Development status of a next generation ECRIS: MARS-D at LBNL.

To demonstrate a Mixed Axial and Radial field System (MARS) as the best magnet scheme for future ECRISs, MARS-D, a demonstrative ECRIS using a NbTi MARS magnet is progressing at Lawrence Berkeley National Laboratory. An optimized MARS design can use either NbTi or Nb3Sn coils with reduced engineering complexities to construct the needed high-field magnets. The optimized magnet design could enhance MARS-D to a next generation ECRIS by producing minimum-B field maxima of 5.6 T axially and 3.2 T radially for operating frequencies up to 45 GHz. In-progress test winding has achieved a milestone demonstrating the fabrication feasibility of a MARS closed-loop coil.

Investigation on the electron flux to the wall in the VENUS ion source.

The long-term operation of high charge state electron cyclotron resonance ion sources fed with high microwave power has caused damage to the plasma chamber wall in several laboratories. Porosity, or a small hole, can be progressively created in the chamber wall which can destroy the plasma chamber over a few year time scale. A burnout of the VENUS plasma chamber is investigated in which the hole formation in relation to the local hot electron power density is studied. First, the results of a simple model assuming that hot electrons are fully magnetized and strictly following magnetic field lines are presented. The model qualitatively reproduces the experimental traces left by the plasma on the wall. However, it is too crude to reproduce the localized electron power density for creating a hole in the chamber wall. Second, the results of a Monte Carlo simulation, following a population of scattering hot electrons, indicate a localized high power deposited to the chamber wall consistent with the hole formation process. Finally, a hypervapotron cooling scheme is proposed to mitigate the hole formation in electron cyclotron resonance plasma chamber wall.

Development of a new superconducting Electron Cyclotron Resonance Ion Source for operations up to 18 GHz at LBNL.

A new superconducting Electron Cyclotron Resonance Ion Source (ECRIS) is under development at LBNL to harness the winding techniques of a closed-loop sextupole coil for the next generation ECRIS and to enhance the capability of the 88-in. cyclotron facility. The proposed ECRIS will use a superconducting closed-loop sextupole coil to produce the radial field and a substantial portion of the axial field. The field strengths of the injection, central and extraction regions are adjusted by a three solenoids outside the closed-loop sextupole coil. In addition to maintaining the typical ECRIS magnetic field configuration, this new source will also be able to produce a dustpan-like minimum-B field to explore possible ECRIS performance enhancement. The dustpan-like minimum-B field configuration has about the same strengths for the maximum axial field at the injection region and the maximum radial pole fields at the plasma chamber walls but it can be substantially lower at the extraction region. The dustpan-like minimum-B will have a field maximum Bmax ≥ 2.6 T for operations up to 18 GHz with a ratio of Bmax/Bres ≥ 4 and higher ratios for lower frequencies. The field maxima of this new source can reach over 3 T both at the injection and the plasma chamber walls which could also support operation at 28 GHz. The source will be built of cryogen-free with the magnets directly cooled by cryo-coolers to simplify the cryostat structure. The source design features will be presented and discussed.

A mode converter to generate a Gaussian-like mode for injection into the VENUS electron cyclotron resonance ion source.

A number of superconducting electron cyclotron resonance (ECR) ion sources use gyrotrons at either 24 or 28 GHz for ECR heating. In these systems, the microwave power is launched into the plasma using the TE01 circular waveguide mode. This is fundamentally different and may be less efficient than the typical rectangular, linearly polarized TE10 mode used for launching waves at lower frequencies. To improve the 28 GHz microwave coupling in VENUS, a TE01-HE11 mode conversion system has been built to test launching HE11 microwave power into the plasma chamber. The HE11 mode is a quasi-Gaussian, linearly polarized mode, which should couple strongly to the plasma electrons. The mode conversion is done in two steps. First, a 0.66 m long "snake" converts the TE01 mode to the TE11 mode. Second, a corrugated circular waveguide excites the HE11 mode, which is launched directly into the plasma chamber. The design concept draws on the development of similar devices used in tokamaks and stellerators. The first tests of the new coupling system are described below.

