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PubMed1991

Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy.

UNLABELLED: LBNF1 cardiac allografts (Tx) are rejected within 36 hr in LEW rats sensitized with BN skin Tx 7 days earlier, compared to 8-day rejection in unmodified hosts. Treatment with cyclosporine or ART-18, an anti-interleukin 2 receptor (IL-2[R]) mAb monoclonal antibody, abrogates accelerated rejection and prolongs mean Tx survival to 42 days and 16 days, respectively. ART-18 given in concert with subtherapeutic dose of CsA extends survival to 25 days. These studies were designed to dissect the early mechanisms leading to ART-18 and/or CsA-mediated abrogation of accelerated Tx injury. No effect of concomitant mAb administration upon CsA through levels was noted in Tx recipients conditioned with both modalities. The beneficial effect of ART-18+CsA treatment was also unrelated to CsA-induced diminished host responses to mAb, as shown by ELISA. In the biodistribution studies 125I-labeled ART-18 accumulated preferentially into host lymphoid tissues and Tx itself and away from the blood. In animals that were concomitantly given "cold" CsA, the clearance of labeled ART-18 from the blood increased further, as did mAb sequestration into the Tx. The sensitized hosts developed high titers of complement-dependent cytotoxic (CDC) antibodies, which peaked at the time of actual Tx loss. ART-18 or CsA alone inhibited CDC, whereas combined therapy decreased further the humoral effects of sensitization. The cell-mediated lymphocytotoxicity assay revealed a similar pattern. CsA, ART-18, and combination therapy each modulated the deposition of IgG, IgM, and C3 in Tx, as shown by immunohistology. However, only CsA or ART-18+CsA therapy abolished or markedly decreased elaboration of IL-2, interferon gamma, and tissue necrosis factor alpha. IN CONCLUSION: (1) the adjunctive low dose of CsA potentiates the inhibitory effects of ART-18 upon humoral and cellular responses, leading to accelerated rejection of cardiac Tx in presensitized rats; (2) the synergistic interaction between both modalities that results in the inhibition of lymphokine production is critical and correlates with long-term Tx survival; (3) the biodistribution patterns of mAb are important--an increased blood level of mAb does not necessarily translate into its higher therapeutic efficacy.

Animals↗

PubMed1992

Maturing thymocytes in accelerated rejection of cardiac allografts in presensitized rats.

LBNF1 cardiac allografts are rejected within 36 hr in LEW rats sensitized with BN skin grafts 7 days earlier (acute rejection in unmodified hosts = 8 days). We have studied and compared the function and migration patterns of thymocytes one day after engraftment in sensitized recipients, unmodified hosts, and normal naive rats. Thymocytes from animals experiencing accelerated rejection were more mature and functionally active, as shown by a significant elevation in percentage of OX-44+ (CD37+) cells, increased alloreactivity to BN and WF antigens, and proliferative responses to Con A and exogenous IL-2. However, the cells could neither lyse BN targets in vitro nor trigger rejection of otherwise indefinitely functioning test cardiac allografts in immunologically unresponsive T cell-deficient (B) rats after adoptive transfer. The traffic of 111In-labeled thymocytes was then evaluated. The migration index increased significantly during accelerated graft rejection, with thymocytes preferentially circulating in the blood, penetrating peripheral lymph nodes--and, interestingly, migrating back to the thymus. Thus, immunoresponsive and functionally active thymocytes, which lack the ability to recognize primed specific antigen, appear during accelerated rejection of cardiac allografts in sensitized rats. These cells migrate to the periphery, and then return in large numbers to their site of origin, the thymus. Hence, this study describes a novel behavior of thymocytes in the state of host alloreactivity that is distinct from the physiological one in otherwise normal thymus.

Animals↗

PubMed1993

Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation.

