Biomedical subjects

F M Wigley

Publications and source records attributed to F M Wigley.

At least 73 records · Page 4Linked to original sources

PubMed1990

The post-occlusive hyperemic response in patients with systemic sclerosis.

We investigated post-ischemic hyperreactive cutaneous blood flow in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis (SSc). Reactive hyperemia was measured over a locally warmed area of skin, using a laser Doppler flowmeter, following 5 minutes of suprasystolic occlusion of blood flow. We found that patients with primary Raynaud's phenomenon had normal post-ischemic blood flow compared with normal controls. In contrast, patients with SSc had reduced levels of baseline and peak blood flow compared with either the primary Raynaud's phenomenon patients or the normal subjects. Infusion of carbaprostacyclin, a potent prostacyclin analog vasodilator, did not increase blood flow in the SSc patients, nor did it restore the reactive hyperemic response. These findings are consistent with the hypothesis that patients with the nonvasoconstricted condition of SSc have fixed structural defects that limit cutaneous microvascular blood flow.

Adult↗

PubMed1989

Preincubation of human synovial cells with IL-1 modulates prostaglandin E2 release in response to bradykinin.

Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.

Adjuvants, Immunologic↗

PubMed1989

New radiographic grading scales for osteoarthritis of the hand. Reliability for determining prevalence and progression.

We developed and evaluated scales for grading the prevalence and progression of the individual radiographic features of osteoarthritis (OA) of the hand. Four equally time-spaced hand radiographs from 50 participants in the Baltimore Longitudinal Study of Aging, who were followed for at least 20 years, were read separately and "blindly" by 4 experienced, trained readers. Eleven hand joints were individually assessed for the presence of osteophytes, joint space narrowing, subchondral cysts, subchondral sclerosis, lateral deformity, and cortical collapse, and were also graded using the Kellgren/Lawrence scale, a global estimate of OA. The intraclass correlation coefficient was used to determine cross-sectional inter- and intrareader reliability. Interreader agreement on OA progression was evaluated using life-table analysis. Each of the grading scales for the individual radiographic features of OA of the hand, except for cysts, were cross-sectionally reliable between readers. Each reader was able to reproduce his original scores almost perfectly when grading the radiographs a second time. Using these scales, the different readers agreed on all the features of longitudinal progression of OA of the hand, except cysts. We believe that this method for grading hand radiographs for OA has proved to be reliable for both cross-sectional and longitudinal studies.

Adult↗

PubMed1989

Rectosigmoid motility and myoelectric activity in progressive systemic sclerosis.

Colon motility and myoelectric slow wave activity were compared in 10 patients with progressive systemic sclerosis and 18 controls. Recordings were made in the rectosigmoid and rectum, 25-30 cm and 10-15 cm from the anal margin, respectively, during two 4-min baselines and in response to stepwise distention of the colon with an air-filled balloon. During baseline, the motility (activity index, defined as cumulated areas of all waves divided by recording time) of the rectosigmoid was similar in patients with progressive systemic sclerosis (0.38 +/- 0.61 in baseline 1, 0.86 +/- 1.33 in baseline 2) and controls (1.15 +/- 2.02 in baseline 1, 0.77 +/- 1.01 in baseline 2). Rectal motility was also similar during baseline in patients with progressive systemic sclerosis (1.43 +/- 2.56 in baseline 1, 1.65 +/- 2.47 in baseline 2) and controls (0.56 +/- 0.80 in baseline 1, 0.62 +/- 0.94 in baseline 2). Patients showed a lower tolerance for balloon distention of the colon (average, 130 vs. 184 ml) and a greater amount of contractile activity than controls after balloon distention (rectosigmoid activity index, 1.05 +/- 1.24 vs. 0.07 +/- 0.14; rectal activity index, 2.75 +/- 3.71 vs. 0.13 +/- 0.31). Maximum tolerable volume of balloon distention was inversely correlated to complaints of diarrhea in patients. Slow wave myoelectric activity did not differentiate patients from controls. These findings suggest that diarrhea, and possibly other gastrointestinal symptoms associated with progressive systemic sclerosis, may be due to decreased compliance of the bowel.

Adult↗

PubMed1989

Characterization of the class I HLA 9.2-kb PVU II restriction fragment length polymorphism. Linkage to HLA-A and lack of disease association.

The strongest reported association between a class I HLA allele and disease is that of HLA-B27 with ankylosing spondylitis (AS). However, it has not been shown whether B27 is the gene that predisposes to the development of AS or if it is merely linked with the disease-susceptibility locus. Furthermore, if B27 itself is the disease-susceptibility gene, there may be epistatic loci that also contribute to the development of AS or modify its clinical manifestation. A class I HLA 9.2-kb Pvu II restriction fragment was recently identified, which, when present in a B27-positive individual, further increased the relative risk for developing AS (from 119 to 297). This study was therefore designed to confirm the association between AS and this restriction fragment length polymorphism (RFLP) and to map the location of this fragment in the genome. The data presented here suggest that the class I HLA 9.2-kb Pvu II RFLP represents a Pvu II polymorphism at the 5' end of the HLA-A locus that is tightly linked with both HLA-A3 and A9 alleles. However, there is no association between this RFLP and AS in a population of patients living in Baltimore.

