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PubMed1994

Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas.

Infection with human immunodeficiency virus type 1 (HIV-1) is associated with a high incidence of lymphoma. Typically, the lymphomas are B-cell in origin, and although they occur in the setting of HIV-1 infection, historical studies have found no evidence for the presence of HIV-1 within the transformed B-cells. We describe a new class of large cell lymphoma wherein HIV p24 expression within the tumor specimens was found to be extremely high. In the first case, HIV was expressed in the tumor-associated transformed T-cells. In three other cases, HIV was found to be highly expressed in tumor-associated macrophages. These tumors exhibited a mixed immunophenotype histologically. Analysis by inverse polymerase chain reaction, using HIV long terminal repeat primers, demonstrated monoclonal HIV integration sites for all four tumors. Direct sequencing of the T-cell lymphoma inverse polymerase chain reaction products identified the HIV integration site within the fur gene, just upstream from the c-fes/fps protooncogene. Using segments of the fur gene as a probe, the other three monoclonal integration sites mapped to the same region. Although the integration and up-regulation of c-fes/fps was localized to the tumor cells within the T-cell lymphoma, the cells containing the monoclonal HIV in the other mixed immunophenotype lymphomas are currently unknown. These observations suggest that HIV may contribute directly to lymphomagenesis and identify a common site of HIV integration within a subset of acquired immunodeficiency syndrome lymphoma.

Base Sequence↗
PubMed1993

[Trans-activating function of integrated hepatitis B virus].

HBV DNAs are often found in integrated form in human hepatocellular carcinoma (HCC). Since transactivation of the X gene has been shown, surveys of collections of HBV integrants with flanking cellular sequence were performed to clarify whether they might exhibit a transactivation. The majority of integrants showed transactivation effect which may to be due to the virus-cell fusion products derived from the 3' truncated X gene. Additionally, it has been found that 3' truncated preS2/S gene in the integrant encodes a transactivator to which C terminal truncation is essential. These results suggest that the transactivating effect of integrated HBV DNAs plays a role in hepatocarcinogenesis by activating cellular genes.

Carcinoma, Hepatocellular↗
PubMed1995

The impact of IAIMS on the work of information experts. Integrated Advanced Information Management Systems.

Integrated Advanced Information Management Systems (IAIMS) programs differ but have certain characteristics in common. Technological and organizational integration are universal goals. As integration takes place, what happens to those implementing the vision? A survey of 125 staff members, or information experts, involved in information or informatics at an IAIMS-funded institution was conducted during the last year of the implementation phase. The purpose was to measure the impact of IAIMS on the jobs of those in the library and related service units, and the computing, telecommunications, and health informatics divisions. The researchers used newly developed scales measuring levels of integration (knowledge of and involvement with other departments), customer orientation (focus on the user), and informatedness (changes in the nature of work beyond automation of former routines). Ninety-four percent of respondents indicated that their jobs had changed a great deal; the changes were similar regardless of division. To further investigate the impact of IAIMS on librarians in particular, a separate skills survey was conducted. The IAIMS librarians indicated that technology and training skills are especially needed in the new, integrated environment.

Analysis of Variance↗
PubMed1995

Problems with integrating legacy systems.

The economic and organizational impact of imposing state-of-the-art technology to the large number of proprietary legacy systems operational in most hospitals requires integrated clinical professional workstations to provide flexible encapsulation mechanisms for these systems rather than reengineering these systems to this new technology. In this paper the implications of different input/output and translation models of legacy systems for their integration into a clinical workstation is described. Examples of legacy systems that have been integrated in the HERMES clinical workstation are presented as examples of the range of difficulties one might encounter. The features that an integrated workstation should offer for integrating a broad range of legacy systems are also addressed in this paper.

Computer Systems↗
PubMed1995

An object-oriented model for the integration of knowledge-based systems.

This paper discusses functional integration, data integration, and knowledge integration as basic problems concerning the integration of knowledge-based systems into a hospital information system. A system model for an integrated knowledge-based system is introduced. Object-oriented models for the systems meta-database, patient database, and knowledge-base are presented. It is expected that the reader is familiar with the basic concepts of the object-oriented approach.

Artificial Intelligence↗
PubMed1996

Integration of adeno-associated virus vectors in CD34+ human hematopoietic progenitor cells after transduction.