We studied the mechanisms by which oral or intravenous administration of allogeneic splenocytes prevents sensitization by skin allografts and development of accelerated rejection of subsequent cardiac allografts. LEW rats were sensitized with BN skin allografts 7 days prior to receiving heterotopic (LEW x BN)F1 vascularized cardiac allografts. While unsensitized cardiac allografts are rejected on days 6-8, control sensitized grafts were rejected within 24 to 48 hr. Oral administration of BN splenocytes during the sensitization phase (between skin and heart grafting) has been found to prevent accelerated allograft rejection and prolong cardiac allograft survival to 7 days. An alternative route of antigen exposure, specifically intravenous administration of BN splenocytes (50 x 10(6) daily for 5 days starting on the day of skin grafting), also prevented accelerated cardiac allograft rejection and prolonged allograft survival to 9 +/- 1 days (n = 5). Immunoperoxidase studies of cardiac allografts harvested 24-48 hr posttransplant showed that, when compared with sensitized controls, animals that received oral splenocytes had reduced deposition of IgG (end-point titer of 1/1000 vs. 1/4000), IgM (1/1000 vs. 1/16000), C3 (1/4000 vs. 1/16000), and fibrin (1/4000 vs. 1/16000). There was also decreased infiltration by macrophages (18 +/- 8 vs. 37 +/- 8 cells/HPF, P < 0.01), T cells (5 +/- 3 vs. 19 +/- 7, P < 0.01), and IL-2R+ T cells (5 +/- 3 vs. 15 +/- 4, P < 0.01), and a significant reduction in the numbers and extent of intragraft mononuclear cells stained with antibodies to IL-1, IL-2, IL-6, IL-8, IFN-gamma, and TNF-alpha. In contrast, these grafts showed markedly increased IL-4 staining (including most mononuclear and all endothelial cells), as compared with control grafts (< 20% of mononuclear cells and only focal endothelial staining). Immunoperoxidase studies of cardiac allografts harvested from rats receiving intravenous splenocytes also showed markedly reduced humoral deposits and cellular infiltrates, comparable to that found in the oral splenocytes-treated group, but showed significantly different cytokine expression. In particular, some intragraft mononuclear cell labeling for IFN-gamma remained, and IL-4 staining was not increased relative to control grafts. Attempts were then made to abrogate spleen cell-induced prolongation of cardiac allograft survival by daily injections of CD4 monoclonal antibody (BWH-4 mAb, 700 micrograms) from the time of cardiac transplantation, therapy previously shown unable to prolong cardiac survival in this model when commenced after skin graft-induced sensitization has occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1994

Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion.

This study evaluated the efficacy and mode of action of rapamycin (RPM) in a model of accelerated (24-hr) rejection of LBNF1 cardiac allografts in specifically sensitized LEW rats. RPM treatment (0.25 mg/kg/day i.p.) between the day of sensitizing skin grafts (day -7) and subsequent heart (day 0) transplantation (Tx), abrogated fulminant rejection and prolonged cardiac allograft survival to 46 +/- 22 days (mean +/- SD, P < 0.0001). The delayed introduction of RPM until day -2 or day -1 was equally effective, whereas treatment initiated after cardiac Tx was ineffectual. Untreated accelerated rejection was associated with strong production of circulating IgM, whereas an IgG alloantibody response was not detected until after rejection was complete. RPM therapy (day -7 to -1) diminished this systemic IgM response and prevented the switch from IgM to IgG alloantibody production. Immunohistologic evaluation at 24 hr after cardiac Tx showed that compared with untreated hosts RPM treatment largely abolished intragraft cellularity, and was associated with decreased mononuclear and endothelial cell activation. Specifically, Ia and ICAM-1 upregulation was abolished, and no cells elaborating IL-2 or IFN-gamma were detected. In addition, RPM treatment prevented intragraft production of the proinflammatory cytokines IL-1 beta, IL-6, and IL-8. The effects of RPM therapy on recipient cellular responses were evaluated in vitro by mixed lymphocyte reaction. Surprisingly, the donor-specific proliferative response of cells from RPM-treated hosts at 1 or 7 days after Tx was markedly increased, compared with cells from rejecting, untreated controls, and bioassay of IL-2 within supernatants of MLR cultures showed comparable levels of IL-2 in both groups. The effects of RPM upon adhesion properties of lymph node lymphocytes were also tested in an in vitro binding assay. The binding of naive cells to sections of cardiac allografts collected from RPM-treated hosts at 24 hr post-Tx was decreased compared with that in untreated recipients. Interestingly, the binding of mononuclear cells to high endothelial venules of peripheral lymph nodes in RPM-treated hosts remained relatively high. Thus, treatment with RPM prevents and/or erases the sensitization, which otherwise leads to accelerated allograft rejection. Abrogation of allograft injury by RPM was associated with profound and long-lasting depression of host IgM and IgG alloantibody responses in the circulation, and selective downregulation of host cellular immunity and endothelial activation at the graft site. In contrast, antigen alloreactivity and endothelial adhesivity in peripheral lymphoid tissues were spared, indicating novel and potent selective effects of RPM therapy in allograft recipients.

