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At least 1,441 records · Page 80Linked to original sources
PubMed2005

Retroviral DNA integration--mechanism and consequences.

Integration of retroviral cDNA into the host cell chromosome is an essential step in its replication. This process is catalyzed by the retroviral integrase protein, which is conserved among retroviruses and retrotransposons. Integrase binds viral and host DNA in a complex, called the preintegration complex (PIC), with other viral and cellular proteins. While the PIC is capable of directing integration of the viral DNA into any chromosomal location, different retroviruses have clear preferences for integration in or near particular chromosomal features. The determinants of integration site selection are under investigation but may include retrovirus-specific interactions between integrase and tethering factors bound to the host cell chromosomes. Research into the mechanisms of retroviral integration site selection has shed light on the phenomena of insertional mutagenesis and viral latency.

DNA↗
PubMed2003

Breaking down barriers: integrating health and care services for older people in England.

Like many other post-industrial societies, England is facing demographic and political pressures to reduce the fragmentation of services for older people. Moreover, current government policies emphasise collaboration and 'partnership', particularly between health and social care services. Recently, two new policy initiatives have enabled the full integration of services to take place, involving formerly separate health and social care organisations-between family doctors (general practitioners) and community health services, and between health and social services organisations. Both initiatives also allow the pooling of previously separate funding streams. This paper presents findings from evaluations of these two initiatives. Drawing on this evidence, the paper concludes that structural integration can transform preoccupations over narrow sectoral responsibilities and boundaries to a 'whole systems' paradigm of service planning and delivery. However, major internal barriers to integration may remain: these include professional domains and identities, and differential power relationships between newly integrated services and professionals. Moreover, the success of these new horizontal, inter-organisational arrangements is profoundly influenced by the wider policy environment and by vertical relationships with national government. Together, these pressures exclude the voices of older people, and therefore call into question whether the considerable organisational upheaval of service integration will be able to deliver the changes valued by older people themselves.

Aged↗
PubMed2003

Development of integrated care in England and the Netherlands: managing across public-private boundaries.

This paper addresses the impact of the public-private mix in the Dutch and English health and social care systems on the development and delivery of integrated care. Integrated care is conceived of as an organisational process of coordination which seeks to achieve seamless and continuous care, tailored to the patients' needs and based on a holistic view of the patient. We describe both systems' structures and characteristics from a historical perspective, which means that developments and processes within the systems are put in the spotlight. We demonstrate that the dividing- or fault-lines, such as the financial split between short-term and long-term care in the Netherlands and the divisions between health and social care as well as between the public, private and voluntary sectors in England have hindered integrated care development and delivery in both countries. Contradictory interests, differences in professional and organisational cultures, power relations, and mistrust between and within these sectors have had a clear impact on integrated care development and delivery within networks of public authorities and public and/or private providers. We explain these phenomena in terms of network theory as a basis for drawing lessons for policy makers and those developing integrated care networks.

Attitude to Health↗
PubMed1999

Inter-agency services in England and The Netherlands. A comparative study of integrated care development and delivery.

In England and the Netherlands there is much comparable experience in developing and delivering integrated services, provided by different health care agencies to people with multiple care demands. The achievement of integrated care provision in such cases appears to be very difficult and laborious in both countries. This article may be considered a first step in exploring the reasons for this and in developing a framework that is not context specific, as a contribution to a more generally applicable analysis of obstacles to integration and the means for overcoming them. After analysing the English and Dutch health and social care systems and their development in recent decades, we conclude that basically there are clear system similarities which are hindering the integration of services, for instance the predominant complexity of the system with a lot of stakeholders having different roles, tasks, interests and power positions. We have identified common mechanisms that play a dominant role in both systems; not only the social, economic and political context, but also the local context, the legal context and funding streams. Other relevant factors are the procedural and structural arrangements at different system levels and the collaborative culture and tradition. The way these mechanisms work in practice, however, is different for England and the Netherlands, due to system differences. In the Netherlands for instance there is a clear emphasis on bargaining in the context of non-hierarchical structured networks, whilst in England hierarchies and the interplay between hierarchies, markets and networks play a more dominant role. In spite of the differences and problems in both countries we have found a similar recognition of interdependence and willingness to pursue integration of services for multi-problem patients.

