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Biomedical subjects

N J Olsen

Publications and source records attributed to N J Olsen.

At least 73 records · Page 4Linked to original sources
PubMed1990

Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis.

PURPOSE: To administer recombinant erythropoietin to patients with rheumatoid arthritis who had significant anemia, while monitoring hematologic and rheumatologic clinical responses as well as potential toxicity. PATIENTS AND METHODS: Seventeen patients with rheumatoid arthritis from five rheumatology care settings were studied. The patients had initial hematocrits of 34% or less and stable clinical status, and were not being treated with second-line drugs or corticosteroids. An 8-week randomized double-blind study involving various dosages of recombinant erythropoietin, as well as placebo, was followed by a 24-week open-label study in which dosage could be titrated to achieve a normal hematocrit. RESULTS: In the 8-week randomized study, four of 13 patients who received injections of recombinant erythropoietin showed a hematologic response, arbitrarily defined as at least a 6-unit increase in hematocrit. None of four placebo-treated patients showed a meaningful hematologic response. All 11 patients who completed the subsequent 24-week open-label study reached a normal hematocrit level at some time during the study, and 10 of 11 showed an increase of hematocrit 6 units or greater. At least one adjustment, i.e., an increase, decrease, or omission of the erythropoietin dosage, was required in all patients to maintain the hematocrit at a target range of 35% for women or 40% for men. Meaningful changes were not seen in patients' capacity to perform activities of daily living or pain levels during either the 8-week randomized study or the 24-week open-label study. No adverse effects were associated with recombinant erythropoietin therapy. CONCLUSION: Patients with rheumatoid arthritis showed excellent hematologic responses to recombinant erythropoietin, without toxicity, during careful monitoring for appropriate dosage adjustment, although a meaningful change in rheumatologic clinical status was not seen.

Activities of Daily Living↗
PubMed1990

Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin.

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Acetylation↗
PubMed1990

Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases.

Several autoantibody-associated variable region (V) genes are preferentially expressed during early ontogenic development, suggesting strongly that they are of developmental and physiological importance. As such, it is possible that polymorphisms in one or more of these genes may alter susceptibility to autoimmune disease. We have searched extensively for a probe related to a developmentally regulated V gene that has the power to differentiate among highly homologous V genes in human populations. Using such a probe (i.e., Humhv3005/P1) related to both anti-DNA and anti-IgG autoantibodies, we studied restriction fragment length polymorphisms in patients with rheumatoid arthritis and systemic lupus erythematosus and found an apparent heavy-chain V (VH) gene deletion that was nearly restricted to the autoimmune patients. These data suggest that deletions of physiologically important VH genes may increase the risk of autoimmunity through indirect effects on the development and homeostasis of the B-cell repertoire.

Arthritis, Rheumatoid↗
PubMed1989

Self-report questionnaire scores in rheumatoid arthritis compared with traditional physical, radiographic, and laboratory measures.

STUDY OBJECTIVE: To assess whether scores on a simple self-report questionnaire to depict the clinical status of patients with rheumatoid arthritis are correlated with traditional measures of physical, radiographic, laboratory, functional, and global status. DESIGN: The self-report questionnaire was administered at the same time the following variables were assessed: American Rheumatism Association functional class, joint count, hand radiograph, erythrocyte sedimentation rate, rheumatoid factor titer, walking time, grip strength, button test, and global self-assessment. SETTING: University rheumatology clinic, the rheumatology clinic of a Veterans Administration hospital, and a private rheumatology practice. PATIENTS: The study included 259 patients who met the criteria of the American Rheumatism Association for a diagnosis of definite or classic rheumatoid arthritis. INTERVENTIONS: Standard rheumatologic care for patients with rheumatoid arthritis. MEASUREMENTS AND MAIN RESULTS: Self-report questionnaire scores were significantly correlated with the joint count, radiographic score, erythrocyte sedimentation rate, grip strength, button test, walking time, American Rheumatism Association functional class, and global self-assessment. Patients were categorized into five questionnaire score categories of 1.00, indicating no dysfunction, and 1.01 to 1.50, 1.51 to 2.00, 2.01 to 3.00, and 3.01 to 4.00, indicating progressive dysfunction. In these five categories, more than ten involved joints were seen in 11%, 37%, 67%, 79%, and 100% of patients, respectively, and erythrocyte sedimentation rates greater than 20 mm/h in 29%, 49%, 64%, 74%, and 85% of patients, respectively. Similar results were seen for other physical and radiographic measures. The questionnaire score was as effective in explaining other measures of clinical status as was any other available measure. CONCLUSIONS: A simple self-report questionnaire provides information similar to many traditional measures in rheumatoid arthritis and appears to be an attractive, cost-effective approach to assessing and monitoring quantitatively the status of an individual patient.