Animals↗

PubMed1997

T cell-dependent acceleration of chemoattractant cytokine gene expression during secondary rejection of allogeneic skin grafts.

Chemoattractant cytokines, chemokines, are likely to play a critical role in directing leukocytes to graft sites and in amplifying intragraft inflammation during rejection. Since second-set graft rejection occurs at an accelerated rate, we hypothesized that chemokine genes would be expressed earlier during secondary allograft rejection than during rejection of primary allografts. We have tested this hypothesis by using Northern blot analysis to compare intragraft expression levels of genes encoding interleukin (IL) 1beta and six chemokines during rejection of C57BL/6 skin grafts on naive and C57BL/6-sensitized BALB/c recipients. Expression levels of IL-1beta, interferon-gamma inducible protein, macrophage inflammatory protein-1 (MIP-1) alpha, and MIP-1beta genes were 10- to 17-fold higher on day 5 after transplantation in C57BL/6 grafts on C57BL/6-presensitized recipients than in C57BL/6 grafts on unprimed recipients. Intragraft expression of the chemokines regulated upon activation, normal T cell expressed and secreted (RANTES), during primary C57BL/6 graft rejection was virtually undetectable at day 7 after primary transplantation, but was expressed at high levels by day 5 after secondary transplantation. In third-party CBA/Ca allografts on unsensitized and C57BL/6-presensitized BALB/c mice, similar levels of IL-1beta, MIP-1alpha, and MIP-1beta expression were observed. High levels of RANTES and interferon-gamma inducible protein expression, however, were observed at day 5 after transplantation in CBA/Ca grafts on C57BL/6-presensitized recipients and correlated with accelerated rejection of the third-party grafts. Although T cells from C57BL/6-presensitized recipients did not express increased reactivity to CBA/Ca stimulator cells in vitro, serum antibodies from these recipients demonstrated reactivity to cells from CBA/Ca and A/J mice. When compared with transfer of unprimed cells, transfer of C57BL/6-primed lymphoid cells to sublethally irradiated BALB/c mice engrafted with C57BL/6 grafts resulted in increased intragraft proinflammatory cytokine gene expression. Deletion of T cells before transfer abrogated the increased intragraft expression of proinflammatory cytokine genes. Collectively, these results indicate that the accelerated expression of chemokine genes during second-set rejection of allogeneic skin grafts is mediated by immune T cells.

Animals↗

PubMed2002

Elimination of donor-specific alloreactivity prevents cytomegalovirus-accelerated chronic rejection in rat small bowel and heart transplants.

BACKGROUND: The primary cause for late failure of vascularized allografts is chronic rejection (CR) characterized by transplant vascular sclerosis (TVS). Cytomegalovirus (CMV) infection accelerates TVS and CR by unclear mechanisms involving direct effects of CMV, indirect effects of the recipient's immune response to CMV, or interactions between CMV and the recipient's alloreactivity. This study examined the role of CMV and the alloreactive response in the development of TVS using bone marrow chimerism (BMC) in rat small bowel (SB) and heart transplantation models. METHODS: Fisher 344 (F344) rat heart or SB grafts were transplanted into F344/Lewis bone marrow chimera. F344 heart or SB grafts transplanted into Lewis recipients (low-dose cyclosporine) were positive controls for the development of TVS. Lewis heart or SB grafts transplanted into Lewis recipients (+/-cyclosporine) were transplantation controls. The effect of rat CMV (RCMV) (5x105 plaque-forming units) on TVS (neointimal index, NI) and graft survival was studied in these groups. RCMV infection was assessed by serologic analysis and quantitative polymerase chain reaction techniques (TaqMan). RESULTS: RCMV infection accelerated the time to graft CR (SB 70-38 days; hearts 90-45 days) and increased the severity of TVS in both the SB allografts (day 38, NI=27 vs. 52) and the heart allografts (day 45, NI=43 vs. 83). Grafts from CMV-infected syngeneic recipients failed to develop TVS and CR. Donor-specific tolerance induced by BMC prevented allograft TVS and CR in both transplant models. In contrast to naïve Lewis recipients, RMCV infection failed to cause allograft TVS and CR in bone marrow (BM) chimeras. CONCLUSIONS: The events in CMV-induced acceleration of TVS involve a crucial interplay between CMV infection and the recipient's alloreactive immune response.

Animals↗

PubMed1994

Coronary endothelial function in cardiac transplant recipients with accelerated coronary disease.