Arthritis, Reactive↗

PubMed1988

HLA-DQw alloantigens and pulmonary dysfunction in rheumatoid arthritis.

HLA-DR4 and keratoconjunctivitis sicca (secondary Sjögren's syndrome) are associated with abnormal pulmonary function in patients with rheumatoid arthritis. Since recent investigations have found that much of the genomic polymorphism of the HLA-DR4 haplotype comes from the closely linked DQw allele, we reanalyzed this set of data to evaluate the relationship between the DQw allotypes and pulmonary function in rheumatoid arthritis. Using a step-wise regression analysis, we found that the presence of DQw1 was a stronger predictor of an abnormal forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and carbon monoxide diffusing capacity (D) than the presence of DR4, keratoconjunctivitis sicca, smoking status, or any other clinical parameter. DQw1-positive patients had a mean (+/- SD) percent of predicted FEV1, FVC, and D of 84.2 (+/- 19.8), 88.0 (+/- 17.9) and 85.6 (+/- 20.9) percent, respectively, all significantly lower than DQw-1 negative patients (p = 0.02, 0.02, and 0.03). Smokers with the heterozygous phenotype, DQw1/DQw3, tended to have obstructive disease of the airways, with a mean (+/- SD) FEV1 of 80.1 +/- 24.4 percent of predicted, compared to 95.7 +/- 12.1 percent of predicted in DQw1/DQw3-negative individuals (p = 0.03). Patients who had a DQw2 allele were more likely to have normal pulmonary function. We conclude that the HLA-DQw1 allotype is a strong predictor of abnormal pulmonary function and that it may identify smoking subjects with rheumatoid arthritis subjects who are prone to develop obstruction of airflow.

Arthritis, Rheumatoid↗

PubMed1988

Characterization of human synovial mast cells.

Human synovium obtained at arthroplasty from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were characterized by assessing mast cell morphology, content and function. Histological studies confirmed significant numbers of mast cells in both RA and OA synovium. Electron microscopic data support the morphologic similarity between human synovial mast cells and human mast cells in lung and intestine. Likewise, synovial mast cells do not appear to be functionally different from pulmonary or intestinal mucosal mast cells. Mast cell suspensions with a cellular histamine content of 4.3 +/- 0.5 pg/cell (mean +/- SEM) released histamine following provocation with anti-IgE and calcium ionophore but not compound 48/80, f-met peptide or bradykinin. Prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) were also released in response to anti-IgE. Auranofin inhibited anti-IgE provoked histamine, PGD2 and LTC4 release while gold sodium thiomalate, cromolyn and indomethacin had no effect on histamine release. Theophylline inhibited anti-IgE induced histamine release only at concentrations greater than or equal to 10(-3) M. Our study argues against functional or morphologic mast cell heterogeneity of human intestinal, lung and synovial origin and suggests that mast cells may have a pathogenic role in both RA and OA.

Antibodies, Anti-Idiotypic↗

PubMed1987

Nicardipine in the treatment of Raynaud's phenomenon. Dissociation of platelet activation from vasospasm.

A new calcium channel blocker, nicardipine, was studied for treatment of Raynaud's phenomenon in a double-blind, placebo-controlled, crossover trial during the winter months. Clinical response was assessed by a patient-kept diary of symptoms and finger systolic pressure that was measured at room temperature and during cold challenge. In vivo platelet activation was determined by measuring plasma levels of the platelet-specific proteins, beta-thromboglobulin and platelet factor 4. When treatment with placebo was compared with treatment with nicardipine, no significant differences were found in the number of Raynaud's attacks per day, the severity of attacks, change in character in Raynaud's phenomenon, use of hands in winter months, patient assessment of medication or objective measurements of finger systolic pressure, and critical closing temperature. There was a reduction of plasma levels of beta-thromboglobulin and platelet factor 4 in the overall study group while taking nicardipine compared with that during the placebo period (mean change 5.0 +/- 2.4 ng/ml, P = 0.054, and 1.4 +/- 0.6 ng/ml, P less than 0.01, respectively). These results demonstrate that while nicardipine was not effective in reducing the episodes of Raynaud's phenomenon, it did inhibit in vivo platelet activation. These findings suggest that platelet activation is not the primary event in the pathogenesis of acute vasospasm in Raynaud's phenomenon, since reduction of platelet activation by the drug did not change the severity of vasospasm.

