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PubMed1992

Hepatocyte transplantation: development of new systems for liver repopulation and gene therapy.

Following recent advances in molecular and cell biology, development of hepatocyte transplantation has been considerably invigorated. To study the fate of hepatocytes transplanted into the liver, new strategies have included the use of endogenously marked transgenic hepatocytes. Release of peripherally quantifiable marker proteins by transgenic hepatocytes has provided noninvasive ways to determine hepatocyte engraftment and prolonged survival. Further characterization of intrasplenic hepatocyte transplantation has established this to be the most suitable method for targeting hepatocytes to the liver. Advances in gene cloning, retrovirology, and gene transfer technology have provided further tools for accomplishing gene therapy. Practical strategies for ex vivo gene therapy involving hepatocytes have been developed by exploiting these new technologies. The potential value of hepatocyte transplantation in acute hepatic failure has begun to be reexamined. Therefore, hepatocyte transplantation can be predicted to provide new ammunition for continuing our assault on untreatable disorders. Resolution of outstanding issues should accelerate this process.

Animals↗
PubMed1977

The organization and structure of the national institutes of health.

In the assessment of domestic federal programs and the agencies responsible for them, few have been as frequently and highly praised as the National Institutes of Health (NIH). Contributing to that success in part is an unusual organization and structure. Based on a series of semiautonomous, disease-oriented program divisions supplemented by several support units with a co-ordinative function performed by the Director, NIH, a remarkable and essential combination of administrative stability and flexibility, as well as scientific and political acceptability, has emerged. The changing environment in which NIH now functions, however, suggests the need for a greater degree of intra-NIH and extra-NIH program integration and co-ordination. Concomitantly, there must be more consistent federal policies, a clearer definition and understanding of "technology transfer" and additional resources for the directors of NIH and the individual Institutes.

Financing, Government↗
PubMed2000

Transition to an all-digital echocardiography laboratory: a large, multi-site private cardiology practice experience.

Acquisition, interpretation, and storage of digital echocardiographic images has many advantages over the standard videotape-based method. Archival, transmission, and comparative interpretation are all optimized with digital echocardiography. A study performed at one site can be immediately available for viewing and analysis at another site by means of standard data transfer technology. Echocardiograms can be interpreted in the context of prior studies, which are readily available for side-by-side comparison. The transition to an all-digital laboratory involves the commitment of persons at multiple levels in the cardiology practice, including administrators, information technology specialists, sonographers, and physicians. Quality of patient care, use of physicians' and sonographers' time, and long-term financial benefit are all areas where improvement may be realized with the use of digital echocardiography. We present our experience in the development of an all-digital echocardiography laboratory, and we conclude that digital echo-cardiography is practical and can be implemented readily in a clinical setting. We performed several correlative analyses during this transition to validate the consistency and accuracy of digital interpretation compared with those of analog methods. The transition process from analog (videotape) to digital, including full wide area network exchange, took approximately 8 months. As technology advances, issues surrounding storage, comparison, and acquisition formats will continue to develop. We hope that our experience will help others make the transition to the digital environment and benefit from the ease of image access, the ability to comparatively interpret echocardiograms, and the superior image quality afforded by this advancement.

Attitude of Health Personnel↗
PubMed2006

Mammalian diversity: gametes, embryos and reproduction.

The class Mammalia is composed of approximately 4800 extant species. These mammalian species are divided into three subclasses that include the monotremes, marsupials and eutherians. Monotremes are remarkable because these mammals are born from eggs laid outside of the mother's body. Marsupial mammals have relatively short gestation periods and give birth to highly altricial young that continue a significant amount of 'fetal' development after birth, supported by a highly sophisticated lactation. Less than 10% of mammalian species are monotremes or marsupials, so the great majority of mammals are grouped into the subclass Eutheria, including mouse and human. Mammals exhibit great variety in morphology, physiology and reproduction. In the present article, we highlight some of this remarkable diversity relative to the mouse, one of the most widely used mammalian model organisms, and human. This diversity creates challenges and opportunities for gamete and embryo collection, culture and transfer technologies.

Animals↗
PubMed1992

Approaches to eliminating chlorofluorocarbon use in manufacturing.

