Reduction of edge-localized mode intensity using high-repetition-rate pellet injection in tokamak H-mode plasmas.

High repetition rate injection of deuterium pellets from the low-field side (LFS) of the DIII-D tokamak is shown to trigger high-frequency edge-localized modes (ELMs) at up to 12× the low natural ELM frequency in H-mode deuterium plasmas designed to match the ITER baseline configuration in shape, normalized beta, and input power just above the H-mode threshold. The pellet size, velocity, and injection location were chosen to limit penetration to the outer 10% of the plasma. The resulting perturbations to the plasma density and energy confinement time are thus minimal (<10%). The triggered ELMs occur at much lower normalized pedestal pressure than the natural ELMs, suggesting that the pellet injection excites a localized high-n instability. Triggered ELMs produce up to 12× lower energy and particle fluxes to the divertor, and result in a strong decrease in plasma core impurity density. These results show for the first time that shallow, LFS pellet injection can dramatically accelerate the ELM cycle and reduce ELM energy fluxes on plasma facing components, and is a viable technique for real-time control of ELMs in ITER.

Resonant pedestal pressure reduction induced by a thermal transport enhancement due to stochastic magnetic boundary layers in high temperature plasmas.

Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p(e) in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q95 resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p(e) reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q95 resonant character of type-I edge localized mode suppression by RMPs.

Serum cytokines in human heart transplant recipients. Is there a relationship to rejection?

Cytokines are important in the pathogenesis of allograft rejection. Some studies have suggested a positive relationship between serum levels of cytokines and rejection, so this study was designed to investigate the presence of a range of cytokines in a large cohort of cardiac transplant recipients. We used enzyme linked immunosorbent assays (ELISA) to examine sequential serum samples from 28 consecutive heart transplant recipients; length of follow up varied between 2 and 566 days (median 357 days). Serum levels of IL-2, 4, 6, 10, TNF-alpha, and IFN-gamma were measured. We compared these results with detailed data on patients' clinical courses, including histological rejection, infection, and therapeutic use of antithymocyte globulin (ATG). No significant relationship was found between rejection and serum cytokine levels for samples taken more than 30 days after transplantation. Prior to this cytokine levels were significantly disturbed by the use of cytolytic therapy for induction immunosuppression. Serum cytokine levels sometimes showed peaks that appeared to be related to rejection, or occasionally to infection, but these relationships were not consistent. Serum TNF-alpha and IL-6 were consistently elevated within a few days of administration of ATG. We conclude that there is no systematic relationship between serum cytokine levels and histological rejection or infection in cardiac transplant recipients.

Rejection in heart transplantation strongly correlates with HLA-DR antigen mismatch.

It is well established that incompatible HLA antigens presented by donor tissue readily evoke an immune response. Prospective HLA matching policies, widespread in European kidney transplant centers have reduced the level of HLA mismatching and have significantly improved graft survival. The influence of HLA incompatibility in heart transplantation remains controversial, and prospective HLA matching is seldom achieved. We examined the role of HLA antigen mismatching on transplant rejection by analyzing 2569 endomyocardial biopsies (EMB) from 157 consecutive orthotopic heart transplants performed from April 1987 to August 1993 in our own center. Biopsies were graded according to the accepted International Classification, with grade 2 and higher indicating rejection. Among 91 patients who received a 2 HLA-DR mismatch transplant 34% of 1624 biopsies analyzed were graded as > or = 2. This frequency fell to 29% of 797 biopsies for 53 patients with a one-HLA-DR mismatch and to 18% of 148 biopsies for 13 patients in the zero-HLA-DR-mismatch group (P < 0.00005). No significant effect on EMB grade frequencies was observed using the same method of analysis with transplants mismatched at the HLA-A or HLA-B loci apart from analysis of HLA-B matched transplants at 3 months posttransplant (P = 0.02). The close linkage of the HLA-B and HLA-DR loci may account for this observation. The results of this study show that heart transplants matched at the HLA-DR locus have a significantly reduced incidence of EMB grades indicative of rejection requiring augmented immunosuppressive therapy. We propose that prospective HLA-DR matching should be adopted for allocation of donor hearts for more efficient use of this precious and limited resource.

Expression of cytokine messenger RNA after heart transplantation: relationship with rejection and serum cytokines.