Gene transfer vectors based on adeno-associated virus (AAV) appear promising because of their high transduction frequencies regardless of cell cycle status and ability to integrate into chromosomal DNA. We tested AAV-mediated gene transfer into a panel of human bone marrow or umbilical cord-derived CD34+ hematopoietic progenitor cells, using vectors encoding several transgenes under the control of viral and cellular promoters. Gene transfer was evaluated by (1) chromosomal integration of vector sequences and (2) analysis of transgene expression. Southern hybridization and fluorescence in situ hybridization analysis of transduced CD34 genomic DNA showed the presence of integrated vector sequences in chromosomal DNA in a portion of transduced cells and showed that integrated vector sequences were replicated along with cellular DNA during mitosis. Transgene expression in transduced CD34 cells in suspension cultures and in myeloid colonies differentiating in vitro from transduced CD34 cells approximated that predicted by the multiplicity of transduction. This was true in CD34 cells from different donors, regardless of the transgene or selective pressure. Comparisons of CD34 cell transduction either before or after cytokine stimulation showed similar gene transfer frequencies. Our findings suggest that AAV transduction of CD34+ hematopoietic progenitor cells is efficient, can lead to stable integration in a population of transduced cells, and may therefore provide the basis for safe and efficient ex vivo gene therapy of the hematopoietic system.

Amino Acid Sequence↗
PubMed1995

Integration of glucoamylase gene from Aspergillus niger into Saccharomyces cerevisiae genome and its stable expression.

Starch digestible delta-integrants were constructed by integrative transformation of a linear YIP plasmid carrying Aspergillus niger glucoamylase cDNA under the control of the MF alpha 1 promoter and its prepro signal and the delta sequence of the Ty element from yeast. The integration of glucoamylase cDNA into Saccharomyces cerevisiae was identified by Southern analysis. The secreted glucoamylase activity of integrants in the medium with soluble starch as a carbon source reached 2.5 u/ml. After ten times of successive transfers in a nonselective medium, the activity of secreted glucoamylase of integrant was approximately at its original level.

Aspergillus niger↗
PubMed1997

Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease.

We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/ lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.

Aged↗
PubMed1997

High-level globin gene expression mediated by a recombinant adeno-associated virus genome that contains the 3' gamma globin gene regulatory element and integrates as tandem copies in erythroid cells.

Recombinant adeno-associated virus (rAAV) vectors are being evaluated for gene therapy applications. Using purified rAAV containing a mutationally marked globin gene (A(gamma)*) and sites 2, 3, and 4 from the locus control region (rHS432A(gamma)*), but lacking a drug-resistance gene, we investigated the relationship between multiplicity of infection (MOI), gene expression, and unselected genome integration in erythroid cells. Most primary erythroid progenitors were transduced as reflected by A(gamma)* mRNA in mature colonies but only at an MOI of greater than 5 x 10(7). Using immortalized erythroleukemia cells as a model, we found that fewer than one half of the colonies that contained the A(gamma)* transcript had an integrated, intact rHS432A(gamma)* genome. rHS432A(gamma)* integrated as a single copy with expression at approximately 50% the level of an endogenous gamma globin gene. A second vector, rHS32A(gamma)*3'RE, containing the regulatory element (RE) from 3' to the chromosomal A(gamma) globin gene, integrated as an intact, tandem head to tail concatamer with a median copy number of 6 with variable expression per copy ranging from approximately onefold to threefold that of an endogenous y globin gene. These results establish that purified rAAV can be used to achieve integration and functional expression of a globin gene in erythroid cells, but only when high MOIs are used.

Dependovirus↗
PubMed1997

Integrated delivery systems: the future for Canadian health care reform?

Influential health care leaders have recently said that it is a misnomer to refer to the current muddle of Canadian health care services and providers as a "system." Consequently, Canadian professionals and citizens have been exposed to increasing numbers of publications recommending that a move to fully and properly Integrated Delivery Systems (IDS) could rectify many of the difficulties with which our current non-system is faced. There is, however, a skepticism that the 'IDS movement' is just another in a series of fads that will come and go, without positively impacting the health care system. In this article, the authors provide arguments for why integration is critically required, an overview of types of integration, the qualities of a fully integrated system, and a discussion of the advantages and cautions to proceeding with IDS development. They conclude with the argument that--despite potential obstacles--the possible advantages of IDSs make it vital that we pursue integration.

Canada↗
PubMed1997

Meeting clinician information needs by integrating access to the medical record and knowledge resources via the Web.

MINDscape is a web based integrated interface to diverse sources of clinical information including both patient specific information (electronic medical record) as well as medical knowledge (the "digital library") to provide "just in time" information at the point of care. It was developed at the University of Washington to meet clinical information needs both as identified locally and by a review of the literature. Beta testing by over 600 clinicians is in progress and medical centers wide access scheduled for Fall 1997. We describe the information needs we sought to meet and the ongoing evaluation approach we are taking to ensure the information needs of a diverse group of clinicians are met. The iterative evolution of the interface from prototype, to alpha to large scale beta testing is reported. Integration of information occurs at three levels: integration of information by patient, integration of information by provider, and integration of patient specific information with medical reference material and decision support tools.

