHIP), a water channel from frog urinary bladder. FA-CHIP has 79% identity with rat Aquaporin 1 (AQP1) and only 42% identity with the kidney collecting duct Aquaporin 2 (AQP2). The purpose of this study was to examine the localization of FA-CHIP in frog urinary bladder. We raised antibodies against peptides of 15 to 17 residues, encompassing the N-ter and C-ter regions of FA-CHIP. Anti-FA-CHIP antibodies were used for Western blotting, indirect immunofluorescence microscopy and gold labeling electron microscopy in urinary bladder and other frog tissues. By Western blotting of frog urinary bladder total homogenate, the antibodies recognized a band of 29 kDa and glycosylated forms of the protein between 40 and 70 kDa. No signal was found on membrane preparations from epithelial cell homogenate. FA-CHIP was also found in frog skin, brain, gall bladder, and lung. In immunofluorescence microscopy on urinary bladder sections, FA-CHIP was localized to endothelial cells of blood capillaries and on mesothelial cells of the serosal face. Red blood cells, epithelial and basal cells were unstained. The localization of FA-CHIP in cell plasma membranes was confirmed by gold labeling electron microscopy. In other positive tissues, FA-CHIP was also localized to capillaries. In brain, plasma membranes of epithelial cells were also stained. In conclusion, like its mammalian homologue AQP1, FA-CHIP appears to be localized to constitutively water permeable cells of frog. Therefore, it belongs to the AQP1 family of proteins although unlike AQP1, FA-CHIP is absent from red blood cells and kidney. In frog urinary bladder and skin, FA-CHIP probably plays an important role in water transport across the barriers in series with the ADH-sensitive epithelial cells.

Functional expression of AQP3 in human skin epidermis and reconstructed epidermis.

The purpose of this study was to examine the presence of aquaporin water channels in human skin and to assess their functional role. On western blots of human epidermis obtained from plastic surgery, a strong signal was obtained with polyclonal anti-aquaporin-3 antibodies. By indirect immunofluorescence on 5 microm cryosections, anti-aquaporin-3 antibodies strongly stained keratinocyte plasma membranes in human epidermis, whereas no staining was observed in the dermis or the stratum corneum or when anti-aquaporin-3 antibodies were preabsorbed with the peptide used for immunization. Similarly, a strong signal with anti-aquaporin-3 antibodies was observed in keratinocyte plasma membranes of reconstructed human epidermis in culture at the air-liquid interface for up to 3 wk. The keratinocyte plasma membrane localization of aquaporin-3 was confirmed at the electron microscope level in prickle cells. In addition an intracellular localization of aquaporin-3 was also detected in epidermis basal cells. Osmotically induced transepidermal water permeability was measured on stripped human skin and on reconstructed epidermis. Water transport across both stripped human skin and 2-3 wk reconstructed epidermis was comparable, inhibited by > 50% by 1 mM HgCl2 and fully inhibited by acid pH. By stopped-flow light scattering, keratinocyte plasma membranes, where aquaporin-3 is localized, exhibited a high, pH-sensitive, water permeability. Although human skin is highly impermeable to water, this is primarily accounted for by the stratum corneum, where a steep water content gradient was demonstrated. In contrast, the water content of viable strata of the epidermis is remarkably constant. Our results suggest that the human epidermis, below the stratum corneum, exhibits a high, aquaporin-3-mediated, water permeability. We propose that the role of aquaporin-3 is to water-clamp viable layers of the epidermis in order to improve the hydration of the epidermis below the stratum corneum.

Functional expression of the human CHIP28 water channel in a yeast secretory mutant.

The temperature-sensitive Saccharomyces cerevisiae mutant strain NY17, deficient in the secretory pathway (sec6-4 mutation), is used for the heterologous expression of the human CHIP28 water channel. After a heat-shock, the protein is present in partially purified post-golgi secretory vesicles. Immunodetection and water transport studies, directly made on the vesicles, showed that CHIP28 is highly expressed and active in the yeast membranes.

Technetium-99m labeling by means of stannous pyrophosphate: application to bleomycin and red blood cells.

A new technique of technetium labeling using stannous pyrophosphate instead of stannous chloride as reducing agent for pertechnetate has been applied to red blood cells and bleomycin. Results are so encouraging that this technique could be extended to other compounds capable of forming stable complexes with reduced technetium. No saline washes of red cells are necessary before or after the addition of pertechnetate. No purification step is performed after labeling of bleomycin.

