Acute phase proteins as disease markers.
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Acute-Phase Proteins↗
Biomedical subjects
I Kushner
Publications and source records attributed to I Kushner.
Explaining the term "arthritis".
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Arthritis↗
Apical fibrocavitary lesions of the lung in rheumatoid arthritis. Report of two cases and review of the literature.
Two patients with rheumatoid arthritis and fibrocavitary lesions in the upper lobes of the lungs are described. Postmortem pathologic studies of the lungs revealed the presence of clinically unsuspected necrobiotic nodules with cavitation and excluded other possible causes such as infections and vasculitis. These findings support the view that apical fibrocavitary disease is a clinically distinct pattern of lung involvement in rheumatoid arthritis.
Aged↗
Genetic analysis of families with multiple cases of rheumatoid arthritis.
We examined the inheritance of susceptibility to RA in families with multiple cases of RA, and studied existence of any linkage between the putative RA disease susceptibility locus and the HLA-DR locus. A pedigree analysis programme, PAP, was used for both analyses. Our investigation suggests that familial RA is the effect, in part, of an inherited autosomal dominant susceptibility gene with incomplete penetrance rather than that of a recessive gene. Linkage analysis indicates a tight linkage between the putative RA disease susceptibility locus and the HLA-DR locus under an autosomal dominant mode of inheritance.
Arthritis, Rheumatoid↗
Studies of translatable mRNA for rabbit C-reactive protein.
C-reactive protein (CRP) mRNA was assayed by cell-free translation of poly(A)-containing liver RNA isolated both from rabbits stimulated to undergo the acute-phase response and from unstimulated control rabbits. No CRP-related translation products were identified until the denaturant methylmercury hydroxide (CH3HgOH) was added to the RNA before cell-free translation. In the presence of the denaturant, a 24000-Da translation product was synthesized which was immunochemically identifiable as the CRP primary translation product. It is likely that rabbit CRP mRNA can form a stable intramolecular duplex which interferes with its translatability in vitro. The 24000-Da CH3HgOH-facilitated cell-free translation product was not detected in poly(A)-containing liver RNA from unstimulated animals, indicating that the concentration of translatable CRP mRNA was dramatically induced during the acute-phase response. On the basis of absorption experiments, the 24000-Da CRP primary translation product was immunochemically more closely related to denatured CRP than to native CRP.
Animals↗
Secretion of C-reactive protein becomes more efficient during the course of the acute phase response.
We studied the kinetics of synthesis and secretion of the acute phase plasma protein, C-reactive protein, in primary hepatocyte cultures prepared from rabbits manifesting differing degrees of the acute phase response to inflammatory stimulus. In cultures prepared from progressively more responsive animals, rate of C-reactive protein secretion increased to a much greater degree than did intracellular C-reactive protein content, resulting in a progressive decrease in the ratio of intracellular content to rate of secretion. This ratio, which represents the time required to secrete the amount of C-reactive protein contained within the intracellular pool, decreased from 18 h in cultures from unstimulated rabbits to 2.5 h in cells from highly responsive animals. In contrast, these ratios for albumin were short and fell within a narrow range (0.8-2.1 h). In pulse-chase labeling experiments, the time required for secretion of 50% of pulse-labeled C-reactive protein varied markedly, ranging from well over 6 h in cells from a minimally responsive animal to about 75 min in cells from a highly responsive rabbit. In contrast, the half-time for secretion of albumin was consistently about 45 min in the same cultures. Taken together, these findings indicate that the process by which C-reactive protein is secreted becomes more efficient during the course of the acute phase response. Recent studies have indicated that secretory proteins pass from the rough endoplasmic reticulum to Golgi at different and characteristic rates, possibly by a receptor-mediated process in which rate of transfer is determined by receptor affinity. We postulate that C-reactive protein secretion is regulated, during the course of the acute phase response, either by alterations in availability of specific receptors or by competition between different secretory proteins for a common receptor.
Animals↗
Spondylitic disease without radiologic evidence of sacroiliitis in relatives of HLA-B27 positive ankylosing spondylitis patients.
We report 2 independently-conducted family studies of HLA-B27 positive probands with ankylosing spondylitis (AS), both of which support the view that the clinical spectrum of AS is broader than ordinarily assumed, and should include individuals who have symptomatic disease but who do not show radiologic evidence of abnormalities of the sacroiliac joints or the spine. In the Cleveland study of 100 relatives of 30 B27 positive AS probands, 9 relatives did not show radiologic abnormalities of the sacroiliac joints or the spine but had symptoms of chronic inflammatory back pain previously reported to be characteristic of AS. These 9 relatives were all subsequently found to possess B27, in contrast with only 27 of 60 asymptomatic relatives (P less than 0.01). In the Leiden study of 101 relatives of 20 randomly chosen B27 positive AS probands, 13 of 86 relatives without radiographic evidence of sacroiliitis reported "thoracic pain and stiffness," as defined in the Rome criteria for AS. Twelve of these 13 symptomatic relatives were B27 positive. In contrast, among the remaining 73 relatives, only 33 were B27 positive (P less than 0.01). The occurrence of these characteristic spondylitic symptoms in B27 positive, but not B27 negative, relatives of AS probands suggests that the spectrum of the clinical manifestations of AS may include individuals with symptomatic disease, but without radiographic evidence of abnormalities of the sacroiliac joints or the spine. The relatively large number of females we found in this group suggests that women are more likely to manifest this variety of disease than are men.
