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PubMed2003

Integrative neuroscience.

A fundamental impediment to an "Integrative Neuroscience" is the sense that scientists building models at one particular scale often see that scale as the epicentre of all brain function. This fragmentation has begun to change in a very distinctive way. Multidisciplinary efforts have provided the impetus to break down the boundaries and encourage a freer exchange of information across disciplines and scales. Despite huge deficits of knowledge, sufficient facts about the brain already exist, for an Integrative Neuroscience to begin to lift us clear of the jungle of detail, and shed light upon the workings of the brain as a system. Integrations of brain theory can be tested using judicious paradigm designs and measurement of temporospatial activity reflected in brain imaging technologies. However, to test realistically these new hypotheses requires consistent findings of the normative variability in very large numbers of control subjects, coupled with high sensitivity and specificity of findings in psychiatric disorders. Most importantly, these findings need to be analyzed and modeled with respect to the fundamental mechanisms underlying these measures. Without this convergence of theory, databases, and methodology (including across scale physiologically realistic numerical models), the clinical utility of brain imaging technologies in psychiatry will be significantly impeded. The examples provided in this paper of integration of theory, temporospatial integration of neuroimaging technologies, and a numerical simulation of brain function, bear testimony to the ongoing conversion of an Integrative Neuroscience from an exemplar status into reality.

Animals↗
PubMed2003

Evaluating the impact of integrated health and social care teams on older people living in the community.

Although it is perceived wisdom that joint working must be beneficial, there is, even at this stage, little evidence to support that notion. The present study is an evaluation of two integrated co-located health and social care teams which were established in a rural county to meet the needs of older people and their carers. This study does identify that patients from the 'integrated teams' may self-refer more and are assessed more quickly. This might indicate that the 'one-stop shop' approach is having an impact on the process of service delivery. The findings also suggest that, in the integrated teams, the initial stages of the process of seeking help and being assessed for a service may have improved through better communication, understanding and exchange of information amongst different professional groups. However, the degree of 'integration' seen within these co-located health and social care teams does not appear to be sufficiently well developed to have had an impact upon the clinical outcomes for the patients/service users. It appears unlikely from the available evidence that measures such as co-location go far enough to produce changes in outcomes for older people. If the Department of Health wishes to see benefits in process progress to benefits to service users, then more major structural changes will be required. The process of changing organisational structures can be enhanced where there is evidence that such changes will produce better outcomes. At present, this evidence does not exist, although the present study does suggest that benefits might be forthcoming if greater integration can be achieved. Nevertheless, until the social services and National Health Service trusts develop more efficient and compatible information systems, it will be impossible to evaluate what impact any further steps towards integration might have on older people without significant external resources.

Aged↗
PubMed2003

Mutations in the C-terminal domain of ALSV (Avian Leukemia and Sarcoma Viruses) integrase alter the concerted DNA integration process in vitro.

Integrase (IN) is the retroviral enzyme responsible for the integration of the DNA copy of the retroviral genome into the host cell DNA. The C-terminal domain of IN is involved in DNA binding and enzyme multimerization. We previously performed single amino acid substitutions in the C-terminal domain of the avian leukemia and sarcoma viruses (ALSV) IN. Here, we modelled these IN mutants and analysed their ability to mediate concerted DNA integration (in an in vitro assay) as well as to form dimers (by size exclusion chromatography and protein-protein cross-linking). Mutations of residues located at the dimer interface (V239, L240, Y246, V257 and K266) have the greatest effects on the activity of the IN. Among them: (a) the L240A mutation resulted in a decrease of integration efficiency that was concomitant with a decrease of IN dimerization; (b) the V239A, V249A and K266A mutants preferentially mediated non-concerted DNA integration rather than concerted DNA integration although they were found as dimers. Other mutations (V260E and Y246W/DeltaC25) highlight the role of the C-terminal domain in the general folding of the enzyme and, hence, on its activity. This study points to the important role of residues at the IN C-terminal domain in the folding and dimerization of the enzyme as well as in the concerted DNA integration of viral DNA ends.

Alpharetrovirus↗
PubMed2004

DNA-dependent PK inhibits adeno-associated virus DNA integration.

