[Stem cell transplantation in metastasized renal cancer].
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Cost-Benefit Analysis↗
Biomedical subjects
M Brune
Publications and source records attributed to M Brune.
Coherent control of an atomic collision in a cavity.
Following a recent proposal by S. B. Zheng and G. C. Guo [Phys. Rev. Lett. 85, 2392 (2000)], we report an experiment in which two Rydberg atoms crossing a nonresonant cavity are entangled by coherent energy exchange. The process, mediated by the virtual emission and absorption of a microwave photon, is characterized by a collision mixing angle 4 orders of magnitude larger than for atoms colliding in free space with the same impact parameter. The final entangled state is controlled by adjusting the atom-cavity detuning. This procedure, essentially insensitive to thermal fields and to photon decay, opens promising perspectives for complex entanglement manipulations.
Journal Article↗
A complementarity experiment with an interferometer at the quantum-classical boundary.
To illustrate the quantum mechanical principle of complementarity, Bohr described an interferometer with a microscopic slit that records the particle's path. Recoil of the quantum slit causes it to become entangled with the particle, resulting in a kind of Einstein-Podolsky-Rosen pair. As the motion of the slit can be observed, the ambiguity of the particle's trajectory is lifted, suppressing interference effects. In contrast, the state of a sufficiently massive slit does not depend on the particle's path; hence, interference fringes are visible. Although many experiments illustrating various aspects of complementarity have been proposed and realized, none has addressed the quantum-classical limit in the design of the interferometer. Here we report an experimental investigation of complementarity using an interferometer in which the properties of one of the beam-splitting elements can be tuned continuously from being effectively microscopic to macroscopic. Following a recent proposal, we use an atomic double-pulse Ramsey interferometer, in which microwave pulses act as beam-splitters for the quantum states of the atoms. One of the pulses is a coherent field stored in a cavity, comprising a small, adjustable mean photon number. The visibility of the interference fringes in the final atomic state probability increases with this photon number, illustrating the quantum to classical transition.
Journal Article↗
A fluorescent sensor of the phosphorylation state of nucleoside diphosphate kinase and its use to monitor nucleoside diphosphate concentrations in real time.
A sensor for purine nucleoside diphosphates in solution based on nucleoside diphosphate kinase (NDPK) has been developed. A single cysteine was introduced into the protein and labeled with the environmentally sensitive fluorophore, N-[2-(iodoacetamido)ethyl]-7-diethylaminocoumarin-3-carboxamide. The resultant molecule shows a 4-fold fluorescence increase when phosphorylated on His117; this phosphorylation is on the normal reaction pathway of the enzyme. The emission maximum of the phosphoenzyme is at 475 nm, with maximum excitation at 430 nm. The fluorescent phosphorylated NDPK is used to measure the amount of ADP and the unphosphorylated to measure ATP. The labeled protein is phosphorylated to > 90%, and the resultant molecule is stable on ice or can be stored at -80 degrees C. The fluorescence responds to the fraction of protein phosphorylated and so to the equilibrium between ADP plus NDPK approximately P and ATP plus NDPK. In effect, the sensor measures the ADP/ATP concentration ratio. The enzyme has a broad specificity for the purine of the nucleotides, so the sensor also can measure GDP/GTP ratios. The fluorescence and kinetic properties of the labeled protein are described. The binding rate constants of nucleotides are approximately 10(5) M(-1) s(-1), and the fluorescence change is at >200 s(-1) when the ADP concentration is >1 mM. Results are presented with two well-defined systems, namely, the kinetics of ADP release from myosin subfragment 1 and GDP release from the small G protein, human rho. The results obtained with this novel sensor agree with those from alternate methods and demonstrate the applicability for following micromolar changes in nucleoside diphosphate in real time.
Adenosine Diphosphate↗
Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
Community-acquired respiratory virus infections are a cause of mortality after stem cell transplantation (SCT). A prospective study was performed at 37 centers to determine their frequency and importance. Additional cases were also collected to allow the analysis of risk factors for severe infection. Forty episodes were collected in the prospective study and 53 additional episodes through subsequent case collection. The frequency of documented respiratory virus infections was 3.5% among 819 allogeneic and 0.4% among 1154 autologous SCT patients transplanted during the study period. The frequency of lower respiratory tract infections (LRTI) was 2.1% among allogeneic and 0.2% among autologous SCT patients. The mortality within 28 days from diagnosis of a respiratory viral infection was 1.1% among allogeneic SCT while no autologous SCT patient died. The deaths of five patients (0.6%) were directly attributed to a respiratory virus infection (three RSV; two influenza A). On multivariate analysis, lymphocytopenia increased the risk for LRTI (P = 0.008). Lymphocytopenia was also a significant risk factor for LRTI in patients with RSV infections. The overall mortality in RSV infection was 30.4% and the direct RSV-associated mortality was 17.4%. For influenza A virus infection, the corresponding percentages were 23.0% and 15.3%. This prospective study supports the fact that community-acquired respiratory virus infections cause transplant-related mortality after SCT.