Production of high intensity 48Ca for the 88-Inch Cyclotron and other updates.

Recently the Versatile ECR for NUclear Science (VENUS) ion source was engaged in a 60-day long campaign to deliver high intensity (48)Ca(11+) beam to the 88-Inch Cyclotron. As the first long term use of VENUS for multi-week heavy-element research, new methods were developed to maximize oven to target efficiency. First, the tuning parameters of VENUS for injection into the cyclotron proved to be very different than those used to tune VENUS for maximum beam output of the desired charge state immediately following its bending magnet. Second, helium with no oxygen support gas was used to maximize the efficiency. The performance of VENUS and its low temperature oven used to produce the stable requested 75 eµA of (48)Ca(11+) beam current was impressive. The consumption of (48)Ca in VENUS using the low temperature oven was checked roughly weekly, and was found to be on average 0.27 mg/h with an ionization efficiency into the 11+ charge state of 5.0%. No degradation in performance was noted over time. In addition, with the successful operation of VENUS the 88-Inch cyclotron was able to extract a record 2 pµA of (48)Ca(11+), with a VENUS output beam current of 219 eµA. The paper describes the characteristics of the VENUS tune used for maximum transport efficiency into the cyclotron as well as ongoing efforts to improve the transport efficiency from VENUS into the cyclotron. In addition, we briefly present details regarding the recent successful repair of the cryostat vacuum system.

Concept for a fourth generation electron cyclotron resonance ion source.

A fourth generation electron cyclotron resonance ion source with an operating frequency between 40 and 56 GHz has the potential to quadruple the heavy-ion beam currents and provide a cost effective upgrade path for heavy ion drivers in use or in the planning stage at radioactive beam facilities. Design studies show it is feasible to produce the required magnetic fields in the plasma chamber, 7 T axially and 4 T in the radial direction with a magnetic structure using commercially available Nb(3)Sn superconducting materials. In this paper we describe the design of such a magnet structure including a 3D analysis of the Lorentz forces generated by the magnetic fields and the necessary clamping structure to stabilize the conductor against these forces.

Recent progress on the superconducting ion source VENUS.

The 28 GHz Ion Source VENUS (versatile ECR for nuclear science) is back in operation after the superconducting sextupole leads were repaired and a fourth cryocooler was added. VENUS serves as an R&D device to explore the limits of electron cyclotron resonance source performance at 28 GHz with its 10 kW gryotron and optimum magnetic fields and as an ion source to increase the capabilities of the 88-Inch Cyclotron both for nuclear physics research and applications. The development and testing of ovens and sputtering techniques cover a wide range of applications. Recent experiments on bismuth demonstrated stable operation at 300 eµA of Bi(31+), which is in the intensity range of interest for high performance heavy-ion drivers such as FRIB (Facility for Rare Isotope Beams). In addition, the space radiation effects testing program at the cyclotron relies on the production of a cocktail beam with many species produced simultaneously in the ion source and this can be done with a combination of gases, sputter probes, and an oven. These capabilities are being developed with VENUS by adding a low temperature oven, sputter probes, as well as studying the RF coupling into the source.

Allergic responses induced by goat milk αS1-casein in a murine model of gastrointestinal atopy.