Delivery of Health Care, Integrated↗
PubMed1999

Integrated care: the impact of governmental behaviour on collaborative networks.

Integration of care is necessary to secure the most appropriate match of the individual demands and the organisational and professional supply. Although this is a basic assumption of all the people involved in health and social care, the magnitude and persistence of obstacles to integration is a common problem in most European countries. In this article, we will explore the role of the Dutch government in the complex interplay of forces around the development of integrated care, within networks of collaborating health and social care agencies. By analysing the behaviour of the Dutch government, we will argue that, in principle, the authorities can play a facilitating role here. For several reasons, however, the government appears not to be able to adequately stimulate the establishment of integrated care arrangements. Examples of such ineffective governmental behaviour are measures with contradictory effects and the adoption of a traditional public finance perspective of comprehensive planning. Our conclusion is that, where local networks play a dominant role in integrated care delivery, the most effective governmental steering should be tailored steering, including a mix of specific steering measures suitable to specific local circumstances, combined with more general steering measures, like financial stimuli, based on legislation.

Community Networks↗
PubMed2003

Preferential integration of a transfected marker gene into spontaneously expressed fragile sites of a breast cancer cell line.

Common fragile sites are non-randomly distributed unstable chromosomal regions thought to be hot spots for recombination. They appear as gaps, breaks and triradial figures when cells are cultured under conditions that inhibit replication or repair of DNA. The removal of replication-inhibitory challenges is followed by repair activation to restore the DNA damage at the fragile site. The breast cancer cell line MDA-MB-436 has a spontaneous and non-random expression pattern of fragile sites that appear to be related to the complex pattern of chromosomal rearrangements. The high frequency of which fragile sites are spontaneously activated should make MDA-MB-436 cells a powerful tool to study in greater detail the DNA sequences of a multiplicity of fragile sites. Here, we have explored if the DNA at spontaneously activated fragile sites in MDA-MB-436 cells can be genetically tagged by the repair-mediated insertion of an exogenously supplied drug resistance gene. The cells were transfected with pSV2Neo, stably transfected clones were selected with neomycin, and the sites of pSV2Neo integration were determined by fluorescent in situ hybridization. Eighty-eight of 100 isolated clones had a non-random distribution of a total of 112 pSV2Neo integrations. Of these, 95 integrations (85%) coincide with the position at which non-random gaps and breaks appear in the MDA-MB-436 cells. Forty-nine (44%) of the 112 integrations appeared to be at position of known fragile sites, 46 (41%) were at the non-random chromosomal sites not previously described as "true" fragile sites. It is possible, however, that these non-random instabilities signal of genomic regions equivalent to fragile sites, that either have not previously been detected due to low level expression or that are activated in a tissue- or cell-type-specific manner. Collectively, our results show a preferential integration of exogenous DNA into fragile sites and other non-random regions of high genomic instability in MDA-MB-436 cells. This approach has provided a platform for the efficient targeted cloning and characterization of a substantial number of both common fragile sites and other non-random instability regions possibly related to breast cancer, and possibly also to other types of cancer.

Adenocarcinoma↗
PubMed2003

Efficient switching of mycobacteriophage L5-based integrating plasmids in Mycobacterium tuberculosis.

We previously used a mycobacteriophage L5-derived integrating vector to demonstrate that glnE and aroK are essential genes in Mycobacterium tuberculosis by showing that we were unable to excise the integrated vector when it carried the only functional copy of these genes. We tested three systems to replace the integrated copy with alternative alleles. The most efficient method was to transform the strain with a second copy of the integrating vector. Excision of the resident vector and integration of the incoming vector occurred at an extremely high efficiency. This technique will allow us to study the role and functionality of essential genes in this important human pathogen.

Alleles↗
PubMedDate not supplied

Mentoring treatment teams to integrate behavioral and psychopharmacological treatments in developmental disabilities.