Interactive simulation of cranial surgery in a computer aided design environment.

Accurate pre-surgical planning is a prerequisite for successful craniofacial surgery. This paper introduces a simulation system developed in a computer aided design (CAD) environment, where a 3-D mathematical model of the skull is entered. The architecture of the program yields a flexible and easy-to-use system that allows the simulation of surgery on the wire frame image of the model. Possible actions simulated are osteotomy, bending, rotation, translation and removal. Numerical values for anatomical distances and the intracranial volume are easily calculated. Information on the techniques used and the numerical data resulting from the simulation can be stored. Plots of intermediate steps of the simulation or of contours of separate pieces permit feed-back to the operating theatre.

Computer-aided craniofacial surgical planning implemented in CAD software.

Accurate presurgical planning is imperative for successful cranial surgery. This article introduces a simulation program developed in a computer-aided design environment. The neurocranium is introduced as a mathematical surface, since this is the part on which the actual operation will be performed. The viscerocranium, which serves as reference, is visualized using small triangular surfaces. The development of the program commenced with a classification of the different surgical techniques mentioned in the literature into six basic actions. The use of mathematically described surfaces has the advantage that the program can simulate actions which change the shape of a surface and perform an on-line estimation of the fracture risk during bending. Three-point bending tests were carried out to provide the necessary data to perform the mathematical check, as these data are not available in the literature. A database with reference distances was introduced to guide the surgeon to obtain the best possible results. During one clinical trial, the computer was taken into the operating room so that the surgical plan developed with the simulation program could be applied to the actual operation.

Improvement of extraction system geometry with suppression of possible Penning discharge ignition.

During the past two years, a new ECR 2.45 GHz type ion source has been developed especially dedicated to intense light ion injector project like IPHI (Injecteur Proton Haute Intensité), IFMIF (International Fusion Materials Irradiation Facility), to reduce beam emittance at RFQ entrance by shortening the length of the LEBT. This new ALISES concept (Advanced Light Ion Source Extraction System) is based on the use of an additional LEBT short length solenoid very close to the extraction aperture. The fringe field of this new solenoid produces the needed magnetic field to create the ECR resonance in the plasma chamber. Such geometry allows first putting the solenoid at ground potential, while saving space in front of the extraction to move the first LEBT solenoid closer and focus earlier the intense extracted beam. During the commissioning of the source in 2011-2012, ALISES has produced about 20 mA extracted from a 6 mm diameter plasma extraction hole at 23 kV. But the magnetic configuration combined to the new extraction system geometry led to important Penning discharge conditions in the accelerator column. Lots of them have been eliminated by inserting glass pieces between electrodes to modify equipotential lines with unfavorable ExB vacuum zones where particles were produced and trapped. To study Penning discharge location, several 3D calculations have been performed with OPERA-3D/TOSCA code to simulate the possible production and trapping of electrons in the extraction system. The results obtained on different sources already built have shown very good agreement with sparks location observed experimentally on electrodes. The simulations results as well as experimental measurements are presented and solutions to prevent possible Penning discharge in future source geometries are established.

Effective shielding to measure beam current from an ion source.

To avoid saturation, beam current transformers must be shielded from solenoid, quad, and RFQ high stray fields. Good understanding of field distribution, shielding materials, and techniques is required. Space availability imposes compact shields along the beam pipe. This paper describes compact effective concatenated magnetic shields for IFMIF-EVEDA LIPAc LEBT and MEBT and for FAIR Proton Linac injector. They protect the ACCT Current Transformers beyond 37 mT radial external fields. Measurements made at Saclay on the SILHI source are presented.

International Fusion Materials Irradiation Facility injector acceptance tests at CEA/Saclay: 140 mA/100 keV deuteron beam characterization.