Up to 3% of young children develop milk allergy and this may influence the development of immune-mediated diseases in later life. One protein that has been associated with allergic reactions to ruminant milk is α(S1)-casein (CN). Studies suggest that goat milk with low levels of α(S1)-CN may reduce allergenicity of milk, but the dose response to α(S1)-CN has not been confirmed. In this study, we examined the immune response to varying levels of goat α(S1)-CN in a mouse model of gastrointestinal allergy. BALB/c mice (aged 5 wk) were given intraperitoneal injections with α(S1)-CN and aluminum as adjuvant at 1 and 3 wk to sensitize mice to the antigen. In wk 5, groups of fasting mice (n=8/group) were challenged 4 times on alternate days by intragastric gavage with saline or 2, 10, or 20mg of α(S1)-CN. Serum levels of specific IgE, IgG(1), and IgG(2a) antibodies and mouse mast cell protease-I were determined. Interleukin-4, IL-10, and IFN-γ responses to 48-h activation with antigen were measured in cultured splenocytes. We determined that mice sensitized with α(S1)-CN had higher titers of specific IgG(1) and IgE antibodies compared with controls; however, groups challenged with differing doses of α(S1)-CN did not differ. The group challenged with the highest dose of α(S1)-CN had a 10-fold increase in mouse mast cell protease-I compared with the group challenged with saline. Both IL-4 and IL-10 were produced in a dose-dependent manner by cultured splenocytes incubated with α(S1)-CN. Overall, α(S1)-CN stimulated the production of cytokines associated with allergic disease in a dose-dependent manner. Thus, milk with lower levels of α(S1)-CN should contribute to a lesser antigenic burden.

A polymorphism of NADPH oxidase p22 phox is associated with reduced susceptibility to acute rejection in renal allograft recipients.

BACKGROUND: Reactive oxygen species (ROS) such as superoxide (O(2)(-)) play important roles in inflammatory processes. By altering the redox environment, ROS modulate the activation of transcription factors and cytokine genes involved in acute cellular rejection. The NAD(P)H oxidase is a multi-subunit enzyme present in leucocytes and endothelial cells, and is a key source of O(2)(-). 3 single nucleotide polymorphisms (SNPs) of the p22 phox subunit were investigated in a large cohort of renal allograft recipients. METHODS: The C242T, A640G and A-930G SNPs were studied in 244 Caucasian patients with end stage renal failure (ESRF) (148 renal allograft recipients and 96 dialysis patients) using standard PCR. Acute rejection was diagnosed by renal biopsy in 66 allograft recipients (44.6%). Normal controls were DNA samples extracted from 131 umbilical cord bloods following uncomplicated obstetric delivery. RESULTS: A highly significant increase in the frequency of the T242 allele in patients with ESRF compared to controls (31.3% vs 16.7%, p<0.0001) and in allograft recipients without acute rejection compared to those with rejection (37.8% vs 27.3%, p<0.0001) was demonstrated. CONCLUSION: These results show that the T242 allele may predispose to the development of ESRF, but paradoxically reduce susceptibility to acute rejection through reduced NAD(P)H oxidase activity.

Effects on adhesion molecule expression and lymphocytes in the bovine mammary gland following intra-mammary immunisation.

Changes to adhesion molecule expression and lymphocyte populations were evaluated in alveolar mammary tissue collected from cows following an immunisation protocol that involved intra-mammary inoculation to induce an IgA response in mammary secretions. The right quarters of the udder were immunised; the left side acted as a control. Antibody titres in secretions showed that at least two animals responded with antigen-specific IgA. Numbers of T-lymphocytes were 4-fold higher in immunised glands compared with controls (P<0.05). IgA-, IgM- and IgG-positive cell numbers were significantly higher (P<0.01) in immunised glands compared with controls in three of the four cows. No mucosal addressin molecule-1 (MAdCAM-1), vascular cell-adhesion molecule-1 (VCAM-1) or peripheral node addressin (PNAd) protein expression was detected on smaller venules that stained positively for von Willebrand factor in alveolar mammary tissues, from either immunised or control glands. Both VCAM-1 and PNAd were detected on smaller venules in supramammary lymph nodes, however, there was no significant difference between immunised and control glands. Quantification of MAdCAM-1 mRNA showed very low expression in both immunised and control alveolar tissue compared with Peyer's patch positive-control tissue. These findings suggest that the bovine mammary gland is capable of a mucosal antibody response; however, MAdCAM-1 is not involved with lymphocyte homing to the mammary gland in this species.