Until quite recently, chlorofluorocarbons (CFCs) had been considered the safest and most benign of industrial chemicals. Their physical and chemical properties made them an integral part of manufacturing processes for electronics products. The recognition that CFCs destroy the stratospheric ozone layer, with consequent enormous consequences to all forms of life on earth, has led to international agreements which will end virtually all possibly before. This impending phaseout of CFCs has caused electronics manufacturers to examine alternative chemicals and processing methods. This manuscript documents the steps AT&T has taken to reach its goal of 100% phaseout of CFCs by years-end 1994. These actions include top-down management support with combined bottom-up thrusts, an internal information gathering and dissemination center, internal technology transfer, and external corporate activism.

Journal Article↗
PubMed2002

piggyBac-mediated germline transformation of the malaria mosquito Anopheles stephensi using the red fluorescent protein dsRED as a selectable marker.

It is estimated that every year malaria infects approximately 300 million people and accounts for the death of 2 million individuals. The Plasmodium parasites that cause malaria in humans are transmitted exclusively by mosquito species belonging to the Anopheles genus. The recent development of a gene transfer technology for Anopheles stephensi mosquitoes, using the Minos transposable element marked with the enhanced green fluorescent protein EGFP (Catteruccia, F., Nolan, T., Loukeris, T. G., Blass, C., Savakis, C., Kafatos, F. C., and Crisanti, A. (2000) Nature 405, 959--962), provides now a powerful tool to investigate the role of mosquito molecules involved in the interaction with the malaria parasite. Such technology, when further developed with additional markers and transposable elements, will be invaluable for analyzing the biology of the vector and for developing malaria-resistant mosquitoes to be used as a tool to control malaria transmission in the field. We report here the germline transformation of A. stephensi mosquitoes using a piggyBac-based transposon to drive integration of the gene encoding for the red fluorescent protein dsRED. A. stephensi embryos were injected with transformation vector pPBRED containing the dsRED marker cloned within the arms of piggyBac. Microscopic analysis of G(1) larvae revealed the presence of seven fluorescent phenotypes whose different molecular origins were confirmed by Southern blotting analysis. Sequencing of the insertion sites in two lines demonstrated that integrations had occurred at TTAA nucleotides in accordance with piggyBac-mediated transpositions.

Animals↗
PubMed2004

Butyric and retinoic mixed ester of hyaluronan. A novel differentiating glycoconjugate affording a high throughput of cardiogenesis in embryonic stem cells.

Embryonic stem (ES) cells can differentiate into specialized cells, including cardiac myocytes, but the efficiency is typically low and the process is incompletely understood. Achieving a high throughput of cardiogenesis from pluripotent cells is therefore a major requirement for future approaches in cardiac cell therapy. Here, we developed a novel ester of hyaluronan linked to both butyric and retinoic acid (HBR), coaxing pluripotent ES cells into a cardiogenic decision. In mouse ES cells, HBR remarkably increased the expression of GATA-4 and Nkx-2.5, acting as cardiac lineage-promoting genes in different animal species, including humans. HBR also enhanced prodynorphin gene expression and the synthesis and secretion of dynorphin B, an endorphin playing a major role in ES cell cardiogenesis. These effects occurred at the transcriptional level. HBR also primed the expression of cardiac-specific transcripts and highly enhanced the yield of spontaneously beating ES-derived cardiomyocytes. These results demonstrate the potential for chemically modifying the gene program of cardiac differentiation in ES cells without the aid of gene transfer technologies and may pave the way for novel approaches in tissue engineering and myocardial regeneration.

Animals↗
PubMed2005

The protozoan parasite Cryptosporidium parvum possesses two functionally and evolutionarily divergent replication protein A large subunits.

