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PubMed2005

Mobilization and mechanism of transcription of integrated self-inactivating lentiviral vectors.

Permanent genetic modification of replicating primitive hematopoietic cells by an integrated vector has many potential therapeutic applications. Both oncoretroviral and lentiviral vectors have a predilection for integration into transcriptionally active genes, creating the potential for promoter activation or gene disruption. The use of self-inactivating (SIN) vectors in which a deletion of the enhancer and promoter sequences from the 3' long terminal repeat (LTR) is copied over into the 5' LTR during vector integration is designed to improve safety by reducing the risk of mobilization of the vector genome and the influence of the LTR on nearby cellular promoters. Our results indicate that SIN vectors are mobilized in cells expressing lentiviral proteins, with the frequency of mobilization influenced by features of the vector design. The mechanism of transcription of integrated vector genomes was evaluated using a promoter trap design with a vector encoding tat but lacking an upstream promoter in a cell line in which drug resistance depended on tat expression. In six clones studied, all transcripts originated from cryptic promoters either upstream or within the vector genome. We estimate that approximately 1 in 3,000 integrated vector genomes is transcribed, leading to the inference that activation of cryptic promoters must depend on local features of chromatin structure and the constellation of nearby regulatory elements as well as the nature of the regulatory elements within the vector.

Animals↗
PubMed1993

Integration of simian virus 40 into cellular DNA occurs at or near topoisomerase II cleavage hot spots induced by VM-26 (teniposide).

Inhibition of DNA topoisomerase II in simian virus 40 (SV40)-infected BSC-1 cells with a topoisomerase II poison, VM-26 (teniposide), resulted in rapid conversion of a population of the SV40 DNA into a high-molecular-weight form. Characterization of this high-molecular-weight form of SV40 DNA suggests that it is linear, double stranded, and a recombinant with SV40 DNA sequences covalently joined to cellular DNA. The majority of the integrants contain fewer than two tandem copies of SV40 DNA. Neither DNA-damaging agents, such as mitomycin and UV, nor the topoisomerase I inhibitor camptothecin induced detectable integration in this system. In addition, the recombination junctions within the SV40 portion of the integrants correlate with VM-26-induced, topoisomerase II cleavage hot spots on SV40 DNA. These results suggest a direct and specific role for topoisomerase II and possibly the enzyme-inhibitor-DNA ternary cleavable complex in integration. The propensity of poisoned topoisomerase II to induce viral integration also suggests a role for topoisomerase II in a pathway of chromosomal DNA rearrangements.

Animals↗
PubMed2001

Site-specific genomic integration in mammalian cells mediated by phage phiC31 integrase.

We previously established that the phage phiC31 integrase, a site-specific recombinase, mediates efficient integration in the human cell environment at attB and attP phage attachment sites on extrachromosomal vectors. We show here that phage attP sites inserted at various locations in human and mouse chromosomes serve as efficient targets for precise site-specific integration. Moreover, we characterize native "pseudo" attP sites in the human and mouse genomes that also mediate efficient integrase-mediated integration. These sites have partial sequence identity to attP. Such sites form naturally occurring targets for integration. This phage integrase-mediated reaction represents an effective site-specific integration system for higher cells and may be of value in gene therapy and other chromosome engineering strategies.

3T3 Cells↗
PubMed2005

High-resolution genome-wide mapping of transposon integration in mammals.

The Sleeping Beauty (SB) transposon is an emerging tool for transgenesis, gene discovery, and therapeutic gene delivery in mammals. Here we studied 1,336 SB insertions in primary and cultured mammalian cells in order to better understand its target site preferences. We report that, although widely distributed, SB integration recurrently targets certain genomic regions and shows a small but significant bias toward genes and their upstream regulatory sequences. Compared to those of most integrating viruses, however, the regional preferences associated with SB-mediated integration were much less pronounced and were not significantly influenced by transcriptional activity. Insertions were also distinctly nonrandom with respect to intergenic sequences, including a strong bias toward microsatellite repeats, which are predominantly enriched in noncoding DNA. Although we detected a consensus sequence consistent with a twofold dyad symmetry at the target site, the most widely used sites did not match this consensus. In conjunction with an observed SB integration preference for bent DNA, these results suggest that physical properties may be the major determining factor in SB target site selection. These findings provide basic insights into the transposition process and reveal important distinctions between transposon- and virus-based integrating vectors.