BACKGROUND: Previous studies with the endothelium-dependent vasodilator substance P have shown a preserved vasodilator response in cardiac transplant recipients with angiographically normal coronary arteries. Although endothelial dysfunction is known to occur in cardiac transplant recipients with accelerated coronary disease, the degree to which the endothelium is affected is not known precisely. The aim of the present study was to examine endothelial function in accelerated coronary disease following cardiac transplantation. METHODS: Thirteen cardiac transplant recipients with epicardial coronary disease underwent substance P infusion. The response to incremental doses of substance P was measured in smooth segments of affected coronary arteries. Substance P was infused over 2 min with a starting dose of 1.4 pmol/min and a maximum of 22.4 pmol/min, reached by doubling the dose in steps, followed by an infusion of 2 mg isosorbide dinitrate over 2 min. RESULTS: Substance P caused less vasodilation at lower concentrations, with a significantly higher dose required to achieve half maximal dilation compared with cardiac transplant recipients with no coronary disease. The mean maximal dilatation achieved with substance P was 22.98 +/- 4.62% compared to 21.95 +/- 4.9% with isosorbide dinitrate; the latter value was not significantly different from the maximal dilation achieved in cardiac transplant recipients without coronary disease. CONCLUSIONS: In cardiac transplant recipients with accelerated coronary disease the functional vasodilatory ability of the coronary endothelium is impaired in segments of apparently unaffected epicardial arteries, which may lead to an increase in the resting vasoconstrictor tone and have important functional and therapeutic implications.

Adult↗

PubMed2001

Accelerated chronic endothelial cell loss after penetrating keratoplasty in glaucoma eyes.

PURPOSE: Accelerated chronic endothelial cell loss may be the main reason for limited prognosis of penetrating corneal grafts in glaucoma eyes. This hypothesis, however, has not yet been proven and is examined in this article. METHODS: Three groups of normal-risk keratoplasty patients were followed up prospectively. Group I consisted of 172 patients (without glaucoma history and without postoperative increase in intraocular pressure), group II comprised 15 patients (with glaucoma history, but without postoperative increase in intraocular pressure), and group III consisted of seven patients (with glaucoma history and with postoperative increase in intraocular pressure). Immune reactions in the postoperative course were an exclusion criterion. Follow-up periods averaged 2.7 +/- 1.7 years (group I), 2.8 +/- 1.7 years (group II), and 2.6 +/- 2.0 years (group III). Only patients with at least three postoperative endothelial cell density values were included in the study. Loss of endothelial cells. mm-2. d-1 was derived from the postoperative endothelial values of each patient by calculating the slope of the regression line for each scatterplot of endothelial cell density values plotted against time. RESULTS: During the follow-up period 0.82 +/- 0.97 cells. mm-2. d-1 were lost in group I, 1.01 +/- 1.04 cells. mm-2. d-1 were lost in group II, 2.67 +/- 2.16 cells. mm-2. d-1 were lost in group III (ANOVA and Gabriel post-hoc test: I/II P = 0.82, I/III P < 0.001, II/III P = 0.004). CONCLUSIONS: Postoperative increase in intraocular pressure may be a possible cause for accelerated endothelial cell loss in glaucoma eyes, but this result is tentative because of the small number of patients included in the two glaucoma groups. Confirmation by long-term observation of larger patients groups is desirable. The result implies good control of intraocular pressure after penetrating keratoplasty. Whether this method is the correct means by which to prevent accelerated endothelial cell loss in such eyes must be shown in future studies.

Aged↗

PubMed2003

Acceleration of healing, reduction of fibrotic scar, and normalization of tissue architecture by an angiotensin analogue, NorLeu3-A(1-7).

Angiotensin peptides have been demonstrated to modulate cellular proliferation, angiogenesis, and dermal repair. In this report, the effects of an analogue of the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7) (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models were used to evaluate the normal (rats) and delayed (diabetic mice) healing responses of full-thickness excision wounds and the healing responses of full-thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil, Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor used clinically for the treatment of diabetic ulcers) in accelerating tissue repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and Regranex were statistically significant (n = 5 per group). Full healing was observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1-7) by day 18 after injury, at which time full healing of wounds on placebo-treated or Regranex-treated diabetic mice was not observed. In the rat incision model, accelerated healing and reduced gross appearance of scarification were observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the healing wounds. This action was more pronounced with longer administration of the peptide after injury. In fact, if systemic administration of the peptide (NorLeu3-A(1-7)) was continued during the remodeling phase, then the formation of new adnexal structures at the center of full-thickness excision wounds was observed, with an increase in the appearance of small immature hair follicles at the sites of the excision wounds. The action of this peptide was blocked by the AT receptor antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that this novel angiotensin peptide has the potential to be of benefit in accelerating wound repair and reducing scar formation.