Individuals with developmental disabilities often have a concomitant psychiatric disorder severe enough to require treatment. The behavioral endpoint of psychiatric disorders may require integrated behavioral and psychopharmacological treatments to stabilize their condition and enhance their quality of life. We used a mindfulness-based mentoring model to facilitate the integration of behavioral and psychopharmacological treatments at the treatment team level. Using a multiple baseline design across treatment teams, we assessed the degree of integration of these two treatment modalities using a 23-item rating scale, and then introduced mentoring successively across the three treatment teams. Following mentoring, six follow-up assessments at monthly intervals were undertaken to assess functioning of the treatment teams in the absence of mentoring. The low levels of integration of behavioral and psychopharmacological treatments occurring during baseline improved significantly within each team commensurate with the mentoring. Further, the enhanced treatment team functioning was maintained during a 6-month follow-up period. Mentoring of treatment teams may be an effective first step in integrating behavioral and psychopharmacological treatments that are deemed essential in the care and treatment of individuals with developmental disabilities and mental illness.

Behavior Therapy↗
PubMed2003

From PACS to integrated EMR.

The integration of medical images as part of the patient record has always been a critical component of documentation and information supporting clinical decisions. In the past two decades the increased number of imaging procedures that allows a more accurate and more specific diagnosis has significantly increased and their role in patient management has grown rapidly. With the evolution toward digital modalities and management of medical images in a fully digital environment with the deployment of enterprise wide Picture Archiving Communication Systems (PACS) a wider and more rapid access to the images by referring physicians and clinicians has become possible. The parallel evolution of electronic medical records (EMR) supporting all other documents and clinical data in electronic format led to the necessity of integrating medial image data with the rest of the patient record. Although the marriage of medical images and patient record data in electronic format seems a very natural and necessary combination it has often been very slow in development due to the lack of standardization and clear understanding of clinical workflows and clinical requirements. Several early implementations demonstrated the added value of combining medical images with the patient record and have shown that the availability of data and images facilitates and improves the accuracy and efficiency of patient management. Recent efforts in industry and the academic community to harmonize and improve the integration of medical images with patient record, with the promotion of new standards and better definitions of clinical workflows and standard mechanism of integration of different types of data into unified data models, has facilitated the deployment of modern EMR. Also, a shift in paradigm due to recent technological revolutions such as the development of the World Wide Web and the concepts of portal servers for accessing data for multiple sources has significantly boosted the trends into open systems which allows easier and more functional integration of medical data from different sources. Furthermore, the emergence of a new strategy for software development, based on open source components, allows software programs to be shared and exchanged between different institutions leading to more rapid deployment of standardized electronic patient record.

Diffusion of Innovation↗
PubMedDate not supplied

Study of human foamy virus proviral integration in chronically infected murine cells.

This report describes integration sites of human foamy virus (HFV) in chronically infected BALB/c murine cells that we isolated by inverse PCR and characterized. We show that integration of HFV proviral genome mainly occurs in highly repetitive and/or transcriptionally active regions and leads to the formation of a 4-bp cellular direct repeat sequence at each provirus extremity. As non-random deletions were previously described in the HFV be/1 transactivator gene as well as in the long terminal repeats (LTRs), these regions were verified in integrated HFV. The analysis reveals that, in the studied chronic state, the defective interfering virus (delta HFV) is the main integrated proviral form and is always associated with a small LTR. Our results show that HFV can use a classic retroviral integration process to enter the host cell genome and stress the importance of delta HFV and the short LTRs in the establishment of the chronic state of infection.

3T3 Cells↗
PubMed1995

Target DNA capture by HIV-1 integration complexes.