Animals↗
PubMed1994

Coexistence of episomal and integrated HPV16 DNA in squamous cell carcinoma of the cervix.

AIMS: To investigate the integration of human papillomavirus (HPV)16 in 13 HPV16 positive cervical squamous carcinomas. METHODS: Samples were investigated by Southern blot analysis of the Pst I digestion pattern, two-dimensional gel-electrophoresis, and in situ hybridisation. RESULTS: Integration of HPV16 was found in all cases. In 12 biopsy specimens episomal HPV16 DNA and integrated HPV16 DNA were seen. The episomal DNA occurred as dimers and multimers. In situ hybridisation showed that both integrated and episomal HPV16 DNA were present in the same cell in most tumour cell nuclei. CONCLUSIONS: An intact episomal E2 gene is present in most cases of these cervical cancers, and could therefore replace the regulatory function of an integrated defective E2 gene.

Blotting, Southern↗
PubMedDate not supplied

Using the IHE scheduled work flow integration profile to drive modality efficiency.

The IHE (Integrating the Healthcare Enterprise) Scheduled Work Flow integration profile describes a communication and work flow environment that provides benefits for radiology departments who want to standardize system software. The IHE technical framework defines this environment by specifying the systems involved and the messages exchanged by those systems. The Modality Worklist is a key component of the Scheduled Work Flow integration profile that allows an operator at each modality in the department to retrieve a list of scheduled procedure steps to perform and to automate the process of entering the correct patient identification information in all the images created with the modality. The IHE technical framework defines two transactions used by the modality to tell the Image Manager and Order Filler what was performed and how many images were acquired: the Modality Procedure Step in Progress and Modality Procedure Step Completed. Users who specify the Scheduled Work Flow integration profile will benefit immediately by achieving a certain baseline of functionality. However, users will derive further benefits of increased operational efficiency through negotiation with the providers of software solutions. The integration profile defines features that are optional; users should evaluate these features and request those that are determined to be beneficial.

Efficiency, Organizational↗
PubMed2001

Housing satisfaction and service use by mentally ill persons in community integrated living arrangements.

OBJECTIVE: In response to provisions of the Omnibus Budget Reconciliation Act of 1987 that sought to reduce the number of mentally ill persons in nursing homes, the Illinois Department of Human Services in 1989 developed small-scale residential treatment programs known as community integrated living arrangements. This study examined satisfaction with residential services and days of hospitalization among residents of these facilities. METHODS: Seventy-four residents from nine randomly selected community integrated living arrangement facilities were surveyed with the Quality of Life Interview to determine their satisfaction with their residence. Data on hospitalization before and after program placement were obtained from residents' charts and from an Illinois Department of Human Services database on utilization of state-operated facilities. RESULTS: Residents of community integrated living arrangement facilities had a mean rating of satisfaction with their residence of 5.2, "mostly satisfied," on a scale from 1 to 7. Residents with continuous supervision and those with intermittent supervision were equally pleased with their living arrangements. Residents' hospital use decreased from a mean of 47.7 days during the year before program placement to 5.3 days during their first year in the program. CONCLUSIONS: The level of satisfaction with the community integrated living arrangement residences was fairly high and was comparable to levels reported in related research on independent living arrangements. The decrease in residents' hospital use in the year after program placement suggests that the community integrated living arrangements help maintain severely mentally ill individuals in the community.