Computer Communication Networks↗
PubMed1998

An integrated approach for a knowledge-based clinical workstation: architecture and experience.

Today, the demand for medical decision support to improve the quality of patient care and to reduce costs in health services is generally recognized. Nevertheless, decision support is not yet established in daily routine within hospital information systems which often show a heterogeneous architecture but offer possibilities of interoperability. Currently, the integration of decision support functions into clinical workstations is the most promising way. Therefore, we first discuss aspects of integrating decision support into clinical workstations including clinical needs, integration of database and knowledge base, knowledge sharing and reuse and the role of standardized terminology. In addition, we draw up functional requirements to support the physician dealing with patient care, medical research and administrative tasks. As a consequence, we propose a general architecture of an integrated knowledge-based clinical workstation. Based on an example application we discuss our experiences concerning clinical applicability and relevance. We show that, although our approach promotes the integration of decision support into hospital information systems, the success of decision support depends above all on an adequate transformation of clinical needs.

Artificial Intelligence↗
PubMed2003

White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study.

BACKGROUND: Imaging and postmortem studies suggest that frontal lobe white matter (FLWM) volume expands until about the age of 44.6 years and then declines. Postmortem evidence indicates that the structural integrity of myelin sheaths deteriorates during normal aging, especially in late myelinating regions such as the frontal lobes. OBJECTIVES: To assess the integrity of FLWM by magnetic resonance imaging and, thus, to provide an important index of brain aging and its relationship to Alzheimer disease (AD). DESIGN: Cross-sectional study. SETTING: Two metropolitan university hospitals and AD research centers. PARTICIPANTS: Two hundred fifty-two healthy adults (127 men and 125 women), aged 19 to 82 years, and 34 subjects with AD (16 men and 18 women), aged 59 to 85 years. MAIN OUTCOME MEASURE: Calculated transverse relaxation rate (R( 2)) of the FLWM (an indirect measure of the structural integrity of white matter). RESULTS: As expected from prior imaging data on FLWM volume, the quadratic function best represented the relationship between age and the FLWM R(2) (P<.001). In healthy individuals, the FLWM R(2) increased until the age of 38 years and then declined markedly with age. The R( 2) of subjects with AD was significantly lower than that of a group of healthy control subjects who were of similar age and sex (P<.001). CONCLUSIONS: The R(2) changes in white matter suggest that the healthy adult brain is in a constant state of change, roughly defined as periods of maturation continuing into middle age followed by progressive loss of myelin integrity. Clinically diagnosed AD is associated with more severe myelin breakdown. Noninvasive measures, such as the determination of the R(2), may have the potential to track prospectively the trajectory of deteriorating white matter integrity during normal aging and the development of AD and, thus, may be a useful marker for medication development aimed at the prevention of AD.

Adult↗
PubMed1997

Clonal integration and expression of human T-cell lymphotropic virus type I in carriers detected by polymerase chain reaction and inverse PCR.

Adult T-cell leukemia (ATL) is a neoplasm of mature helper (CD4) T lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) has been suggested to be the causative virus of ATL. HTLV-I integrates its proviruses into random sites in host chromosomal DNA. Clonal integration has been observed in patients with ATL, including smoldering, chronic, and acute states. However, random and/or polyclonal integration has only been reported in a few asymptomatic HTLV-I carriers. To clarify the clonality of HTLV-I-infected cells in carriers, we used an inverse polymerase chain reaction (IPCR), which is more sensitive than Southern blot analysis. We used the peripheral blood momonuclear cells (PBMC) from 16 asymptomatic carriers and the separated CD4-positive cells. No cases showed either a monoclonal or polyclonal integration of the HTLV-I provirus by Southern blot. But, using IPCR, 7 of 16 cases showed either mono- or oligoclonal integration. In addition, the populations of clonal provirus in the total PBMC were frequently different from those in the CD4-positive cells. Three cases showed expression of HTLV-I tax/rex mRNA in the total PBMC, but no such expression was found in CD4-positive cells. In this study, an unexpected frequency of clonal HTLV-I provirus DNA was observed in HTLV-I carriers. These findings indicate that the clonal but nonmalignant proliferation of HTLV-I-infected cells already occurs even in HTLV-I carriers, and therefore that some other step is necessary to induce malignant proliferation.

Adolescent↗
PubMed1998

Gene trap integrations expressed in the developing heart: insertion site affects splicing of the PT1-ATG vector.

