Strengthen international academic cooperation and exchanges: prospects in the 21st century Summary of the First World Chinese Congress of Digestion

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The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells

Previous studies have shown that retinoic acid (RA), similar to tumor necrosis factor-alpha (TNF-alpha), can act as a bifunctional regulator of the growth of bone marrow progenitors, in that it can stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF)- or interleukin-3 (IL-3)-induced GM colony formation, but potently inhibit G-CSF-induced growth. The present study, using highly enriched human CD34+ as well as Lin- murine bone marrow progenitor cells, demonstrates a potent inhibitory effect of 9-cis-RA on burst-forming unit-erythroid (BFU-E) colony formation regardless of the cytokine stimulating growth. Specifically, 9-cis-RA potently inhibited the growth of BFU-E response to erythropoietin (Epo) (100%), stem cell factor (SCF) + Epo (92%), IL- 3 + Epo (97%), IL-4 + Epo (88%), and IL-9 + Epo (100%). Erythroid colony growth was also inhibited when CD34+ progenitors were seeded at one cell per well, suggesting a direct action of RA. Using synthetic ligands to retinoic acid receptors (RARs) and retinoid X receptors (RXRs) that selectively bind and activate RAR-RXR or RXR-RXR dimers, respectively, we dissected the involvement of the two retinoid response pathways in the regulation of normal myeloid and erythroid progenitor cell growth. Transactivation studies showed that both the RAR (Ro 13- 7410) and RXR (Ro 25-6603 and Ro 25-7386) ligands were highly selective at 100 nmol/L. At this concentration, Ro 13-7410 potently inhibited G- CSF-stimulated myeloid as well as SCF + Epo-induced erythroid colony growth. At the same concentration, Ro 25-6603 and Ro 25-7386 had little or no effect on G-CSF-induced colony formation, whereas they inhibited 75% and 53%, respectively, of SCF + Epo-stimulated BFU-E colony growth. Thus, the RAR-RXR response pathway can signal growth inhibition of normal bone marrow myeloid and erythroid progenitor cells. In addition, we demonstrate a unique involvement of the RXR-RXR pathway in mediating growth inhibition of erythroid but not myeloid progenitor cells.     

Loss of myeloid differentiation antigens precedes blastic transformation in chronic myelogenous leukemia

In order to determine whether antigenic patterns alter with disease progression and are thereby suggestive of impending blast crisis in chronic myelogenous leukemia, 50 bone marrow biopsy specimens from 32 patients were examined retrospectively using indirect immunoperoxidase labeling with three monoclonal antibodies that detect myeloid antigens. Monoclonal antibodies PMN13F6, PMN7C3, and PMN8C7 detect human neutrophil antigens that first appear at the myeloblast, promyelocyte, and metamyelocyte stages of differentiation, respectively, and persist throughout later differentiation. Percentages of antigen-positive bone marrow cells during the chronic phase were compared with percentages of antigen-positive cells at blast transformation, and time from bone marrow biopsy until blast crisis was correlated with the percentage of bone marrow cells expressing these antigens. Bone marrow biopsy samples from patients in the chronic phase who continue to remain clinically stable 4 to 106 months after biopsy expressed PMN13F6 antigen on 82% +/- 9% (mean +/- SD) of cells, PMN7C3 antigen on 62% +/- 14% of cells, and PMN8C7 on 68% +/- 14% of cells. Bone marrow biopsy specimens obtained from patients 1 or more years prior to blast transformation expressed PMN13F6 antigen on 81% +/- 12%, PMN7C3 antigen on 71% +/- 16%, and PMN8C7 on 64% +/- 16% of cells. Bone marrow biopsy samples obtained between 2 months and 1 year prior to blast crisis expressed PMN13F6 antigen on 68% +/- 15%, PMN7C3 on 51% +/- 17%, and PMN8C7 antigen on 46% +/- 18% of cells. Bone marrow biopsy specimens taken at the time of blast transformation expressed PMN13F6 antigen on 20% +/- 25%, PMN7C3 antigen on 19% +/- 25%, and PMN8C7 antigen on 13% +/- 25% of cells. The difference between the mean of antigen-positive cells from bone marrow biopsy samples obtained at the time of blast crisis was significant compared with the mean of positive cells from biopsy specimens obtained at all other phases of the disease (P less than .001 for all three antibodies). There was a positive correlation between loss of myeloid antigens and disease progression as determined by simple regression of log time and correlation analysis (PMN13F6, r = .6533, P less than .005; PMN7C8, r = .6304, P less than .005; PMN8C7, r = .5215, P less than .05). There was a negative correlation between percentage of immature cells and time to blastic crisis (r = -.6206, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional differences between CD38- and DR- subfractions of CD34+ bone marrow cells