Chicago↗
PubMed2002

Service systems integration and outcomes for mentally ill homeless persons in the ACCESS program. Access to Community Care and Effective Services and Supports.

OBJECTIVE: The authors evaluated the second of the two core questions around which the ACCESS (Access to Community Care and Effective Services and Supports) evaluation was designed: Does better integration of service systems improve the treatment outcomes of homeless persons with severe mental illness? METHODS: The ACCESS program provided technical support and about $250,000 a year for four years to nine sites to implement strategies to promote systems integration. These sites, along with nine comparison sites, also received funds to support outreach and assertive community treatment programs to assist 100 clients a year at each site. Outcome data were obtained at baseline and three and 12 months later from 7,055 clients across four annual cohorts at all sites. RESULTS: Clients at all sites demonstrated improvement in outcome measures. However, the clients at the experimental sites showed no greater improvement on measures of mental health or housing outcomes across the four cohorts than those at the comparison sites. More extensive implementation of systems integration strategies was unrelated to these outcomes. However, clients of sites that became more integrated, regardless of the degree of implementation or whether the sites were experimental sites or comparison sites, had progressively better housing outcomes. CONCLUSIONS: Interventions designed to increase the level of systems integration in the ACCESS demonstration did not result in better client outcomes.

Community Mental Health Services↗
PubMed1997

Creating integrated service systems for homeless persons with mental illness: the ACCESS Program. Access to Community Care and Effective Services and Supports.

The Access to Community Care and Effective Services and Supports (ACCESS) demonstration program was initiated in 1993 by the U.S. Department of Health and Human Services as part of a national agenda to end homelessness among persons with serious mental illness. Demonstration projects have been established in nine states to develop integrated systems of care for this population. This paper provides an overview of the ACCESS program and presents definitions of services integration and systems integration. Evaluating the effectiveness of integration strategies is a critical aspect of the program. The authors describe the evaluation design and the integration strategies being evaluated and summarize findings from a formative evaluation of the project's first two years. The evaluation revealed several problems that were addressed by providing technical assistance to the states. States were helped to articulate a broader mission of addressing system-level barriers, develop an expanded plan, strengthen the authority of interagency councils, involve leaders at the state and agency levels, and develop joint funding strategies.

Adult↗
PubMed2006

Integrating asthma prevention and control: the roles of the coalition.

Activities addressing pediatric asthma are often fragmented. Allies coalitions promoted integration, the alignment of concurrent asthma control activities across and within sectors. Systems integration describes activities from an organizational perspective. Activities included developing a shared vision, promoting consistency in asthma education and self-management support, improving adherence to clinical guidelines, advocating jointly for policy change, and seeking funds collaboratively. Service integration describes activities focused on ensuring seamless, comprehensive services through coordination within and across organizations. Activities included use of community health workers (CHWs) and nurses for care coordination, program cross-referral, and clinical quality improvement. Integration is a sustainable role for coalitions as it requires fewer resources than service delivery and results in institutionalization of system changes. Organizations that seek integration of asthma control may benefit.

Asthma↗
PubMed2002

Lentiviral vector transduction of NOD/SCID repopulating cells results in multiple vector integrations per transduced cell: risk of insertional mutagenesis.

