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PubMed1987

Two-pulse temporal integration functions in the fovea and peripheral retina.

The temporal integration of luminous energy was compared in the fovea and at 7 degrees eccentricity using two-pulse stimuli and two methodologies. The two-pulse stimuli consisted of two 1-msec. light pulses separated by intervals of darkness ranging from 1 to 400 msec.; they were provided by a glow modulator tube transilluminating a 21.8' opal glass target. In Exp. 1 (equal-performance design), integration functions were generated using a forced-choice staircase procedure to estimate threshold luminance. The data for two Os showed that the critical duration (CD), and thus the period of complete integration, was briefer in the fovea than at 7 degrees. Beyond the CD, integration continued to differ for the two retinal locations. In the fovea, two-pulse stimuli beyond CD evidenced partial integration and at the longest stimulus durations no integration or inhibition. In contrast, at 7 degrees stimuli beyond CD appeared to evidence probability summation. In Exp. 2 (equal-energy design), integration functions were generated by measuring the detectability of two-pulse stimuli of different durations but equal in total luminous energy. A signal-detection procedure yielded measures of both response frequency and signal detectability, P(A). The data for two Os showed that for both measures CD was briefer in the fovea than at 7 degrees. Also, in the fovea, long two-pulse stimuli appeared to show no integration or inhibition. Both experiments then showed a foveal-peripheral difference in two-pulse measures of visual temporal integration, with the fovea evidencing less integration. In addition, the forced-choice and signal-detection procedures showed that these loci differences in integration were independent of the Os' response criterion.

Adult↗
PubMed2006

Research integrity and misconduct: a clarification of the concepts.

The commercialization of research and the ever changing scientific environment has led scholars to shift the focus from promoting research integrity to regulating misconduct. As a result, most literature explains research integrity in terms of avoidance of misconduct. The purpose of the paper is to stimulate reflection and discussion on research integrity and research misconduct. This article explores the meaning of research integrity and research misconduct, and how research integrity can be promoted to ensure safer research and scholarship. We believe that the discussion can help clarify some hazy areas in the research and publication processes, and appreciate some crucial aspects that they may have seen taken for granted. The purpose of this article is to share with the readers some clarification or analysis of the two concepts namely: research integrity and misconduct. The objectives are: (1) To explore and analyse the concepts of research integrity and research misconduct from the educational or developmental perspective and not the legal perspective as others in literature have done. (2) To stimulate the reflection and discussion on strategies to promote research integrity and thus prevent research misconduct Literature review and concept analysis was undertaken to clarify the two concepts. We argue that the two concepts can be viewed along a continuum, i.e. where research integrity ends, research misconduct starts. We also argue that it is the responsibility of the research community at large to always ensure that the scientific ethics balance is maintained throughout the research process to ensure research integrity and avoid research misconduct. We also argue that research integrity is interlinked with morality while misconduct is interlinked with immorality.

Attitude of Health Personnel↗
PubMed2005

[Evaluating the integrated force induced by high quality magnet and elastics in orthodontic fixed appliance].

PURPOSE: To investigate the stability and effective working distance of integrated forces induced by high quality magnet and elastics in orthodontic fixed appliance. METHODS: N48 NdFeB magnets resembling brackets in size and volume were combined with 1/8, 3/16, 1/4, and 3/8 inch orthodontic elastics respectively to induce integrated forces that had super-long working distance. Magnetic, elastic, and integrated forces were tested by universal material test system and curves of the forces were draw. The characteristics of integrated forces, complementary effects of magnetic and elastic forces, and the proportion between elastic and magnetic forces in integrated forces at different extension distances were analyzed. Unpaired t test was used to analyze the differences between integrated and elastic forces. RESULTS: With the increase of the extension distance, the magnitude of the magnetic forces decreased significantly and the elastic forces increased in a liner manner, while the integrated forces were stable and changed mildly. Four kinds of integrated forces achieved 86 g, 138 g, 163 g, and 192 g stable forces within super-long distance respectively. Magnetic forces accounted for 34.94%-93.98% of the integrated force at 3 mm distance, 12.60%-37.89% at 6 mm distance, and only 2.69%-5.98% at 12 mm distance. The differences between four integrated forces and elastic forces at 3 mm (P<0.01), 6 mm (P<0.01), and 9 mm distance (P<0.05) were significant. CONCLUSION: Integrated forces composed of magnetic and elastic forces were a new ideal stable orthodontic force with super-long working distance.