Angiotensin I↗

PubMed2004

Accelerated cutaneous nodulosis during infliximab therapy in a patient with rheumatoid arthritis.

Up to one fourth of patients with rheumatoid arthritis (RA) may have extraarticular findings such as subcutaneous nodules. These are discrete subcutaneous granulomatous nodules located on extensor surfaces, especially of the elbows. Over the past 10 to 15 years, there have been reports of accelerated cutaneous nodulosis in patients receiving methotrexate therapy. Recently, antitumor necrosis factor alpha (anti-TNFalpha) biologic therapy has become commonplace in the management of RA, especially in methotrexate-resistant or toxic patients. There have been recent reports of accelerated nodulosis in patients with RA on etanercept. We describe what we believe is the first case of accelerated cutaneous nodulosis resulting from infliximab anti-TNFalpha therapy in a patient with RA. One year after the initiation of infliximab, with RA in remission, our patient noted the rapid development of rheumatoid nodules of both hands. A biopsy was characteristic of a rheumatoid nodule, revealing palisading granulomas and fibrinoid necrosis.

Journal Article↗

PubMed2026

Exposure to size-specific particulate matter accelerates DNA methylation aging in people with HIV.

BACKGROUND: People with HIV (PWH) face accelerated aging and increased health risks, with DNA methylation age (DNAmAge) as a critical senescence biomarker. Particulate matter is linked to DNAmAge acceleration (DNAmAA) in general population, but its impact in PWH remains unstudied. METHODS: Thirty-two PWH from Wuhan, China, were enrolled in a prospective panel study with follow-up, and each participant underwent at least two repeated measurements during the study period. Portable air quality monitor measured PM 1 , PM 2.5 , and PM 10 exposures 72 h preblood sampling. We analyzed genome-wide DNA methylation in peripheral blood and calculated six AA metrics. Linear mixed-effects and weighted quantile sum regression models evaluated associations between particulate matter exposure and DNAmAA. RESULTS: Significant associations between particulate matter exposure and DNAmAA were observed at various lag windows. For every 10 μg/m 3 increase in 24-h average PM 2.5 , Hannum DNAmAA, Pheno DNAmAA, Grim DNAmAA, SkinBlood DNAmAA, and Elastic DNAmAA increased by 0.266 years [95% confidence interval (CI): 0.035-0.480], 0.421 years (95% CI: 0.032-0.701), 0.336 years (95% CI: 0.073-0.546), 0.295 years (95% CI: 0.021-0.495), and 0.254 years (95% CI: 0.034-0.445), respectively. PM 10 contributed most substantially to the cumulative PM effect on epigenetic AA in the lag0-24 h window. CONCLUSION: Short-term particulate matter exposure, particularly PM 10 , significantly accelerates epigenetic aging in PWH, highlighting the need to integrate air quality management into healthy aging strategies for this vulnerable population.

China↗

PubMed2006

The status and evolution of plasma Wakefield particle accelerators.

The status and evolution of the electron beam-driven Plasma Wakefield Acceleration scheme is described. In particular, the effects of the radial electric field of the wake on the drive beam such as multiple envelope oscillations, hosing instability and emission of betatron radiation are described. Using ultra-short electron bunches, high-density plasmas can be produced by field ionization by the electric field of the bunch itself. Wakes excited in such plasmas have accelerated electrons in the back of the drive beam to greater that 4 G eV in just 10 cm in experiments carried out at the Stanford Linear Accelerator Centre.

Journal Article↗

PubMed2006

Bubble regime of wake field acceleration: similarity theory and optimal scalings.

A similarity theory is developed for ultra-relativistic laser-plasmas. It is used to compare and optimize possible regimes of three-dimensional wake field acceleration. The optimal scalings for laser wake field electron acceleration are obtained analytically. The main message of the present work is that the bubble acceleration regime [see Pukhov A. & Meyer-ter-Vehn J. 2002. Appl. Phys. B74, 355] satisfies these optimal scalings.

Journal Article↗

PubMed1981

Characterization of 3': 5' -cyclic AMP phosphodiesterase in Klebsiella aerogenes and its role in substrate-accelerated death.