Efficient vector transduction of hematopoietic stem cells is a requirement for successful gene therapy of hematologic disorders. We asked whether human umbilical cord blood CD34(+)CD38(lo) nonobese diabetic/severe combined immunodeficiency (NOD/SCID) repopulating cells (SRCs) could be efficiently transduced using lentiviral vectors, with a particular focus on the average number of vector copies integrating into these primitive progenitor cells. Mouse bone marrow was analyzed by fluorescence-activated cell-sorter scanner and by semiquantitative polymerase chain reaction (PCR) to determine the transduction efficiency into SRCs. Lentiviral vector transduction resulted in an average of 22% (range, 3%-90%) of the human cells expressing green fluorescent protein (GFP), however, multiple vector copies were present in human hematopoietic cells, with an average of 5.6 +/- 3.3 (n = 12) copies per transduced cell. To confirm the ability of lentiviral vectors to integrate multiple vector copies into SRCs, linear amplification mediated (LAM)-PCR was used to analyze the integration site profile of a selected mouse showing low-level engraftment and virtually all human cells expressing GFP. Individually picked granulocyte macrophage colony-forming unit colonies derived from the bone marrow of this mouse were analyzed and shown to have the same 5 vector integrants within each colony. Interestingly, one integration site of the 5 that were sequenced in this mouse was located in a known tumor-suppressor gene, BRCA1. Therefore, these findings demonstrate the ability of lentiviral vectors to transduce multiple copies into a subset of NOD/SCID repopulating cells. While this is efficient in terms of transduction and transgene expression, it may increase the risk of insertional mutagenesis.

ADP-ribosyl Cyclase↗
PubMed2006

IntNetDB v1.0: an integrated protein-protein interaction network database generated by a probabilistic model.

BACKGROUND: Although protein-protein interaction (PPI) networks have been explored by various experimental methods, the maps so built are still limited in coverage and accuracy. To further expand the PPI network and to extract more accurate information from existing maps, studies have been carried out to integrate various types of functional relationship data. A frequently updated database of computationally analyzed potential PPIs to provide biological researchers with rapid and easy access to analyze original data as a biological network is still lacking. RESULTS: By applying a probabilistic model, we integrated 27 heterogeneous genomic, proteomic and functional annotation datasets to predict PPI networks in human. In addition to previously studied data types, we show that phenotypic distances and genetic interactions can also be integrated to predict PPIs. We further built an easy-to-use, updatable integrated PPI database, the Integrated Network Database (IntNetDB) online, to provide automatic prediction and visualization of PPI network among genes of interest. The networks can be visualized in SVG (Scalable Vector Graphics) format for zooming in or out. IntNetDB also provides a tool to extract topologically highly connected network neighborhoods from a specific network for further exploration and research. Using the MCODE (Molecular Complex Detections) algorithm, 190 such neighborhoods were detected among all the predicted interactions. The predicted PPIs can also be mapped to worm, fly and mouse interologs. CONCLUSION: IntNetDB includes 180,010 predicted protein-protein interactions among 9,901 human proteins and represents a useful resource for the research community. Our study has increased prediction coverage by five-fold. IntNetDB also provides easy-to-use network visualization and analysis tools that allow biological researchers unfamiliar with computational biology to access and analyze data over the internet. The web interface of IntNetDB is freely accessible at http://hanlab.genetics.ac.cn/IntNetDB.htm. Visualization requires Mozilla version 1.8 (or higher) or Internet Explorer with installation of SVGviewer.

Algorithms↗
PubMed2006

PathSys: integrating molecular interaction graphs for systems biology.

BACKGROUND: The goal of information integration in systems biology is to combine information from a number of databases and data sets, which are obtained from both high and low throughput experiments, under one data management scheme such that the cumulative information provides greater biological insight than is possible with individual information sources considered separately. RESULTS: Here we present PathSys, a graph-based system for creating a combined database of networks of interaction for generating integrated view of biological mechanisms. We used PathSys to integrate over 14 curated and publicly contributed data sources for the budding yeast (S. cerevisiae) and Gene Ontology. A number of exploratory questions were formulated as a combination of relational and graph-based queries to the integrated database. Thus, PathSys is a general-purpose, scalable, graph-data warehouse of biological information, complete with a graph manipulation and a query language, a storage mechanism and a generic data-importing mechanism through schema-mapping. CONCLUSION: Results from several test studies demonstrate the effectiveness of the approach in retrieving biologically interesting relations between genes and proteins, the networks connecting them, and of the utility of PathSys as a scalable graph-based warehouse for interaction-network integration and a hypothesis generator system. The PathSys's client software, named BiologicalNetworks, developed for navigation and analyses of molecular networks, is available as a Java Web Start application at http://brak.sdsc.edu/pub/BiologicalNetworks.