Different groups of cytokines may initiate or inhibit the rejection process. We used the polymerase chain reaction to study the expression of cytokine mRNA for interleukin (IL)-2, -4, -6 and -10, tumor necrosis factor-alpha, and interferon-gamma in 187 biopsy specimens from 24 human cardiac transplant recipients 5-555 days after transplantation. Cytokine levels in the serum were also measured. Cytokine mRNA was detected in 38.5% of biopsy specimens. IL-10 mRNA was detected more frequently with mild or absent rejection (11.6% in grades 0 and 1 - vs. 1.4% in grades 2 and 3, P=0.01). Up to 90 days after transplantation, IL-2 mRNA was detected more frequently with moderate rejection (13% in grades 2 and 3 vs. 0% in grades 0 and 1, P=0.076), and IL-4 mRNA was detected more frequently with mild or absent rejection (16% in grades 0 and 1 - vs. 0% in grades 2 and 3, P=0.061). More than 90 days after transplantation, IL-2 mRNA was detected more frequently with mild or absent rejection (10% in grades 0 and 1 vs. 0% in grades 2 and 3, P=0.078). Serum IL-4 levels corresponding to biopsy specimens positive for IL-4 mRNA were higher than those corresponding to specimens negative for IL-4 mRNA (59 pg/ml vs. 32 pg/ml medians, P=0.028). Our results suggest that IL-10 and possibly IL-4 (T helper 2 cytokines) may suppress graft rejection, whereas IL-2 (T helper 1 cytokine) may promote cellular rejection. In addition, cytokine profiles may change with length of time after transplantation. The association of elevated serum levels of IL-4 with increased expression of intragraft IL-4 mRNA may suggest release of this cytokine from the graft into the circulation.

Influence of tumor necrosis factor-alpha gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in cardiovascular disease. Polymorphism of the TNF-alpha gene promoter region (position -308) influences an individual's production of TNF-alpha. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-alpha have been found in recipients with cardiac transplant vasculopathy and because TNF-alpha blockade can prevent the disease in rabbits, we investigated the effect of TNF-alpha promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients. METHODS: Using sequence-specific primers to the TNF-alpha gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-alpha genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. RESULTS: We found that 31.9% of recipients and 27.0% of donors were high TNF-alpha producers. The presence of the high-producing TNF-alpha allele led to an earlier diagnosis of vasculopathy; 3.42 years (+/- 91.3 days) vs 3.84 years (+/- 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (+/- 87.3 days) vs 3.78 years (+/- 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-alpha polymorphism had no effect on the freedom from vasculopathy when considering either recipient (p = 0.99) or donor (p = 0.86) TNF-alpha genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. CONCLUSIONS: Polymorphism at position -308 in the promoter region of the TNF-alpha gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.

Polymorphism of the transforming growth factor-beta 1 gene correlates with the development of coronary vasculopathy following cardiac transplantation.

BACKGROUND: Expression of transforming growth factor-beta1 (TGF-beta1) is central to vascular repair due to its effects on smooth muscle cell, monocyte/macrophage, leucocyte, and extracellular matrix accumulation and proliferation. Genetic polymorphism at position +915 of the TGF-beta1 gene determines the degree of cytokine production in response to injury. We investigated this allelic variation on the development of cardiac transplant-related coronary vasculopathy (CV). METHODS: Using sequence-specific primers to the TGF-beta1 gene region of interest, a polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 129 cardiac transplant recipients. An association was sought between the presence of a high- (GG) or low/intermediate-producing (CC/GC) genotype and the development of coronary vasculopathy diagnosed by coronary angiography. RESULTS: C allele carriers made up 10.9% of the recipient population but were significantly less likely to develop coronary vasculopathy (p = 0. 0361). Mean time to diagnosis was 1240.5 days in G homozygotes relative to 2266.5 days in C allele carriers (p = 0.002). Pre- and 1-year posttransplant clinical variables were equivalent between the 2 groups. Multivariate analysis identified the GG genotype (p = 0. 042, hazard ratio 3.01, [95% CI, 1.056-10.99]), donor age (p = 0.002, hazard ratio 1.063, [95% CI, 1.029-1.097]), and number of acute-rejection episodes of grade 3 or greater in the first year (p = 0.029, hazard ratio 1.11, [95% CI, 1.05-1.26]) as significant predictors of vasculopathy. CONCLUSION: This study demonstrates a correlation between a high-producing TGF-beta1 genotype and an earlier onset of cardiac-transplant coronary vasculopathy. This gives an important insight into the pathophysiology of cardiac transplant vasculopathy and suggests new treatment options.

Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-beta1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population. METHODS: Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors. RESULTS: TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy (P=0.03). Median time to diagnosis was 6.0 years (3.9-8.72) in +915*C allele carriers compared to 2.75 years (2.10-4.22) in *G/G homozygotes (p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09-9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02-1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01-1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development. CONCLUSIONS: Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.

Influence of interleukin-10 polymorphism on the development of coronary vasculopathy following cardiac transplantation.

BACKGROUND: Interleukin-10 (IL-10), an important anti-inflammatory cytokine has been implicated in the pathogenesis of acute rejection and long term graft tolerance. Polymorphism in the IL-10 promoter at positions -1082, -819 and -592, correlates with IL-10 production. Haplotype inheritance of these alleles determines whether individuals are high, intermediate, or low producers of IL-10. We investigated the effect of this polymorphism on the development of cardiac transplant vasculopathy (CV). METHODS: CV was defined at routine surveillance coronary angiography as any abnormality in 1 or more epicardial vessels. Recipient and donor DNA was amplified by PCR using primers to the 3 allele sites. After identifying the phenotype by electrophoresis, freedom from CV was analysed by Kaplan-Meier and the log rank test. RESULTS: One hundred and forty eight recipients and 135 donors were studied. High, intermediate and low producers made up 26.4, 47.3 and 26.3% of recipients and 35.6, 48.2 and 16.2% of donors (P=0.42). No significant differences were noted between the phenotype groups. The recipient and donor genotypes, when considered in isolation, had no effect on the freedom from CV; recipients: P=0.85; donors: P=0.52. When the recipient and donor genotypes were combined for an individual patient the freedom from CV was again unaffected; high producing IL-10 allele in donor or recipient: P=0.76, low producing IL-10 allele in donor or recipient: P=0.51. Increasing donor age and acute rejection episodes and the presence of a high producing TGF-beta1 phenotype were independent risk factors for CV. CONCLUSIONS: Polymorphism of the IL-10 promoter region fails to predict the development of CV and cannot be used as a genetic risk marker. This may be due to the effects of immunosuppressive treatment.

A novel polymorphism of the gene encoding furin, a TGF-beta1 activator, and the influence on cardiac allograft vasculopathy formation.

BACKGROUND: Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 activation. We investigated for polymorphism within the promoter region of the gene for furin (fur). Allelic variation of the fur gene, in conjunction with TGF-beta1 polymorphism, was subsequently related to the development of CV. METHODS AND RESULTS: The fur gene promoter region (position -1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position -231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10-4.32), *C/T heterozygotes 2.97 years (2.09-4.24), *T/T homozygotes 2.65 years (2.33-4.08), (P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset (P=0.54). Ninety-three percent of recipients were high TGF-beta1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing. CONCLUSIONS: We have described a novel polymorphism at position -231* in the gene encoding furin. The fur -231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.

Actuarial analysis of late results after closed mitral valvotomy.

The long-term results of closed mitral valvotomy performed between 1978 and 1985 in 198 patients with noncalcific mitral stenosis were analyzed. Follow-up data were available on 185 patients (93%); 1 patient died in the postoperative period, and 12 foreign patients were lost to follow-up. At the 4-year and 8-year intervals, 91% and 80% of patients, respectively, were event free (not in need of further operative procedures). By multivariate analysis, the factor preoperative mild mitral regurgitation showed a tendency to influence the event-free period. By univariate analysis, postoperative mitral regurgitation significantly reduced the event-free period. Twenty-one patients subsequently underwent mitral valve replacement; 8 for mitral regurgitation, 10 for mitral stenosis, and 3 for mixed mitral regurgitation and stenosis. By multivariate analysis, the reason for reoperation significantly influenced the length of the event-free period. The patients with mitral regurgitation required mitral valve replacement sooner than those with mitral stenosis. Advanced age, sex, previous valvotomy, preoperative New York Heart Association Functional Class, low mitral valve leaflet excursion, and pulmonary hypertension had no influence on the long-term result.

Impact of stenting on coronary angioplasty procedures.