We describe the characterisation of three gene trap integrations in embryonic stem cells in which the lacZ reporter gene is repressed by retinoic acid (RA) in vitro and is expressed in the developing heart in vivo. In one of these, the gene trap vector has integrated into a gene that is located on chromosome 17 and is homologous to the human transcription factor gene, TFEB. Embryonic and adult cardiac expression of both the fusion transcript and the endogenous gene was confirmed. However, we show that the integration has not resulted in a null allele, because wild type transcripts, possibly resulting from splicing around the vector, are observed in homozygous tissue. The other two cardiac-expressing gene trap integrations have occurred into exons on chromosomes 1 and 5 and have used cryptic donor sites within the vector to generate functional fusion transcripts. One of these exon integrations results in a lethal neonatal phenotype.

Animals↗
PubMed2002

Fabrication of a glass-implemented microcapillary electrophoresis device with integrated contactless conductivity detection.

Glass microdevices for capillary electrophoresis (CE) gained a lot of interest in the development of micrototal analysis systems (microTAS). The fabrication of a microTAS requires integration of sampling, chemical separation and detection systems into a microdevice. The integration of a detection system into a microchannel, however, is hampered by the lack of suitable microfabrication technology. Here, a microfabrication method for integration of insulated microelectrodes inside a leakage-free microchannel in glass is presented. A combination of newly developed technological approaches, such as low-temperature glass-to-glass anodic bonding, channel etching, fabrication of buried metal interconnects, and deposition of thin plasma-enhanced chemical vapour deposition (PECVD) silicon carbide layers, enables the fabrication of a CE microdevice with an integrated contactless conductivity detector. The fabrication method of this CE microdevice with integrated contactless conductivity detector is described in detail. Standard CE separations of three inorganic cations in concentrations down to 5 microM show the viability of the new microCE system.

Biosensing Techniques↗
PubMed2002

Specific enzymatic treatment of bovine and human articular cartilage: implications for integrative cartilage repair.

OBJECTIVE: Chondrocyte death in articular cartilage wound edges and the subsequent lack of matrix-producing cells in the interface area are considered to be a major cause of impaired cartilage wound healing and poor integrative cartilage repair. This study was undertaken to investigate whether enzymatic matrix digestion can be used to stimulate integrative cartilage repair via a mechanism of local increase in the amount of vital chondrocytes in cartilage wound edges. METHODS: Full-thickness bovine articular cartilage samples were cultured in vitro for 14 days in standard medium. Samples were either left untreated or treated for 48 hours with 0.3% hyaluronidase or 30 units/ml highly purified collagenase VII. Nuclear and cytoplasmic changes were analyzed to determine cell viability, and the number of vital chondrocytes in wound edges was determined. Subsequently, we investigated whether increased chondrocyte density in the lesion edges resulted in better wound healing. Finally, full-thickness human tibial plateau cartilage explants were tested with similar enzyme treatment protocols to determine the clinical value of our results. RESULTS: In bovine explants a rapid onset of chondrocyte death was observed in wound edges in all treatment groups. This led to low chondrocyte density in a band of 0-150 microm from the lesion edges in untreated and hyaluronidase-treated explants. Treatment with 30 units/ml collagenase resulted in a significant increase in chondrocyte density in this area. The integration experiments demonstrated improved integration of the lesion edges after treatment with collagenase. In human articular cartilage an increase in chondrocyte density at the lesion edges could also be achieved, but only when proteoglycans were depleted from the wound edges prior to collagenase treatment. CONCLUSION: Treatment with highly purified collagenase improves integrative cartilage repair, possibly by increasing the cell density at cartilage wound edges.

Adult↗
PubMed2003

Maintaining data integrity in microarray data management.

Gene expression microarrays are a relatively new technology, dating back just a few years, yet they have already become a very widely used tool in biology, and have evolved to a wide range of applications well beyond their original design intent. However, while the use of microarrays has expanded, and the issues of performance optimization have been intensively studied, the fundamental issue of data integrity management has largely been ignored. Now that performance has improved so greatly, the shortcomings of data integrity control methods constitute a greater percent of the stumbling blocks for investigators. Microarray data are cumbersome, and the rule up to this point has mostly been one of hands-on transformations, leading to human errors which often have dramatic consequences. We show in this review that the time lost on such mistakes is enormous and dramatically affects results; therefore, mistakes should be mitigated in any way possible. We outline the scope of the data integrity issue, to survey some of the most common and dangerous data transformations, and their shortcomings. To illustrate, we review some case studies. We then look at the work done by the research community on this issue (which admittedly is meager up to this point). Some data integrity issues are always going to be difficult, while others will become easier-one of our goals is to expedite the use of integrity control methods. Finally, we present some preliminary guidelines and some specific approaches that we believe should be the focus of future research.

Algorithms↗