Dental Stress Analysis↗
PubMed1990

Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis.

Hepatitis B virus (HBV) DNA integrates into human hepatocyte DNA. We have gathered the available data on the structure of the integrants from human hepatocellular carcinomas, and classified them into those that seem to represent primary integrants and those that are the products of secondary rearrangements. By means of structural analyses of the possible primary integrants, we deduced that the replication intermediates of the viral genome are the preferred substrates for integration. The integrated HBV DNA and the target cellular DNA are invariably associated with deletions, possibly reflecting the substrate for, and the mechanism of, the integration reaction. The target cell DNA sequence, as well as the target site of integration in chromosomes, seems to be selected randomly, suggesting that HBV DNA integration should bring about random mutagenic effects. Several samples recovered from hepatocellular carcinomas show that the integrated HBV DNA can mediate secondary rearrangements of chromosomes, such as translocations, inversions, deletions and (possibly) amplifications. Thus, HBV DNA integration causes multiple mutagenic effects. We argue that during hepatitis infection, the tendency of rearrangement of hepatocyte chromosomes is combined with the forcible turnover of cells. This is a constantly operating system for the selection of cells that grow better than average cells, possibly involving important steps in multistaged hepatocarcinogeneses.

Carcinoma, Hepatocellular↗
PubMed1986

Stable integration of woodchuck hepatitis virus DNA in transplanted tumors and established tissue culture cells derived from a woodchuck primary hepatocellular carcinoma.

The fate of integrated woodchuck hepatitis viral (WHV) DNA was systematically investigated in DNA samples from primary hepatocellular carcinoma (HCC) of woodchucks, solid tumors transplanted in athymic mice derived from a primary HCC of woodchuck, and an established cell line of tissue culture originating from the transplanted tumor. In four of five woodchuck primary HCCs, WHV DNA integration was demonstrated in addition to various amounts of extrachromosomal replicative intermediate WHV DNA. The integration pattern of the primary HCCs does not indicate a common integration site on the host chromosome. The integration pattern in the established cells is identical to that in the transplanted tumor and similar but slightly different from that of the primary HCC. No extrachromosomal or replicative intermediates of WHV DNA were detected in the transplanted tumors or in the established cells of tissue culture. There are three integration sites on the chromosomes of the established cells. Results of Southern hybridization and restriction maps of cloned fragments suggest that all of these integrated WHV DNA sequences are not a complete genome but a part of the genome. A small portion corresponding to the cohesive region of the genome was not detected in all of these integrated WHV DNA. A positive role of WHV DNA integration on the generation of HCC is strongly suggested by the high incidence of WHV DNA integration in woodchuck primary HCCs and the stable maintenance of a certain mode of WHV DNA integration in the hepatoma-derived cell populations during passages of transplantation or serial growth of tissue culture.

Animals↗
PubMed2026

Integration of ear and hearing care services in low- and middle-income health systems: a systematic review and qualitative synthesis.

Hearing loss is a global public health burden and mostly affects those living in low- and middle-income countries (LMICs). One approach to address ongoing challenges is the World Health Organization's recommendation for the integration of ear and hearing care (EHC) services into healthcare packages. However, little is known about EHC integration approaches, particularly in LMICs additionally, these approaches have not been investigated through a health systems lens. This qualitative review aimed to describe the various approaches to the EHC service integration in LMICs and to identify enabling and constraining factors. We reviewed 17 studies, with a focus on LMICs, using adaptations of the Valentijn integration and World Health Organization EHC frameworks, following the PRISMA guidelines. Our investigation showed that most integration approaches were at micro or individual level. Enabling factors for integration of EHC services were training, mentorship, collaboration, technology, inclusion of EHC in healthcare packages and investment in EHC services. Barriers were challenges with training, facilities and equipment, policy implementation and resourcing of EHC services. We further described factors influencing healthcare seeking behaviour and the use of integrated EHC services, such as access and ability to pay, referral systems and communication and awareness. This study describes the complex nature of EHC integration and ways to support integration. Key considerations are the level of integration, training to address workforce issues and factors influencing service utilisation as we work towards health system strengthening.