Activities of Daily Living↗
PubMed1989

Antiproliferative effects of methotrexate on peripheral blood mononuclear cells.

Methotrexate was added to cultured mononuclear cells from the peripheral blood of normal individuals and patients with rheumatoid arthritis (RA) to study the drug's effects on mononuclear cell proliferation and antibody synthesis. In the presence of methotrexate, marked antiproliferative effects (to levels less than 15% of baseline) were seen with 3H-deoxyuridine, but not with 3H-thymidine, as the marker of cell division. This difference was not due to altered kinetics of proliferation or the presence of salvage nucleotides in the culture medium. The absence of suppression of antibody production preactivated by pokeweed mitogen in vitro and the low levels of suppression of spontaneous IgM rheumatoid factor production by blood mononuclear cells from RA patients suggested a relative resistance of activated cells to the effects of methotrexate. The effects of methotrexate on both cell proliferation and antibody synthesis were completely reversed by the addition of high concentrations of exogenous folinic acid. The results suggest that methotrexate has effects on immunocompetent cells that may contribute to the efficacy of this drug in the treatment of RA and other autoimmune diseases.

Antibody Formation↗
PubMed1989

Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies.

Two anemic patients with rheumatoid arthritis were treated with recombinant human erythropoietin (EPO) for 5 months. Both patients showed significant increases in hematocrit, red cell volumes, and marrow erythroid and megakaryocyte progenitor cells. No significant toxic effects from EPO were observed. These data indicate that EPO may be effective in overcoming the pathogenetic factors that limit erythropoiesis in rheumatoid arthritis.

Adult↗
PubMed1989

Increased thymic size and thymocyte interleukin 2 production in androgen-resistant mice.

The functional significance of androgen receptors in thymocytes is unknown. To investigate whether such receptors might mediate androgen-induced effects on thymocyte proliferation or differentiation we examined mice bearing a known defect in the gene coding for the androgen receptor. This mutation, termed testicular feminization (Tfm/Y), renders these mice resistant to the action of androgenic hormones. Testicular feminization mice were found to have large thymuses that were an average of 2.8 times as heavy as those of their unaffected male litter mates, and contained up to 36 times as many thymocytes. Similar findings were observed when Tfm mice were compared with C57Bl/6 control mice. Thymocytes from androgen-resistant mice produced several times more interleukin 2 in culture than did thymocytes from control mice. A small but significant reduction in the population of cells bearing neither CD4 nor CD8 surface markers ('double negatives') was observed in the androgen-resistant mice. These data indicate that androgen resistance is associated in the Tfm/Y mouse with alterations in thymocyte number, phenotype, and function that may be attributable to lack of androgen action during thymic development.

Androgens↗
PubMed1989

A highly informative probe for two polymorphic Vh gene regions that contain one or more autoantibody-associated Vh genes.

Efforts to determine the role of specific Ig variable region (V) genes in human autoimmune responses have been hampered by the lack of suitably polymorphic probes. Recently we isolated a heavy chain V (Vh) gene, designated Humhv3005, that is 99% homologous to the 1.9III Vh gene and can encode an anti-DNA antibody. To study the relation between these two genes, different DNA fragments from the isolated Humhv3005 clone were used to probe Southern blots of human genomic DNA. A 1.6-kb Eco RI fragment (designated hv3005/E1.6) was found to hybridize with only one band in Eco RI-digested DNA, and with two major bands in Bam HI-digested DNA. Importantly, the sizes of the latter two bands were indistinguishable from the corresponding Bam HI fragment sizes of the isolated hv3005 clone and the isolated 1.9III clone, respectively. Population and family studies with the hv3005/E1.6 probe revealed five different hybridization patterns of these two characteristic bands, which defined nine possible genotypes for two human Ig Vh gene loci. Together the data demonstrate that hv3005/E1.6 is a highly informative probe for an autoantibody-associated Vh gene(s), and should prove useful in elucidating the role of Ig Vh genes in autoimmune diseases.

Autoantibodies↗
PubMed1988

Class II human leukocyte antigen genes and T cell receptor polymorphisms in patients with rheumatoid arthritis.

