Biomedical subjects
Publications and source records attributed to M Yaron.
A 40 year old woman with rheumatoid arthritis developed pure red cell aplasia after treatment with D-penicillamine 500 mg/day. D-Penicillamine was stopped and short term treatment with steroids resulted in complete recovery of bone marrow.
Fifty-one patients with rheumatoid arthritis (RA) were examined for their immune response potential to human collagen type II and III. It was found that T cells of 57% of patients with RA proliferated to collagen type III whereas only 27% of T cells of patients with osteoarthritis (OA) and healthy controls responded to this antigen by proliferation (p less than 0.04). A lower percentage (38%) of patients with RA had proliferative responses to collagen type II in comparison to 17% of responders in healthy controls. The capability to produce T cell helper factors specific to collagen type III was found to be significantly higher in patients treated with nonsteroidal antiinflammatory drugs (NSAID) (60%) in comparison to patients with OA (16%) and healthy controls (13%). Immunoregulatory drugs affected the specific T helper function in response to collagen type III but did not change the proliferative responses to collagen type II and III in patients with RA. HLA analyses revealed a significant difference in the frequency of HLA-DRw10 between our sample of patients with RA and healthy controls.
Forty-one patients with rheumatoid arthritis were treated for 2 weeks at a Tiberias spa hotel. Randomized into 2 groups, Group 1 received a combination of mineral baths and mud packs, and Group 2 had tap water baths only. Both groups had a significant but temporary improvement in Ritchie index. Group 1 showed a significant improvement in grip strength. No improvement was noticed in morning stiffness, 15 meter walk time and laboratory variables of disease activity in either group. Twelve patients with osteoarthritis (OA) received 2 weeks of treatment with mineral baths and mud packs. Statistically significant improvement for a period of 6 months was noticed in night pain, pain on passive motion, tenderness on palpation and in the index of severity of OA of the knee.
The effects of binary combinations of the recombinant human cytokines, interleukin-1 beta (rHuIL-1 beta), tumor necrosis factor alpha (rHuTNF alpha), and gamma-interferon (rHu gamma-IFN) on the production of prostaglandin E (PGE), hyaluronic acid (HA), and collagenase by human synovial fibroblasts in culture were investigated. All 3 were stimulated by rHuIL-1 beta and rHuTNF alpha alone, but not by rHu gamma-IFN. Stimulation with rHuIL-1 beta and rHuTNF alpha occurred at femtomolar and picomolar concentrations, respectively, and maximal stimulation by rHuIL-1 beta was several times greater than that by rHuTNF alpha. Stimulation of PGE and collagenase production with rHuIL-1 beta or rHuTNF alpha was depressed by rHu gamma-IFN, depending on the concentration used. In contrast, stimulation of HA production with rHuIL-1 beta or rHuTNF alpha was unaffected or increased somewhat with rHu gamma-IFN. Combinations of rHuIL-1 beta or rHuTNF alpha had marked synergistic effects on PGE and collagenase production. However, when rHuIL-1 beta effects were maximal, rHuTNF alpha had an additive effect. These cytokines had only additive effects on HA production, however, and when rHuIL-1 beta effects were maximal, rHuTNF alpha produced no further stimulation. These data suggest that the secretory activities of synovial fibroblasts can be influenced by a combination of cytokines and is dependent on the type of cytokine present and its concentration.
We have recently shown that methotrexate (MTX) inhibits interleukin-1 (IL-1) activity in vitro. This effect may play an important role in the rapid antiinflammatory action of MTX in rheumatoid arthritis. In the present study, we showed that the inhibition of IL-1 activity in vitro by MTX is dependent on folate pathways since, after the addition of leucovorin, the inhibitory effect of MTX was abolished. These findings may shed more light on the mechanism of action of MTX in rheumatoid arthritis. They also point to the fact that some IL-1 activities may be dependent on intracellular folate pathways.