Humans↗
PubMed2001

Integrating primary medical care with addiction treatment: a randomized controlled trial.

CONTEXT: The prevalence of medical disorders is high among substance abuse patients, yet medical services are seldom provided in coordination with substance abuse treatment. OBJECTIVE: To examine differences in treatment outcomes and costs between integrated and independent models of medical and substance abuse care as well as the effect of integrated care in a subgroup of patients with substance abuse-related medical conditions (SAMCs). DESIGN: Randomized controlled trial conducted between April 1997 and December 1998. SETTING AND PATIENTS: Adult men and women (n = 592) who were admitted to a large health maintenance organization chemical dependency program in Sacramento, Calif. INTERVENTIONS: Patients were randomly assigned to receive treatment through an integrated model, in which primary health care was included within the addiction treatment program (n = 285), or an independent treatment-as-usual model, in which primary care and substance abuse treatment were provided separately (n = 307). Both programs were group based and lasted 8 weeks, with 10 months of aftercare available. MAIN OUTCOME MEASURES: Abstinence outcomes, treatment utilization, and costs 6 months after randomization. RESULTS: Both groups showed improvement on all drug and alcohol measures. Overall, there were no differences in total abstinence rates between the integrated care and independent care groups (68% vs 63%, P =.18). For patients without SAMCs, there were also no differences in abstinence rates (integrated care, 66% vs independent care, 73%; P =.23) and there was a slight but nonsignificant trend of higher costs for the integrated care group ($367.96 vs $324.09, P =.19). However, patients with SAMCs (n = 341) were more likely to be abstinent in the integrated care group than the independent care group (69% vs 55%, P =.006; odds ratio [OR], 1.90; 95% confidence interval [CI], 1.22-2.97). This was true for both those with medical (OR, 3.38; 95% CI, 1.68-6.80) and psychiatric (OR, 2.10; 95% CI, 1.04-4.25) SAMCs. Patients with SAMCs had a slight but nonsignificant trend of higher costs in the integrated care group ($470.81 vs $427.95, P =.14). The incremental cost-effectiveness ratio per additional abstinent patient with an SAMC in the integrated care group was $1581. CONCLUSIONS: Individuals with SAMCs benefit from integrated medical and substance abuse treatment, and such an approach can be cost-effective. These findings are relevant given the high prevalence and cost of medical conditions among substance abuse patients, new developments in medications for addiction, and recent legislation on parity of substance abuse with other medical benefits.

Adult↗
PubMed2006

Strategies for integrating primary health services in middle- and low-income countries at the point of delivery.

BACKGROUND: Strategies to integrate primary health care aim to bring together inputs, organisation, management and delivery of particular service functions to make them more efficient, and accessible to the service user. In some middle and low income countries, services have been fragmented by separate vertical programmes established to ensure delivery of particular technologies. We examined the effectiveness of integration strategies at the point of delivery. OBJECTIVES: To assess the effects of strategies to integrate primary health care services on producing a more coherent product and improving health care delivery and health status. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group specialised register (August 2005), MEDLINE (1966 to September 2005), EMBASE (1988 to 2005), Socio Files (1974 to September 2005), Popline (1970 to September 2005), HealthStar (1975 to September 2005), Cinahl (1982 to September 2005); Cab Health (1972 to 1999), International Bibliography of the Social Sciences (1970 to 1999), and reference lists of articles. We also searched the Internet and World Health Organization (WHO) library database, hand searched relevant WHO publications and contacted experts in the field. SELECTION CRITERIA: Randomised trials, controlled before and after studies, and interrupted time series analyses of integration strategies in primary health care services. Health services in high-income countries were excluded. The primary outcomes were indicators of health care delivery, user views on any measure of service coherence, and health status. We also sought information on comparative costs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study quality. MAIN RESULTS: Three cluster randomised trials and two controlled before and after studies were included, with three types of comparison: integration by adding on an additional component to an existing service (family planning); integrated services versus single special services (for sex workers); integrated delivery systems versus a vertical service (for family planning); and packages of enhanced primary child care services (integrated management of childhood illnesses) vs. routine child care. Interventions were complex and in some studies inputs varied substantially between comparison arms. Overall, no consistent pattern emerged. Only one study attempted to assess the user's view of the service provided. AUTHORS' CONCLUSIONS: Few studies of good quality, large and with rigorous study design have been carried out to investigate strategies to promote service integration in low and middle income countries. All describe the service supply side, and none examine or measure aspects of the demand side. Future studies must also assess the client's view, as this will influence uptake of integration strategies and their effectiveness on community health.