Computer Graphics↗
PubMed2006

Psychosocial environment for the integrated education opportunities of the disabled in Lithuania.

BACKGROUND: The policy of the diminution of the social isolation of the disabled is the main objective of the strategy of the EU new policy concerning the disabled. Lithuanian society faces this objective as well. For this reason, this study aiming at providing the theoretical basis for and predicting the possible psycho-social environment in an integrated education system, as well as at the evaluation of the reasons for the formation of a positive approach to the disabled, is especially relevant, since it creates the prerequisites for the optimisation of the process of the integration of disabled schoolchildren into the general system of education. METHOD: The sample of the study consisted of 2471 children from the same schools: not integrated (1958), integrated (126) and special schools (382). Empirical methods: questionnaire poll, comparative analysis. The statistical analysis was carried out using SAS. RESULTS: Our study showed that the majority of schoolchildren without disabilities and disabled schoolchildren have positive intentions for interpersonal interactions (>82%) and positive emotions (>69%) independently of the discrepant character of interpersonal contacts, different conditions of education and family life, and despite of low level of knowledge. CONCLUSION: The results of the study confirmed positive intentions for interpersonal interaction between disabled schoolchildren and schoolchildren without disabilities, as well as a positive character of emotions, and disprove the unsound myth of the opponents of the social integration of the disabled stating that disabled children in comprehensive schools would undoubtedly experience offence from their peers without disabilities.

Adolescent↗
PubMed2004

From parallel practice to integrative health care: a conceptual framework.

BACKGROUND: "Integrative health care" has become a common term to describe teams of health care providers working together to provide patient care. However this term has not been well-defined and likely means many different things to different people. The purpose of this paper is to develop a conceptual framework for describing, comparing and evaluating different forms of team-oriented health care practices that have evolved in Western health care systems. DISCUSSION: Seven different models of team-oriented health care practice are illustrated in this paper: parallel, consultative, collaborative, coordinated, multidisciplinary, interdisciplinary and integrative. Each of these models occupies a position along the proposed continuum from the non-integrative to fully integrative approach they take to patient care. The framework is developed around four key components of integrative health care practice: philosophy/values; structure, process and outcomes. SUMMARY: This framework can be used by patients and health care practitioners to determine what styles of practice meet their needs and by policy makers, healthcare managers and researchers to document the evolution of team practices over time. This framework may also facilitate exploration of the relationship between different practice models and health outcomes.

Complementary Therapies↗
PubMed2005

Integrating complementary and alternative medicine into academic medical centers: experience and perceptions of nine leading centers in North America.

BACKGROUND: Patients across North America are using complementary and alternative medicine (CAM) with increasing frequency as part of their management of many different health conditions. The objective of this study was to develop a guide for academic health sciences centers that may wish to consider starting an integrative medicine program. METHODS: We queried North American leaders in the field of integrative medicine to identify initial sites. Key stakeholders at each of the initial sites visited were then asked to identify additional potential study sites (snowball sampling), until no new sites were identified. We conducted structured interviews to identify critical factors associated with success and failure in each of four domains: research, education, clinical care, and administration. During the interviews, field notes were recorded independently by at least two investigators. Team meetings were held after each visit to reach consensus on the information recorded and to ensure that it was as complete as possible. Content analysis techniques were used to identify key themes that emerged from the field notes. RESULTS: We identified ten leading North American integrative medical centers, and visited nine during 2002-2003. The centers visited suggested that the initiation of an integrative medicine program requires a significant initial outlay of funding and a motivated "champion". The centers had important information to share regarding credentialing, medico-legal issues and billing for clinical programs; identifying researchers and research projects for a successful research program; and strategies for implementing flexible educational initiatives and establishing a functional administrative structure. CONCLUSION: Important lessons can be learned from academic integrative programs already in existence. Such initiatives are timely and feasible in a variety of different ways and in a variety of settings.

