A comprehensive information resource on traditional, complementary, and alternative medicine: toward an international collaboration.

OBJECTIVES: A prototype for a comprehensive information resource for traditional complementary and alternative medicine (TCAM) has been developed to fill the considerable needs of a broad audience for worldwide access to TCAM information. The proposed resource is to be a comprehensive, vocabulary-controlled, integrated, standardized, multimedia information resource for TCAM. It will facilitate international cooperation, promote synergistic development of individual resources, promote dissemination of TCAM knowledge, and map the interrelationships among the TCAM traditions. METHODS: We organized two workshops for representatives of international databases that contain significant information on various aspects of alternative medicine. For the first workshop, we prepared and demonstrated a prototype named Complementary and Alternative Medicine Digital Library (CAMed) to illustrate the anticipated structure, content, and functionality of the comprehensive resource. We then constructed a second prototype to demonstrate the possibilities of searching across the collaborating databases and presented it to the representatives at the second workshop. OUTCOMES: Representatives of nine international databases attended the two workshops, in Bangalore, India (1998), and in Seoul, Korea (1999). We presented the prototypes at the workshops. Prototype I uses a Web interface, and supports browsing and searching from a variety of access points. Prototype II demonstrates a functional system that provides simultaneous access to selected represented databases by searching thesauri of these databases through our system. The group formalized itself as the International Collaboration for Information on Complementary and Traditional Medicine (IC2TM) with a goal of fully realizing the potential of the project.

Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia.

Hematopoietic progenitor cells in 2 myeloproliferative disorders, juvenile chronic myelomonocytic leukemia and polycythemia vera, are known to be hypersensitive to cytokines that control normal progenitor cell proliferation, differentiation, and survival in their respective granulocyte/macrophage and erythroid lineages. Because thrombopoietin controls these functions in the normal megakaryocytic lineage, we asked the question: Are megakaryocytic progenitor cells in the myeloproliferative disorder essential thrombocythemia (ET) hypersensitive to thrombopoietin? Peripheral blood mononuclear cells from patients with ET, or secondary (reactive) thrombocytosis (2 degrees T), or healthy volunteers were grown in strictly serum-free agarose culture containing interleukin 3 (IL-3) and all-trans-retinoic acid, with various concentrations of PEG-rHu megakaryocyte growth and development factor (MGDF). The concentration of cytokine at half-maximum colony number served as a measure of progenitor cell sensitivity. Hypersensitivity to PEG-rHu MGDF was found in circulating progenitors from 18 of 20 (90%) informative patients with presumptive diagnosis ET, 1 of 8 (12.5%) 2 degrees T patients, and none of the 22 healthy volunteers. Median MGDF sensitivity ratio in ET patients was approximately 53 times greater than in the controls. This hypersensitivity, which was also directed to rHu thrombopoietin, was highly specific with respect to cytokine, disease, and cell lineage. We propose that, despite their single pluripotential cell origin, the different clinicopathologic phenotypes in different chronic myeloproliferative disorders are determined by lineage-restricted hypersensitivities of hematopoietic progenitor cells to endogenous cytokines. This work emphasizes the importance of stringent serum-free conditions for revealing true sensitivities to cytokines. The findings also offer a basis for evolving a positive test for ET, a diagnosis now made essentially by exclusion.

Madingley, Madding, Mad scenarios: an exercise in futurology.

The Madingley scenarios were created to suggest potential contrasting futures (around year 2020) that could develop from the same driving forces. Those contrasting futures are named 'Trust their Guidance' and 'Find my Way', respectively. Trust their Guidance depicts a world where institutions have succeeded in adapting to the changing world and have strengthened their power and control on nations. Find my Way depicts a world where empowered individuals have taken responsibility for optimising their own lives. The discussion of these scenarios raised a number of questions including the purpose and role of governments, differences between societies, fundamental vs superficial change and, applied to the area of homeopathy, the role and responsibility of the homeopathic community in shaping the future of this medical approach.

Factors that shape alternative medicine: the role of the alternative medicine research community.

The documented prevalence of alternative medicine practices in the United States warrants a critical evaluation of this field. Although adequate scientific evaluation is needed, it is doubtful that such research will take place unless other factors are taken into account that remain overlooked. We have previously proposed a conceptual definition of alternative medicine practices and outlined those sociological, political, economic, and regulatory factors independent of the alternative healthcare community that could potentially hamper the optimal evaluation of alternative medicine. In the present article, we discuss other relevant issues to which the alternative healthcare community contributes. These factors originate both from within biomedicine (e.g., demands for specific scientific approaches, explanatory models) and within the alternative medicine community itself (e.g., the use of jargon, insularity, a profit-minded research agenda).

Is the scientific publishing of complementary and alternative medicine objective?