Child↗
PubMed2005

Service integration and teen friendliness in practice: a program assessment of sexual and reproductive health services for adolescents.

PURPOSE: To aid front-line program administrators and providers in adopting national reproductive health recommendations, this exploratory case study examines the implementation of service integration and teen friendliness as strategies to improve adolescent sexual and reproductive health. METHODS: The project team conducted semi-structured interviews with administrators, providers, and adolescent clients from 10 clinical adolescent sexual and reproductive health service agencies in Alameda County, California. Programs were placed into a topology of integrated service delivery models. The teen friendliness of each program was assessed. Spearman rank correlations were calculated to evaluate the relationship between integration and teen friendliness. RESULTS: Clinical programs exhibited a great range of service delivery models within the integration topology. Human immunodeficiency virus (HIV) counseling and testing services were poorly integrated into clinic services. Teen friendliness and integration showed a negative, but not statistically significant, correlation (R = -.45, p = .19). CONCLUSION: Programs have made different levels of commitment to service integration or teen friendliness policies. Lessons learned through the integration of sexually transmitted disease (STD) and family planning services may assist efforts to better integrate HIV services for adolescents. Further work to elucidate the relationship between integration and teen friendliness is needed. Periodic reviews can ensure that recommended clinical guidelines, specifically annual risk assessment, are being met, as well as identifying achievable next steps to improve adolescent sexual and reproductive health service delivery.

Adolescent↗
PubMed2006

Retroviral DNA integration: HIV and the role of LEDGF/p75.

To replicate, a retrovirus must integrate a DNA copy of its RNA genome into a chromosome of the host cell. Integration is not random in the host genome but favors particular regions, and preferences differ among retroviruses. Several mechanisms might play a part in this favored integration targeting: (i) open chromatin might be preferentially accessible for viral DNA integration; (ii) DNA replication during cell division might facilitate access of integration complexes to favored sites; and (iii) cellular proteins bound to the host chromosome might tether integration complexes to favored regions. This review summarizes recent advances in understanding the mechanisms of retroviral integration, focusing on LEDGF/p75--the first cellular protein shown to have a role in directing HIV DNA integration. Studies on LEDGF/p75 indicate that it directs HIV integration site selection by a tethering interaction, whereas the chromatin accessibility or cell cycle models are less well supported. Understanding viral integration will help improve the safety of retrovirus-based vectors used in gene therapy.

Chromatin↗
PubMed2006

Integration bias of gammaretrovirus vectors following transduction and growth of primary mouse hematopoietic progenitor cells with and without selection.

The recent recognition that recombinant retrovirus vectors can induce oncogenic transformation has stimulated much interest in the pattern of vector integration sites. We report here on the integration pattern of a gammaretrovirus reporter vector following transduction and ex vivo culture of primary mouse bone marrow progenitor cells in the absence and presence of drug selection. Using a novel method of cloning junction fragments, we observed no bias for integrations within genes, but did observe a bias for integrations within gene-dense regions and especially near transcriptional start sites of highly active genes, similar to previous reports in other cell types. We also document a novel bias for integrations within or near a class of genes that encode nuclear-localized proteins. We found that drug selection resulted in an increase in the frequency of recovered integration events that were located within the beginning of genes, integration events that were located in less gene-dense regions, and integration events that were oriented in an antisense direction relative to flanking gene transcription. Taken together, these studies provide new insights into the nature of retrovirus vector integration patterns in primary cells and demonstrate that selection based on vector expression can bias the integration site repertoire.

Animals↗
PubMed2006

HIV integration site selection: targeting in macrophages and the effects of different routes of viral entry.