Adolescent↗
The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensity conditioning.
The efficacy of allogeneic, haemopoietic stem cell transplantation (HSCT) is limited by concomitant toxicity. This has led to the development of less toxic, reduced intensity conditioning (RIC) protocols, whose therapeutic benefit is largely related to an associated, immunity-mediated graft-versus-malignancy effect rather than by the cytotoxic treatment itself. Murine HSCT models suggests that acute graft-versus-host disease (GVHD) increases with the intensification of the conditioning regimen mediated by loss of integrity of the gut mucosa barrier. The present study was undertaken to investigate gastro-intestinal (GI) permeability during allogeneic HSCT with RIC. In 17 patients (myeloablative conditioning in nine, RIC in eight), intestinal permeability was assessed by a (51)Cr-EDTA absorption test before the start of cytotoxic treatment the day before stem cell infusion (day -1) and 4, 7 and 14 days after stem cell infusion. Patients receiving RIC did not develop any significant increase in intestinal permeability during the transplantation course but in myeloablatively conditioned patients there was a significant increase in intestinal permeability the day before the stem cell infusion (P < 0.005), on day 4 (P < 0.005), on day 7 (P < 0.01) and on day 14 (P < 0.005) after stem cell infusion, compared with the baseline. Myeloablative conditioning also revealed increased intestinal permeability on day 7 compared with the RIC (P < 0.05). The finding of preserved intestinal-barrier function during allogeneic HSCT with RIC is discussed, with reference to the hypothesis that GI tract damage may be an important initiating event of GVHD.
Adult↗
Langerhans cells and T cells in oral graft versus host disease and oral lichen planus.
Chronic graft versus host disease (cGVHD) of the oral mucosa, following allogeneic stem cell transplantation, and oral lichen planus (OLP) are both mucosal diseases where the immune system is involved in the pathogenesis. Although the aetiology of the two conditions is different, they present with a similar clinical appearance. This study compares the two diseases regarding the distribution of cells, which are expressing cell surface markers of interest for inflammatory responses. Monoclonal antibodies (MoAbs) were used in standard immunohistochemical procedures. CD1a+, CD80+ and CD86+ cells in the epithelium of OLP- and cGVHD lesions had the dendritic morphology of Langerhans cells (LC). Higher frequencies of CD1a+ LC as well as CD25+ cells were observed in the OLP epithelium than in the cGVHD epithelium. The OLP lesions showed higher frequencies of subepithelial cells expressing CD1a, CD86, CD4, CD8 and CD25 than the cGVHD lesions. Notably there was a significantly higher frequency of CD25+ cells in the epithelium and the connective tissue of OLP than in cGVHD. These cells might represent regulatory T cells. In conclusion, cGVHD and OLP show marked differences at the cellular level despite similar clinical appearance. Hence, the findings indicate differences in the regulation of the inflammatory response between the two conditions.
Adult↗
The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity.
Genomic effects of T are exerted via the AR. The length of the polymorphic CAG repeat sequence in the AR gene is inversely correlated with the transcriptional regulation of target genes by T. In 110 healthy men (20-50 yr), we investigated the interactions among this polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery. The number of CAG repeat had no significant correlations with serum concentrations of total or free T. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeat with serum levels of high density lipoprotein cholesterol (partial r = 0.44; P < 0.001) and flow-mediated vasodilatation (partial r = 0.37; P < 0.001). The association of CAG repeat with high density lipoprotein (HDL) cholesterol was independent of body fat content and serum levels of free T, which both had significant negative correlations with HDL cholesterol. The association of CAG repeat with flow-mediated vasodilatation was independent of cigarette smoking and serum levels of free T and low density lipoprotein cholesterol, which also were correlated with flow-mediated vasodilatation. We conclude that a low number of CAG repeat in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are both important risk factors for coronary heart disease.