Bias expressed by conventional journals against the field of "alternative," "integrative," or "complementary" medicine has been said to drive the appearance of new journals dedicated to this field. We examined two examples of recent articles on complementary and alternative medicine that appeared in two major medical journals in 1998. One is an editorial on the risks of alternative medicine, published in The New England Journal of Medicine and the other is a study on Therapeutic Touch, published in the Journal of the American Medical Association. We evaluated whether information and opinions presented in this editorial and article are objective or not. We found that these examples reflect, at best, misinformation or misunderstanding of the field, or at worst, disingenuousness. We consider the possibility that this apparent bias may be due to the fact that some of the concepts implicit in alternative medicine are outside the current biomedical framework. Yet, it is only by exploring knowledge outside the boundaries of existing dogmas that real (as opposed to incremental) progress can occur.

Methodologic considerations for research in traditional (alternative) medicine.

The widepsread use, in the United States and other western countries, of alternative medical practices often derived from traditional systems of health has intensified the need to evaluate their safety and effectiveness. These practices tend to generate polarized attitudes of either acceptance or rejections. Opponents reject them because, they claim, good scientific research has not supported their use. Proponents insist that current scientific methodologies are not appropriate to evaluate these practices. This article briefly examines these issue, suggesting that the answer lies between these 2 extreme positions. Various methodologic issues are considered, and suggestions are made to adapt scientific methodology, where appropriate, to respect the particularities of alternative medicine.

Progress in complementary and alternative medicine: contribution of the National Institutes of Health and the Food and Drug Administration.

Since the creation of the Office of Alternative Medicine (OAM) at the National Institutes of Health (NIH), progress has been made in the evaluation and, where appropriate, the clinical and scientific acceptance of "complementary and alternative" medicine (CAM). This progress is due in part to initiatives jointly conducted by the NIH and the U.S. Food and Drug Administration (FDA). In particular, advances in the evaluation and acceptance of two CAM practices, acupuncture and botanical medicine, have resulted from ongoing cooperation between the two agencies. The legalization of the use of acupuncture needles in 1996 came as a result of a workshop sponsored by the OAM with the participation of the FDA, which explored key regulatory issues. Prompted by similar regulatory issues, as well as by the initiation of NIH-funded research projects, the OAM sponsored an international symposium to examine the evidence for and the role of botanical medicine in the United States. This conference generated a series of workshops sponsored by the Drug Information Association in conjunction with NIH and FDA, which explored the scientific, regulatory, and policy issues of heterogeneous botanical products. These efforts resulted in the initiation of a large randomized multicenter clinical trial (sponsored by the National Institute of Mental Health) of the botanical, St. John's wort, for the treatment of depression, and the formation of internal working groups within the FDA that are drafting a guidance policy for the development of botanicals as drugs in the United States. This document is expected to be available in the near future.

Circulating erythroid progenitors in polycythemia vera are hypersensitive to insulin-like growth factor-1 in vitro: studies in an improved serum-free medium.

We have investigated the question of erythropoietin (Epo) hypersensitivity versus Epo independence as the basis for the endogenous erythroid bursts (EEBs) that develop in cultures without added Epo from hematopoietic cells of polycythemia vera (PV) patients. Using an improved serum-free (SF) medium containing interleukin (IL)-3, but no insulin-like growth factor-1 (IGF-1), and devoid of contaminants that influence erythropoiesis, we compared circulating normal and PV early erythroid progenitors (BFU-E) with respect to their responses in vitro to recombinant human (rHu) Epo. Cultures were seeded with Ficoll-Hypaque density-separated peripheral blood (PB) mononuclear cells (MNCs), and erythroid bursts, together with their component colonies of > or = 50 cells, were scored in situ at 13 to 16 days of culture. The Epo dose-response curve of BFU-E from PV patients was found to be statistically indistinguishable from that of normal subjects. This observation provides compelling evidence against the Epo-hypersensitivity hypothesis. In the complete SF medium minus Epo, the sensitivity of BFU-E to IGF-1 was much greater in PV than in normals, the dose-response curve being shifted to the left by at least 2 orders of magnitude. These data show that the erythroid progenitor cell response in PV is hypersensitive to IGF-1, and independent of Epo. The data also emphasize the importance of truly SF medium conditions for assessment of progenitor cell sensitivities to recombinant growth factors. Depletion of adherent cells totally prevented erythroid burst formation by normal circulating progenitors, but did not prevent the hypersensitive response to IGF-1 of such cells from PV patients. Hence, again unlike its normal counterpart, the progenitor cell response in PV appears to be independent of adherent cell control.

Superoxide dismutase halts cycling of murine erythroid progenitor cells prior to S phase in vitro and possibly in vivo.