OBJECTIVE: To compare patient selection and outcome of coronary angioplasty procedures before and after the widespread availability and use of stents. SUBJECTS AND METHODS: Group 1 consisted of 252 consecutive patients and group 2 comprised 389 patients who underwent angioplasty between April 1993 and March 1994, and April 1995 and March 1996, respectively, in a tertiary cardiothoracic centre. Clinical variables were collected before the procedures. Endpoints included in-hospital death, the need for repeat coronary angiography, repeat angioplasty, and coronary artery bypass surgery. Lesions were classified under American Heart Association/American College of Cardiology criteria in 100 randomly selected patients from each group. RESULTS: 311 and 482 angioplasty procedures were performed in patients from groups 1 and 2, respectively. One or more stents were deployed in nine (4%) and 179 (46%, p < 0.01) patients, respectively. The success rate was higher in group 2 than in group 1 patients (483/523 (92%) v 274/372 (88%), respectively, p < 0.05). There were significantly more single vessel angioplasty procedures (198/252 (79%) v 272/389 (70%), p < 0.05), type A lesions (30/116 (26%) v 19/130 (15%), p < 0.05), patients with stable angina (220/252 (87%) v 311/389 (80%), p < 0.05), and fewer acute myocardial infarction patients (1/252 (0%) v 12/389 (3%), p < 0.05) treated in group 1 than in group 2, respectively. Similar numbers of angioplasty were performed in the left anterior descending, left circumflex, and right coronary arteries. There were no significant differences in the in-hospital mortality or the need for repeat coronary angiography, angioplasty, or bypass surgery at 24 hours or six months after the initial procedure. CONCLUSION: Patients undergoing angioplasty in the stenting era had features associated with an increased risk of complication. Despite this, the primary success rate was higher, and the complication rate and the need for subsequent revascularisation were similar in the two groups, supporting the widely held clinical impression that stenting has made a valuable impact on the practice of angioplasty.

A two photon absorption laser induced fluorescence diagnostic for fusion plasmas.

The quality of plasma produced in a magnetic confinement fusion device is influenced to a large extent by the neutral gas surrounding the plasma. The plasma is fueled by the ionization of neutrals, and charge exchange interactions between edge neutrals and plasma ions are a sink of energy and momentum. Here we describe a diagnostic capable of measuring the spatial distribution of neutral gas in a magnetically confined fusion plasma. A high intensity (5 MW/cm(2)), narrow bandwidth (0.1 cm(-1)) laser is injected into a hydrogen plasma to excite the Lyman ß transition via the simultaneous absorption of two 205 nm photons. The absorption rate, determined by measurement of subsequent Balmer α emission, is proportional to the number of particles with a given velocity. Calibration is performed in situ by filling the chamber to a known pressure of neutral krypton and exciting a transition close in wavelength to that used in hydrogen. We present details of the calibration procedure, including a technique for identifying saturation broadening, measurements of the neutral density profile in a hydrogen helicon plasma, and discuss the application of the diagnostic to plasmas in the DIII-D tokamak.

Charge exchange recombination detection of low-Z and medium-Z impurities in the extreme UV using a digital lock-in technique.

More sensitive detection of charge exchange recombination lines from low-Z elements, and first-time detection from the medium-Z elements nickel and copper, has been achieved in DIII-D plasmas with a digital lock-in technique. That portion of the extreme UV spectrum varying synchronously in time with the square-wave modulation of a high energy, neutral heating beam is extracted by forming a scalar product of a correlation function with the data record of each pixel in the linear array detector. The usual, dense array of collisionally excited, metallic lines from the tokamak plasma is strongly suppressed, leaving only a sparse spectrum of lines dominated by charge exchange recombination transitions from fully stripped, low-Z elements. In plasmas with high metal content, charge exchange recombination lines from the Li-like ions of nickel and copper have been positively identified.

Doppler coherence imaging and tomography of flows in tokamak plasmas (invited).

This article describes the results of spatial heterodyne Doppler "coherence imaging" of carbon ion flows in the divertor region of the DIII-D tokamak. Spatially encoded interferometric projections of doubly ionized carbon emission at 465 nm have been demodulated and tomographically inverted to obtain the spatial distribution of the carbon ion parallel flow and emissivity. The operating principles of the new instruments are described, and the link between measured properties and line integrals of the flow field are established. An iterative simultaneous arithmetic reconstruction procedure is applied to invert the interferometric phase shift projections, and the reconstructed parallel flow field amplitudes are found to be in reasonable agreement with UEDGE modeling.