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Prevention and control of hepatitis B in China.

About 170 million Chinese are infected chronically with HBV and 10% suffer from chronic hepatitis. Around half a million Chinese die from hepatitis B caused hepatocellular carcinoma and endstage cirrhosis each year. From 1983 to the present, a controlled clinical trial involving 80,000 children on a universal hepatitis B vaccination programme to prevent chronic hepatitis, hepatocellular carcinoma, and endstage cirrhosis was implemented in Qidong, China. A pilot study demonstrated that the HBsAg rate reached the adult level before the fifth year of age, and neonatal vaccination with either plasma-derived or recombinant hepatitis B vaccines provided a similar 75% protective efficacy against HBV infection. The high rate of follow-up and blood tests coverage of the cohorts provided data to show 75% protection at the tenth to eleventh years of age against serum HBsAg and also against prolonged hepatic dysfunction. The strategy of controlling hepatitis B nationwide was based on the universal immunisation of newborns, beginning in cities and then the rural areas. The large-scale vaccine source was provided by domestic plants through technology transfer, first providing plasma-derived vaccine replaced completely by recombinant DNA vaccine in 1997. An official survey in 1999 using a cluster sampling of 25,878 children from 31 provinces reported an average coverage rate of three dose of hepatitis B vaccination of 70.7%, being higher in urban areas. The Ministry of Public Health of China has planned to integrate hepatitis B vaccination into the nationwide EPI program with Government-provided vaccines starting January 1, 2002.

Child↗

Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction.

It is well known that compression speed can have significant effects on the compaction properties of pharmaceutical powders. This is a challenge during scale up and technology transfer when tableting speeds are significantly increased. This study examined the effects of tableting speed on the compressibility (solid fraction vs. compaction pressure), tabletability (tensile strength vs. compaction pressure), and compactibility (tensile strength vs. solid fraction) of four common direct compression excipients and a placebo formulation. The tabletability and compressibility of some of these materials were observed to be speed dependent whereas the compactibility of all materials tested was essentially independent of tableting speed. It is therefore proposed that the compactibility profile (tensile strength vs. solid fraction) is a predictor that is independent of tableting speed and can be used to predict tablet strength during formulation development and scale up.

Compressive Strength↗

United States Department of Agriculture-Agricultural Research Service: advances in the molecular genetic analysis of insects and their application to pest management.

USDA-ARS scientists have made important contributions to the molecular genetic analysis of agriculturally important insects, and have been in the forefront of using this information for the development of new pest management strategies. Advances have been made in the identification and analysis of genetic systems involved in insect development, reproduction and behavior which enable the identification of new targets for control, as well as the development of highly specific insecticidal products. Other studies have been on the leading edge of developing gene transfer technology to better elucidate these biological processes though functional genomics and to develop new transgenic strains for biological control. Important contributions have also been made to the development and use of molecular markers and methodologies to identify and track insect populations. The use of molecular genetic technology and strategies will become increasingly important to pest management as genomic sequencing information becomes available from important pest insects, their targets and other associated organisms.

Agriculture↗

Documenting the pesticide processes module of the ARS RZWQM agroecosystem model.

We describe the theory and current development state of the pesticide process module of the USDA-Agricultural Research Service Root Zone Water Quality Model, or RZWQM. Several processes which are significant in determining the fate of a pesticide application are included together in this module for the first time, including application technique, root uptake, ionic dissociation, soil depth dependence of persistence, volatilization, wicking upward in soil and aging of residues. The pesticide module requires a large number of parameters to run (as does the RZWQM model as a whole) and it is becoming clear that RZWQM will find most interest and use as part of a 'scenario' in which all data requirements are supplied and the predictions of the system compared with a real (usually partial) data set. Such a scenario may then be modified to examine the response of the system to changes in inputs. It also has significant potential as a technology transfer or teaching tool, providing detailed understanding of a specific agronomic system and its potential impacts on the environment.

Agriculture↗

Glucocorticoid-regulated VEGF expression in ischemic skeletal muscle.

Vascular endothelial growth factor (VEGF) is a potent neovascular inducer. Gene therapeutic delivery of a plasmid DNA encoding VEGF has been shown to impart collateral vessel development in animal models of hindlimb ischemia. Constitutive, long-lived expression of VEGF through gene transfer, however, may result in hypervascularization and/or leaky blood vessels. To that end, the introduction of regulated VEGF gene transfer technology may provide a safer and more controlled therapy for ischemic tissues. We developed a glucocorticoid-regulated plasmid vector (pNGVL-hAP/GRE(5)-vegf-pA) for modulating VEGF gene expression. This plasmid possessed five tandem repeats of the glucocorticoid-responsive element and adenovirus major-late promoter driving the expression of the VEGF(165) cDNA. Intramuscular delivery of this plasmid to mice, and subsequent treatment with the synthetic glucocorticoid dexamethasone (DEX), led to greatly enhanced VEGF expression. Similar delivery to the gracillis muscle of New Zealand white rabbits that had undergone ligation of their femoral artery to induce ischemia exhibited increased VEGF expression and collateral vessel development only in the presence of DEX. Additionally, reintroduction of DEX at a time point during which initial VEGF transgene levels had subsided resulted in a vigorous reinduction of VEGF transgene expression. This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization.