Adolescent↗

PubMed1987

HLA-DR4 and pulmonary dysfunction in rheumatoid arthritis.

Rheumatoid arthritis is associated with an increased frequency of the B cell alloantigen HLA-DR4, and preliminary work has suggested an association between HLA-DR4 and obstructive lung disease in subjects with rheumatoid arthritis. To prospectively evaluate the influence of HLA-DR4 on pulmonary involvement in patients with rheumatoid arthritis, pulmonary function was measured in four groups of subjects with rheumatoid arthritis in whom HLA-DR4 and smoking status was known: 16 DR4-positive smokers (six current and 10 exsmokers), 16 DR4-negative smokers (six current and 10 exsmokers), eight DR4-positive nonsmokers, and eight DR4-negative nonsmokers. Significant reductions in one-second forced expiratory volume and forced vital capacity were observed in DR4-positive subjects compared with DR4-negative subjects irrespective of cigarette smoking status. In addition, patients with keratoconjunctivitis sicca (secondary Sjögren's syndrome) demonstrated significant reductions in one-second forced expiratory volume, forced vital capacity, and ratio of one-second forced expiratory volume to forced vital capacity compared with those patients without evidence of secondary Sjögren's syndrome. It is concluded that the presence of the HLA-DR4 antigen and secondary Sjögren's syndrome are associated with abnormal pulmonary function in patients with rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1987

Acute effects of nifedipine on digital blood flow in human subjects with Raynaud's phenomenon: a double blind placebo controlled trial.

In order to determine the acute effect of nifedipine, a calcium channel blocker, on digital hemodynamics in patients with Raynaud's phenomenon, we studied 21 patients in a double blinded, placebo controlled trial. Digital blood flow at room temperature was measured by venous occlusion plethysmography as perfusion pressures were lowered by elevating the hand above the level of the heart. After placebo, there was a small reduction in digital blood flow without any alteration in the perfusion pressure. After nifedipine, there was a significant reduction in both perfusion pressure and digital blood flow at each level of hand elevation. When analyzed as pressure-flow relationships, there was no significant change after nifedipine, indicating that the fall in blood flow could be accounted for by the reduction in perfusion pressure. Four of the placebo group developed Raynaud's phenomenon after the baseline study, whereas none developed Raynaud's phenomenon after nifedipine. Our results suggest that although nifedipine may reduce vascular reactivity, caution is warranted in use of this drug in patients with threatened digital ischemia because of the possibility that digital blood flow may be reduced.

Adult↗

PubMed1987

Systemic sclerosis (scleroderma): clinical, genetic, and serologic subsets.

Immunogenetic markers, autoantibodies, and clinical features were studied in 47 patients, 35 Caucasian and 12 black, with systemic sclerosis. Twenty-two had generalized scleroderma, while 25 had limited skin involvement. HLA-DR1 (RR = 2.1, p = 0.08) and DR5 (RR = 2.1, p = 0.08) were increased in Caucasian patients vs controls as was the supertypic specificity HLA-DRw52 (RR = 2.8, p = 0.02, pc = 0.04). HLA-DR6.1 was increased in black patients vs controls (RR = 15.4, p = 0.008, pc = 0.088). There were no significant increases in any of the complement allotypes in either racial group. Anticentromere antibody was noted in 10 patients, all Caucasian; 7 had limited disease. Anti-Scl-70 was noted in 4 patients; all had generalized disease (p = 0.036). HLA-DR2 was present in all anti-Scl-70 positive patients (RR = 22.5, p = 0.006). Our results suggest that clinical subsets of systemic sclerosis can be defined by genetic and serological markers.

Adult↗

PubMed1987

Reproducibility of cold provocation in patients with Raynaud's phenomenon.

Twenty-five patients with Raynaud's phenomenon had serial cold challenges during a double blinded drug trial. The data were analyzed to determine the reproducibility of cold provocation in the induction of critical closure of the digital artery in patients with Raynaud's phenomenon. Finger systolic pressure (FSP) was measured after local digital cooling using a digital strain gauge placed around the distal phalanx. Nineteen of 25 patients completed the study. The prevalence of inducing a Raynaud's attack decreased with each successive cold challenge from 74% of patients at initial challenge to 42% at the 3rd challenge. A lower temperature was required to induce a Raynaud's attack at last challenge (10.6 +/- 0.6 degrees C) compared to the first cold challenge (13.2 +/- 1.0 degrees C). Our data demonstrate adaptation to a laboratory cold challenge through the winter months in patients with Raynaud's phenomenon and show it is an important factor in objectively assessing drug efficacy in the treatment of Raynaud's phenomenon.

Adult↗

PubMed1986

Membrane attack complex of complement in rheumatoid synovial tissue demonstrated by immunofluorescent microscopy.