Very little is known about protozoan replication protein A (RPA), a heterotrimeric complex critical for DNA replication and repair. We have discovered that in medically and economically important apicomplexan parasites, two unique RPA complexes may exist based on two different types of large subunit RPA1. In this study, we characterized the single-stranded DNA binding features of two distinct types (i.e. short and long) of RPA1 subunits from Cryptosporidium parvum (CpRPA1A and CpRPA1B). These two proteins differ from human RPA1 in their intrinsic single-stranded DNA binding affinity (K) and have significantly lower cooperativity (omega). We also identified the RPA2 and RPA3 subunits from C. parvum, the latter of which had yet to be reported to exist in any protozoan. Using fluorescence resonance energy transfer technology and pull-down assays, we confirmed that these two subunits interact with each other and with CpRPA1A and CpRPA1B. This suggests that the heterotrimeric structure of RPA complexes may be universally conserved from lower to higher eukaryotes. Bioinformatic analyses indicate that multiple types of RPA1 are present in the other apicomplexans Plasmodium and Toxoplasma. Apicomplexan RPA1 proteins are phylogenetically more related to plant homologues and probably arose from a single gene duplication event prior to the expansion of the apicomplexan lineage. Differential expression during the life cycle stages in three apicomplexan parasites suggests that the two RPA1 types exercise specialized biological functions.

Amino Acid Sequence↗
PubMed2006

MAPK-activated protein kinase-2 (MK2)-mediated formation and phosphorylation-regulated dissociation of the signal complex consisting of p38, MK2, Akt, and Hsp27.

The p38 MAPK and heat shock protein 27 (hsp27) form a signaling complex with serine/threonine kinase Akt and MAPK-activated protein kinase-2 (MK2), which plays an important role in controlling stress-induced apoptosis and reorganizing actin cytoskeleton. However, regulation of the complex is poorly understood. In this study, the interaction between p38 and hsp27 was visualized in single living L929 cells using fluorescence resonance energy transfer technology, while their association with Akt was examined by immunoprecipitation analysis. Under normal growth conditions, p38 kinase constitutively interacts with hsp27. When cells were exposed to H(2)O(2) or stimulated by arachidonic acid, this interaction was disrupted. However, inhibition of the activation of p38 and Akt by selective inhibitors or overexpression of the kinase-dead mutant of p38 diminished such effects. Furthermore, mutation of phosphorylation sites of hsp27 renders the interaction resistant to H(2)O(2) and arachidonic acid. It was interesting to find that the interaction disappeared in the cells from MK2-knock-out mice or the cells treated with lemptomycin B that blocks export of MK2 from nucleus to cytosol. However, MK2 is not required for the association of hsp27 with Akt. This study suggests that MK2 mediates the incorporation of p38 into the pre-existing complex of hsp27 with Akt. Phosphorylation of hsp27 finally breaks the signaling complex.

Animals↗
PubMed2003

Bilateral environmental and occupational health program with India.

In spite of considerable economic progress in recent years, India continues to face challenges dealing with poverty, unemployment, malnutrition, disease and disability. The governments of India and the United States have formed a collaborative effort to address outstanding issues in the fields of environmental and occupational health. The Joint Statement on Indo-U.S. Collaboration in Environmental and Occupational Health, which was approved by the Minister of the Indian Union of Health and Family Welfare and the Secretary of Health and Human Services of the United State in Geneva in May of 2002, formalizes the collaborative relationship and calls for the development of Implementation Guidelines. The Implementation Guidelines establish a Joint Working Group, which is responsible for identifying and implementing the collaborative projects. The collaborating organizations have identified three broad areas for collaboration: emergency preparedness and response; training, education, and technology transfer; and research. Within the three broad areas, the organizations have identified two subject areas for initiation: arsenicosis and asbestosis. Researchers and health officials in both India and the U.S. share interest in both research and interventions efforts in these subject areas. As many as 42 million people in the West Bengal area of India may be exposed to arsenic in drinking water at concentrations of health concern. Similarly, as many as 10 million industrial or mine workers in India may be exposed to asbestos or other dusts at concentrations of health concern. The first Joint Working Group meeting is scheduled for March 2003 in New Delhi and will consider these subject areas in developing collaborative projects. Other tasks being undertaken by the signatory agencies include expanding the relationship to include academic and nongovernmental organizations and obtaining funds for the various projects from governmental and nongovernmental sources.

Arsenic Poisoning↗
PubMed2006

Introducing evidence-based practices into substance abuse treatment using organization development methods.