Several studies have previously demonstrated enrichment in primitive progenitor cells in subfractions of CD34+ bone marrow (BM) cells not expressing CD38 or HLA-DR (DR) antigens. However, no studies have directly compared these two cell populations with regard to their content of primitive and more committed progenitor cells. Flow cytometric analysis of immunomagnetic isolated CD34+ cells demonstrated little overlap between CD34+CD38- and CD34+DR- progenitor subpopulations in that only 12% to 14% of total CD34+DR- and CD34+CD38- cells were double negative (CD34+CD38-DR-). Although the number of committed myeloid progenitor cells (colony-forming units granulocyte- macrophage) was reduced in both subpopulations, only CD34+CD38- cells were significantly depleted in committed erythroid progenitor cells (burst-forming units-erythroid). In single-cell assay, CD34+CD38- cells showed consistently poorer response to single as opposed to multiple hematopoietic growth factors as compared with unfractionated CD34+ cells, indicating that the CD34+CD38- subset is relatively enriched in primitive hematopoietic progenitor cells. Furthermore, CD34+CD38- and CD34+DR- cells, respectively, formed 3.2-fold and 1.6-fold more high proliferative potential colony-forming cell (HPP-CFC) colonies than did unfractionated CD34+ cells. Finally, CD34+CD38-DR- cells were depleted in HPP-CFCs as compared with CD34+CD38+DR+ cells. The results of the present study suggest that both the CD38- and DR- subfractions of CD34+ bone marrow cells are enriched in primitive hematopoietic progenitor cells, with the CD34+CD38- subpopulation being more highly enriched than CD34+DR- cells.     

Complaints about dental practitioners: an analysis of 6 years of complaints about dentists,dental prosthetists,oral health therapists,dental therapists and dental hygienists in Australia

Background

Previous research has found dental practitioners at elevated risk of complaint compared with other health professions. This study aimed to describe the frequency, nature and risk factors for complaints involving dental practitioners.

Methods

We assembled a national dataset of complaints about registered health practitioners in Australia between January 2011 and December 2016. We classified complaints into 23 issues across three domains: health, performance and conduct. We compared rates of complaints about dental practitioners and other health practitioners. We used negative binomial regression analysis to identify factors associated with complaints.

Results

Dental practitioners made up 3.5% of health practitioners, yet accounted for approximately 10% of complaints. Dental practitioners had the highest rate of complaints among fourteen health professions (42.7 per 1000 practitioners per year) with higher rates among dentists and dental prosthetists than allied dental practitioners. Male practitioners were at a higher risk of complaints. Most complaints about dentists related to treatments and procedures (59%). Around 4% of dentists received more than one complaint, accounting for 49% of complaints about dentists. In 60% of closed cases no regulatory action was required. Around 13% of complaints resulted in restrictive actions, such as conditions on practice.

Conclusion

Improved understanding of patterns may assist regulatory boards and professional associations to ensure competent practice and protect patient safety.     

Bifunctional effects of tumor necrosis factor alpha (TNF alpha) on the growth of mature and primitive human hematopoietic progenitor cells: involvement of p55 and p75 TNF receptors

Tumor necrosis factor alpha (TNF alpha) has previously been reported to have both inhibitory and stimulatory effects on hematopoietic progenitor cells. Specifically, TNF alpha has been proposed to stimulate early hematopoiesis in humans. In the present study we show that TNF alpha, in a dose-dependent fashion, can potently inhibit the growth of primitive high proliferative potential colony-forming cells (HPP-CFCs) stimulated by multiple cytokine combinations. Using agonistic antibodies to the p55 and p75 TNF receptors or TNF alpha mutants specific for either of the two TNF receptors, we show that both receptors can mediate this inhibition. In contrast, the potent stimulation of interleukin-3 (IL-3) plus granulocyte-macrophage colony- stimulating factor (GM-CSF) induced HPP-CFC colony formation observed at low concentrations of TNF alpha (2 ng/mL) was only a p55-mediated event. Moreover, the stimulatory effects of TNF alpha on GM-CSF or IL-3- induced colony formation, as well as the inhibition of G-CSF-induced colony growth, were also exclusively signaled through the p55 TNF receptor. Taken together, our results suggest that the inhibitory effects of TNF alpha on primitive bone marrow progenitor cells are mediated through both p55 and p75 TNF receptors, whereas the p55 receptor exclusively mediates the bidirectional effects on more mature, single factor-responsive bone marrow progenitor cells as well as stimulation of IL-3 plus GM-CSF-induced HPP-CFC colony growth.     