Animals↗

Directions for future research in drug abuse prevention.

This paper describes future directions for research in drug abuse prevention from six perspectives that are relevant to NIH: integrated demand and supply reduction, strategic prevention that addresses whole populations and high risk groups, comprehensive or extended prevention that includes multiple channels and periods for intervention delivery, technology transfer, prevention research methods development, and finally, the overarching perspective of interfacing basic and social science research approaches. Specific research questions are summarized that represent each perspective, with implications for NIH policy.

Drug and Narcotic Control↗

Research priorities for alcoholism treatment.

The goals of the current NIAAA review process were to assess the breath, coverage, and balance of the treatment research portfolio and to identify areas for increased attention. Both alcoholism treatment experts and non-alcohol-related treatment experts were called upon to help with this task. Our group was encouraged by the fact that results from previous reviews have effectively been incorporated into the institute portfolio, particularly in the areas of the pharmacotherapy and psychotherapy development programs. The present review identified the five priority areas: mechanisms of action of treatment, combination and sequencing of treatments, health-seeking patterns and processes, concurrent disorders, and understanding help agent behaviors. In addition, several methodological and/or conceptual issues emerged that it was felt, crosscut these areas. These issues included greater emphasis on intervention testing in special populations, patient-treatment matching, measurement techniques, and technology transfer. Finally, several mechanisms of funding were outlined, including across-institute initiatives that could facilitate larger scale translational work such as comorbidity studies and/or studies of combined treatments. All the above were deemed important by the advisory committee, but an overarching emphasis was placed on understanding the mechanisms of action of treatment. For example, it is important to know that a particular pharmacotherapy reduces craving and also how this comes about. Similarly, it is key to the continued refinement of psychosocial treatments that the active components and their mechanisms of change be clarified. Such mechanism studies are crucial for the development of more heuristic and more accurate theoretical formulations that must guide our understanding of alcohol dependence if treatment, relapse, and recovery are to become more scientifically grounded.

Alcoholism↗

The way ahead--the new technology in an old society.

Biotechnology is one of the most important scientific and technological revolutions of the last century and has greatly benefited various aspects of human life. The potentials are enormous and many breakthroughs have already been achieved in the area of healthcare, food, agricultural products and environmental production. The developments in this important area provide immediate benefits to mankind and offer environmentally friendly technologies for sustainable development. The Department of Biotechnology, Government of India, set up in 1986, has played an important catalytic role in promoting this revolutionary field. Research and development, technology validation and demonstration, technology transfer, human resource development, setting up of Centers of Excellence and promoting industry-academia interactions have been some of the major achievements during the last 15 years. A unique feature of this Department is the strong interaction with scientists and institutes across the country to promote biotechnology research and development efforts for commercialization and also to benefit the rural population for socio-economic development. A large number of research institutes/universities and organizations across the country have been supported in the areas of agriculture, healthcare, environment and industry. In addition, basic research has also been an important thrust area. In order to ensure that the benefits of biotechnology reach the masses at large, a very stringent biosafety mechanism has been adopted. India is a country rich in biodiversity with two hot spots and has a strong base of expertise available in nearly all fields--thus biotechnology could flourish leading to a Bioindustrial Revolution. We are today poised to be the leaders in this field in the 21st Century.

Agriculture↗

The role of surveillance in polio eradication and identification of emerging viral encephalitis.

In 1988, when the World Health Assembly resolved to eradicate paralytic poliomyelitis, polio was endemic in 125 countries on 5 continents with an estimated 350,000 cases annually. By 2002, the number of countries was reduced to 7 and the number of cases by greater than 99%. Instrumental in this extraordinary progress is the timely detection and investigation of all cases of acute flaccid paralysis and the examination of stool samples in an accredited WHO Global Network laboratory. The Network consists of 124 National Poliovirus Laboratories, 15 Regional Reference Laboratories, and 7 Global Specialized Laboratories. Network Laboratories are held accountable to rigid performance standards for quality and timeliness in testing more than 60,000 stool samples annually. The Network is a hierarchical system in which polioviruses are isolated and identified in National Laboratories, differentiated as to wild or vaccine origin in Regional Reference Laboratories, and sequenced in Specialized Laboratories. Findings are promptly relayed to Regional and national program managers for immunization strategic planning, monitoring surveillance quality, and assessing eradication progress. Lessons from the Polio Laboratory Network demonstrate the value of a central coordinating body, an effective communication infrastructure, and full partnerships with peer epidemiology and medical sectors. Post-eradication polio surveillance will continue for many years. The Network legacy for other public health initiatives is access to an existing laboratory infrastructure and human resources with the proven ability to achieve technology transfer and quality laboratory performance even in resource-poor countries.