Adult↗
Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine.
Natural killer (NK) cells are deficient in patients with chronic myelogenous leukemia (CML), but the mechanisms responsible for the dysfunction are not completely understood. This study reports that CML cells effectively inhibit the baseline and interleukin-2 (IL-2)-induced NK cell cytotoxicity against a CML cell-derived line (K562). A sizable fraction of NK cells subsequently acquired features characteristic of programmed cell death/apoptosis. The CML cell-mediated inhibition of NK cells required triggering of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated formation of reactive oxygen species (ROS) and was prevented by catalase, a scavenger of ROS, and by histamine, acting via H(2)-receptor-mediated inhibition of ROS production in CML cells. In contrast, nonmalignant neutrophilic granulocytes inhibited NK cells via ROS production without the requirement of exogenous NADPH oxidase-triggering stimuli. We propose that paracrine production of ROS may contribute to the dysfunction of NK cells in CML and that histamine may serve as an autocrine inhibitor of ROS formation in leukemic granulocytes. (Blood. 2000;96:1961-1968)
Apoptosis↗
Step-by-step engineered multiparticle entanglement
After quantum particles have interacted, they generally remain in an entangled state and are correlated at a distance by quantum-mechanical links that can be used to transmit and process information in nonclassical ways. This implies programmable sequences of operations to generate and analyze the entanglement of complex systems. We have demonstrated such a procedure for two atoms and a single-photon cavity mode, engineering and analyzing a three-particle entangled state by a succession of controlled steps that address the particles individually. This entangling procedure can, in principle, operate on larger numbers of particles, opening new perspectives for fundamental tests of quantum theory.
Journal Article↗
A Secondary beta Deuterium Kinetic Isotope Effect in the Chorismate Synthase Reaction.
Chorismate synthase (EC 4.6.1.4) is the shikimate pathway enzyme that catalyzes the conversion of 5-enolpyruvylshikimate 3-phosphate (EPSP) to chorismate. The enzyme reaction is unusual because it involves a trans-1,4 elimination of the C-3 phosphate and the C-6 proR hydrogen and it has an absolute requirement for reduced flavin. Several mechanisms have been proposed to account for the cofactor requirement and stereochemistry of the reaction, including a radical mechanism. This paper describes the synthesis of [4-(2)H]EPSP and the observation of kinetic isotope effects using this substrate with both Neurospora crassa and Escherichia coli chorismate synthases. The magnitude of the effects were (D)(V) = 1.08 +/- 0.01 for the N. crassa enzyme and 1.10 +/- 0.02 on phosphate release under single-turnover conditions for the E. coli enzyme. The effects are best rationalised as substantial secondary beta isotope effects. It is most likely that the C(3)-O bond is cleaved first in a nonconcerted E1 or radical reaction mechanism. Although this study alone cannot rule out a concerted E2-type mechanism, the C(3)-O bond would have to be substantially more broken than the proR C(6)-H bond in a transition state of such a mechanism. Importantly, although the E. coli and N. crassa enzymes have different rate limiting steps, their catalytic mechanisms are most likely to be chemically identical. Copyright 2000 Academic Press.
Journal Article↗
Alleviating oxidative stress in cancer immunotherapy: a role for histamine?
Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells, but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions between monocytes/macrophages and T-cells/natural killer-cells, and in particular the role of such interactions for the outcome of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy should be supplemented with compounds that alleviate toxicity inflicted by monocyte/macrophage-derived reactive oxygen metabolites within and around tumors. The hypothesis is founded on data demonstrating that (i) functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen metabolites, generated by neighboring monocytes/macrophages, (ii) interleukin-2 only weakly activates T-cells or natural killer cells in an environment of oxidative stress, and (iii) inhibitors of the formation of reactive oxygen metabolites or scavengers of reactive oxygen metabolites synergize with interleukin-2 to activate these lymphocyte subsets. We also review the preclinical background to the use of histamine dihydrochloride, an inhibitor of reactive oxygen metabolite formation in monocytes/macrophages, as a supplement to cancer immunotherapy with interleukin-2.
Cell Communication↗
Remission inversion and no transplant-related mortality--a single centre experience of autologous stem cell transplantation in malignant lymphoma.