Immune components of bovine colostrum and milk.

Colostrum and milk provide a complete diet for the neonate. In ruminants, colostrum is also the sole source of initial acquired immunity for the offspring. Milk therefore plays an important role in mammalian host defense. In colostrum, the concentration of immunoglobulins is particularly high, with IgG being the major immunoglobulin class present in ruminant milk, in contrast to IgA being the major immunoglobulin present in human milk. Immunoglobulins are transported into mammary secretions via specialized receptors. In addition to immunoglobulins, both colostrum and milk contain viable cells, including neutrophils and macrophages, which secrete a range of immune-related components into milk. These include cytokines and antimicrobial proteins and peptides, such as lactoferrin, defensins, and cathelicidins. Mammary epithelial cells themselves also contribute to the host defense by secreting a range of innate immune effector molecules. A detailed understanding of these proteins and peptides offers great potential to add value to the dairy industry. This is demonstrated by the wide-ranging commercial applications of lactoferrin derived from bovine milk. Knowledge of the immune function of milk, in particular, how the gland responds to pathogens, can be used to boost the concentrations of immune factors in milk through farm management practices and vaccination protocols. The latter approach is currently being used to maximize yields of bovine milk-derived IgA directed at specific antigens for therapeutic and prophylactic use. Increasingly sophisticated proteomics technologies are being applied to identify and characterize the functions of the minor components of milk. An overview is presented of the immune factors in colostrum and milk as well as the results of research aimed at realizing this untapped value in milk.

Adhesion molecule expression in the bovine mammary gland.

The bovine mammary gland requires lymphocytes for immune protection of the gland from foreign pathogens and, in addition, to transfer immune protection to the neonate via colostrum and milk. The process of homing primed lymphocytes to tissues is mediated by the interaction of cell-adhesion molecules displayed on the surface of lymphocytes and counter receptors displayed on the vascular endothelium. This study was conducted to identify the cell-adhesion molecules involved in homing lymphocytes to the bovine mammary gland at four different physiological stages; pregnant, colostral, lactation and involution. The expression and distribution of adhesion molecules in alveolar tissues and supramammary lymph nodes from the mammary glands of healthy cows was determined in situ by immunohistochemical analysis and compared with bovine Peyer's patch, used as a typical mucosal-associated lymphoid tissue and positive control. The mucosal addressin molecule, MAdCAM-1, was not detected in bovine mammary tissues at any of the four different physiological stages. Absence of MAdCAM-1 expression was verified by quantitative real-time RT-PCR analysis. Transcription levels of MAdCAM-1 mRNA were found to be more then 5 x 10(3)-fold lower in mammary alveolar tissues compared with bovine Peyer's patch tissues. In contrast to MAdCAM-1, phase-dependent protein expression of VCAM-1 was detected in both mammary alveolar tissues and the supramammary lymph nodes, with the highest expression observed in colostral phase cows. The protein expression in mammary alveolar tissues was limited to larger venules, although in colostral phase cows, VCAM-1 was also detected around the alveoli perimeter. In the supramammary lymph node, VCAM-1 protein was observed on both small and large venules. PNAd was detected in supramammary lymph nodes at all physiological stages of the mammary gland; however, it was not found in mammary alveolar tissues. Lymphocytes expressing beta7 were not detected in mammary tissues and lymphocytes expressing CD62L were only observed in the supramammary lymph nodes. Overall the data suggest that MAdCAM-1 and VCAM-1 are not involved in homing lymphocytes to the bovine mammary gland; whereas, VCAM-1 and PNAd may have this role in the supramammary lymph node.

A multicentre, randomised trial examining the effect of test procedures measuring emergence from post-traumatic amnesia.