Encephalitis, Viral↗

Recent advances in stem cell neurobiology.

1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense ethical and legislative considerations. The present chapter aims to review some recent aspects of stem cell research applicable to developmental neurobiology and the potential applications in clinical neuroscience.

Animals↗

Antisense oncogene and tumor suppressor gene therapy of cancer.

Rapid advances in cancer gene therapy are driven by an explosive development of gene transfer technology and a strong demand for seeking alternatives to unsatisfactory conventional cancer therapies. Discovery of the genetic basis of cancer has indicated that cancer is a disease of genes. Among a variety of approaches to gene therapy of cancer, antisense oncogene and tumor suppressor gene therapy of cancer are the two strategies that aim at correcting genetic disorders of cancer through suppression of the abnormal expression of the proliferative genes. The potential effectiveness of these approaches is promised by their precise targeting at the mechanisms of the disease. Examples of several preclinical studies of these types of approaches that led to the approval of clinical trials are reviewed. Limitation and future development of these approaches are also discussed.

Animals↗

Targeting cancer cell death with a bcl-XS adenovirus.

Transformation is a complex cellular process that requires several genetic abnormalities. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. This has been recently shown in an in vivo model, where overexpression of Bcl-XL, is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56]. Frequently, overexpression of a member of the Bcl-2 family results in a block in cell death and appears to nullify many built-in cellular defense mechanisms against cancer. Such a block presents a problem because radiation and chemotherapy, standard cancer treatments, ultimately exert their effect by induction of apoptosis and would also be made less effective. Therefore, to better treat cancer it may be necessary to develop novel methods to overcome the effects of the Bcl-2 family. One way to approach this problem is to target the cause--the molecular machinery that allows a cancer cell to survive. Advances in our understanding of apoptosis has identified the Bcl-2 family as a mediator of most apoptosis pathways, including those initiated by oncogenes, tumor suppressor genes, growth factor withdrawal, and external damaging signals. Therefore, functional inhibition of Bcl-2 family members is lethal to many cancer cells. Using gene transfer technology, we can now deliver genes that accomplish this goal. Further investigation will reveal whether this translates to improved therapy in the future.

Adenoviridae↗

The state psychiatric center as an academically affiliated tertiary care hospital.

Conventional wisdom views state psychiatric hospitals as a problem as much as a solution in the fight against mental illness. The legacy of the historic shortcomings of these hospitals--overcrowding, dreary environment, ineffective treatments, understaffing--frames the discussions of their future. The authors argue that a positive, constructive mission and vision for state hospitals is emerging in New York. This vision calls for fewer, smaller, specialized centers redefined as academically affiliated, community based, consumer oriented, tertiary care centers. To transform these centers, a major reengineering is proposed, including centralized treatment, patient and family participation, continuing education for all staff, outcome research, specialization, multi-service campuses, and technology transfer programs. With this transformation, State Psychiatric Centers become partners in efforts to improve the quality of life for people with mental illness throughout society.

Combined Modality Therapy↗

Challenges and future directions for tailored communication research.

As informatics technology advances, a growing number of research trials on tailored communications provide an accumulation of promising evidence to support their efficacy. These trials also reveal gaps and opportunities for future research. The scope and boundaries of tailoring must be redefined in terms of both new technology and the trade-offs between complexity, demand burden on participants, and the minimal information required for effective and efficient tailoring. Basic and methods research is needed to broaden theory, develop a common language, standardize measures, and isolate the key mediating mechanisms that facilitate tailored communications. Applied research must consider more rigorous research designs for efficacy trials and conduct more effectiveness trials to investigate the mechanisms of technology transfer to enhance large-scale diffusion of tailored communications. The role of contextual variables needs to be examined, as well as their interaction with different population groups, and also the channels, modes, and methods of tailored message delivery. Research is also needed on the feasibility of tailoring across clusters of multiple risk factors to identify the commonalities, differences, and interrelations among diverse behaviors. The potential cost-effectiveness of tailored communications must also be examined. No matter how efficacious, tailored communications delivered to large populations (i.e. mass-customization) will not make a public health impact unless proven to be practical and cost-efficient.