Between 1989 and 1998 93 patients with malignant lymphoma were treated, in our centre, with high-dose chemotherapy and autologous stem cell transplantation. Diagnosis according to the REAL-classification were: 38 patients with high-grade lymphoma (diffuse large B-cell lymphoma (DLCL) (n = 26), anaplastic T-cell (n = 5), lymfoblastic (n = 3) and others (n = 4)), 31 patients with low-grade lymphoma (follicular (n = 18), mantle cell (n = 4), B-CLL (n = 3) and others (n = 6)) and, finally, 24 patients with Hodgkin's disease. The source of stem cells was bone marrow (14 patients), peripheral blood stem cells (64 patients) or a combination of both sources (15 patients). There was no early ( < 100 days) transplant-related mortality. One patient died 11 months post-transplant in unexplained liver failure and all other causes of death were related to relapse of lymphoma. So far, no case of myelodysplastic syndromes or secondary acute leukacmia's has occurred. Overall survival (OS) and progression-free survival (PFS) are: (a) DLCL (26 patients, 4-year probability) OS 40%. PFS 33%; (b) follicular (18 patients, 3-year probability) OS 79%, PFS 52%; (c) Hodgkin's lymphoma (24 patients, 5-year probability) OS 65%, PFS 55%. Out of 52 evaluable patients, 34 (65%) have reached remission inversion. The most important findings are no early transplantation-related mortality, remission inversion in a majority of patients, and so far no cases of secondary myelodysplastic syndromes (MDS) acute myelogenous leukaemias (AML). Concerning OS and PFS, our results seem to be in accordance with other centres.
Adolescent↗
Cardiovascular load of competitive golf in cardiac patients and healthy controls.
PURPOSE: Sports in cardiovascular patients (CVP) should serve for risk factor management, increase of exercise capacity, and reintegration into daily life. Competition of cardiac patients with healthy sportsmen is often discouraged and thus reintegration hampered. Golf, with its endurance component and exceptional rules (e.g., the handicap) should be an alternative. METHODS: In 20 male golfers (65.2 +/- 6.1 yr, 1.4 +/- 0.3 W x kg(-1) body weight (approximately 4.8 METs)) with cardiovascular diseases and eight controls (C) (62 +/- 5 yr, 2 +/- 0.4 W x kg(-1) body weight (approximately 6.9 METs)), the performance assessed in the laboratory (ergospirometry, serum lactate) allowed for comparison of the cardiovascular load on the golf course (lactate, Holter monitoring, blood pressure, urine catecholamines). RESULTS: In comparison with in the hospital, resting heart rates were significantly (P < 0.001) elevated in both groups immediately before the tournament (CVP: 76.1 +/- 10.8 vs 90.1 +/- 8.6 bpm; C: 74.8 +/- 6.3 vs 92.3 +/- 9.7 bpm). On the course, the mean heart rates of the patients were closer (P < 0.01) to the anaerobic threshold (105.4 +/- 11.0 vs 115.3 +/- 10.8 bpm) in comparison with controls (100.5 +/- 7.3 vs 125.6 +/- 16.6 bpm) corresponding to 0.9 +/- 0.3 W x kg(-1) (approximately 3.1 METs) or 76.0 +/- 13.1%VO2max (CVP) and to 0.9 +/- 0.2 W x kg(-1) (approximately 3.1 METs) or 55.3 +/- 9.1%VO2max (C). Serum lactate levels were 1.36 +/- 0.7 mmol x L(-1) (approximately 12.4 +/- 6.4 mg x dL(-1)) (CVP) and 1.1 +/- 0.4 mmol x L(-1) (approximately 9.1 +/- 3.6 mg x dL(-1)) (C). In patients, arrhythmias were lower in quantity and quality (LOWN) in comparison with other activities as registered by means of the 24-Holter-ECG. CONCLUSION: In cardiovascular patients, competitive golf reaches an intensity that may positively influence cardiovascular risk factors, depending on the type of the course and may provide patients the desired integration with healthy sportsmen.
Aged↗
Histamine: a novel approach to cancer immunotherapy.
The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-alpha (IFN-alpha) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-alpha to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties of histamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2-receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-alpha to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-alpha is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.
Drug Therapy, Combination↗
[Cranialization of the frontal sinus. Indications, technique and results].
