Costs and effectiveness of nonsteroidal anti-inflammatory drugs: the importance of reducing side effects.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
J L Wagner
Publications and source records attributed to J L Wagner.
Molecular analysis of six dog leukocyte antigen class I sequences including three complete genes, two truncated genes and one full-length processed gene.
We have isolated six distinct dog leukocyte antigen (DLA) class I sequences. An additional functional nonclassical class I gene, DLA-79, was characterized previously. This brings the number of isolated canine class I sequences to seven. These seven loci account for nearly all class I sequences detected in genomic DNA by Southern blotting. With approximately seven members, the class I gene family in dog is considerably less complex than in either human or mouse. Three of the six sequences described in this article contain complete class I genes. These genes have the typical arrangement of exons and introns, and their predicted protein sequences have the features expected of expressed class I molecules. Two sequences contain truncated genes. These genes, having only partial class I homology and disruptive mutations, are clearly nonfunctional. The remaining locus contains a full-length processed gene which is unique among characterized class I loci. Sequence comparisons were performed to examine evolutionary relationships among the family members. Two sequences, DLA-64 (complete) and -53 (truncated), appear to be chimeras presumably formed by interlocus recombination. Using the reverse transcription-polymerase chain reaction, mRNA originating from each of the three complete genes was identified in canine peripheral blood leukocytes. DLA-79 specific transcripts were identified previously. Thus, each of the four complete canine class I genes is transcribed in vivo.
Amino Acid Sequence↗
Effects of ketamine sedation on glucose clearance, insulin secretion and counterregulatory hormone production in baboons (Papio hamadryas).
Since the effects of ketamine sedation seem to differ between subspecies of baboons, we assessed the endocrine response to an intravenous glucose tolerance test (IVGTT) in 12 hamadryas baboons. The first phase insulin secretion, basal insulin, and glucose levels, as well as the glucose clearance, were significantly lower in sedated baboons as compared to fully awake animals. Glucagon and cortisol were significantly higher, while growth hormone was lower during ketamine sedation. Papio hamadryas appears to be a promising pre-clinical model for the study of endocrine replacement therapy in insulin-dependent diabetes. However, the data obtained must be interpreted with the knowledge that the anesthetic employed to allow for testing of the animals does have an effect on the parameters described in this report.
Anesthetics, Dissociative↗
Histocompatibility testing of dog families with highly polymorphic microsatellite markers.
The dog has served traditionally as a model for marrow and organ transplantation. A key component of any study of transplantation is histocompatibility typing of donors and recipients. Towards the development of a less expensive, more simplified typing system within canine families, a new highly polymorphic microsatellite marker for the canine Major Histocompatibility Complex class II region was isolated and characterized. In addition, we report on the application of class I and class II microsatellite-based markers for following the inheritance of the alleles within the canine analog of the human HLA loci, DLA, through multi-generation pedigree.
Alleles↗
Bone marrow transplantation for severe aplastic anemia from genotypically HLA-nonidentical relatives. An update of the Seattle experience.
This report updates the results of marrow transplantation at the Fred Hutchinson Cancer Research Center for patients with severe aplastic anemia whose donors were HLA-nonidentical relatives. Between 1970 and 1993, 40 patients received transplants for severe aplastic anemia from related donors other than HLA genotypically matched siblings. Nine patients (group 1) were conditioned with cyclophosphamide (Cy) at 50 mg/kg for 4 doses and received marrow from phenotypically HLA-matched relatives. With the exception of one accidental death, all patients are alive and disease free 3-18 years after transplantation. Thirty-one patients received marrow from HLA-mismatched relatives who differed by one or more loci. Fifteen of these patients (group 2) received Cy at 50 mg/kg for 4 doses without total body irradiation (TBI) and none survived. Because of failure to sustain engraftment in 9 of 14 evaluable patients in group 2, the regimen for HLA-mismatched patients was changed in 1984 to include Cy at 60 mg/kg for 2 doses and TBI was added at 1200 cGy to increase immunosuppression (group 3). Sixteen patients in group 3 received marrow grafts after failure to respond to immunosuppressive therapy. Eight of the 16 patients in group 3 remain alive without disease between 1.5 and 11.3 years after transplantation. In conclusion, transplants from phenotypically HLA-identical related donors can be carried after Cy alone and results are comparable to those observed with genotypically HLA-identical siblings. Transplants from related donors mismatched for one or more HLA loci require a more intensive conditioning regimen, for example, one containing TBI, to achieve sustained engraftment.
