Space-charge transport limits of ion beams in periodic quadrupole focusing channels

It has been empirically observed in both experiments and particle-in-cell simulations that space-charge-dominated beams suffer strong growth in statistical phase-space area (degraded quality) and particle losses in alternating gradient quadrupole transport channels when the undepressed phase advance sigma_0 increases beyond about 85 degrees per lattice period. Although this criterion has been used extensively in practical designs of strong focusing intense beam transport lattices, the origin of the limit has not been understood. We propose a mechanism for the transport limit resulting from classes of halo particle resonances near the core of the beam that allow near-edge particles to rapidly increase in oscillation amplitude when the space-charge intensity and the flutter of the matched beam envelope are both sufficiently large. When coupled with a diffuse beam edge and/or perturbations internal to the beam core that can drive particles outside the edge, this mechanism can result in large and rapid halo-driven increases in the statistical phase-space area of the beam, lost particles, and degraded transport. A core-particle model is applied to parametrically analyze this process. Extensive self-consistent particle in cell simulations are employed to better quantify space-charge limit and verify core-particle model predictions.Comment: 17 pages, 5 figures. Submitted to Nuclear Instruments and Methods A. Includes a long version of a conference talk (trans_limits_talk.pdf) presented on the topic at the "Coulomb'05 -- High Intensity Beam Dynamics" workshop (Senigallia, Italy, 12-16 September 2005). This talk presents further supporting information/plots not included in the abbreviated, draft-format manuscrip

MOE11 Emittance Growth from the Thermalization of Space-Charge Nonuniformities

Beams injected into a linear focusing channel typically have some degree of space-charge nonuniformity. In general, injected particle distributions with systematic charge nonuniformities are not equilibria of the focusing channel and launch a broad spectrum of collective modes. These modes can phase-mix and have nonlinear wave-wave interactions which, at high space-charge intensities, results in a relaxation to a more thermal-like distribution characterized by a uniform density profile. This thermalization can transfer self-field energy from the initial space-charge nonuniformity to the local particle temperature, thereby increasing beam phase space area (emittance growth). In this paper, we employ a simple kinetic model of a continuous focusing channel and build on previous work that applied system energy and charge conservation quantify emittance growth associated with the collective thermalization of an initial azimuthally symmetric, rms matched beam with a radial density profile that is hollowed or peaked. This emittance growth is shown to be surprisingly modest even for high beam intensities with significant radial structure in the initial density profile.Comment: Paper MOE11, XX International Linac Conference, Monterey, CA 21-25 August 2000 3 pages, 3 figure

Efficient computation of matched solutions of the Kapchinskij-Vladimirskij envelope equations for periodic focusing lattices

A new iterative method is developed to numerically calculate the periodic, matched beam envelope solution of the coupled Kapchinskij-Vladimirskij (KV) equations describing the transverse evolution of a beam in a periodic, linear focusing lattice of arbitrary complexity. Implementation of the method is straightforward. It is highly convergent and can be applied to all usual parameterizations of the matched envelope solutions. The method is applicable to all classes of linear focusing lattices without skew couplings, and also applies to all physically achievable system parameters -- including where the matched beam envelope is strongly unstable. Example applications are presented for periodic solenoidal and quadrupole focusing lattices. Convergence properties are summarized over a wide range of system parameters.Comment: 20 pages, 5 figures, Mathematica source code provide

Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals.

HIV-specific CD8+ T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8+ T cells were almost exclusively TIGIT+, had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIThi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4+ T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8+ T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future "cure" strategies requiring potent HIV-specific CD8+ T cells

Transverse centroid oscillations in solenoidially focused beam transport lattices

Linear equations of motion are derived that describe small-amplitude centroid oscillations induced by displacement and rotational misalignments of the focusing solenoids in the transport lattice, dipole steering elements, and initial centroid offset errors. These equations are analyzed in a local rotating Larmor frame to derive complex-variable"alignment functions" and"bending functions" that efficiently describe the characteristics of the centroid oscillations induced by mechanical misalignments of the solenoids and dipole steering elements. The alignment and bending functions depend only on properties of the ideal lattice in the absence of errors and steering and have associated expansion amplitudes set by the misalignments and steering fields. Applications of this formulation are presented for statistical analysis of centroid deviations, calculation of actual lattice misalignments from centroid measurements, and optimal beam steering

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

PurposeAbnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change.MethodsIn addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.ResultsOver treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.ConclusionIntrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome

Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

<p>Abstract</p> <p>Background</p> <p>Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients.</p> <p>Methods</p> <p>As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD. Due to genotypic variations in the chitotriosidase gene, these were also evaluated.</p> <p>Results</p> <p>We document elevations in chitotriosidase activity in the plasma of patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs. controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n = 16, median 0 ng/mL/hr, p < 0.0001). In addition, activity levels of plasma and CSF chitotriosidase prior to transplant correlated with progression as determined by the Moser/Raymond functional score 1 year following transplantation (p = 0.002 and < 0.0001, respectively).</p> <p>Conclusions</p> <p>These findings confirm elevation of chitotriosidase activity in patients with active C-ALD, and suggest that these levels predict prognosis of patients with C-ALD undergoing transplantation.</p