In the framework of the ITER broader approach, the International Fusion Materials Irradiation Facility (IFMIF) deuteron accelerator (2 × 125 mA at 40 MeV) is an irradiation tool dedicated to high neutron flux production for future nuclear plant material studies. During the validation phase, the Linear IFMIF Prototype Accelerator (LIPAc) machine will be tested on the Rokkasho site in Japan. This demonstrator aims to produce 125 mA/9 MeV deuteron beam. Involved in the LIPAc project for several years, specialists from CEA/Saclay designed the injector based on a SILHI type ECR source operating at 2.45 GHz and a 2 solenoid low energy beam line to produce such high intensity beam. The whole injector, equipped with its dedicated diagnostics, has been then installed and tested on the Saclay site. Before shipment from Europe to Japan, acceptance tests have been performed in November 2012 with 100 keV deuteron beam and intensity as high as 140 mA in continuous and pulsed mode. In this paper, the emittance measurements done for different duty cycles and different beam intensities will be presented as well as beam species fraction analysis. Then the reinstallation in Japan and commissioning plan on site will be reported.

Advanced light ion source extraction system for a new electron cyclotron resonance ion source geometry at Saclay.

One of the main goal of intense light ion injector projects such as IPHI, IFMIF, or SPIRAL2, is to produce high current beams while keeping transverse emittance as low as possible. To prevent emittance growth induced in a dual solenoid low energy transfer line, its length has to be minimized. This can be performed with the advanced light ion source extraction system concept that we are developing: a new ECR 2.45 GHz type ion source based on the use of an additional low energy beam transport (LEBT) short length solenoid close to the extraction aperture to create the resonance in the plasma chamber. The geometry of the source has been considerably modified to allow easy maintenance of each component and to save space in front of the extraction. The source aims to be very flexible and to be able to extract high current ion beams at energy up to 100 kV. A specific experimental setup for this source is under installation on the BETSI test bench, to compare its performances with sources developed up to now in the laboratory, such as SILHI, IFMIF, or SPIRAL2 ECR sources. This original extraction source concept is presented, as well as electromagnetic simulations with OPERA-2D code. Ion beam extraction in space charge compensation regime with AXCEL, and beam dynamics simulation with SOLMAXP codes show the beam quality improvement at the end of the LEBT.

Transport of intense ion beams and space charge compensation issues in low energy beam lines (invited).

Over the last few years, the interest of the international scientific community for high power accelerators in the megawatt range has been increasing. For such machines, the ion source has to deliver a beam intensity that ranges from several tens up to a hundred of mA. One of the major challenges is to extract and transport the beam while minimizing the emittance growth and optimizing its injection into the radio frequency quadrupole. Consequently, it is crucial to perform precise simulations and cautious design of the low energy beam transport (LEBT) line. In particular, the beam dynamics calculations have to take into account not only the space charge effects but also the space charge compensation of the beam induced by ionization of the residual gas. The physical phenomena occurring in a high intensity LEBT and their possible effects on the beam are presented, with a particular emphasis on space charge compensation. Then, beam transport issues in different kind of LEBTs are briefly reviewed. The SOLMAXP particle-in-cell code dedicated to the modeling of the transport of charge particles under a space charge compensation regime is described. Finally, beam dynamics simulations results obtained with SOLMAXP are presented in the case of international fusion materials irradiation facility injector.

Note: emittance measurements of intense pulsed proton beam for different pulse length and repetition rate.

The high intensity ion source (SILHI), in operation at CEA-Saclay, has been used to produce a 90 mA pulsed proton beam with pulse length and repetition rates suitable for the European Spallation Source (ESS) linac. Typical r-r(') rms normalized emittance values smaller than 0.2π mm mrad have been measured for operation in pulsed mode (0.01 < duty cycle < 0.15 and 1 ms < pulse duration < 10 ms) that are relevant for the design update of the Linac to be used at the ESS in Lund.

Light ion source for proton∕deuteron production at CEA Saclay for the Spiral2 project.

The production of rare radioactive ion beam (RIB) far from the valley of stability is one of the final purposes of the Spiral2 facility in Caen. The RIB will be produced by impinging a deuteron beam onto a carbon sample to produce a high neutron flux, which will interact with a uranium target. The primary deuteron beam is produced by an ion source based on ECR plasma generation. The deuteron source and the low energy beam transport (LEBT) has been assembled and tested at CEA Saclay. Diagnostics from other laboratories were implemented on the LEBT in order to characterize the deuteron beam produced and compare it to the initial simulations. The ion source has been based on a SILHI-type source, which has demonstrated good performances in pulsed and continuous mode, and also a very good reliability on long term operation. The 5 mA of deuteron beam required at the RFQ entrance is extracted from the plasma source at the energy of 40 kV. After a brief description of the experimental set-up, this article reports on the first beam characterization experiments.