Adolescent↗
Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells.
A novel cytokine originally designated murine CTLA-8 was described as a cDNA isolated from an activated T cell hybridoma produced by fusing a mouse cytotoxic T cell clone and a rat T lymphoma. This cDNA, which contains mRNA instability sequences characteristic of many cytokines, encoded a putative secreted protein that was homologous to the ORF13 gene of Herpesvirus saimiri. The human homolog to this molecule has recently been identified as the proinflammatory cytokine IL-17. We describe the isolation of a cDNA encoding mouse IL-17 from a cDNA library generated from alpha beta TCR + CD4-CD8- thymocytes using a subtraction technique that enriched for activation specific genes. This cDNA shares 87.3% amino acid identity to the previously described murine CTLA-8. Comparison of murine CTLA-8 to a cDNA we isolated from activated rat splenocytes revealed that murine CTLA-8 is, in fact, the rat homolog of IL-17. Mouse IL-17 mRNA is specifically expressed by activated alpha beta TCR + CD4-CD8- T cells, a small subset with a potentially important role in immune regulation. Mouse, rat, and human IL-17 can induce IL-6 secretion in mouse stromal cells, indicating that all homologs can recognize the mouse receptor.
Animals↗
Preclinical large animal models for hematopoietic stem cell transplantation.
The use of large animal models for marrow and stem cell transplantation has become increasingly important. Large animal models have recently been used for studying the principles of hematopoiesis and illustrate the relative slow rate of stem cell turnover compared with mice. Furthermore, large animals are used to study the effectiveness of varying conditioning regimens, as well as the influence of growth factors and various immunosuppressive agents such as corticotropin-releasing factor and mycophenolate mofetil on graft-versus-host disease and graft rejection. Large animal models have become useful in studying the combination of hematopoietic stem cell and solid organ transplants for the establishment of long-term tolerance in major histocompatibility complex-mismatched settings.
Animals↗
Molecular analysis and polymorphism of the DLA-DQA gene.
A full-length cDNA clone and two overlapping genomic clones corresponding to the canine DQA class II gene were isolated and sequenced. Restriction mapping and sequence data allow identification and orientation of the five exons corresponding to the alpha (alpha) chain. Sequence analysis of exon 2 amplified from 17 unrelated dogs of various breeds identified seven alleles. The structure of the canine DQA gene is similar to HLA-DQA1 and other mammalian DQA genes. This study will serve as a reference for developing a typing system for the DLA-DQA gene for donor and recipient matching in the canine model for organ and bone marrow transplantation.
Amino Acid Sequence↗
Molecular analysis of the DLA DR region.
The dog is an important model for studying organ transplantation. In order to develop a DNA-based typing system, a genomic analysis of the canine DR region of the MHC was undertaken. Southern analysis suggests the presence of two DRB genes in most dogs and all have one DRA gene. One dog out of 200 examined contains only one DRB gene. The DRA gene was mapped in one lambda phage clone. One DRB gene (DRBB1) was localized to two overlapping phage clones. Another DRB gene (DRBB2) was localized to two overlapping phage clones. Sequence analysis of the two DRB genes suggests that one gene is intact (DRBB1) and one gene is a pseudogene (DRBB2) because it lacks a splice acceptor signal for exon 3 and lacks exons 2 and exon 4. Intron 1 and 2 sequence data from DRBB1 allow amplification of the polymorphic exon 2 which, in turn, can serve as a basis for developing a typing system for DRB.
Amino Acid Sequence↗
Molecular analysis of DLA-DRBB1 polymorphism.
The polymorphism of the canine major histocompatibility complex class II DRB gene, DRBB1, was analyzed. Exon 2 that encodes the polymorphic beta 1 domain was amplified by the polymerase chain reaction (PCR). The PCR product from 250 dogs was cloned and sequenced. Eighteen alleles were identified. Most of the variation in amino acid composition occurred at positions in the peptide binding site. Inheritance of these sequences showed Mendelian segregation with one or two alleles per dog. Cluster analysis of the nucleotide and predicted amino acid sequences subdivided the canine DRBB1 alleles into three major allelic groups. The number of nonsynonymous changes was higher than the number of synonymous changes in the putative antigen recognition sites indicative of positive selection. The data generated can serve as a basis for developing a typing assay for the canine DRBB1 gene.