Recent studies have shown that recombinant adeno-associated virus (rAAV) can persist in episomal form; however, factors affecting rAAV persistence are poorly understood. DNA-dependent PK (DNA-PK) is a DNA repair enzyme, which we previously found played an important role in determining the molecular fate of the rAAV genome in mouse skeletal muscle. In the present study, we tested the effect of DNA-PK on AAV serotype 2 integration in vitro and in vivo in mouse liver. In an in vitro integration system, addition of DNA-PK decreased AAV integration, whereas antibody against DNA-PKcs increased integration. In vivo, matched doses of a recombinant AAV serotype 2 vector were injected into the portal vein of either C57BL/6 (DNA-PKcs(+/+)) or severe combined immunodeficient (DNA-PKcs(-/-)) mice. After partial hepatectomy to stimulate hepatocyte proliferation, retention of vector genomes and of transgene expression was substantially higher in severe combined immunodeficient mice, indicating that in the absence of DNA-PKcs, a greater proportion of genomes integrated into the cellular genome. In summary, we have provided evidence that DNA-PK inhibits AAV integration both in vitro and in vivo.

Animals↗
PubMed1994

Tethering human immunodeficiency virus 1 integrase to a DNA site directs integration to nearby sequences.

Certain retrovirus and retrotransposons display strong biases in the selection of host DNA sites for integration. To probe the possibility that simple tethering of the retroelement integrase protein to a target DNA site is sufficient to direct integration, the activities of a hybrid composed of human immunodeficiency virus 1 integrase and lambda repressor were analyzed. In in vitro reactions containing several target DNAs, the lambda repressor-integrase hybrid was found to direct integration selectively to targets containing lambda operators. Addition of lambda repressor blocked selective integration, indicating that binding to the operators was required. The lambda repressor-integrase hybrid protein directed integration primarily to sites near the operators on the same face of the B-DNA helix, indicating that target DNA was probably captured by looping out the intervening sequences. Such hybrid integrase proteins may be useful for directing retroviral integration to specific sequences in vivo.

Bacteriophage lambda↗
PubMed1996

The recombination signals for adeno-associated virus site-specific integration.

The adeno-associated virus (AAV) genome integrates site specifically into a defined region of human chromosome 19 (termed AAVS1). Using a functional assay for AAV integration into AAVS1 DNA propagated as an episome, we obtained evidence that a 33-nucleotide AAVS1 DNA sequence contains the minimum signal required for targeted integration. The recombination signal comprises a DNA-binding motif for the AAV regulatory Rep protein [Rep binding site (RBS)] separated by an eight-nucleotide spacer from a sequence that can act as a substrate for Rep endonucleolytic activity [terminal resolution site (TRS)]. Mutations in either the AAVS1-encoded RBS or TRS elements abort targeted integration. Since both the RBS and TRS elements are present in the viral origin of replication and are required for AAV replication, targeted integration into chromosome 19 AAVS1 DNA may involve a replicative type of recombination that is discussed. An additional chromosome 19 element, which is responsible for DNA rearrangements in episomes propagating AAVS1 DNA, was identified and shown not to be required for AAV episomal integration, despite its location adjacent to the recombination signal.

Base Sequence↗
PubMed2004

Structural organization of avian retrovirus integrase in assembled intasomes mediating full-site integration.

Retrovirus preintegration complexes (PIC) purified from virus-infected cells are competent for efficient concerted integration of the linear viral DNA ends by integrase (IN) into target DNA (full-site integration). In this report, we have shown that the assembled complexes (intasomes) formed in vitro with linear 3.6-kbp DNA donors possessing 3'-OH-recessed attachment (att) site sequences and avian myeloblastosis virus IN (4 nm) were as competent for full-site integration as isolated retrovirus PIC. The att sites on DNA with 3'-OH-recessed ends were protected by IN in assembled intasomes from DNase I digestion up to approximately 20 bp from the terminus. Several DNA donors containing either normal blunt-ended att sites or different end mutations did not allow assembly of complexes that exhibit the approximately 20-bp DNase I footprint at 14 degrees C. At 50 and 100 mm NaCl, the approximately 20-bp DNase I footprints were produced with wild type (wt) U3 and gain-of-function att site donors for full-site integration as previously observed at 320 mm NaCl. Although the wt U5 att site donors were fully competent for full-site integration at 37 degrees C, the approximately 20-bp DNase I footprint was not observed under a variety of assembly conditions including low NaCl concentrations at 14 degrees C. Under suboptimal assembly conditions for intasomes using U3 att DNA, DNase I probing demonstrated an enhanced cleavage site 9 bp from the end of U3 suggesting that a transient structural intasome intermediate was identified. Using a single nucleotide change at position 7 from the end and a series of small size deletions of wt U3 att site sequences, we determined that sequences upstream of the 11th nucleotide position were not required by IN to produce the approximately 20-bp DNase I footprint and full-site integration. The results suggest the structural organization of IN at the att sites in reconstituted intasomes was similar to that observed in PIC.

