Exploitation of host cell signaling machinery: activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis

Intracellular pathogens, particularly those that target host mononuclear phagocytes, have evolved strategies to either evade or inhibit cellular mechanisms of host defense. Mycobacterium tuberculosis and Leishmania donovani exemplify a diverse group of microorganisms that have developed the ability to invade and replicate within host macrophages, leading to disease expression. Recent studies have suggested that the pathogenesis of intracellular infection may involve interference with host cell signaling. Drawing upon examples from in vitro models that focused on M. tuberculosis and L. donovani, we review evidence that activation of host cell phosphotyrosine phosphatases may contribute to pathogenesis. A leading candidate appears to be the Src homology 2 domain containing phosphotyrosine phosphatase SHP-1, the activation of which may contribute to the development of infection and disease progression.     

Emergence of translocation t(9;11)-positive leukemia during treatment of childhood acute lymphoblastic leukemia

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.     

Chairman’s Editorial: Reprioritizing Radiologist Education: Teaching Old Dogs New Tricks

Journal of Digital Imaging -     

Genetic control of experimental lyme arthritis in the absence of specific immunity

Host genetics play an important role in determining resistance or susceptibility to experimental Lyme arthritis. While specific immunity appears to regulate disease resolution, innate immunity appears to regulate disease severity. Intradermal infection with Borrelia burgdorferi yields severe arthritis in C3H/He (C3H) mice but only minimal arthritis in BALB/c mice. Intradermal infection of immunodeficient C3H SCID mice also results in severe arthritis, but arthritis of only moderate severity in BALB/c SCID mice. In the present study, we examined immunodeficient recombinase-activating gene-knockout (RAG-1(-/-)) (RAG-) mice from resistant C57BL/6 (B6) and DBA/2 (DBA) mouse strains. B. burgdorferi-infected B6 RAG- and DBA RAG- mice had little or no ankle swelling, a low occurrence of inflammatory infiltrates in tibiotarsal joints, and low arthritis severity scores in comparison to RAG+ and RAG- BALB/c or C3H mice. Few differences in spirochete DNA levels in ankles of resistant and susceptible RAG- mice were seen. These data suggest that resistance to arthritis development following B. burgdorferi infection is not necessarily dependent on an acquired immune response and can occur despite the presence of high spirochete burden. Thus, genes expressed outside the specific immune response can be central regulators of experimental arthritis.     

Lining cell and intimal smooth muscle cell response and Evans blue staining in abdominal aorta of young swine after denudation by balloon catheter

Young male Yorkshire swine underwent denudation of the abdominal aorta by transfemoral intraarterial ballooning followed by the intravenous injection of Evans blue dye at intervals up to 28 days after ballooning. A small number of swine were also sacrificed 30 min after ballooning. Approximately half the swine were fed a hypercholesterolemic diet, while the others received a mash diet. Quantitation by light microscopy showed that ballooning had removed 99% of the endothelial cells and approximately 50% of the native intimal smooth muscle cells. Three hours after ballooning, the entire luminal surface of the abdominal aorta was stained with Evans blue. By 3 days, a continuous cellular lining had been reformed over at least one-fifth of the denuded surface and the area stained with Evans blue had sharply decreased. The number of intimal smooth muscle cells had returned to nearly normal values, and continued to increase steadily from that day onward. By 8 days, the continuous lining cells had further increased in number and most could be identified as endothelial cells by electron microscopy. Proliferation of the intimal smooth muscle cells and endothelial cells appeared independent, and not influenced by each other. From 8 to 28 days, the percentage of reendothelialized aortic surface increased and Evans blue staining decreased so that by 28 days, values for both were close to those in nonballooned controls. The rate of return of endothelial cells with consequent decrease in Evans blue staining did not appear to be influenced by the hypercholesterolemic diet in any consistent manner. However, at Day 28, the number of intimal smooth muscle cells was approximately four times greater in the hypercholesterolemic group than in the mash-fed and ballooned group. Thirty minutes postballooning, layers of platelets covering most of the surface were adherent to the denuded abdominal aorta. By 3 hr, they were found only as scattered clumps and became even scarcer at later times. If adherent platelets were a factor in the intimal smooth muscle cell proliferation, they appear to have been operative only in the immediate postballooing period.     

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

„Klar bleiben“ – ein Wettbewerb für Schulklassen zur Reduktion des Alkoholkonsums

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Alkohol ist in Deutschland im Jugendalter die populärste Droge. Alkoholpräventionsprogramme, die im Setting Schule...     

Emotionale Erschöpfung und Berufszufriedenheit von Lehrpersonal während der COVID-19-Pandemie

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Die COVID-19-Pandemie hat den beruflichen Alltag von Lehrpersonal erheblich verändert. Das Ziel dieser Arbeit ist es, die...     

Die Generationen Y und Z – Neue Herausforderungen für Führungskräfte im Krankenhaus

Die Anaesthesiologie - In dieser Studie wurden die Studierenden der Generationen Y und Z des Studiengangs Humanmedizin an der Georg-August-Universität Göttingen...