Alleles↗
Antibody responses to two encephalomyocarditis virus vaccines in rhesus macaques (Macaca mulatta).
Two groups of rhesus macaques (Macaca mulatta) housed in rodent-controlled outdoor corrals were inoculated with two different encephalomyocarditis virus (EMCV) vaccines. One group (n = 45) received a vaccine made from an inactivated field isolate of virus cultured during an outbreak at a zoo in Florida. This vaccine produced fourfold increases in the titers of 28 animals (62%); the increases persisted for at least 18 months (last test) after a single injection of the vaccine. The other group (n = 51) received a vaccine made from an inactivated porcine field strain of the virus. This vaccine did not produce titers in any of the vaccinees.
Animals↗
Measuring defensive medicine using clinical scenario surveys.
For more than two decades, advocates of malpractice system reform have claimed that the most damaging and costly result of the U.S. medical malpractice system is the practice of defensive medicine, in which physicians order tests and procedures primarily because of fear of malpractice liability. In this article, we discuss the issues raised by different definitions of defensive medicine and propose a working definition to guide measurement of the concept. We also consider the strengths and weaknesses of available approaches for measuring defensive medicine. Finally, we describe an empirical approach to measuring defensive medicine using clinical scenario surveys. The results suggest that, if physicians actually practice as they say they would in these surveys, defensive medicine does exist, although not to the extent suggested by anecdotal evidence or direct physician surveys. The results also suggest that defensive medicine varies considerably across clinical situations. In all of the scenarios, many physicians chose aggressive patient management styles even though conservative management was considered medically acceptable by the expert panels that developed the scenarios. In most cases, medical indications, not malpractice concerns, motivated clinical choices. Our results highlight the limitations of surveys as a method of measuring the extent of defensive medicine. The implications of managed care and health care reform for defensive medicine are also discussed.
Attitude of Health Personnel↗
DLA-identical bone marrow grafts after low-dose total body irradiation: effects of high-dose corticosteroids and cyclosporine on engraftment.
Previous studies found that marrow allografts from DLA-identical littermates resulted in survival of 60% of recipient dogs after an otherwise lethal dose of 450 cGy of total body irradiation (TBI), either because of successful allografts or autologous recovery after rejection of the allografts. Forty percent of dogs died with marrow aplasia after allograft rejection. The current study asked whether allogeneic engraftment could be enhanced and survival improved by treating allograft recipients with high doses of corticosteroids or with cyclosporine (CSP), administered either before or after transplantation. Five dogs in group 1 received corticosteroids beginning on day -5 and ending on day 32 after transplant. The starting dose was 12.5 mg of prednisone per kilogram orally twice daily. All five dogs rejected their allografts; three died early with marrow aplasia and two showed endogenous marrow recovery. Nine dogs received CSP from day -6 to day -1 before transplantation at a dose of 20 mg/kg/d intravenously administered in divided doses. All nine dogs rejected the marrow allograft; six died with marrow aplasia and three survived with endogenous marrow recovery. Seven dogs received CSP after transplantation at a dose of 30 mg/kg/d orally from day -1 to day 35. All seven had sustained allografts (two mixed chimeras and five complete donor-type chimeras) and became healthy long-term survivors without graft-versus-host disease. These results extend previous observations and confirm that grafts of marrow from DLA-identical littermates improved survival of dogs exposed to low but otherwise lethal doses of TBI. Additional therapy with high-dose corticosteroids administered peritransplantation and posttransplantation or CSP administered before transplantation neither enhanced the rate of allogeneic engraftment nor improved survival; however, CSP administered after transplantation resulted in successful allografts and event-free survival in all cases.
Adrenal Cortex Hormones↗
Carcinoma of the male breast: update 1994.