Human leukocyte antigen (HLA) typing was performed in 174 patients with rheumatoid arthritis and 222 white control subjects. Increases in HLA-DR4 and HLA-DR1 were observed as in previous studies. Each of these appeared to be inherited as dominant risk factors. Southern blotting with a DR-beta probe after digestion of genomic DNA with the restriction enzyme Bam HI showed seven bands. Three of them correlated with DR4 and were increased in rheumatoid arthritis patients. Subsets of DR4 were determined by polymerase chain reaction amplification followed by hybridization with oligonucleotide probes. Dw4 was increased in rheumatoid arthritis patients, and the frequency of the other subsets appeared to be similar in rheumatoid arthritis patients and control subjects. A polymorphism associated with the T cell receptor V-beta-8 gene family was significantly increased in rheumatoid arthritis patients.

Arthritis, Rheumatoid↗
PubMed1988

In vitro rheumatoid factor synthesis in patients taking second-line drugs for rheumatoid arthritis. Independent associations with disease activity.

Rheumatoid arthritis (RA) patients whose unstimulated peripheral blood mononuclear cells produce high levels of IgM rheumatoid factor (IgM-RF) in vitro have more severe disease activity. RA patients being treated with second-line agents, including gold salts, penicillamine, or methotrexate, tend to be low producers or nonproducers of IgM-RF in vitro. The possibility that low production or nonproduction of IgM-RF in vitro may be explained by treatment with second-line agents alone, irrespective of disease activity, was analyzed in 133 RA patients whose disease status was assessed by multiple laboratory and clinical measures. The results indicate that treatment with second-line agents and in vitro IgM-RF synthesis are independently associated with disease activity.

Anti-Inflammatory Agents↗
PubMed1988

Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis.

Possible associations between HLA-DR4 and laboratory, radiographic, joint count, functional, and demographic measures of clinical status were analyzed in 154 white patients with rheumatoid arthritis. Overall, 65 percent of the patients were HLA-DR4 positive, similar to other series. HLA-DR4 was associated significantly with the presence of rheumatoid factor and more severe radiographic changes. HLA-DR4 was not associated with significant differences in demographic, joint count, or functional measures of clinical status. HLA-DR1 was not associated significantly with differences in the presence of rheumatoid factor, radiographic changes, or other measures of clinical status. Selective associations of HLA-DR4 with rheumatoid factor and radiographic scores were more marked in men than in women. Patients who were putatively homozygous for HLA-DR4 were all seropositive and had more severe radiographic changes than patients who were heterozygous for HLA-DR4.

Activities of Daily Living↗
PubMed1988

HLA-DR4 and other genetic markers in rheumatoid arthritis.

In a new series of RA patients the association with HLA-DR4 was again found to be highly significant. Also increased were the DR4 associated antigens DRw53 and DQw3. Hybridization of a DQ-beta probe to Bg1 II-digested DNA showed that a variant of DQw3, characterized by a 4.3 kb fragment and related to the serological specificity TA10, was markedly increased among DR4 positive RA patients. HLA-DR1 was also increased in RA and appeared to be independent of the increase of DR4. Although the DR1 association was weaker, it was observed in both patients with and without RF. In contrast, DR4 was found to be increased significantly only in the RF positive group of patients, as previously observed. Development of RA in multiple-case families was found to be linked to the inheritance of DR4 positive haplotypes. The possible role of risk factors associated with polymorphic markers of the T-cell receptor genes was investigated. An allelic marker associated with one of the variable gene subfamilies of the beta-chain was found to be associated with RA. The results suggest that susceptibility for development of RA is influenced by alleles of the T-cell receptor in conjunction with the class II HLA factors with which the T-cell receptor interacts in the course of the immune response.

Alleles↗
PubMed1988

Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebo-controlled trial.

Recombinant human erythropoietin (r-HuEPO) was administered in two phases to 12 patients with chronic renal insufficiency (creatinine clearances of 0.17-0.51 ml/second [10-30 ml/minute]) and uremic anemia. In addition to the routine tests done as part of a multicenter clinical trial, our patients had serial red cell mass measurements, quantitation of bone marrow stem cells, and marrow cytogenetic analysis. During the first eight weeks (acute phase), an equal number of patients was randomized to placebo or one of three doses of r-HuEPO (50, 100 or 150 unit/kg intravenously three times weekly). All three patients receiving 150 unit/kg responded by increasing their packed cell volume (PCV) to the normal range within eight weeks. There were lesser responses in PCV at the two lower doses of r-HuEPO and no response in the placebo group. The 51Cr red cell mass also increased significantly in a dose-related manner in patients receiving r-HuEPO but did not change in the placebo group. Marrow studies revealed increases in erythroid, megakaryocyte, and granulocyte-monocyte progenitor cells in those patients on r-HuEPO, but no mutagenic effects were seen. Subsequently, ten patients received open label r-HuEPO. During this maintenance phase, all ten achieved or maintained a normal PCV. Several adverse events occurred, but none were definitely linked to r-HuEPO. Recombinant human erythropoietin is an effective and potent treatment of anemia caused by renal failure.

