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  • 1
    Electronic Resource
    Electronic Resource
    Bingley : Emerald
    International journal of public sector management 12 (1999), S. 198-204 
    ISSN: 0951-3558
    Source: Emerald Fulltext Archive Database 1994-2005
    Topics: Political Science , Economics
    Notes: In the first article (IJPSM Vol. 11 No. 6) on integrated local service systems (ILSS) we outlined the key features of this type of application of computers using the benefit service as an example. The second article (IJPSM, Vol. 12 No. 1) described the advantages and disadvantages of the system both as technology and as an information technology strategy. For this third and final article some of the evidence for the increasing demand for an ILSS is referred to with a complementary description of the supply side. As the information available suggests that such systems will be developed and, in some senses, already have been introduced, we then provide information to assist any local authority, or part of a local authority such as a benefits service, with the preparation of a specification prior to tendering for an ILSS.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 795 (1996), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Bingley : Emerald
    International journal of public sector management 11 (1998), S. 468-471 
    ISSN: 0951-3558
    Source: Emerald Fulltext Archive Database 1994-2005
    Topics: Political Science , Economics
    Notes: Computer systems can support the delivery of services to many separate organizations and the provision of direct critizen access to local services. Discusses the options available for supplying the systems necessary to fulfill these functions. Adopting a middleware approach, allows for relevant information to be extracted from separate systems for display at the front end or enables information entered at the front end to be transferred to one or more of the back-end applications.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Bingley : Emerald
    International journal of public sector management 12 (1999), S. 77-80 
    ISSN: 0951-3558
    Source: Emerald Fulltext Archive Database 1994-2005
    Topics: Political Science , Economics
    Notes: Computer systems can support the delivery of services to many separate organizations and the provision of direct citizen access to local services. Discusses the options available for supplying the systems necessary to fulfill these functions. Adopting a middleware approach, allows for relevant information to be extracted from separate systems for display at the front end or enables information entered at the front end to be transferred to one or more of the back-end applications. The advantages and disadvantages are outlined. An ILSS provides a strategy for using IT to support an operation such as the administration of benefits.
    Type of Medium: Electronic Resource
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  • 5
  • 6
    Publication Date: 2004-11-16
    Description: Human Herpes virus 8 (HHV8) associated multicentric Castleman’s disease (MCD) is an unusual multifocal lymphoid hyperplasia induced by HHV8 infected B cells and associated with a characteristic systemic syndrome attributed to raised levels of IL-6. Most cases develop on a background of immunosuppression, often as a result of human immunodeficiency virus (HIV) infection. Despite the haematological problems at presentation and the difficulties in initial diagnosis, the bone marrow appearances of MCD have not been so far described. In this study we examined the pathology of bone marrow in 13 patients with MCD, 11 of whom had HIV infection, with a view to identifying features that may be helpful in early diagnosis. Patients typically presented with fever, lymphadenopathy, hepatosplenomegaly and cytopaenias. Bone marrow aspirates showed mild to moderate trilineage dysplasia, a mild plasmacytosis, and a mild eosinophilia similar to that seen in HIV infected patients without MCD. Bone marrow biopsies showed hypercellularity, architectural disorganisation, variably prominent dysplasia especially in megakaryocytes, mild eosinophilia, and a polytypic plasmacytosis representing 5–20% of all cells. Interestingly, two cases showed marked megakaryocytic and granulocytic hyperplasia with reticulin fibrosis, similar to the effects of IL-6 on the marrow in experimental systems. Importantly, in 3 cases there were small lymphoid follicles typical of MCD in diagnostic nodal specimens. Depleted germinal centres were surrounded by mantle zones containing scattered large plasmablasts which expressed HHV8 latent nuclear antigen (LNA) and showed lambda immunoglobulin light chain restriction. Furthermore, varying numbers of dispersed interstitial HHV8-LNA positive plasmablasts were present in 11/13 cases. Double immunohistochemical staining confirmed the B cell phenotype of these plasmablasts. The presence of these cells was highly specific for MCD as rare single HHV8 positive cells were identified in only 4 of 66 control bone marrow biopsies from HIV positive patients. Each of these 4 patients had Kaposi’s sarcoma and 1 also had a primary effusion lymphoma. HHV8 positive cells were not identified in bone marrow biopsies from 23 other HIV positive patients with lymphoma. These results suggest that the presence of HHV8 positive plasmablasts in bone marrow biopsies, within characteristic lymphoid follicles and/or the interstitium, is highly specific and sensitive for MCD. As the examination of bone marrow is the first diagnostic test performed in virtually all MCD patients, the features described in this study should greatly enhance the chances of early diagnosis by either providing the tissue diagnosis or prompting a lymph node biopsy and further investigations. Furthermore, the HHV8 positive cells within the bone marrow may play an important pathogenetic role in the haematological disturbances typically seen in MCD.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2014-12-06
