Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes

Objective: Involvement of cytotoxic T lymphocytes (CTL) in heart transplant rejection as well as in viral myocarditis is well established, but the precise mechanisms whereby infiltrating CTL damage the myocardium are unknown. The aim of the study was to investigate how CTL derived perforin, the serine protease granzyme A, and the combination of both, damage guinea pig ventricular myocytes. Methods: Action potentials and membrane currents were recorded by means of the whole cell configuration from guinea pig ventricular myocytes. Results: Resembling the effects of CTL derived lytic granules, perforin caused gradual myocyte shortening and contracture, leading to complete loss of the rod shaped morphology and to cell destruction. These changes were preceded by shortening of action potential duration and reduction of resting potential and action potential amplitude, followed by complete inexcitability. Granzyme A alone was ineffective, but accelerated the deleterious effects of perforin on the morphological and electrophysiological properties of myocytes. The effects of perforin were further evaluated by measuring membrane currents by means of the whole cell voltage clamp. Perforin induced discrete changes in membrane current, reminiscent of single ion channels, with large conductance and open time of up to several seconds. Linear regression analysis of the channel I-V relations resulted in a conductance of 890 pS and a reversal potential of −7.6 mV. These results suggest that perforin induces large non-selective channels, which can account for most of the observed adverse effects. Conclusions: As CTL participate in the immunological rejection of the transplanted heart, it is conceivable, but remains to be shown, that part of this damage is inflicted by perforin containing lytic granules. Cardiovascular Research 1994;28:643-64

Position resolution and efficiency measurements with large scale Thin Gap Chambers for the super LHC

New developments in Thin Gap Chambers (TGC) detectors to provide fast trigger and high precision muon tracking under sLHC conditions are presented. The modified detectors are shown to stand a high total irradiation dose equivalent to 6 Coulomb/cm of wire, without showing any deterioration in their performance. Two large (1.2 x 0.8 m^2) prototypes containing four gaps, each gap providing pad, strips and wires readout, with a total thickness of 50 mm, have been constructed. Their local spatial resolution has been measured in a 100 GeV/c muon test beam at CERN. At perpendicular incidence angle, single gap position resolution better than 60 microns has been obtained. For incidence angle of 20 degrees resolution of less than 100 micron was achieved. TGC prototypes were also tested under a flux of 10^5 Hz/cm^2 of 5.5-6.5 MeV neutrons, showing a high efficiency for cosmic muons detection.Comment: Presented at the 12 Vienna conference on Instrumentation, February 201

Successful umbilical cord blood transplantation for Fanconi anemia using preimplantation genetic diagnosis for HLAmatched donor

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, and a high incidence of myelodysplasia and acute myeloid leukemia. Stem cell transplantation is the only curative treatment. In the absence of matched-sibling donor, an alternative mismatched family or matched unrelated donor can be used, but the results are inferior to the matched-sibling transplant and carry a high risk of morbidity and mortality. Preimplantation genetic diagnosis (PGD) has been increasingly used in recent years for mutation analysis for many genetic disorders and results in the birth of healthy children, saving the need for the termination of pregnancy of an affected embryo. The use of PGD for combined analysis of mutation and HLAmatching was reported for the first time in 2001. This enables the birth of an unaffected child who can serve as a donor for an affected sibling in need for stem cell transplantation. We report successful cord blood transplantation for a Fanconi anemia patient from his HLA-matched sibling, born after PGD that included mutation analysis for Fanconi anemia and HLA typing. PGD can provide an unaffected donor for a sibling affected by genetic disease in the absence of a compatible related donor. Am

A search for heavy Kaluza-Klein electroweak gauge bosons at the LHC

The feasibility for the observation of a certain leptonic Kaluza-Klein (KK) hard process in {\em pp} interactions at the LHC is presented. Within the $S^1/Z_2$ TeV$^{-1}$ extra dimensional theoretical framework with the focus on the KK excitations of the Standard Model $\gamma$ and $Z^0$ gauge bosons, the hard-process, $f\bar f \to \sum_n\left(\gamma^*/Z^*\right)_n \to F \bar F$, has been used where $f$ is the initial state parton, $F$ the final state lepton and $\left(\gamma^*/Z^*\right)_{n}$ is the $n^{\rm th}$ KK excitation of the $\gamma/Z^0$ boson. For this study the analytic form for the hard process cross section has been independently calculated by the authors and has been implemented using the {\sc Moses} framework. The Moses framework itself, that has been written by the authors, was used as an external process within the {\sc Pythia} Monte Carlo generator which provides the phase space generation for the final state leptons and partons from the initial state hadrons, and the simulation of initial and final state radiation and hadronization. A brief discussion of the possibility for observing and identifying the unique signature of the KK signal given the current LHC program is also presented.Comment: 16 pages 10 figures, MCnet number: MCnet/10/06, Accepted by JHE

Bose-Einstein Correlations of Three Charged Pions in Hadronic Z^0 Decays

Bose-Einstein Correlations (BEC) of three identical charged pions were studied in 4 x 10^6 hadronic Z^0 decays recorded with the OPAL detector at LEP. The genuine three-pion correlations, corrected for the Coulomb effect, were separated from the known two-pion correlations by a new subtraction procedure. A significant genuine three-pion BEC enhancement near threshold was observed having an emitter source radius of r_3 = 0.580 +/- 0.004 (stat.) +/- 0.029 (syst.) fm and a strength of \lambda_3 = 0.504 +/- 0.010 (stat.) +/- 0.041 (syst.). The Coulomb correction was found to increase the \lambda_3 value by \~9% and to reduce r_3 by ~6%. The measured \lambda_3 corresponds to a value of 0.707 +/- 0.014 (stat.) +/- 0.078 (syst.) when one takes into account the three-pion sample purity. A relation between the two-pion and the three-pion source parameters is discussed.Comment: 19 pages, LaTeX, 5 eps figures included, accepted by Eur. Phys. J.

The Kinetics of Early T and B Cell Immune Recovery after Bone Marrow Transplantation in RAG-2-Deficient SCID Patients

The kinetics of T and B cell immune recovery after bone marrow transplantation (BMT) is affected by many pre- and post-transplant factors. Because of the profoundly depleted baseline T and B cell immunity in recombination activating gene 2 (RAG-2)-deficient severe combined immunodeficiency (SCID) patients, some of these factors are eliminated, and the immune recovery after BMT can then be clearly assessed. This process was followed in ten SCID patients in parallel to their associated transplant-related complications. Early peripheral presence of T and B cells was observed in 8 and 4 patients, respectively. The latter correlated with pre-transplant conditioning therapy. Cells from these patients carried mainly signal joint DNA episomes, indicative of newly derived B and T cells. They were present before the normalization of the T cell receptor (TCR) and the B cell receptor (BCR) repertoire. Early presentation of the ordered TCR gene rearrangements after BMT occurred simultaneously, but this pattern was heterogeneous over time, suggesting different and individual thymic recovery processes. Our findings early after transplant could suggest the long-term patients' clinical outcome. Early peripheral presence of newly produced B and T lymphocytes from their production and maturation sites after BMT suggests donor stem cell origin rather than peripheral expansion, and is indicative of successful outcome. Peripheral detection of TCR excision circles and kappa-deleting recombination excision circles in RAG-2-deficient SCID post-BMT are early markers of T and B cell reconstitution, and can be used to monitor outcome and tailor specific therapy for patients undergoing BMT

Study of ordered hadron chains with the ATLAS detector

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