Adult↗
Recurrent rheumatic fever in adults.
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Adult↗
Intravenous pulse methylprednisolone followed by alternate day corticosteroid therapy in lupus erythematosus: a prospective evaluation.
We explored the feasibility of using intravenous pulse methylprednisolone followed by alternate day steroids for treatment of active systemic lupus erythematosus (SLE) in an attempt to avoid longterm daily steroid therapy. Our study was terminated after 11 trials because sustained control of disease activity was possible in only a minority of patients. Pulse therapy was initially very effective: there was rapid improvement in clinical symptoms, and significant improvement of serum anti-DNA (p less than .01) and C3 (p less than .05), but not in other laboratory tests, within 2 weeks of pulse treatment. On followup, alternate day steroids had to be discontinued in 7 trials; 3 patients experienced recurrence of their presenting symptoms, and 4 demonstrated worsening of laboratory abnormalities reflective of active renal disease. Despite the efficacy of pulse for initial management of active SLE, only 4 patients could be successfully maintained on a subsequent alternate day steroid regimen for prolonged periods.
Adolescent↗
Heterotopic ossification presenting as arthritis.
We report 4 patients with arthritis as a presenting manifestation of heterotopic ossification. This cause of arthritis has only recently been noted. The synovial fluids from all 4 patients showed low leukocyte counts (90, 670, 167 and 500/mm3) while the protein concentrations were discordantly high in 3 cases (3.1, 5.3, 4.3 and 2.6 g/dl, respectively). The mechanism for the relatively elevated synovial protein concentration is unknown. These findings may be useful for the early diagnosis of heterotopic ossification.
Adult↗
Iron, ferritin, and AIDS.
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Acquired Immunodeficiency Syndrome↗
Pregnancy and systemic sclerosis.
Pregnancy has been reported infrequently in patients with systemic sclerosis. Consequently, the outcome and appropriate management of such patients is uncertain. We review the obstetric experience of 19 female patients with systemic sclerosis, and report 2 women in whom 3 pregnancies occurred during the course of disease. Maternal complications included hypertension during 2 of these pregnancies and congestive heart failure during 1. There were 2 premature deliveries, although all 3 infants survived. Our experience with these patients and a review of the available literature suggest that, in patients with systemic sclerosis, fertility may be reduced and complications of pregnancy may be more frequent.
Adult↗
Does drug therapy slow radiographic deterioration in rheumatoid arthritis?
Many clinicians believe that slow-acting therapeutic agents, such as fold, penicillamine, the antimalarials, and cytotoxic drugs, can retard joint destruction in rheumatoid arthritis. We reviewed 60 published studies employing these drugs to evaluate critically the evidence that drug therapy can slow the radiographic progression of disease. Seventeen studies were found that included radiographic assessment of both treated and control groups; they were analyzed using methodologic criteria known to be important in affecting the results of drug trials. In addition to numerous qualitative methodologic deficiencies, many studies showed inadequacies in sample size and duration of treatment, and the drug dosage used varied from one study to another. We found evidence suggesting that both gold and cyclophosphamide can retard radiographic progression of joint destruction. At present, there are too few technically adequate studies to permit even provisional conclusions concerning other agents.
Antimalarials↗
Synthesis and secretion of C-reactive protein by rabbit primary hepatocyte cultures.
The synthesis and secretion of the acute-phase protein C-reactive protein by rabbit primary hepatocyte cultures was investigated. Hepatocytes prepared from animals that had received inflammatory stimuli 18-24 h before cell isolation were found to incorporate radiolabelled amino acids into C-reactive protein throughout the 48 h culture period. Intracellular C-reactive protein was found to be in steady state and there was no significant degradation of extracellular C-reactive protein, permitting direct estimation of rate of synthesis from rate of extracellular accumulation. Both C-reactive protein and total secreted protein were synthesized at constant rates for at least 24 h in culture. Mean rate of accumulation of newly synthesized total proteins in medium of cultures from six stimulated animals was 40% greater than was found in cultures from nine control (unstimulated) animals; this difference did not achieve statistical significance (0.05 less than P less than 0.10). Mean rate of C-reactive-protein synthesis represented 3.9% of total secreted-protein synthesis in cultures prepared from stimulated animals compared with 0.3% in cultures from control animals (P less than 0.001). Further, there was a correlation between C-reactive-protein synthesis by cultured hepatocytes and serum C-reactive-protein concentration at time of hepatocyte isolation (P less than 0.001). Rates of C-reactive-protein synthesis by hepatocyte cultures from stimulated animals were in good agreement with those previously measured in isolated perfused livers and those calculated from results of studies in vivo.