Cost-Benefit Analysis↗

Agrobacterium-mediated transformation (AMT) of Trichoderma reesei as an efficient tool for random insertional mutagenesis.

Filamentous fungus Trichoderma reesei QM9414 was successfully transformed with Agrobacterium tumefaciens AGL-1 for random integration of transforming DNA (T-DNA). Co-cultivation of T. reesei conidia or protoplasts with A. tumefaciens in the presence of acetosyringone resulted in the formation of hygromycin B-resistant fungal colonies with high transformation frequency. Nine randomly selected resistant clones were proved to be stable through mitotic cell division. The integration of the hph gene into T. reesei genome was determined by PCR and dot blot analysis. Transgenic T. reesei strains were analyzed using TAIL-PCR for their T-DNA contents. The results showed that T-DNA inserts occurred evidently by fusing DNA at T-DNA borders via random recombination, which suggests that Agrobacterium-mediated transformation is a potentially powerful tool towards tagged mutagenesis and gene transfer technology for T. reesei.

Agrobacterium tumefaciens↗

Inducible nitric oxide synthase: from cloning to therapeutic applications.

Elucidation of the many roles of nitric oxide (NO) in homeostasis and disease states has uncovered many areas where manipulation of NO production would be of therapeutic benefit. Recent advances in gene transfer technology and the cloning of the inducible nitric oxide synthase (iNOS) gene have led to the development of strategies for gene therapy to increase NO production for the treatment of disorders ranging from vascular restenosis to impaired wound healing. This review summarizes the current status of iNOS gene therapy research.

Animals↗

The Cooperative Groups: past and future.

The Cooperative Group system of the National Cancer Institute (NCI) has been in existence since the 1950s and has evolved to comprise 11 groups, the membership of which includes universities, Community Clinical Oncology Programs, and Cooperative Group Outreach Programs. The Cooperative Groups serve as models for cancer clinical trials throughout the world. However, in today's changing healthcare environment in the USA the Cooperative Groups need to adjust how they operate to ensure the continuation of their leadership role in cancer clinical trials. Government funds, the main source of support for the Cooperative Groups' activities, are shrinking and currently funding is only 50% of the recommended level. If the Cooperative Groups are to remain at the forefront, adjustments must be made in several areas: the Cooperative Groups need to provide an efficient and rapid scientific and legal mechanism to execute large phase III studies of the increasingly important portfolio of compounds being developed by industry more effectively. Industry has come to rely on contract research organizations for expedited testing of their products due to perceived inefficiency in these areas in the Cooperative Group mechanism. The Cooperative Groups are uniquely situated to provide in-depth evaluation of the newest therapies for regulatory agencies and interested health insurers, as well as provide health outcomes data, which are now much sought after by the healthcare industry. Managed care is shaping medical practice, including cancer care, throughout the USA. Finally, the Cooperative Groups need to foster greater international cooperation to speed technology transfers. The leaders of the Cooperative Groups are discussing new approaches to address these deficiencies, while complementing the existing NCI structure and recognizing the independence of each group. The objectives of these new approaches would be: to establish a structure whereby better contracts with industry for conducting trials can be established; to enhance international cooperation in clinical trials; to encourage greater involvement of third-party payers in clinical trials; to build on the scientific breadth of the members; to identify the most appropriate therapies to consider for reimbursement; to establish a framework which builds on the strengths of each of the members; and to integrate health outcomes and economic measures into the protocol activities. The Cooperative Groups are making changes to ensure they remain the leaders in cancer clinical trials well into the 21st century. The benefits of these adjustments will be realized not only by patients, but also by health professionals and the healthcare industry.

Humans↗

Genetic transformation of conifers and its application in forest biotechnology.

Genetic modification of conifers through gene transfer technology is now an important field in forest biotechnology. Two basic methodologies, particle bombardment and Agrobacterium-mediated transformation, have been used on conifers. The use of particle bombardment has produced stable transgenic plants in Picea abies, P. glauca, P. mariana, and Pinus radiata. Transgenic plants have been produced from Larix decidua, Picea abies, P. glauca, P. mariana, Pinus strobus, P. taeda, and P. radiata via Agrobacterium-mediated transformation. Agrobacterium-mediated transformation has advantages over particle bombardment such as a simpler integration pattern and a limited rearrangement in the introduced DNA. At present, genetic transformation of conifers has been directed toward improving growth rate, wood properties and quality, pest resistance, stress tolerance, and herbicide resistance, which will drive forestry to enter a new era of productivity and quality.

Agrobacterium tumefaciens↗