BACKGROUND: Dissemination of evidence-based practices (EBPs) in addiction settings is a national priority. We tested Organization Development (OD) methods for dissemination. METHODS: Using OD in two addiction treatment programs we developed an organization-specific treatment plan using employee work teams with the goals of changes in organizational policies and procedures and improvement in practitioner skills. RESULTS: OD was effectively applied, but EBPs were premature for these addiction programs because they first needed to address more fundamental aspects of client-clinician interaction and agency treatment philosophy. CONCLUSION: The OD approach in addiction treatment is complementary to other technology transfer efforts by being: (a) "organization-centered," engaging practitioners at all levels; (b) "needs-focused," addressing concerns of the particular organization; (c) flexible in its responsiveness to readiness for change; and (d) relatively affordable. However, before absorbing EBPs, substance abuse treatment organizations must develop strengths in delivering fundamental aspects of care.

Evidence-Based Medicine↗
PubMedDate not supplied

A multisite study of the effectiveness of methamphetamine treatment: an initiative of the Center for Substance Abuse Treatment.

In 1998, responding to national and regional epidemiological data indicating that methamphetamine (MA) abuse was a growing problem in the United States, the Center for Substance Abuse Treatment (CSAT) initiated a multisite MA treatment study. Through a collaborative approach among CSAT, seven treatment sites, and a coordinating center, the study compares the clinical and cost effectiveness of a manualized, cognitive-behavioral outpatient treatment developed by the Matrix Center in Los Angeles to the treatment approaches currently employed by the treatment sites. The study also explores technology transfer issues associated with integrating the Matrix approach within existing treatment settings. CSAT's approach to the initiation and management of this type of study is discussed.

Central Nervous System Stimulants↗
PubMedDate not supplied

A descriptive analysis of participant characteristics and patterns of substance use in the CSAT methamphetamine treatment project: the first six months.

The CSAT Methamphetamine Treatment Project (MTP) is a multisite study with a two-fold purpose: to assess the feasibility and outcomes generated by a technology transfer of the Matrix treatment model for methamphetamine (MA) abuse into several community-based treatment programs, and specifically to compare outcomes of treatment as usual at each site with outcomes of the Matrix model, as implemented in each site. The study comprises seven sites, geographically situated in Hawaii, Northern and Southern California, and Montana. This article presents a demographic description of the cohort, and describes patterns of drug use, abuse, and related problems among the 169 participants recruited in the first six months of the study, from April through September 1999. Specific analyses presented include: demographic composition of the sample with respect to gender, age, ethnicity, education completed, employment status, and income; primary drug used, and mean percent of days using various drugs including MA, alcohol, and marijuana; and percent of sample reporting various routes of drug administration. Mean baseline Addiction Severity Index composite scores are presented that describe medical, employment, alcohol, drug, legal, family/social, and psychiatric status for the sample. Also presented here are comparisons of this preliminary population to other populations reported in the literature. This early subset of MTP participants is similar to other methamphetamine-abusing populations described in the literature in age, years of education, income, and mean years of use. However, because of its multisite structure and the locations of its constituent sites, the MTP population has greater variation in ethnic makeup than do populations from other studies, offering an opportunity to provide useful new information about drug use patterns and treatment responses in populations not previously studied.

Adult↗
PubMedDate not supplied

Ten steps to developing a national agenda to address financial conflicts of interest in industry sponsored clinical research.

Financial liaisons between clinical researchers, research institutions, and industrial sponsors have gained momentum in recent years. In the process, it has been argued by many that trust in the research infrastructure is being eroded by the financial conflicts of interest that emerge from these arrangements. Yet, the financial resources of industry are needed to continue technology transfer from the bench to the bedside. Policy makers and government regulators are currently struggling to determine how to best manage financial conflicts of interest that emerge from these liaisons. Various organizations and government entities have proposed different strategies. This paper explores the limitations of existing measures and recommends that a unified national agenda is needed. We propose 10 steps to develop an agenda to address financial conflicts of interest in industry-sponsored clinical research.

Biomedical Research↗
PubMed1996

A community support group for HIV-seropositive drug users: is attendance associated with reductions in risk behaviour?