Aged↗
PubMed1987

Androgen receptors in human thymocytes.

On the basis of a variety of evidence androgenic hormones are thought to exert modulatory effects on immune function. Because specific actions of these hormones are exerted through receptor-mediated mechanisms, we have examined the human thymus gland for the presence of specific high-affinity androgen receptors. Cytosolic extracts of whole human thymus were found to contain 6.5 (+/- 2.6) fmol of specific [3H]methyltrienolone binding per mg protein. The receptor sedimented at 8s on sucrose density gradient centrifugation analysis. Thymic fibroblast lines derived from these glands did not express sufficient receptor content to account for the findings in whole thymus cytosolic extracts. Purified thymocyte preparations (greater than 99.3% pure as assessed by flow cytometry with monoclonal anti-thymocyte marker OKT11) contained 3.34 (+/- 1.2) fmol receptor per mg cytosolic protein. Mature peripheral blood lymphocytes, human T cells obtained from thoracic duct drainage, and the human T cell line Jurkat were not found to contain these receptors. These studies demonstrate for the first time that a high affinity androgen receptor is present in maturing human thymocytes. A functional role for these receptors is suggested by dihydrotestosterone-mediated decreases in interleukin 2-like activity produced by cultured human thymocytes.

Binding, Competitive↗
PubMed1987

Immunologic studies of rheumatoid arthritis patients treated with methotrexate.

Immunologic functions of peripheral blood mononuclear cells were studied in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). Spontaneous IgM rheumatoid factor (IgM-RF) synthesis by unstimulated cultured blood mononuclear cells was seen in only 3 of 18 MTX-treated patients, compared with 31 of 54 RA patients who were not receiving long-acting drugs. Total IgM production by unstimulated cultured mononuclear cells, pokeweed mitogen-induced antibody synthesis, and plasma levels of IgM-RF were also lower in MTX-treated patients than in other RA patients. The numbers of circulating B cells, T4 and T8 cells, the T4:T8 cell ratio, and mitogen-induced proliferation indices were similar in MTX-treated and non-MTX-treated patients. Eleven additional patients were studied prospectively after initiation of MTX therapy. All showed significant decreases in spontaneous IgM-RF synthesis, with declining IgM-RF:IgM ratios, including all of the 9 who were studied during the first 24 hours of treatment. The results indicate that MTX has rapid effects on IgM-RF synthesis, and this action might be associated with its therapeutic efficacy in RA.

Arthritis, Rheumatoid↗
PubMed1987

High levels of in vitro IgM rheumatoid factor synthesis correlate with HLA-DR4 in normal individuals.

The association between the HLA-DR4 histocompatibility antigen and in vitro synthesis of IgM and IgM rheumatoid factor (IgM-RF) by blood mononuclear cells was investigated in 35 normal subjects. In vitro cultures of T and B cells were stimulated with pokeweed mitogen, and the secreted IgM-RF, tetanus antibody, and total IgM protein were measured by solid-phase radioimmunoassay. In cultures containing unseparated T cells, IgM-RF production in the DR4+ and DR4- subgroups was not significantly different. However, depletion of OKT8+ cells containing T suppressor cells resulted in significantly higher IgM and IgM-RF synthesis in the DR4+ subgroup. Moreover, 6 of the 8 highest levels of IgM-RF were produced by DR4+ individuals, while only 7 of the remaining 27 individuals were DR4+ (P = 0.035). Ratios of secreted IgM-RF:IgM indicated that there was a relative enrichment for IgM-RF- specific B cell precursors in DR4+ high responders, although total numbers of circulating B cells were not increased. High responder B cells had high levels of responsiveness when mixed with T helper cells from low responders, whereas low responder B cells consistently produced low responses, even when cocultured with T helper cells from high responder donors. The data suggest that a subset of normal individuals has a pokeweed mitogen-responsive lymphocyte population that contains a B cell subpopulation specific for IgM-RF synthesis and that this condition is associated with HLA-DR4. In certain individuals who have the DR4 type, there may be a component of a susceptible genetic background, upon which other factors act to induce IgM-RF synthesis and which may produce clinical manifestations of rheumatoid arthritis.

Adult↗