We have studied the selection of HIV DNA integration sites in primary macrophages to investigate two questions. First, mature macrophages do not divide, allowing us to investigate whether HIV integration targeting differs between dividing cells and nondividing cells. We sequenced and analyzed 754 unique integration sites and found that integration in macrophages is favored in active transcription units (TUs), as was observed previously for other cell types. However, HIV integration in genes was slightly less favored in macrophages than in dividing PBMC or T cell lines. Second, we compared integration targeting by HIV-vector particles bearing either of two different envelope proteins (HIV R5 Env or VSV-G) to determine whether the mechanism of entry influenced subsequent integration targeting. Integration sites generated by HIV R5- or VSV-G-bearing particles showed no significant differences in their distributions in the human genome. Analysis of additional published integration site sequences also indicated that the route of entry did not affect integration site selection for other viral envelopes as well.

Base Sequence↗
PubMed2001

A method to maintain introduced DNA sequences stably and safely on the bacterial chromosome: application of prophage integration and subsequent designed excision.

By application of prophage integration and subsequent intended excision, a method to maintain an introduced DNA sequence stably onto a bacterial chromosome has been proposed. Recently-constructed integration plasmids using Campbell-type prophage integration system in Lactobacillus casei strain Shirota and its temperate phage phi FSW was modified for this purpose and a chloramphenicol (Cm)-resistance gene was used as a model passenger DNA. On the integration plasmid having an erythromycin (Em)-resistance gene as a selection marker, N- and C-terminally-truncated Cm-resistance genes were inserted into both sides of the attP of phi FSW, within which the site-specific recombination took place with the attB of phi FSW on the recipient chromosome through the phi FSW integrase. Primary integrants of the modified plasmid (integration-excision vector) exhibiting Em-resistant and Cm-sensitive phenotype generated Em-sensitive and Cm-resistant derivatives under the nonselective conditions. Sequence analyses showed that one copy of the complete Cm-resistance gene resided at the attachment site on the host chromosome and the other vector-derived sequences were excised probably by endogenous homologous recombination in the host cells to derive final integrants. The Cm-resistant phenotype of the final integrants was stable for more than 50 generations under non-selective conditions. Frequency of the homologous recombination suggests that negative selection is also adoptable. Thus, this method using the integration-excision vector gives a stable and safe derivatives of the strain and is likely to be applicable to various bacteria, since Campbell-type prophage integration system and homologous recombination are prevalent among bacteria.

Bacteriophages↗
PubMed2001

Integration of information systems: assessing its quality.

Due to organizational and technological changes the need for integrating information systems within healthcare institutions, has increased enormously. Although the technical means for systems integration have definitely matured, integration methodologies are still in their infancy. Two important questions regarding systems integration are hardly ever addressed in a systematic way: how to derive integration requirements, and how to check whether the requirements are met in a given integrated system. These two questions must be answered if we want to assess or improve the quality of integration of a given set of systems. In this article we present a nine-step method for deriving integration requirements from a business process model, and we assess the quality of integration of a given integrated system against these requirements. The method is demonstrated by elaborating two case studies from the health care domain.

Computer Simulation↗
PubMed2003

A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques.

Persistent infections with high-risk human papillomaviruses (HPVs) induce dysplastic lesions of the lower genital tract. Some of these lesions eventually progress to invasive cancers, particularly of the uterine cervix. In many advanced preneoplastic cervical lesions and most derived carcinomas, HPV genomes are found to be integrated into the host cell chromosomes. Although HPV integration seems to play an important role in the progression of cervical dysplasia, the underlying mechanisms are still unclear. To investigate the pathogenic role of genomic integration of HPV genomes in greater detail, we analysed integration sites of HPV16 and 18 genomes in 21 anogenital precancerous and cancerous lesions using a ligation-mediated chain reaction (DIPS) and the recently described amplification of papilloma virus oncogene transcripts (APOT) assay. On the genomic level, only singular integration events were observed in individual neoplastic cell clones. At many integration sites, a short overlap between HPV and genomic sequences was observed, suggesting that the integration of HPV genomes is mediated by nonhomologous sequence-specific recombination. APOT analysis revealed that the majority of integrated HPV genomes was actively transcribed. These data suggest that in the progression of cervical preneoplasia to invasive carcinomas, integration of viral genomes occurs only at single or few chromosomal loci in a given cell clone. Disruption of cellular genes might support malignant transformation in rare cases; however, it is not a pathogenic prerequisite. The main function of HPV integration seems to be the stabilization of oncogene transcription.