    Description: Childhood sporadic Burkitt lymphoma (BL) is a highly aggressive mature B-cell lymphoma. Patients require intensive chemotherapy which results in prolonged periods of hospitalisation for distressing and dangerous side effects. Additionally those with refractory disease or those that relapse have an extremely poor prognosis. As a result, there is an urgent need to develop new targeted treatments that have undergone rigorous pre-clinical evaluation. The aim of this project is to develop improved models for target selection and pre-clinical validation to reduce the failure of translation of novel agents. Two models are being developed. Firstly, xenotransplantation of BL cell lines is being used to optimise transplantation protocols and to provide an orthotopic assay for in vivo functional genomic (RNAi) screening. This is currently being used in genome-wide target identification screens. Secondly, cryopreservation of viable BL blasts is allowing development of a patient-derived xenograft model, suitable for validation of candidate targets by both RNAi and pharmacological inhibition and for testing novel therapeutic agents. The sporadic BL cell lines CA46 and RAMOS have been transplanted into NOD/LtSz-scid IL-2Rg-/- (NSG) and RAG2-/-gc-/- (RAG2) mice at reducing cell doses (105, 104 and 103 cells/mouse). This approach will identify the optimal conditions for orthotopic engraftment. Prior to transplantation, cells were transduced with the lentiviral vector pSLIEW expressing green fluorescent protein (analysis and cell sorting) and firefly luciferase (in vivo bioluminescent imaging). Engraftment was then monitored in real-time using the Caliper in vivo imaging system (IVIS). CA46 and RAMOS cell lines have been transduced with SLIEW, sorted to high purity (〉90%) and engrafted in both NGS and RAG2 mice. IVIS imaging of mice transplanted with CA46 cells showed that rate of engraftment was relative to cell dose. All six mice showed a bioluminescent signal over the femurs by 3 weeks post transplantation, indicative of bone marrow (BM) engraftment. Analysis of BM by flow cytometry confirmed engraftment in the two mice analysed, as determined by GFP positivity and presence of the human B-cell markers CD10, CD19 and CD20. Renal enlargement was observed in all mice analysed, with dense infiltration by mature lymphoid blasts evident microscopically. Immunohistochemistry confirmed infiltration with human CD20 positive cells. Splenic enlargement was observed in five out of six mice and engraftment was again confirmed histologically. Onset of disease was rapid. Mice were killed when they showed signs of ill health (see table). A similar pattern of engraftment was observed in NSG and RAG2 mice transplanted with RAMOS cells, although signal intensity was not relative to transplanted cell dose. Bioluminescent signal over the femur was detected in four out of six mice by 3 weeks post transplantation. NSG and RAG2 mice receiving 103 cells, with no IVIS signal, were negative for BM engraftment by flow cytometry. Renal enlargement was not observed, however focal renal lesions were evident macroscopically in three out of six mice. These lesions were composed of human CD20 positive cells. Splenic enlargement was not observed, although a degree of splenic engraftment was identified histologically. Onset of disease was also rapid. Following the initial cell line model development, we are now able to transplant the first patient-derived BL sample. If successful, primograft material will be labelled with luciferase (pSLIEW) and re-transplanted, allowing in vivo imaging. When combined with in vivo RNAi screening, this advanced pre-clinical model for target selection and validation may help reduce target drop-out during early phase clinical trials. This is a critical step, not only to avoid exposing children to ineffectual and potentially toxic drugs, but also to avoid delay in the development of new effective therapies. Abstract 5501. TableCA46DoseSpleenKidneyBMSurvival (days)RAMOSDoseSpleenKidneyBMSurvival (days) RAG2105+++++na29 RAG2105+++++31104+++++++38104-/+-/++29103+++na38103--/+-39 NSG105++na23 NSG105-+++37104++++++31104-/+-/+na30103+++++na38103-++-39 CD20 positivity for spleen and kidney; none (-), 〈 10% (-/+), 10 - 50% (+), 〉 50% (++), 100% (+++). For BM engraftment (CD10, CD19 and CD20 positive); no engraftment (-), engrafted (+), not assessed (na). Disclosures No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2013-11-21
    Description: Key Points Ten cases of an indolent T-cell lymphoproliferative disease of the gastrointestinal tract are reported. It is important to recognize this condition because it can be mistaken for aggressive T-cell lymphoma, which may lead to unnecessary therapy.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2020-08-27
    Description: Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2014-02-06
    Description: Key Points Diverse patient groups with GATA2 mutation develop mononuclear cytopenia and elevated Flt3 ligand. Progressive cytopenias, rising Flt3 ligand, and terminal differentiation of lymphoid cells accompany clinical progression.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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