Chloramphenicol: a dangerous drug?
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Biomedical subjects
Publications and source records attributed to F H Gardner.
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A patient with aplastic anemia, who had been unresponsive to androgens, antithymocyte globulin, high-dose methylprednisolone, and cyclosporine, responded to treatment with 3-beta-etiocholanolone, nandrolone decanoate, and prednisolone acetate. Six months following initiation of therapy, she became red cell and platelet transfusion independent with neutrophils persistently over 1,000/microliters. A sustained partial remission has persisted for over 2 years. This observation suggests that a combined hematostimulatory approach may be of benefit, even in patients with long-standing refractory aplasia.
Long-term bone marrow cultures (LTMC) were initiated with marrow from five normal subjects and eight patients with aplastic anemia (AA). Near confluent to confluent adherent layers developed in all cultures from normal subjects and AA patients. When present, the 'cobblestone' areas in LTMC from AA subjects were smaller than those observed in the LTMC from normal subjects. The decline in total and viable cell numbers in the LTMC was similar for both normal subjects and AA patients. Granulocyte-macrophage colony-forming units (CFU-gm) were present in nonadherent cells (NAC) from normal LTMC for a mean of 5.2 weeks. CFU-gm were present in the NAC of only two of the eight AA cultures for one week. The absent or small 'cobblestone' areas and the absence of CFU-gm production in AA-LTMC suggest a decrease in the reproductive potential of adherent hematopoietic stem cells, which may be the result of either an abnormal hematopoietic stem cell or an abnormal stromal microenvironment or both.
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During the past 9 years, 43 adult patients with severe aplastic anaemia have been treated with a combination of 3 alpha etiocholanolone and nandrolone decanoate in an uncontrolled pilot study. Eleven patients were considered acute and the remainder as chronic severe aplasia. 50% (22 patients) had a haematopoietic recovery and 40% have had a sustained remission varying from 1.5 to 8 years. Three patients who did not respond to 3 alpha etiocholanolone had a haematologic response when treated with the isomer 3 beta etiocholanolone. The recovery did not appear to be associated with age or duration of marrow aplasia. In view of the reproducible chemical structure of these androstanes, we believe this group of steroids should be evaluated further in the treatment of severe aplastic anaemia.
Dyskeratosis congenita (DC) is a rare familial hematologic disorder that has various modes of inheritance. We have studied 2 siblings with DC. 1 sibling had thrombocytopenia, which responded to therapy with nandrolone decanoate and oxymetholone. Platelets were abnormally small, which indicates that a qualitatively abnormal megakaryocytopoiesis is a feature of DC. Myeloid and erythroid progenitors in specimens of the blood and bone marrow from both siblings were either absent or greatly reduced in numbers. The qualitatively abnormal megakaryocytopoiesis, and the quantitative abnormality of hematopoietic progenitor cells committed to myelopoiesis and erythropoiesis, indicates involvement of the pluripotent stem cell in DC. Cytogenetic studies of the bone marrow and peripheral blood lymphocytes from these patients showed normal karyotypes, a normal sister chromatid exchange frequency, and a rapid proliferation of peripheral T lymphocytes, a feature of the disorder that has not been reported previously.
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Anatomical observations have indicated a decrease of marrow cellularity with age, but these changes are not associated with anemia in the healthy geriatric patient. Aged patients with refractory anemia should be studied by utilizing red cell volume (MCV) and red cell heterogeneity (RDW). A classification with these indices initially can separate the anemias for a more fruitful investigation. By old age the anemias of hereditary red cell membrane or hemoglobin disorders should be known to the patient. In the absence of tumor, elderly patients have an increasing frequency of refractory anemias that can be called preleukemia or myelodysplastic syndrome. Morphological observations have emphasized the importance of abnormal megakaryocytes and platelets in all phases of preleukemia, and these cytologic changes should be used to guide the physician in the early diagnosis of the syndrome complex. This group of refractory anemias have a limited survival, but nonspecific marrow stimulation can be effective and should be tried. With a more complete classification of the chromosomal abnormalities in the myelodysplastic syndrome, a more accurate prognosis can be anticipated. The anemias of marrow aplasia and ineffective iron utilization (anemia of chronic disease) are found frequently in the elderly, and the physician may offer more effective therapy by an early diagnosis.