BACKGROUND: Post-traumatic amnesia (PTA) tests that record different PTA durations in the same patient, thereby raising measurement accuracy issues, have been reported previously. A major problem lies in determining the end point of PTA. AIMS: To delineate areas of discrepancy in PTA tests and to provide independent verification for a criterion signalling emergence from PTA. METHODS: In a randomised design, two related PTA procedures were compared, one purportedly more difficult (Westmead PTA Scale, WPTAS) than the other (Modified Oxford PTA Scale, MOPTAS). Eighty two patients in the early stages of PTA were examined daily until emergence, by using the Galveston Orientation and Amnesia Test (GOAT) and the WPTAS/MOPTAS. A short battery of cognitive and behavioural measurements was made on three occasions: at the early stage of PTA (time 1), towards the end of PTA when the maximum score (12/12) was first obtained (time 2) and at the traditional criterion for emergence (scoring 12/12 for 3 consecutive days; time 3). RESULTS: No significant difference was recorded in PTA duration between the MOPTAS and WPTAS. Both scales recorded longer PTA durations than the GOAT. By using Kaplan-Meier survival analyses, the WPTAS was found to show a more protracted pattern of emergence at the end stage of PTA than the MOPTAS. A time lag of > or = 1 week in the resolution of disorientation as compared with amnesia was observed in 59% cases. Significant improvements occurred on all independent measurements between time 1 and time 2, but on only 2 of 5 cognitive measurements between time 2 and time 3. CONCLUSIONS: Although no significant differences in the duration of PTA on the MOPTAS/WPTAS were recorded, emergence from the late stages of PTA occurred more promptly with the MOPTAS. The need for inclusion of both orientation and memory items in PTA tests is highlighted by the frequency of disorientation-amnesia dissociations. The patterns of results on the independent measures suggest that patients who are in PTA for > 4 weeks have probably emerged from PTA when they first score 12/12 on the MOPTAS/WPTAS, and this criterion can replace the traditional criterion.

A novel polymorphism in the 5' flanking region of the glucose transporter (GLUT1) gene is strongly associated with diabetic nephropathy in patients with Type 1 diabetes mellitus.

Glucose transporter 1 (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. Recent studies have suggested that polymorphisms in the GLUT1 gene are associated with susceptibility to diabetic nephropathy (DN) in patients with diabetes mellitus. In this study, a novel polymorphism (A-2841T) in the 5' flanking region of GLUT1 was examined in 288 patients with Type 1 diabetes mellitus (T1DM) and 101 normal controls. The polymorphisms were amplified and the fragment digested with the enzyme HpyCH4V. There was a highly significant increase in the frequency of the TT-2841 genotype in patients with nephropathy (n=131) compared with those with either no microvascular complications after a 20-year duration of diabetes (uncomplicated; n=72; 54.5% vs. 2.7%, chi=79.4, P<.000001). There was no difference between the uncomplicated group and those who only had retinopathy (n=50; 2.7% vs. 4.0%, respectively). The frequency in recently diagnosed patients was 17.1% and only 2.0% in normal controls. In contrast, the AA genotype was found in 13.6% of the nephropaths, 76.3% of uncomplicated, 48.0% of retinopaths, and 65% of normal controls. These results confirm previous reports of an association between the GLUT1 gene and susceptibility to DN but not retinopathy. The localisation of this polymorphism suggests that it may be involved in the expression of the gene.

Social, neuroradiologic, medical, and neuropsychologic correlates of sexually aberrant behavior after traumatic brain injury: a controlled study.