Attachment Sites, Microbiological↗
PubMedDate not supplied

Integrating approaches to psychotherapy in psychosis*.

OBJECTIVE: The evidence base for specific psychological treatments for psychosis is now well established, but many practitioners see themselves as integrationist in approach. The basic tenets of integration are explored with an emphasis on understanding how different levels of need can be conceptualized and then used to 'adapt' a treatment to meet those needs in an individual. The needs are then incorporated into an integrated treatment formulation. METHOD: The evidence base is strongest for cognitive behavioural and family approaches, but the present paper summarizes concepts from two specific models of therapy that are intrinsically integrational in their approach: cognitive analytic therapy and psychodynamic interpersonal therapy. RESULTS: Both approaches show aspects of integration. However, following this approach to integration to its limit would ultimately lead to one undifferentiated therapy. CONCLUSIONS: Both approaches share a common set of values of developing specific ways of increasing collaboration and working together, and these values are shown to underpin adaptive ways of working with psychosis, but further critical analysis of the development of integrative models is needed.

Adult↗
PubMed1997

Lack of site-specific integration of the recombinant adeno-associated virus 2 genomes in human cells.

The adeno-associated virus 2 (AAV)-based vector system has been suggested for its potential use in human gene therapy because the wild-type (wt) AAV genome appears to integrate into the human chromosomal DNA in a site-specific manner. We systematically investigated the integration patterns of the recombinant AAV genomes lacking one or both the viral coding sequences. Four recombinant AAV genomes were constructed containing the genes for resistance to tetracycline (TcR) and the herpesvirus thymidine kinase (TK) promoter-driven gene for resistance to neomycin (neoR; vTc.Neo), the genes for resistance to ampicillin (ApR) and TK-neoR (vAp.Neo), the genes for AAV replication (rep) genes and TK-neoR (vRep.Neo), and the AAV capsid (cap) genes and TK-neoR (vCap.Neo). The integration pattern of each of the recombinant AAV genomes in individual clonal isolates of the human nasopharyngeal carcinoma cell line (KB) analyzed on Southern blots using a neo-specific DNA probe was distinctly different. In addition, in none of the clones examined was the proviral genome covalently linked to the previously described AAV right-junction (Rt.Jn.) human chromosomal DNA fragment, the putative specific-site of integration for the wt AAV genome. Furthermore, whereas a 276-bp DNA fragment could be readily amplified from each of these clones, using a neo-specific primer-pair by polymerase chain reaction (PCR), no amplified DNA product was obtained using the neo- and the Rt.Jn. primer-pair under identical conditions. Fluorescence in situ hybridization (FISH) analyses further revealed the lack of integration of the recombinant AAV into human chromosome 19, even in the presence of a functional rep gene as determined by rescue of the recombinant AAV genome in the presence of adenovirus. These data suggest that the recombinant AAV genomes integrate at sites that are different from that characterized for the wt AAV genome. These studies may have implications in the development of the AAV-based vector system for its potential use in human gene therapy.

DNA Transposable Elements↗
PubMed2006

Modulating target site selection during human immunodeficiency virus DNA integration in vitro with an engineered tethering factor.

The mechanisms controlling retroviral integration have been the topic of intense interest, in part because of adverse clinical events that occurred during retrovirus-mediated human gene therapy. Here we investigate the use of artificial tethering interactions to constrain retroviral integration site selection in an in vitro model. During normal infection, HIV DNA integration is favored in active cellular transcription units. One component of the targeting mechanism is the cellular LEDGF/p75 protein. LEDGF/p75 binds tightly to HIV integrase (IN) protein, and depletion of LEDGF/p75 from target cells results in reduced integration in transcription units, suggesting integration targeting by a tethering mechanism. We constructed and analyzed fusions of LEDGF/p75 or its IN-binding domain (IBD) to the DNA-binding domain of phage lambda repressor protein (lambdaR). In the presence of the lambdaR-LEDGF/p75 fusions, increased strand transfer by IN was seen in target DNA near lambdaR-binding sites in vitro . These data support the idea that a direct interaction between LEDGF/p75 and IN can mediate targeting via a tethering mechanism, and provide proof of concept for the idea that protein-protein interactions might be engineered to constrain integration site selection during human gene therapy.

Base Sequence↗
PubMed2004

ISYMOD: a knowledge warehouse for the identification, assembly and analysis of bacterial integrated systems.