Biopsy↗
PubMed2004

[Integrated delivery systems in California--success and failure determining factors for the first 10 years and impetus for Germany].

Since the coming into effect of the Health Care Modernization Act (Gesundheitsmodernisierungsgesetz) the conditions for integrated health care delivery are favourable in Germany. However, comprehensive approaches are a long time in coming. In contrast, integrated health care delivery as an integral part of the spreading of managed care entered a further stage of development, which enables health care decision makers to draw conclusions regarding the further development of integrated health care delivery in Germany. Based on case studies integrated delivery systems in the San Francisco Bay Area have been analyzed with the objective to evaluate pitfalls and successful strategies for integrated health care delivery. The major pitfalls refer to an insufficient local focus, a lack of actual integration and the application of per capita reimbursement (which is a key subject on the political agenda in Germany as well) within integrated delivery systems. On the contrary, successful strategies include achieving a dynamic tension between centralized and decentralized coordination, internal and external relationship management, well organised human resource management including a well-defined corporate policy and a comprehensive implementation of information technology. Based on US experiences with integrated delivery systems implications for the design of integrated health care delivery in Germany are discussed.

California↗
PubMed2006

Selection of cervical keratinocytes containing integrated HPV16 associates with episome loss and an endogenous antiviral response.

Integration of high-risk human papillomavirus (HRHPV) into the host genome is a key event in cervical neoplastic progression. Integration is associated with deregulated expression of the viral oncogenes E6 and E7 and acquisition of a selective growth advantage for cells containing integrants. Overexpression of the viral transcriptional regulator E2 from heterologous promoters has an inhibitory effect on transcription from integrated HRHPV. Therefore, we hypothesized that loss of E2-expressing episomes from cells in which integration had previously occurred would be required for such cells to gain a growth advantage. Using the unique W12 model of cervical squamous carcinogenesis, we show that cells containing integrated HPV16 reproducibly emerged during long-term culture when there had been a rapid fall in episome numbers. During the period of emergence, it is possible to isolate single-cell clones containing an intracellular mixture of the integrant being selected and episomes at reduced load. The lower level of E2 expression seen in such cells is associated with partial inhibition of transcription from the HPV16 integrant. Full deregulation is not observed until complete loss of E2-expressing episomes occurs. Microarray analysis showed that episome loss was closely associated with endogenous activation of antiviral response genes that are also inducible by the type I IFN pathway. Taken together, our results indicate that episome loss, associated with induction of antiviral response genes, is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. We conclude that cervical carcinogenesis requires not only HRHPV integration, but also loss of inhibitory episomes.

Cell Line↗
PubMed1999

Nontargeted stable integration of recombinant adeno-associated virus into human leukemia and lymphoma cell lines as evaluated by fluorescence in situ hybridization.

A number of studies on human epithelial cells of varying origin have demonstrated integration of recombinant adeno-associated virus (AAV) vectors into a variety of chromosomes compared with the site-specific integration on chromosome 19 predominantly observed for wild-type (wt) AAV. We have constructed a recombinant AAV (rAAV) vector and tested the integration into hematopoietic cells, using the human acute myeloid leukemia cell line AML5 and the human non-Hodgkin's lymphoma cell line OCI-LY18 as targets. The integration sites were visualized by fluorescence in situ hybridization (FISH). Positive signals were observed for chromosomes 1, 2, 3, 8, 14, 15, 19, and Y. The majority of cells demonstrated integration into one specific site. A minority showed simultaneous integration into more than one chromosome. The frequency of observed integrations was not uniformly distributed among chromosomes; for instance, in AML5 chromosome 2 seemed to be favored. Colony-derived AML5 clones bore unique integration patterns indicating successful transduction of clonogenic progenitor cells with high proliferative potential. The integration was stable and observed for more than 12 months after transduction. FISH has been shown to be a powerful tool for detailed analyses of rAAV integration patterns and can be used to evaluate targets and transduction conditions.

Acute Disease↗