BACKGROUND: The early steps of human immunodeficiency virus 1 (HIV-1) replication involve reverse transcription of the viral RNA and integration of the resulting cDNA into a host chromosome. The DNA integration step requires the integration machinery ('preintegration complex') to bind to the host DNA before connecting the viral and host DNAs. Here, we present experiments that distinguish among three possible pathways of target-DNA capture: repeated binding and release of target DNA prior to the chemical strand-transfer step; binding followed by facilitated diffusion along target DNA (sliding); and integration at the initial target-capture site. The mechanism of target-DNA capture has implications for the design of gene therapy methods, and influences the interpretation of results on the selection of integration target sites in vivo. RESULTS: We present new in vitro conditions that allow us to assemble HIV-1 integrase--the virus-encoded recombination enzyme--with a viral DNA and then to trap assembled complexes bound to target DNA. We find that complexes of integrase and viral DNA do not slide along target DNA substantially after binding. We confirm and extend these results by analyzing target capture by a hybrid protein composed of HIV-1 integrase linked to a sequence-specific DNA-binding domain. We find that the integrase domain binds quickly and tightly under the above conditions, thereby obstructing function of the fused sequence-specific DNA-binding domain. We also monitor target-DNA capture by HIV-1 preintegration complexes purified from freshly infected cells. Partially purified complexes commit quickly and stably to the first target DNA added, whereas preintegration complexes in crude cytoplasmic extracts do not. The addition of extracts from uninfected cells to partially purified complexes blocks quick commitment. CONCLUSIONS: Under new conditions favorable for the analysis of target-DNA capture in vitro, HIV-1 integrase complexes bind quickly and stably to target DNA without subsequent sliding. Parallel studies of preintegration complexes support a model in which target-site capture in vivo is reversible as a result of the action of cellular factors.

Binding Sites↗
PubMed2001

Integrating services for schizophrenia and substance abuse.

Over the past decade, several studies have attempted to determine whether integrating psychiatric and substance abuse treatment leads to better outcome for patients with comorbid schizophrenia and substance use disorders. A recent (1999) Cochrane Review (1) analyzed the effectiveness of prospective randomized studies of integrated treatment approaches, and concluded that there was no clear evidence for superiority of integrated treatment. This paper describes one such integrated treatment approach, in Beth Israel Medical Center's COPAD (Combined Psychiatric and Addictive Disorders) program. We summarize findings from an initial outcome study and a recent replication study; and describe clinical and research issues relevant to this population. Our data suggests the benefits of integrated treatment for patients with addictive disorders and schizophrenia, at least with regard to treatment retention. Clinical issues for such patients include identification of patients at risk, proper assessment and treatment planning, decision-making about mainstreaming vs. referral to specialized programs, and the importance of initial engagement and ongoing reengagement in successful treatment.

Adolescent↗
PubMed2002

Molecular indications for in vivo integration of the avian leukosis virus, subgroup J-long terminal repeat into the Marek's disease virus in experimentally dually-infected chickens.

Marek's disease virus, a herpesvirus, and avian leukosis virus, subgroup J, a retrovirus, are oncogenic viruses of poultry. Both viruses may infect the same flock, the same bird and the same cell. In a double-infected cell, the retroviral DNA can integrate into the cellular or the Marek's disease virus (MDV) genome. The retroviral-long terminal repeat (LTR) integration into MDV was first described by Isfort et al., (Proc Natl Acad Sci 89, 991-995, 1992) following tissue culture co-infection. The recombinant virus isolated, RM1, had altered biological properties compared to the parental MDV (Witter R.L., Li D., Jones D., and Kung H.-J., Avian Dis 41, 407-421, 1997) . The issue of retroviral sequence integration into herpesviruses in vivo, in cases of double-virus infection is of wide significance in general virology and veterinary medicine; it also represents a special case of gene transposition. Using the avian system, we aimed to determine occurrence of such integrations in vivo. Chickens were experimentally co-infected with both avian leukosis virus (ALV) subgroup J and with MDV. To demonstrate the presence of the retroviral LTR in the MDV genome we applied the Hot Spot-combined PCR assay (Borenshtain R. and Davidson I., J Virol Meth 82, 119-127, 1999) that consisted of two consecutive steps of amplification. By that HS-cPCR assay, certain MDV genomic sites, defined as HS for integration were specifically amplified, the HS step, and then subjected to screening in an attempt to detect LTR inserts. The screening was achieved by amplification using heterologous primer sets, one for the MDV hot spot and the other for the retroviral LTR, the cPCR step. The products were Southern blotted and hybridized with MDV and ALV-LTR probes. Chimeric molecules were detected and evidenced by an intense signal in 3/10 chickens and weakly in other 3/10 birds. Detection was by LTR amplification, sequencing and multiple alignment to the ALV-J-LTR sequence. The present study indicated that chimeric molecules were produced in vivo.

