XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome

The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.     

Gene therapy: X-SCID transgene leukaemogenicity

Gene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective therapeutic gene IL2RG, which encodes the gamma-chain of the interleukin-2 receptor, in a mouse model of the disease and found that tumours appeared in a proportion of cases. Here we show that transgenic IL2RG does not necessarily have potent intrinsic oncogenic properties, and argue that the interpretation of this observation with respect to human trials is overstated.     

Asphyxie-Schutz durch Schweres Wasser (D2O)

Summary In rats a 25% D₂O content of total body water was found to prolong survival time and the period of revivability in asphyxia by a better maintenance of cardiovascular function and gasp activity.

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Herrn Prof. Dr. W. Isselhard zum 50. Geburtstag gewidmet.     

Limits of language

Zusammenfassung Unsere Alltagssprache ist nur zur Beschreibung von Phänomenen, welche im menschlichen Wahrnehmungsbereich der Gleichzeitigkeit liegen, geeignet. Die Diskussion von Begriffen, wie z. B. Kausalität und Zufall, erfordert eine sprachlichea-priori-Begrenzung der Signalfortbewegung (Wilkinson). Eine solche neue Sprache muss auch informationstheoretische Konzepte enthalten.     

Phenethylamine content of human urine and rat brain,its alterations in pathological conditions and after drug administration

Zusammenfassung Nachweis, dass die Phenethylamin-ausscheidung bei endogener, nicht aber bei sekundär atypischer Depression signifikativ vermindert, bei Manie und Schizophrenie aber entsprechend erhöht ist. Die Behandlung der endogenen, nicht aber der sekundären Depression mit trizyklischen antidepressiven Mitteln erhöht die Phenethylaminausscheidung. Der Phenethylamingehalt im Rattengehirn wird durch Reserpin signifikant vermindert, durch Iproniazid, Imipramin und Chlorimipramin jedoch signifikant erhöht.     

On factors involved in the mechanism of ‘Taste-blindness’

Zusammenfassung Der genetisch kontrollierte, hohe Geschmacksschwellenwert — Geschmacksblindheit — gegenüber Phenylthioharnstoff (PTC) und anderen bitteren, strukturell ähnlichen Anti-Schilddrüsensubstanzen, scheint durch die Qualität und Quantität des löslichen Speichel-Enzym-Systems Tyrosiniodinase bedingt zu sein.PTC-Geschmacksblinde sind «Alles-Esser», PTC-Schmecker hingegen weisen eine erhöhte kulinarische Selektivität auf. Diese Tatsache ist um so interessanter, als der Schwellenwert der beiden Gruppen gegenüber den klassischen Geschmacksqualitäten — süss, salzig, sauer und bitter — derselbe ist.     

Possible biosynthesis of D-lysergic acid diethylamide-like compounds from mescaline

Zusammenfassung Die Hypothese einer Biosynthese vond-Lysergsäure-diäthylamidähnlichen Substanzen aus Meskalin in der Leber und im Gehirn wird postuliert.     

Three-dimensional imaging of atomic four-body processes

To understand the physical processes that occur in nature we need to obtain a solid concept about the 'fundamental' forces acting between pairs of elementary particles. It is also necessary to describe the temporal and spatial evolution of many mutually interacting particles under the influence of these forces. This latter step, known as the few-body problem, remains an important unsolved problem in physics. Experiments involving atomic collisions represent a useful testing ground for studying the few-body problem. For the single ionization of a helium atom by charged particle impact, kinematically complete experiments have been performed since 1969 (ref. 7). The theoretical analysis of such experiments was thought to yield a complete picture of the basic features of the collision process, at least for large collision energies. These conclusions are, however, almost exclusively based on studies of restricted electron-emission geometries. Here, we report three-dimensional images of the complete electron emission pattern for the single ionization of helium by the impact of C6+ ions of energy 100 MeV per a.m.u. (a four-body system) and observe features that have not been predicted by any published theoretical model. We propose a higher-order ionization mechanism, involving the interaction between the projectile and the target nucleus, to explain these features.