Animals↗
The value of quantitative sacroiliac scintigraphy in detection of sacroiliitis.
To evaluate clinical usefulness of quantitative sacroiliac scintigraphy (QSS) in detecting sacroiliitis, we used a modified, pixel by pixel technique for calculating sacroiliac joint/sacrum uptake ratios (sacroiliac joint index - SII). We studied 90 controls, 18 selected patients with active sacroiliitis, 2 ankylosing spondylitis patients with completely ankylosed sacroiliac joints, 14 patients with nonspecific low back pain and 5 patients with rheumatoid arthritis. In the controls, we found that the SII decreases with increasing age (P less than 0.001) and is higher in males than in females (P less than 0.005). In the patients with active sacroiliitis, 9 out of 14 older than 30 had an abnormal SII; 3 of these patients showed no radiographic or CT abnormalities of the sacroiliac joints. None of the 4 patients with sacroiliitis under 30 years of age had values which fell out of the normal range for their age and sex. Only 1 of the 14 patients with non-inflammatory low back pain had an abnormally high SII. A borderline SII was found in 1 of the 5 patients with rheumatoid arthritis. QSS may be useful in detecting active sacroiliitis, sometimes even before the occurrence of radiologic abnormalities. However, because of its low sensitivity, its clinical usefulness is limited, especially in patients under 30 years of age.
Adolescent↗
Study of HLA antigens in familial and sporadic rheumatoid arthritis.
Patients with familial and non-familial (sporadic) forms of rheumatoid arthritis (RA) were studied to investigate possible HLA heterogeneity. HLA-DR4 was present in 75% of familial and 59% of sporadic RA patients. The frequency distribution of A2, B8, B27, Cw3 and DR3 differed somewhat between the two groups; however, the differences were not statistically significant in this small group of patients. Studies of a larger number of patients are indicated to explore the possibility of genetic subgroups in RA.
Arthritis, Rheumatoid↗
Genetics of HLA-associated disease; rheumatoid arthritis.
An association between rheumatoid arthritis (RA) and the HLA antigen DR4 supports the view that genes in the HLA region are important in susceptibility to this disease. To further define the basis for genetic susceptibility to RA, we analyzed HLA haplotype sharing among affected and unaffected individuals in 29 multiple-case families with definite or classic RA. We have observed a non-random distribution of HLA haplotypes to unaffected as compared with affected offspring in sibships containing two or more affected individuals having 3 of 4 parental haplotypes. These data support the view that susceptibility to RA is determined, at least in part, by genes in the HLA region of chromosome 6.
Arthritis, Rheumatoid↗
In vivo studies of serum C-reactive protein turnover in rabbits.
We determined the plasma half-life of the acute phase protein C-reactive protein (CRP) both in normal rabbits and in rabbits that had received inflammatory stimuli. Rabbit CRP was purified from acute phase serum by Cx-polysaccharide affinity chromatography, radiolabeled, and rendered pyrogen-free. Six unstimulated rabbits were injected intravenously with (125)1-CRP prepared by the lactoperoxidase method and four were injected with CRP labeled by methylation using [(14)C]formaldehyde. Blood samples were obtained at 0.25 h and at intervals thereafter. Plasma half-life of CRP was calculated from the data generated during the first 12 h, by which time an average of 86% of labeled protein had disappeared from the blood stream. The mean half-life for CRP was 4.45+/-0.2 h, with no significant difference (0.40 < P < 0.45) between (125)1- and (14)C-labeled CRP. In six animals stimulated with either endotoxin or turpentine 24 h before injection of labeled CRP, a mean half-life of 5.8+/-0.6 h was found, not significantly different (0.30 < P < 0.35) from unstimulated rabbits. We equated fractional catabolic rate to fractional disappearance rate, since the rate constant for passage of CRP from vascular to extravascular compartment can be assumed to be relatively small compared to the observed fractional disappearance rate. Fractional catabolic rate was independent of serum CRP concentration; average fractional catabolic rate in all 16 animals was 14+/-0.8% h(-1) of the plasma pool. We were able to estimate rate of CRP synthesis, based on steady-state assumptions of pool sizes in those rabbits whose serum CRP levels did not change substantially during the period of study. Values as low as 6.7 mug/kg per h in the unstimulated animals and as high as 560 mug/kg per h in the stimulated animals were found.
Animals↗