Academic Medical Centers↗
PubMed2006

Collaborating while competing? The sustainability of community-based integrated care initiatives through a health partnership.

BACKGROUND: To improve health-care delivery, care providers must base their services on community health needs and create a seamless continuum of care in which these needs can be met. Though, it is not obvious that providers apply this vision. Experiments with regulated competition in the health systems of many industrialized countries trigger providers to optimize individual organizational goals rather than improve population health from a community perspective. Thus, a tension exists between the need to collaborate and the need to compete. Despite or because of this tension, community health partnerships are being promoted, and this should enforce a needs-based and integrated care delivery. METHODS: In this single case study, we retrospectively explored how local health-care providers in Amsterdam collaborated for more than 30 years, interacting with the changes to the national health-care system. In-depth analysis of interviews, documents and literature focused on the complex relationship between the activities of this health partnership, its nature and its changing context. RESULTS: The findings revealed that the partnership itself was successful and sustainable over time, although the partnership lost its initial broad explorative nature and narrowed its strategic focus towards care of the elderly. Furthermore, the realized projects--although they enforced integrated care--lost their community-based character. This declining scope of community-based integrated care seems to have been influenced by the incremental introduction of regulated competition in Dutch health care. This casts doubts on the ability of health partnerships to apply a vision of community-based integrated care within the context of competition. CONCLUSION: Collaborating health-care providers can build seamless continuums of care in a competitive environment, although these will not automatically maximize community health with limited resources. Active policies with regard to health system design, incentive structures and population-based performance measures are warranted in order to insure that community-based integrated care through health partnerships will be more than just policy rhetoric.

Aged↗
PubMed2006

Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin.

BACKGROUND: The early events of the HIV-1 life cycle include entry of the viral core into target cell, assembly of the reverse transcription complex (RTCs) performing reverse transcription, its transformation into integration-competent complexes called pre-integration complexes (PICs), trafficking of complexes into the nucleus, and finally integration of the viral DNA into chromatin. Molecular details and temporal organization of these processes remain among the least investigated and most controversial problems in the biology of HIV. RESULTS: To quantitatively evaluate maturation and nuclear translocation of the HIV-1 RTCs, nucleoprotein complexes isolated from the nucleus (nRTC) and cytoplasm (cRTC) of HeLa cells infected with MLV Env-pseudotyped HIV-1 were analyzed by real-time PCR. While most complexes completed reverse transcription in the cytoplasm, some got into the nucleus before completing DNA synthesis. The HIV-specific RNA complexes could get into the nucleus when reverse transcription was blocked by reverse transcriptase inhibitor, although nuclear import of RNA complexes was less efficient than of DNA-containing RTCs. Analysis of the RTC nuclear import in synchronized cells infected in the G2/M phase of the cell cycle showed enrichment in the nuclei of RTCs containing incomplete HIV-1 DNA compared to non-synchronized cells, where RTCs with complete reverse transcripts prevailed. Immunoprecipitation assays identified viral proteins IN, Vpr, MA, and cellular Ini1 and PML associated with both cRTCs and nRTCs, whereas CA was detected only in cRTCs and RT was diminished in nRTCs. Cytoplasmic maturation of the complexes was associated with increased immunoreactivity with anti-Vpr and anti-IN antibodies, and decreased reactivity with antibodies to RT. Both cRTCs and nRTCs carried out endogenous reverse transcription reaction in vitro. In contrast to cRTCs, in vitro completion of reverse transcription in nRTCs did not increase their integration into chromatin. CONCLUSION: These results suggest that RTC maturation occurs predominantly in the cytoplasm. Immature RTCs containing RT and incomplete DNA can translocate into the nucleus during mitosis and complete reverse transcription, but are defective for integration.

Cell Division↗