MOTIVATION: Complex biological functions emerge from interactions between proteins in stable supra-molecular assemblies and/or through transitory contacts. Most of the time protein partners of the assemblies are composed of one or several domains which exhibit different biochemical functions. Thus the study of cellular process requires the identification of different functional units and their integration in an interaction network; such complexes are referred to as integrated systems. In order to exploit with optimum efficiency the increased release of data, automated bioinformatics strategies are needed to identify, reconstruct and model such systems. For that purpose, we have developed a knowledge warehouse dedicated to the representation and acquisition of bacterial integrated systems involved in the exchange of the bacterial cell with its environment. RESULTS: ISYMOD is a knowledge warehouse that consistently integrates in the same environment the data and the methods used for their acquisition. This is achieved through the construction of (1) a domain knowledge base (DKB) devoted to the storage of the knowledge about the systems, their functional specificities, their partners and how they are related and (2) a methodological knowledge base (MKB) which depicts the task layout used to identify and reconstruct functional integrated systems. Instantiation of the DKB is obtained by solving the tasks of the MKB, whereas some tasks need instances of the DKB to be solved. AROM, an object-based knowledge representation system, has been used to design the DKB, and its task manager, AROMTasks, for developing the MKB. In this study two integrated systems, ABC transporters and two component systems, both involved in adaptation processes of a bacterial cell to its biotope, have been used to evaluate the feasibility of the approach.

ATP-Binding Cassette Transporters↗
PubMed1996

Integrating MCH/FP and STD/HIV services: current debates and future directions.

The issue of integrating MCH/FP and STD/HIV services has gained an increasingly high priority on public health agendas in recent years. In the prevailing climate of health sector reform, policy-makers are likely to be increasingly pressed to address the broader concept of "reproductive health' in the terms consolidated at the Cairo International Conference on Population and Development, and the UN Conference on Women in Beijing. Integrated MCH/FP and STD/HIV services could be regarded as a significant step towards providing integrated reproductive health services, but clarity of issues and concerns is essential. A number of rationales have emerged which argue for the integration of these services, and many concerns have been voiced. There is little consensus, however, on the definition of "integrated services' and there are few documented case studies which might clarify the issues. This paper reviews the context in which rationales for "integrated services' emerged, the issues of concern and the case studies available. It concludes by suggesting future directions for research, noting in particular the need for country-specific and multi-dimensional frameworks and the appropriateness of a policy analysis approach.

Child↗
PubMed2004

A revisionist view of the integrated academic health center.

Like many academic health centers that had expanded aggressively during the 1990s, the nation's first vertically integrated academic health center, the University of Pennsylvania Health System, was profoundly challenged by the dramatic and unanticipated financial impacts of the Balanced Budget Act of 1997. The author explains why-although Penn's Health System had lost $300 million over two years and its debts threatened to cause serious financial and educational damage to the rest of the University-Penn chose to manage its way out of the financial crisis (instead of selling or spinning off its four hospitals, clinical practices, and possibly even its medical school). A strategy of comprehensive integration has not only stabilized Penn's Health System financially, but strengthened its position of leadership in medical education, research, and health care delivery. The author argues that a strategy of greater horizontal integration offers important strategic advantages to academic health centers. In an era when major social and scientific problems demand broadly multidisciplinary and highly-integrated approaches, such horizontally integrated institutions will be better able to educate citizens and train physicians, develop new approaches to health care policy, and answer pressing biomedical research questions. Institutional cultural integration is also crucial to create new, innovative organizational structures that bridge traditional disciplinary, school, and clinical boundaries.

Academic Medical Centers↗
PubMed2003

Development of the Micromonospora carbonacea var. africana ATCC 39149 bacteriophage pMLP1 integrase for site-specific integration in Micromonospora spp.

Micromonospora carbonacea var. africana ATCC 39149 contains a temperate bacteriophage, pMLP1, that is present both as a replicative element and integrated into the chromosome. Sequence analysis of a 4.4 kb KpnI fragment revealed pMLP1 att/int functions consisting of an integrase, an excisionase and the phage attachment site (attP). Plasmids pSPRH840 and pSPRH910, containing the pMLP1 att/int region, were introduced into Micromonospora spp. by conjugation from Escherichia coli. Sequence analysis of DNA flanking the integration site confirmed site-specific integration into a tRNAHis gene in the chromosome. The pMLP1 attP element and chromosomal bacterial attachment (attB) site contain a 24 bp region of sequence identity located at the 3' end of the tRNA. Integration of pMLP1-based plasmids in M. carbonacea var. africana caused a loss of the pMLP1 phage. Placement of an additional attB site into the chromosome allowed integration of pSPRH840 into the alternate attB site. Plasmids containing the site-specific att/int functions of pMLP1 can be used to integrate genes into the chromosome.