Analysis of Epstein-Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations

While Epstein-Barr virus (EBV) infection is associated with the development of certain lymphoid and epithelial tumors, the role of the virus in the pathogenesis of these malignancies remains unknown. It has been suggested that EBV strain variation may contribute to tumor development. Two major strains of EBV, type 1 and type 2, have been identified on the basis of genetic polymorphisms and other minor genetic variations give rise to distinct EBV isolates. We analyzed EBV strain variation in healthy individuals and compared them with EBV isolates present in lymphoid and epithelial neoplasms from the same geographic regions. In particular, the incidence of the 30-bp latent membrane protein (LMP1) gene deletion, recently implicated in the development of more aggressive forms of virus-positive lymphomas and Hodgkin's disease [HD], was examined in the normal population. While a preferential association of the LMP1 deletion with the type 2 strain of EBV was observed, there was no increased incidence of virus isolates carrying this deletion in HD, Burkitt's lymphoma, or virus-associated carcinomas compared with the appropriate normal population. A polymorphism in the BamHI F region of the EBV genome, previously identified in Chinese populations, was found at increased incidence in European HD biopsies. Overall, we found that most of the EBV gene polymorphisms detected in EBV isolates from healthy virus carriers occurred with similar frequency in virus-associated tumors from the same geographical region.     

Interleukin-12 enhances peripheral hematopoiesis in vivo

Interleukin 12(IL-12) is a cytokine that supports the proliferation and activation of cytotoxic T lymphocytes and natural killer (NK) cells. Recent evidence has suggested that IL-12 also has hematopoietic activities in vitro. We report studies that show that IL-12 has significant in vivo hematopoietic stimulating activity that includes enhancement of peripheral (splenic) hematopoiesis and mobilization of hematopoietic progenitor cells to the peripheral circulation. A single injection of recombinant murine IL-12 significantly reduced the number of bone marrow (BM) colony-forming unit granulocyte-macrophage (CFU-GM) in a time-dependent manner, while concomitantly stimulating high proliferative potential. In contrast, splenic CFU-GM and HPP were increased in a time- and dose-dependent manner. Chronic administration of IL-12 resulted in significant splenic hyperplasia with increased progenitor cells, increased circulating progenitor cells, and BM hypoplasia with decreased progenitor cells. These data show that IL-12 has significant in vivo hematopoietic effects that include the ability to mobilize progenitor cells to the peripheral circulation, which may prove to be of significant benefit for peripheral blood stem cell transplantation. Thus, IL-12 has potential to be an important agent for clinical transplantation because of its hematopoietic mobilization and its previously shown immune augmenting and therapeutic activities. This combination of hematopoietic and immune functions is unique and not achievable with currently used hematopoietic growth factors.     

Increased radiosensitivity of a subpopulation ot T-lymphocyte progenitors from patients with Fanconi's anemia

In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST (patients, D37 = 198 R; normals, D37 = 309 R, p = 0.057) and colony formation assay (patients, D37 = 53 R; normals, D37 = 109 R, p = 0.016). No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed.     

Loss of bone mineral density in Chinese pre-menopausal women with systemic lupus erythematosus treated with corticosteroids

The adverse effect of disease and chronic corticosteroid therapy on bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) has been reported in several studies of Caucasian populations. As the factors controlling bone homeostasis may be different in Asian populations, we measured BMD in 52 pre-menopausal Chinese women (mean age 34.1 +/- 8.0 yr) with SLE (mean disease duration 6.4 +/- 4.5 yr) treated with prednisone (mean daily dose 11.4 +/- 10.8 mg/day). Lumbar spine, hip (total and subregions) and total body BMDs were measured in the SLE patients using dual-energy X-ray absorptiometry (DEXA), and compared with those from healthy controls matched for age, sex and body mass index. Compared to controls, SLE patients were found to have lower BMD (g/cm2) at several sites: the lumbar spine (0.98 vs 0.90, P = 0.001), Ward's triangle (0.72 vs 0.67, P = 0.03), total body (1.04 vs 1.01, P = 0.04) and total hip (0.87 vs 0.82, P = 0.05). There was no correlation between BMD at any region and duration of disease, activity of disease or prednisone therapy (mean daily dose, cumulative dose or treatment duration). When BMDs were compared between controls and SLE patients, subgrouped according to those not on calcium and those arbitrarily receiving calcium supplements (1 g/day), significantly lower BMDs were found in those not on calcium compared to both controls and SLE patients on calcium. BMDs in SLE patients on calcium were not different from those in controls. The low prevalence of osteoporosis in our SLE patients (4-6%) suggests significant loss of BMD in Chinese SLE patients on corticosteroid therapy is less than that reported in Caucasians (12-18%).