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A 26-year-old woman presented with the classic manifestations of malignant atrophic papulosis, a rare disease of unknown cause. We report the results of our immunologic studies, which may help to explain why treatment with systemic immunosuppressant therapy has not been effective.
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The effect of marrow stromal cells (MSC) on the clonal growth of a human malignant T-lymphoblast (MTL) cell line was investigated in a bilayer culture system. The MSC consistently stimulated clonal growth of MTL, and no stimulatory humoral factor was present in the medium conditioned by the MSC. These observations and other reports suggest that marrow stromal cells may provide a microenvironment in vivo that is not only conducive to the growth of malignant lymphoblasts, but may actually enhance proliferation of malignant T-lymphoblasts in the bone marrow.
Eight patients with anemia and chronic renal disease being maintained by chronic hemodialysis were evaluated with In-111 chloride bone marrow imaging and bone marrow core biopsies. There was no correlation between the erythrocyte cellularity of the marrow and the indium bone marrow scan grade in any patient. Bone marrow imaging can not be used as an indicator of the presence of erythroid marrow in these patients.
Despite the successful recovery of young patients with aplastic anemia following bone marrow transplants, additional patients have had benefit from immune suppression therapy, predominantly antithymus globulin (ATG). There exists a large residual pool of patients who have not been able to benefit from these modalities because of 1) lack of compatible siblings, 2) age, 3) duration of illness prior to diagnosis. Historically oral androstanes have been helpful in the treatment of chronic aplastic anemia. The long-range survival in large cooperative groups of patients treated with androstanes have indicated that both severe and chronic aplastic anemia have had responses similar to immune suppressive therapy. There is a need to have further investigations to seek the most effective anabolic agents. Many group studies have shortened treatment schedules when an erythropoietic response has been obtained, rather than continue therapy until the maximum platelet count is achieved. Such abbreviation of therapy may hasten a hematological relapse. Clinics also should evaluate parenteral androstanes since they appear to be more hematopoietic. Also the investigation of different androstane metabolites, i.e. etiocholanolone, should be pursued to determined if a more effective stimulus of stem cell proliferation can be achieved. In the recovery phase of the aplastic anemia patients treated with immune suppression or androstanes the peripheral blood reflects an altered proliferation of the marrow stem cell. The majority of these patients continue to have abnormalities in red cells (macrocytosis) and decreased platelet size.
We studied the myeloid colony-stimulating activity (CSA) of marrow stromal cells (MSC) derived from normal subjects and patients with aplastic anemia, acute leukemia, and other myeloproliferative disorders. CSA of the MSC was determined in a bilayer system. Feeder layers with varying numbers of MSC (10(4) to 2 X 10(5)) were used. Of 40 MSC tested, 39 stimulated myeloid colony formation by the normal target marrow mononuclear cells. The optimal concentration of MSC exhibiting the maximal stimulation of myeloid progenitors (CFU-GM) varied with different MSC. MSC from normal subjects and from patients with acute leukemia and myeloproliferative disorders were potent stimulators of CFU-GM differentiation. In contrast, MSC from patients with aplastic anemia had poor CSA, suggesting that the marrow microenvironment is functionally abnormal in aplastic anemia.
Aliquots (0.1 mL) of whole-blood pools prepared to contain various concentrations of phenylalanine were applied to filter-paper collection cards, dried, and stored in sealed bags. We measured the phenylalanine content of the dried blood spots by bioassay, fluorometry, and "high-performance" liquid chromatography, and found that the concentrations remained constant for two years when samples were kept at -20 degrees C or lower. Intra- and interlaboratory studies showed that results for phenylalanine were greater for laboratories using bioassay procedures than for those using fluorometric procedures. Further, CVs (both among- and within-laboratory) obtained with fluorometric procedures were nearly half as great as the CVs obtained by laboratories using bioassay techniques.
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