Attachment Sites, Microbiological↗
PubMed2003

Adeno-associated virus integrates site-specifically into human chromosome 19 in either orientation and with equal kinetics and frequency.

Adeno-associated virus type 2 (AAV-2) establishes latency by site-specific integration into a unique locus, AAVS1, on human chromosome 19 (chr19). To study the kinetics and frequency of chr19-specific integration, a rapid, sensitive and quantitative real-time PCR assay specific for AAV inverted terminal repeat (ITR)-chr19 junction sequences was developed. Since the assay only detected right-hand AAV ITR-specific integration events, the development of a complementary left-hand ITR-specific real-time PCR assay is described. The time-course of left-hand ITR-dependent AAV integration at AAVS1 of chr19 was determined in AAV-2-infected HeLa cells. Both the kinetics and frequencies of left-hand ITR-dependent integration were found to be similar to those of the right-hand ITR. In addition, left-hand ITR-specific fusion sequences and chromosomal breakpoints within AAVS1 were variable, yet were the same as those found in right-hand ITR-chr19 junction sequences. Thus, the AAV-2 genome integrates site-specifically into chr19 with similar efficiency in either orientation.

Chromosomes, Human, Pair 19↗
PubMed2002

Evaluating self-managed integrated community teams.

After briefly describing self-managed integrated community teams, the authors explore potential and actual methods of evaluating their structures, processes and outcomes. Primary health care staff in three comparable sites were studied using non-participant observation, interviews, focus groups and questionnaires. After describing the fieldwork, the authors examine integrated team structures, which are characterised by a large number of barriers that integrated teams face. Processes surrounding different working practices are explored next. Ways of unifying health care professional practice in integrated teams are suggested using evidence from both the literature and fieldwork. Outcomes that emerged after one year of the new teams' lives are discussed in detail. The difficulty in establishing acceptable outcomes, especially the validity and reliability of outcome measures, is considered. Throughout, the positive and negative aspects of integrated teams emerging from the fieldwork are compared and contrasted with issues in the literature. Finally, recommendations are made to help strengthen integrated teams in the UK.

Attitude of Health Personnel↗
PubMed2006

A decade on: has the use of integrated care pathways made a difference in Lanarkshire?

This article aimed to: (1) review the work carried out in Lanarkshire between 1996 and 1999 on a Scottish Executive funded project and (2) to discuss the situation from 1999 to 2006. (1) This 3-year project led to the successful development and implementation of over 100 integrated care pathways in an urban teaching hospital (Glasgow) and a district general hospital (Lanarkshire) and was the first in-depth study of integrated care pathways to be undertaken in Scotland. The main report on the project was produced in 1999 (Clinical Audit and Quality using Integrated Pathways of Care) and reported increased adherence to British Thoracic Society and Scottish Intercollegiate Guidelines Network guidelines and multiple best practice statements, and improved standards of documentation. The general findings were that process indicators were improved by integrated care pathway use and there was some suggestion of improved length of stay with no apparent effect on outcome. Evidence was found that integrated care pathways have made a difference for both patients and staff. (2) This provides an update of integrated care pathway development in a changing environment within NHS Lanarkshire and examines some of the key factors for success.

Adult↗
PubMed2005

Vertical and horizontal integration of knowledge and skills - a working model.

The new integrated outcomes-based curriculum for dentistry was introduced at the University of Pretoria in 1997. The first participants graduated at the end of 2001. Educational principles that underpin the new innovative dental curriculum include vertical and horizontal integration, problem-oriented learning, student-centred learning, a holistic attitude to patient care and the promotion of oral health. The aim of this research project was to develop and assay a model to facilitate vertical integration of knowledge and skills thereby justifying the above mentioned action. The learning methodology proposed for the specific outcome of the Odontology module, namely the diagnosis of dental caries and the design of a primary preventive programme, included problem-solving as the driving force for the facilitation of vertical and horizontal integration, and an instructional design for the integration of the basic knowledge and clinical skills into a single learning programme. The paper describes the methodology of problem-oriented learning as applied in this study together with the detail of the programme. The consensus of those teachers who represent the basic and clinical sciences and who participate in this learning programme is that this model is practical and can assist vertical as well as horizontal integration of knowledge.

Attitude to Health↗