The osteoplastic frontal sinus surgery with obliteration of the sinus has been established in the therapy of frontal sinus diseases that can not be drainaged permanently or healed through an endonasal access. The obliteration of the frontal sinus is endangered in cases of multiple fracturing of the posterior frontal sinus wall or if it has been destroyed by an inflammatory process. In these problematic cases obliteration bears the danger of complications and cranialization of the frontal sinus is therefore the method of choice. We review 8 patients who were operated on using the cranialization technique. Indications for surgery were a combined fracture of the anterior and posterior frontal sinus wall (3), a pyocele of the frontal sinus with extensive destruction of the posterior wall (4) and a large osteoma of the posterior frontal sinus wall (1). The frontal sinus was exposed through a coronal incision, the mucosa and the posterior wall were completely removed and the frontal sinus obliterated with fat tissue. The anterior sinus wall was replaced after obliteration of the sinus or reconstructed with calvarian bone transplants. The follow up period was 1.8 years (11 months to 8 years). All patients underwent postoperatively a clinical ENT-examination and radiological assessment by CT-Scan or MRI. The overall functional and esthetic outcome was excellent. There were no serious complications nor any recurrence. The cranialization of the frontal sinus is a reliable and safe variation of the classical osteoplastic frontal sinus surgery with fat obliteration.
Abscess↗
Phosphate release during microtubule assembly: what stabilizes growing microtubules?
The molecular mechanism underlying microtubule dynamic instability depends on the relationship between the addition of tubulin-GTP to a growing microtubule and its hydrolysis in the microtubule lattice to tubulin-GDP, with release of inorganic phosphate (Pi). Since this relationship remains controversial, we have re-examined the release of Pi upon microtubule assembly using a fluorometric assay for Pi, based on the phosphate-binding protein of Escherichia coli [Brune M., Hunter, J. L., Corrie, J. E. T., and Webb, M. R. (1994) Biochemistry 33, 8262-8271]. Microtubule assembly and Pi release were monitored simultaneously in a standard fluorimeter as an increase in the turbidity and fluorescence, respectively, in tubulin-GTP solutions assembled under conditions supporting dynamic instability. At the steady state of assembly, Pi release is nonlinear with respect to time, proceeding at a rate determined by the following: (a) the intrinsic GTPase activity of the nonpolymerized tubulin-GTP, and (b) the microtubule number concentration, which decreases progressively. Direct observation of the time course of nucleated microtubule assembly indicates that Pi release is closely coupled to microtubule elongation, even during the initial stages of assembly when uncoupling of tubulin-GTP addition and GTP hydrolysis would be most evident. Studies of the inhibition and reversal of the growth phase by cytostatic drugs show no evidence of a burst of Pi release. We conclude that nucleotide hydrolysis can keep pace with tubulin-GTP addition rates of 200 molecules per second per microtubule and that extended caps of tubulin-GTP or tubulin-GDP-Pi are not generated in normal assembly, nor are they required to stabilize growing microtubules or to support the phenomenon of dynamic instability of microtubules at the steady state.
Animals↗
The efficiency of contraction in rabbit skeletal muscle fibres, determined from the rate of release of inorganic phosphate.
1. The relationship between mechanical power output and the rate of ATP hydrolysis was investigated in segments of permeabilized fibres isolated from rabbit psoas muscle. 2. Contractions were elicited at 12 degrees C by photolytic release of ATP from the P3 -1-(2-nitrophenyl) ester of ATP (NPE-caged ATP). Inorganic phosphate (Pi) release was measured by a fluorescence method using a coumarin-labelled phosphate binding protein. Force and sarcomere length were also monitored. 3. ATPase activity was determined from the rate of appearance of Pi during each phase of contraction. The ATPase rate was 10.3 s-1 immediately following release of ATP and 5. 1 s-1 during the isometric phase prior to the applied shortening. It rose hyperbolically with shortening velocity, reaching 18.5 s-1 at a maximal shortening velocity > 1 ML s-1 (muscle lengths s-1). 4. Sarcomeres shortened at 0.09 ML s-1 immediately following the photolytic release of ATP and at 0.04 ML s-1 prior to the period of applied shortening. The high initial ATPase rate may be largely attributed to initial sarcomere shortening. 5. During shortening, maximal power output was 28 W l-1. Assuming the free energy of hydrolysis is 50 kJ mol-1, the efficiency of contraction was calculated from the power output at each shortening velocity. The maximum efficiency was 0.36 at a shortening velocity of 0.27 ML s-1, corresponding to a force level 51 % of that in the isometric state. 6. At the maximal shortening velocity, only 10 % of the myosin heads are attached to the thin filaments at any one time.
Adenosine Triphosphatases↗