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Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases.
Background: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. Methods and Findings: Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. Conclusions: The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.
Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have anti-inflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.
Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising ~45 000 well-characterized ES cell lines which currently represent ~40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website (www.genetrap.org) allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function.
Das Projekt LaMedica (http://www.lamedica.de) hat zum Ziel, eine multimediale Lehr- und Lernplattform zu entwickeln, Inhalte für die Medizin zu erstellen und diese in die Lehre zu implementieren. Es wurde eine on-line Autorenumgebung geschaffen, die sehr unterschiedliche didaktische Ansätze unterstützt: systematische und vernetzte Wissensvermittlung, fallbasiertes Lernen, Erstellung von Vorlesungen und Lernerfolgskontrolle. Die Lehrinhalte können zielgruppenspezifisch aufbereitet und dargestellt werden und richten sich insbesondere an Studenten, Ärzte in der Weiterbildung und Fachärzte. Eine on-line Medien-Datenbank unterstützt die Wiederverwendung und den Austausch von Inhalten auf der Basis eines Content-Management-Systems durch Verwendung des Learning Objects Metadata Standards (LOM). Die Förderung erfolgt durch das BMBF (FKZ NM054A).
Celiac disease
(2006)
Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.