Cyclic AMP phosphodiesterase in Klebsiella aerogenes is a soluble cytoplasmic enzyme with an apparent Km of 0.9 mM and a pH optimum of 7.0. It was inhibited by EDTA, Mg2+ and other metal ions. The enzyme activity was inhibited or activated by some nucleotides but not by any metabolite except pyruvate. It was inhibited by the methylxanthines, caffeine, theophylline and methylisobutylxanthine. During starvation or substrate-accelerated death, the enzyme activity remained essentially constant. It is postulated that during substrate-accelerated death the enzyme acts as a drain on the cellular cyclic AMP levels. The cyclic nucleotide concentrations during substrate-accelerated death are proposed to be controlled directly by adenylate cyclase.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

p63 deficiency activates a program of cellular senescence and leads to accelerated aging.

The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.

Aging↗

PubMed2000

Simple model for mixing at accelerated fluid interfaces with shear and compression

A simple model was recently described for predicting linear and nonlinear mixing at an unstable planar interface between two fluids of different density subjected to an arbitrary time-dependent variable acceleration history [J. D. Ramshaw, Phys. Rev. E 58, 5834 (1998)]. Here we generalize this model to include the Kelvin-Helmholtz (KH) instability resulting from a tangential velocity discontinuity delta u, as well as the effects of a uniform anisotropic compression or expansion of the mixing layer as a whole. The model consists of a second-order nonlinear ordinary differential equation of motion for the half-width h of the mixing layer. This equation is derived by combining the wavelength renormalization hypothesis used in the earlier model with a suitable expression for the rate of change of the kinetic energy of the mixing layer. The resulting generalized model contains no additional free parameters, and reduces to the previous model in the absence of tangential velocities and compression. It also reduces in the linear regime to the correct linearized stability equation for an accelerated shear layer with compression [J. D. Ramshaw, Phys. Rev. E 61, 1486 (2000)]. For a pure incompressible KH instability in the nonlinear regime, the model predicts that h = eta magnitude of delta u t, where eta = [alpha(2 - theta)/square root of theta(1 - theta)]square root of rho 1 rho 2/(rho 1 + rho 2), and alpha and theta are parameters appearing in the nonlinear Rayleigh-Taylor and Richtmyer-Meshkov growth laws. For equal densities and the same parameter values previously used to match variable-acceleration experimental data, we find eta = 0.10, in close agreement with experimental data for free shear layers.

Journal Article↗

PubMed2001

Simulation and design of stable channel-guided laser wakefield accelerators.

Most laser wakefield accelerator (LWFA) experiments to date have operated in the self-modulated (SM) regime and have been self-guided. A channel-guided LWFA operating in the standard or resonant regime is expected to offer the possibility of high electron energy gain and high accelerating gradients without the instabilities and poor electron beam quality associated with the SM regime. Plasma channels such as those produced by a capillary discharge have demonstrated guiding of intense laser pulses over distances of several centimeters. Optimizing the performance in a resonant LWFA constrains the on-axis plasma density in the channel to a relatively narrow range. A scaling model is presented that quantifies resonant LFWA performance in terms of the maximum accelerating gradient, dephasing length, and dephasing-limited energy gain. These performance quantities are expressed in terms of laser and channel experimental parameters, clearly illustrating some of the tradeoffs in the choice of parameters. The predicted energy gain in this model is generally lower than that indicated by simpler scaling models. Simulations agree well with the scaling model in both low and high plasma density regimes. Simulations of a channel-guided, self-modulated LWFA are also presented. Compared with the resonant LWFA regime, the requirements on laser and channel parameters in the SM regime are easier to achieve, and a channel-guided SM-LWFA is likely to be less unstable than a self-guided SM-LWFA.

Journal Article↗

PubMed2003

Model of nonlinear kinetic Alfvén waves with dissipation and acceleration of energetic electrons.

The acceleration of energetic electrons has long been one of the most outstanding problems in astrophysics and space physics, and some recent observations from space satellites show that low-frequency electromagnetic fluctuations in the auroral ionosphere and magnetosphere can often be identified as the kinetic Alfvén modes. A model of nonlinear kinetic Alfvén waves is presented here, in which the effect of electron collisional dissipation has been taken into account. The result is a dissipative solitary kinetic Alfvén wave (DSKAW), which can produce a local shocklike structure with a net electric potential drop and which can thereby accelerate efficiently the electrons to the order of the local Alfvén velocity. Since Alfvénic fluctuation is the most common electromagnetic activity in extensive cosmic plasma environments, the present result suggests that the DSKAW could play an important role in the acceleration and energization of cosmic plasmas.

Journal Article↗