Although support groups for HIV-seropositive persons are a potential source of emotional support and information, there has been little assessment of such groups as to their role in changing risk behaviour for transmission. The present study combines observations from over 52 group sessions with baseline and follow-up interview data to assess changes in sex and drug behaviour among seropositive drug users participating in an ongoing group for African Americans. The sample of 100 adults was recruited from drug treatment centres and from the community in Atlanta, Georgia. At the 6-month interview, frequency of group attendance was associated mainly with healthier drug behaviour, the topic most frequently discussed by members. Findings suggest that training for support group facilitators needs to target two areas for technology transfer: successful strategies for reducing both high-risk sex and drug behaviour and methods for introducing these behavioural change tools into a setting designed for socio-emotional support. We conclude that community support groups are an untapped opportunity for low-cost prevention services.

Adult↗
PubMed1996

Regional training in AIDS prevention for health and behavioural science leaders in north-eastern Brazil.

This article reports results of a World AIDS Foundation-funded training programme in North-Eastern Brazil. Training objectives were: (1) to increase the effectiveness of existing medical and behavioural HIV-related services; (2) to prepare professionals to implement and evaluate social skills-based AIDS prevention programmes incorporating metacontingency systems; (3) to prepare professionals to disseminate training content in North-Eastern Brazil; and (4) to promote local involvement in regional AIDS programme planning. Fifty-eight health and behavioural sciences leaders from 5 North-Eastern Brazilian states represented a variety of institutions actually or potentially involved in AIDS prevention. Training activities focused on programme planning and evaluation and social skills training. Written pre- and post-test data indicate that all participants had a basic understanding of AIDS transmission at baseline. Significant knowledge increases (p < 0.01) resulted in all domains trained except for programme evaluation. For the two social skills evaluated (Condom Use Negotiation and Social Skills Trainer), significant improvements (p < 0.01) resulted in verbal and non-verbal content, assertiveness and anxiety, with the exception of near-significant levels (p < 0.10) achieved for assertiveness and anxiety on the 'Trainer' skill. Participants cofacilitated follow-up trainings in their respective states. These trainings demonstrated a successful model for technology transfer. More focused training is needed in programme design and evaluation methods.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

The research base of community-based rehabilitation.

This paper provides an overview of the current research on community-based rehabilitation (CBR) which can be found in the public domain. A brief background to the concept of CBR is given, and it is shown how much of this published research reflects the fundamental principles of CBR service delivery, technology transfer, community involvement, and organization and management. Specific research is discussed under these headings. Additional topics reviewed include the target populations of, and disabilities addressed in, CBR research, and the epidemiology of disability. A summary of locations where the research has taken place is also presented. It is concluded that, while there is still a need for additional research and evaluation in the extensive field of CBR, there has been some reluctance to either undertake or permit such activities. However, CBR and ultimately the disabled can only benefit from placing research and evaluation of CBR into the public domain.

Community Health Services↗
PubMed2000

Malignancy: Gene Therapy Vaccines in Acute Myeloid Leukemia : A Need for Clinical Evaluation.

In the last decade our understanding of the processes that govern cell growth and differentiation, malignant transformation, and metastasis has become quite sophisticated. These new insights have revolutionized our ability to diagnose and to formulate prognoses for patients with cancer, and have inspired the design and development of novel therapeutic strategies that are based on modern gene-transfer technologies and act at the gene level. Gene therapy, broadly defined as the introduction of genetic material (transgenes) into a patient's cells with an intent to confer a therapeutic benefit, represents the most direct application of recombinant DNA technology in the clinical setting. The challenging concept of modifying the genetic properties of human cells captivated very quickly the interest of clinical and molecular oncologists, and currently, numerous gene therapy clinical trials in cancer patients are under investigation worldwide. Most of these studies involve manipulating the patient's immune response to tumors. The identification of tumor-specific antigens stimulating humoral and cellular responses in cancer patients, together with a better understanding of the molecular mechanisms controlling T cell activation have dramatically accelerated the search for potent cancer vaccines. In this review, we highlight important principles of cancer immunity and cancer vaccines, we discuss critical features of genetic manipulation of tumor cells, and particularly focus on preclinical studies on gene therapy vaccines in acute myeloid leukemia (AML).

Journal Article↗