OBJECTIVE: To identify social, neuroradiological, medical, and neuropsychological correlates of sexually aberrant behavior (SAB) after traumatic brain injury (TBI). DESIGN: A controlled study using a retrospective file review. SETTING: A brain injury unit providing inpatient and outpatient rehabilitation services. PARTICIPANTS: A sample of males (n = 25) exhibiting SABs and a control group (n = 25) matched for gender, severity of injury, age at injury, and time after injury. MAIN OUTCOME MEASURES: A protocol that recorded data on demographic, injury, radiological, medical, and neuropsychological variables. RESULTS: The SAB group had a significantly higher incidence of postinjury psychosocial disturbance in areas of nonsexual crime and failure to return to work than the matched TBI group. There were no significant differences between the two groups in the incidence of premorbid psychosocial disturbance or postinjury radiological, medical, or neuropsychological variables. CONCLUSIONS: The study results caution against simplistic explanations of SAB as the product of damage to the frontal-lobe systems or premorbid psychosocial disturbance. Furthermore, the results suggest that a wide-ranging assessment of people with TBI who exhibit SABs is required, because results of neuropsychological examination alone cannot be considered conclusive. Future research into the etiology of SABs could examine additional factors such as lack of insight, lack of empathy, and premorbid history of family dysfunction.

NFkappaB polymorphisms and susceptibility to type 1 diabetes.

Nuclear factor kappa B (NFkappaB) is an important transcription factor that is involved in the response to oxidative stress and inflammation. Recent studies suggest that it may be involved in the development of diabetic microvascular complications. A highly polymorphic (CA) dinucleotide repeat microsatellite has been identified in the regulatory region of the NFkappaB gene. The aim of this study was to investigate whether this polymorphic region was associated with susceptibility to type 1 diabetes, or its late complications. Genomic DNA was extracted from the peripheral blood of 217 patients with type 1 diabetes mellitus (T1DM) and 111 normal healthy controls. In our population 18 alleles (A1-A18) were identified. There was a highly significant decrease in the frequency of allele 146 bp (A14) in type 1 diabetes (0.03) compared with the normal controls (0.28) (chi(2) = 79.8, Pc = 0.00001). In contrast, the frequency of the allele 138 bp (A10) was significantly increased in patients with type 1 diabetes (0.17) compared with the normal controls (0.02) (chi(2) = 32.8, P < 0.00000). These results demonstrate that the NFkappaB gene may play a role in the susceptibility to type 1 diabetes: individuals with the A10 allele may be more likely to develop diabetes compared with the A14 allele.

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.

BACKGROUND: Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose. METHODS: PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay. RESULTS: ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007). CONCLUSION: These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.

Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of morbidity and mortality in patients with type 1 diabetes mellitus. Recent studies suggest that genetic factors, including polymorphisms in the flanking region of the aldose reductase gene (5'ALR2), play an important role in the pathogenesis of nephropathy. Glucose transporter (GLUT1) activity has been implicated in renal hypertrophy and extracellular matrix formation in mesangial cells. The aim was to investigate the frequency of a polymorphism within the GLUT1 gene in 186 Caucasoid patients with type 1 diabetes and 104 normal controls. METHODS: Amplimers flanking the Xba-I polymorphic site in the second intron were employed to amplify DNA from subjects. The amplified DNA was restricted with endonuclease Xba-I, separated by gel electrophoresis, and visualized. In the absence of an Xba-I site, a fragment of 1.1 kilobase was seen, whereas fragments of 0.9 and 0.2 were generated if the Xba-I site was present. RESULTS: There was a highly significant increase in the frequency of the 1.1 allele in those patients with nephropathy (N = 70) compared with those with no proteinuria or retinopathy after 20 years of diabetes (uncomplicated N = 44, 61.4 vs. 40.9%, respectively, P < 0.001). The 1.1/1.1 genotype was also significantly increased in the nephropathy group compared with the uncomplicated group of patients (37.1 vs. 13.6%, respectively, P < 0.01). The frequency of the 1.1/1.1 genotype was similar in 30 patients with retinopathy but not nephropathy when compared with the uncomplicated group of patients (13.6 vs. 16.7%). Furthermore, only 8 out of 49 patients with DN had the Z+2 5'ALR2 DN "protective" allele and the 0.9 GLUT1 allele in contrast to 21 out of 39 uncomplicated patients (P < 0.0002). CONCLUSION: These results suggest that the GLUT1 gene together with the aldose reductase gene are associated with susceptibility to DN in patients with type 1 diabetes.