Mice of the C57BL/6 (B6) strain show a much lower proportion of marrow erythroid progenitor cells (BFU-E) in DNA synthesis in vivo than mice of the congeneic B6S strain. However, when assayed in vitro marrow cells from both strains show high proportions of BFU-E in S-phase. BFU-E from normal B6 mice have been previously shown to be specifically inhibited from entering S-phase in vitro by the antioxidant enzyme superoxide dismutase (SOD), however, in this study we have found that BFU-E taken from the marrow of B6S mice or B6 mice which have been subjected to bleeding are insensitive to SOD inhibition in vitro. Comparisons of results from in vivo and in vitro cycling assays done with cells from both strains indicate that a large proportion of marrow BFU-E in normal B6 mice are halted in the pre-S portion of the cell cycle in vivo, and these halted cells are prevented from going into S-phase in vitro by SOD. The insensitivity to SOD inhibition shown by BFU-E from B6S and bled B6 mice can be attributed to the absence of accumulation of SOD-susceptible cells in pre-S phase in these mice in vivo, and there is evidence to suggest that the difference in BFU-E cycling seen in vivo may be due to interactions between SOD and factors which stimulate cycling of BFU-E.

Superoxide dismutase specifically inhibits erythroid cell DNA synthesis and proliferation.

The antioxidant enzyme superoxide dismutase (SOD) was previously shown to inhibit both the proliferation of murine erythroid DA-1 cells growing in the presence of Interleukin-3 (IL-3) and the DNA synthesis of marrow erythroid progenitor cells (BFU-E) in vitro. We show here that the inhibition of marrow cell DNA synthesis by SOD is specific for BFU-E and erythroid precursors (CFU-E), with other myeloid progenitors (CFU-GM) and stem cells (CFU-S) being unaffected, and IL-3 blocks the inhibitory effects of SOD on BFU-E in a dose-dependent manner. Extending earlier observations on the effects of SOD on cell proliferation, it was found that SOD was capable of inhibiting DA-1 cell proliferation supported by either IL-3 or erythropoietin (epo), but had no effect on IL-3 dependent FDCP-1 cells, nor on epo-dependent HCD-57 cells. Of several murine erythroleukemia cell lines tested, only those transformed with Friend SFFVa virus were inhibited by SOD, while those transformed with Friend SFFVp or MuLV virus were not affected. These results show that the effects of SOD are not antagonistic to particular growth factors but rather the inhibition is specific for erythroid cells, and cells of the proper stage can be inhibited even if they have been transformed to factor independence.

Purification of an inhibitor of erythroid progenitor cell cycling and antagonist to interleukin 3 from mouse marrow cell supernatants and its identification as cytosolic superoxide dismutase.

We have isolated a protein from media conditioned by a murine marrow-derived cell line (PB6) and from mouse marrow supernatants that antagonizes interleukin 3-dependent proliferation of cells in culture and reversibly inhibits DNA synthesis of erythroid progenitor cells (BFU-E) in vitro. This protein, p16 (monomer Mr = 16 kD on SDS-PAGE), was purified to homogeneity and amino acid sequencing of a polypeptide fragment yielded a sequence identical to that of murine cytosolic Cu,Zn-containing superoxide dismutase (SOD). The identification of p16 as SOD was confirmed by the detection of SOD enzymatic activity in pure p16 fractions, and when a commercial human erythrocytic SOD preparation was tested it showed the same cell inhibitory activities as p16. These observations show that superoxide dismutase is able to affect the cycling and growth factor responses of hematopoietic cells, activities that have not previously been associated with this enzyme.

Interleukin 3 opposes the action of negative regulatory protein (NRP) and of transforming growth factor-beta (TGF-beta) in their inhibition of DNA synthesis of the erythroid stem cell BFU-E.

DNA synthesis of the early erythropoietic progenitor cell (erythroid burst-forming unit, BFU-E) is inhibited by a growth factor that we have called negative regulatory protein (NRP). This protein appears to act during the S-phase of the cell cycle and to be specific to the BFU-E. It is nontoxic and its action is readily reversible by washing the cells. Erythropoietic burst formation by BFU-E in culture is promoted by interleukin 3 (IL-3). In the present work, using the hydroxyurea suicide assay method, we investigated the effects on DNA synthesis of exposing BFU-E of mouse bone marrow in vitro to NRP, IL-3, and combinations of NRP and IL-3. We found that the action of NRP on BFU-E DNA synthesis was opposed by IL-3 within the 45 min that it took to carry out the cell suicide assay. We also studied transforming growth factor-beta (TGF-beta) and found that its action on DNA synthesis of BFU-E was identical to that of NRP in time scale, reversibility, and opposition by IL-3, although the two have different molecular properties. According to the competence-progression model, regulation of cell proliferation occurs at two sites: 1) the G0 to G1 transition, where competence factors (e.g., platelet-derived growth factor [PDGF] and interleukin 1 [IL-1]) act, and 2) during G1-phase, where progression factors (e.g., interleukin 2 [IL-2] and IL-3) act. Our data indicate that cell proliferation may also be regulated at a third site, during S-phase. Here, the decision as to whether or not DNA synthesis will proceed appears to depend on a balance between positive and negative regulatory signals.