Interleukin-1 (IL-1) has been shown to regulate glycosaminoglycan (GAG) synthesis. We therefore investigated whether an IL-1 inhibitor or IL-6 modulates IL-1 biologic activities in human synovial cells and cultured articular cartilage. We found that in the presence of a constant amount of IL-1 beta, stimulation of hyaluronic acid (HA) synthesis by the IL-1 inhibitor was inhibited in a dose-dependent manner. Similarly, the decrease in sulfated GAG synthesis induced by IL-1 was reversed by the addition of the IL-1 inhibitor. In contrast, IL-6 did not affect the production of HA, prostaglandin E2, or collagenase in synovial cells, nor did it affect GAG in organ cultures when tested in the presence or absence of IL-1 beta. Hence, IL-6 was ineffective in modulating IL-1 bioactivities on HA or sulfated GAG synthesis. These results emphasize the importance of IL-1 and IL-1 inhibitor in connective tissue destruction and raise questions concerning the role of IL-6 in this pathogenesis.
Most studies of immune function in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) show only marginal effects on humoral or cellular immune responses. These include measurements of lymphocyte subsets, proliferative responses to mitogens, immunoglobulin production, rheumatoid factor and immune complexes. The mechanism of action of MTX in RA might be more antiinflammatory than immunosuppressive. This is supported by the rapid clinical response to drug treatment and by data from in vitro and animal studies. The inhibition of interleukin-1 (IL-1) activity or other inflammatory cytokines by MTX may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action. MTX has crucial effects on the cascade of events initiated by some cytokines (IL-1, IL-6, tumor necrosis factor), which plays a major role in RA and other inflammatory diseases.
Axial computed tomographic (CT) scan of the lumbosacral region was performed in 220 patients. The patient population was divided into three groups. The control group included 40 elderly patients without calcification of the ligamenta flava. The second group included 150 patients with posterior protrusion of the intervertebral discs. The third group included 30 patients with spinal stenosis. More than 80% of the patients of the second and the third group had calcification of the ligamenta flava. The diagnostic and practical importance of these findings is discussed.
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Recombinant human cytokines were compared for their effects on glycosaminoglycan (GAG) synthesis in human synovial fibroblast cultures and human articular cartilage explant cultures. In fibroblast cultures, recombinant human interleukin-1 alpha (rHuIL-1 alpha), rHuIL-1 beta, and recombinant human tumor necrosis factor alpha (rHuTNF alpha) stimulated hyaluronic acid (HA) production and, to a lesser extent, sulfated GAG production, while recombinant human gamma-interferon did not have a significant effect. Half-maximal stimulation of HA by rHuIL-1 beta was 0.14 pM, while stimulation for rHuIL-1 alpha and rHuTNF alpha was 1.6 pM and 32 pM, respectively. Indomethacin (10 micrograms/ml) had no influence on HA stimulation by cytokines, while hydrocortisone (2-10 micrograms/ml) caused a significant reduction. In articular cartilage cultures, the cytokines inhibited production of sulfated GAGs. The activity of rHuIL-1 beta was greater than that of rHuIL-1 alpha (half-maximal inhibition at 0.71 pM and 4.7 pM, respectively) and both were considerably more active than rHuTNF alpha; gamma-interferon again had no significant effect. Neither indomethacin nor hydrocortisone influenced cytokine-induced inhibition by either rHuIL-1 preparation. These studies indicate that cytokines released during an inflammatory process may affect GAG synthesis in human joint tissues and may have opposite effects on GAG synthesis in different types of connective tissues.
To explore the possibility that the mechanism of action of methotrexate (MTX) in rheumatoid arthritis (RA) is related to modulation of interleukin-1 (IL-1), the effects of MTX on IL-1 production and activity were evaluated. Human peripheral blood mononuclear cells and murine peritoneal and splenic cells were stimulated by lipopolysaccharide to produce IL-1. No inhibition of IL-1 synthesis or secretion caused by MTX treatment could be demonstrated either in vitro or in vivo, in patients with RA or in mice treated with MTX. We did show, however, that MTX had an inhibitory effect on IL-1 activity in 2 assays that demonstrate 2 different functions of IL-1. In a 2-step assay using LBRM-33-1A5 (1A5) and CTLD cells, MTX inhibited the secretion of IL-2 by 1A5 lymphoma cells in response to phytohemagglutinin and IL-1. In an assay using D10.G4.1 (D10) cells, MTX inhibited IL-1-induced proliferation of the D10 T cell clone. No effect of the drug on IL-2 activity was observed. The results demonstrate that MTX is capable of inhibiting some IL-1 activities without affecting IL-1 production or secretion. We propose that the inhibition of IL-1 activity or IL-1-dependent events may be one of the mechanisms of action of MTX in RA.