In many ways, male and female breast cancers are similar, but do have some notable differences. Although the underlying etiology of male breast cancer may be partially due to hormonal or environmental changes, this disease is rare compared to female breast cancer. Most often, it presents as a painless lump, with estrogen receptor-positive infiltrating ductal carcinoma being the most common pathologic type. The main component of local therapy is either a radical or a modified radical mastectomy, with adjuvant chemotherapy proving useful. Estrogen receptor-positive tumors respond well to hormonal therapy. More research is needed in order to: (1) further characterize the molecular biological properties of male breast cancer tumors, (2) further investigate the role of adjuvant chemotherapy, and define successful regimens, and (3) determine optimal chemotherapy regimens in the treatment of metastatic disease. As this disease is a relatively rare condition, whenever possible, all patients should be allowed to participate in national cooperative group studies.
Breast Neoplasms, Male↗
Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells.
PURPOSE: It has been recognized that enhanced antioxidant defenses can contribute to the resistance of cancer cells displaying multidrug resistance (MDR) that arises in conjunction with the overexpression of P-glycoprotein (Pgp). The purpose of this study was to determine if the defenses against oxidant stress in MDR human leukemia cells (HL-60/AR) that overexpress multidrug-resistance-associated protein (MRP), but not Pgp, contribute to the mechanism of drug resistance in this cell line. METHODS: HL-60/AR cells were evaluated in comparison with wild-type cells with respect to sensitivity to the oxidants hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (t-BuOOH), the activities and amounts of the antioxidant enzymes catalase and glutathione peroxidase (GSH-Px), and the effects that manipulation of the activities of these enzymes may have on cellular sensitivity to the oxidants and to daunorubicin. We also evaluated the ability of the cells to generate daunorubicin semiquinone free radical as measured by electron spin resonance (ESR) spectroscopy. RESULTS: HL-60/AR cells were > 10-fold resistant to the cytotoxic effects of the H2O2 or t-BuOOH as compared with parental, drug-sensitive HL-60 cells. This phenomenon could be attributed largely to elevated activity and protein levels of catalase in HL-60/AR cells. Furthermore, inhibition of catalase by 3-amino-1,2,4-triazole (AT) diminished the resistance of HL-60/AR to these oxidants by > 80% or > 50%, respectively. Despite these findings, AT was incapable of causing sensitization of HL-60/AR cells to the cytotoxic effects of daunorubicin. We found that the activity and amount of selenium-dependent glutathione peroxidase (GSH-Px) was no greater in HL-60/AR cells than in HL-60 cells. Cultivation of cells in selenium-deficient medium caused a marked reduction in GSH-Px activity in HL-60/AR cells and a profound inhibition of GSH-redox cycling manifested by a decrease in baseline hexose monophosphate shunt activity (HMPS) and markedly blunted stimulation of the HMPS by the oxidant t-BuOOH in both wild-type and resistant cells. These variations in GSH-Px activity and GSH-redox cycling, however, were not associated with an alteration in cellular sensitivity to daunorubicin. The failure of catalase inhibition or selenium manipulation of GSH-Px activity to affect daunorubicin cytotoxicity was not due to the inability of these cells to produce free-radical species of daunorubicin, since ESR studies revealed that the generation of daunorubicin semiquinone free radical by HL-60/AR cells was equal to and, in fact, 3-fold that obtained with HL-60 cells. CONCLUSIONS: In comparison with parental HL-60 cells, MRP-overexpressing HL-60/AR cells have demonstrable alterations in antioxidant defenses that are manifested by cellular resistance to the cytotoxic effects of H2O2 and t-BuOOH and by elevated protein levels and activity of catalase. Whether these alterations are epiphenomena or are related to overexpression of MRP remains to be determined. However, it does appear that the enhanced antioxidant defenses observed in HL-60/AR cells do not contribute to the resistance to daunorubicin manifested by this cell line. Although HL-60/AR cells generate daunorubicin semiquinone free radical to an extent equal to or greater than that observed in HL-60 cells, the failure of alterations in GSH-Px activity or inhibition of catalase to change the sensitivity of HL-60/AR cells to daunorubicin suggests that the cytotoxicity of daunorubicin in these cells in not mediated through H2O2 or other peroxide species detoxified by these enzymes.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Nucleotide sequence and polymorphism analysis of canine DRA cDNA clones.
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Amino Acid Sequence↗
Technology assessment and public health.
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Clinical Trials as Topic↗
Health technology and health reform.
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Cholesterol↗