Animals↗
PubMed1999

Analysis of integrated healthcare networks' performance: a contingency-strategic management perspective.

Few empirical analyses have been done in the organizational researches of integrated healthcare networks (IHNs) or integrated healthcare delivery systems. Using a contingency derived contact-process-performance model, this study attempts to explore the relationships among an IHN's strategic direction, structural design, and performance. A cross-sectional analysis of 100 IHNs suggests that certain contextual factors such as market competition and network age and tax status have statistically significant effects on the implementation of an IHN's service differentiation strategy, which addresses coordination and control in the market. An IHN's service differentiation strategy is positively related to its integrated structural design, which is characterized as integration of administration, patient care, and information system across different settings. However, no evidence supports that the development of integrated structural design may benefit an IHN's performance in terms of clinical efficiency and financial viability.

Cross-Sectional Studies↗
PubMed1997

Organizational development strategies for integrating mental health services.

The recent debates about health care reform have focused attention on the need to develop organized systems of care capable of delivering comprehensive services which are coordinated or integrated. Achieving service integration has emerged as a central and pressing objective in most mental health systems in response to existing difficulties with fragmentation of care. However, attempts at service integration often fail at the implementation stage as provider agencies zealously guard their organizational boundaries and struggle with each other for power and control. In this article, the authors formulate an organizational development approach to service integration that focuses on reducing the rigid maintenance of agency boundaries by developing informal networks among staff of local provider agencies. Eight strategies, drawn from the research literature on services integration and recently implemented by a local mental health authority, are described as potential tools for use by systems managers in accomplishing these goals.

Community Health Planning↗
PubMed1999

Integration complexes derived from HIV vectors for rapid assays in vitro.

Of three enzymes encoded by HIV-reverse transcriptase, protease, and integrase-only the first two have been exploited clinically as inhibitor targets. Efforts to develop inhibitors of purified integrase protein have yielded many compounds, but none with clinical utility. A different source of integration activity for studies in vitro is provided by replication intermediates isolated from HIV-infected cells. These preintegration complexes (PICs) can direct integration of the endogenously synthesized viral cDNA into an added target DNA in vitro. Despite their authentic activities, assays of PICs have not been widely used due to technical obstacles, particularly the requirement for handling large amounts of infectious HIV. Here, we describe greatly improved methods for producing PICs using HIV-based vectors that are capable of establishing an integrated provirus but not a spreading infection. We also report the development of a PIC integration assay using DNA-coated microtiter plates, which speeds assays of PIC integration in vitro. We used this method to screen a library of chemicals related to known integrase inhibitors and found a new compound, quinalizarin sulfate, that displayed enhanced activity against PICs.

Anti-HIV Agents↗
PubMed2005

A role for LEDGF/p75 in targeting HIV DNA integration.

HIV DNA integration is favored in active genes, but the underlying mechanism is unclear. Cellular lens epithelium-derived growth factor (LEDGF/p75) binds both chromosomal DNA and HIV integrase, and might therefore direct integration by a tethering interaction. We analyzed HIV integration in cells depleted for LEDGF/p75, and found that integration was (i) less frequent in transcription units, (ii) less frequent in genes regulated by LEDGF/p75 and (iii) more frequent in GC-rich DNA. LEDGF is thus the first example of a cellular protein controlling the location of HIV integration in human cells.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Retroviral DNA integration: reaction pathway and critical intermediates.

The key DNA cutting and joining steps of retroviral DNA integration are carried out by the viral integrase protein. Structures of the individual domains of integrase have been determined, but their organization in the active complex with viral DNA is unknown. We show that HIV-1 integrase forms stable synaptic complexes in which a tetramer of integrase is stably associated with a pair of viral DNA ends. The viral DNA is processed within these complexes, which go on to capture the target DNA and integrate the viral DNA ends. The joining of the two viral DNA ends to target DNA occurs sequentially, with a stable intermediate complex in which only one DNA end is joined. The integration product also remains stably associated with integrase and likely requires disassembly before completion of the integration process by cellular enzymes. The results define the series of stable nucleoprotein complexes that mediate retroviral DNA integration.

Blotting, Western↗