We reviewed the patterns of injuries sustained by 12 consecutive fallers and jumpers in whom primary impact was onto the feet. The fall heights ranged from 20 to 100 ft. The 12 patients sustained 49 significant injuries. Skeletal injuries were most frequent and included 15 lower extremity fractures, four pelvic fractures, and nine spinal fractures. In two patients, paraplegia resulted. Genitourinary tract injuries included bladder hematoma, renal artery transection, and renal contusion. Thoracic injuries included rib fractures, pneumothorax, and hemothorax. Secondary impact resulted in several craniofacial and upper extremity injuries. Chronic neurologic disability and prolonged morbidity were common. One patient died; the patient who fell 100 ft survived. After initial stabilization, survival is possible after falls or jumps from heights as great as 100 feet It is important to recognize the skeletal and internal organs at risk from high-magnitude vertical forces.
Methotrexate (MTX) levels were studied following intravenous MTX in both serum and synovial fluid (SF) of rheumatoid arthritis patients. Two hours after injection serum MTX levels were higher than those of SF. At 24 hours SF levels of MTX exceeded those of the serum, while at 72 hours both blood and SF concentrations were undetectable. The localization of parenteral MTX in the SF may have importance in the understanding of its mechanism and site of action in rheumatoid arthritis.
Cultured human synovial fibroblasts were stimulated with human recombinant interleukin 1 beta to overproduce prostaglandin E (PGE) and hyaluronic acid (HA). Diclofenac, indomethacin and hydrocortisone inhibited stimulation of PGE production. Half-maximal inhibition occurred at 1.10 x 10(-9), 2.79 x 10(-8) and at 5.52 x 10(-8) M, respectively. Diclofenac or indomethacin had no effect on HA production, while hydrocortisone had an inhibitory effect (half-maximal inhibition at 2.76 x 10(-7) M). This model could be a useful in vitro indicator for the in vivo pharmacological actions of anti-inflammatory drugs.
A 65 year old woman with rheumatoid arthritis developed marrow aplasia and jaundice owing to D-penicillamine treatment. Recovery of bone marrow was ineffective, and the patient finally died despite intensive therapeutic measures. The rare coexistence of myelotoxicity and hepatotoxicity is presented and discussed.
The coincidence of skin eruption and remission induced by gold has not previously been reported. In 50 out of 247 patients with rheumatoid arthritis treated with gold salts (Solganal) between 1977 and 1987 treatment was stopped owing to adverse reactions. Skin rashes were present in 31 patients, 10 had nephropathy, and nine patients had aphthous stomatitis. All 31 patients who developed skin eruption entered a concomitant clinical and laboratory remission. The remission satisfied the American Rheumatism Association preliminary criteria and was accompanied by a significant decrease of mean erythrocyte sedimentation rate from 43 (SD 13) to 25 (11) mm/h. Disease was exacerbated in 23 patients after three to 60 months. Eight patients are in remission at present, five to 68 months after gold treatment was discontinued. In contrast, no remission was noticed among the 19 patients with nephropathy or stomatitis.
Sequential daily measurements of erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) were performed for one week after an I.V. injection of 7.5-13 mg methotrexate (MTX) in 18 patients with rheumatoid arthritis. Early decreases of ESR and CRP were observed. Serum CRP was more sensitive than ESR, displaying more pronounced falls from baseline to both the minimal and to the 7th day levels. Patients receiving their first dose of MTX (n = 9) exhibited a more prominent reduction of CRP levels in comparison to veteran MTX users (n = 9). The prompt response of acute phase reactants to MTX may correspond to the relatively rapid clinical effect of the drug in RA. It may also support an antiinflammatory mechanism of action of low dose MTX.
Direct coronal high resolution computed tomography (CT) examination of the temporomandibular joints (TMJ) was performed in 40 patients with rheumatoid arthritis (RA). The patients were divided into 3 groups. Group 1 included patients with juvenile rheumatoid arthritis (JRA). Four patients of this group had disability of the TMJ associated with overgrowth of one of the mandibular condyles. This phenomenon has not yet been reported. Group 2 consisted of 10 patients with RA with clinically asymptomatic TMJ, 4 of whom had mild erosions of the condylar head seen on CT, consistent with RA. The majority of patients in Group 3, with clinically symptomatic TMJ showed CT changes of various degrees, which are discussed in this paper. Mild bone changes, not demonstrated by conventional procedures, were clearly seen by CT. Coronal view of the CT examination had advantages over other projections.