Rheumatoid and osteoarthritic synovial membranes were examined for evidence of terminal complement pathway activation. Using antiserum highly specific for C9 neoantigen, immunofluorescent microscopy was employed to study synovial membrane specimens from 4 patients with rheumatoid arthritis, one patient with psoriatic arthritis, and 5 patients with osteoarthritis. C9 neoantigen was detected in 3 of the 4 rheumatoid membranes, the one psoriatic membrane, and one of the 5 osteoarthritic membranes. Activation of the terminal pathway of complement through C9 should be added to the spectrum of immunologic events known to occur in some rheumatoid synovial membranes.

Adult↗

PubMed1985

Nifedipine in the treatment of Raynaud's phenomenon. Evidence for inhibition of platelet activation.

Platelet activation has been reported to occur in patients with Raynaud's phenomenon; however, the effect of calcium channel blockers and thromboxane synthetase inhibitors has not been previously studied. The effect of two drugs that potentially inhibit platelet activation were studied: nifedipine, a calcium channel blocker, and dazoxiben, a specific thromboxane synthetase inhibitor. Two platelet-specific proteins released during platelet activation, beta-thromboglobulin and platelet factor 4, were measured during a double-blind clinical trial of these two drugs in patients with Raynaud's phenomenon. The plasma beta-thromboglobulin level was significantly elevated in the patient population (53.8 +/- 7.6 ng/ml) during the placebo period compared with that in a normal control population (27.0 +/- 3.1 ng/ml) (p less than 0.01). The plasma platelet factor 4 level was 8.7 +/- 2.2 ng/ml in the patients compared with 6.5 +/- 1.0 ng/ml in the normal subjects (p = NS). These findings indicate the presence of in vivo platelet activation in patients with Raynaud's phenomenon. Nifedipine lowered the levels of beta-thromboglobulin to near the normal range (33.4 +/- 4.6 ng/ml). The inhibition of platelet activation by nifedipine was associated with clinical improvement in Raynaud's phenomenon with fewer and less intense episodes. Beta-thromboglobulin was not lowered by dazoxiben (58.1 +/- 9.0 ng/ml) compared with the placebo. The reduction of beta-thromboglobulin levels by nifedipine indicates that in vivo platelet activation was inhibited by this agent. Since this was associated with a reduced frequency of attacks, it is not clear whether this was a direct effect of the drug on platelet activation, leading to decreased frequency of vasospasm, or an effect on vascular smooth muscle leading to decreased vasospasm and a secondary decrease in platelet activation.

Adult↗

PubMed1985

Digital pressure-flow relationships in subjects with Raynaud's phenomenon.

In order to determine whether subjects with Raynaud's phenomenon have altered digital hemodynamics in the warm basal condition, we characterized the digital pressure-flow relationships in seven subjects with Raynaud's phenomenon and compared the results with age and sex matched control subjects. Digital pressure-flow relationships were measured by the use of a plethysmographic technique during passive elevation of the arm. Normal subjects demonstrated a positive finger systolic pressure at zero flow (48.3 mmHg), indicative of a critical closing pressure, however, the closing pressure was significantly higher in the subjects who had a history of Raynaud's phenomenon (64.7 mmHg, p less than .001). In contrast, there was no significant difference found in the conductance measured as the slope of the pressure-flow relationship. Subjects with Raynaud's phenomenon demonstrated a correlation between finger systolic pressure and critical closing pressure suggesting that these subjects may regulate arterial pressure through a critical closing pressure mechanism.

Adult↗

PubMed1985

Incidence of lung cancer in systemic sclerosis.

During a study of lung function in patients with systemic sclerosis, we followed 71 patients with this diagnosis for a mean of 5 years. During this period, 3 cases of lung cancer were observed in the group, giving a post hoc incidence of lung cancer of 8.6 cases/1000 persons/year compared to an expected incidence of 0.52 cases/1000 persons/year. The relative risk ratio for lung cancer in systemic sclerosis patients is 16.5. There was no definite association of lung cancer with cigarette smoking, but all 3 patients had either radiographic or pulmonary function evidence of interstitial pulmonary fibrosis. Although bronchoalveolar carcinoma is the most prevalent histologic type of lung cancer associated with systemic sclerosis in the reported cases in the literature, this was not present in any of our patients.

Female↗

PubMed1984

Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon.

The prostaglandin thromboxane A2 causes platelet aggregation and vasoconstriction and may be important in the pathogenesis of Raynaud's phenomenon. Therefore, a randomized, double-blind, placebo-controlled trial was conducted to assess the effectiveness of dazoxiben, a selective thromboxane synthetase inhibitor, in the treatment of Raynaud's phenomenon and to compare it with nifedipine, a calcium channel blocker. Twenty-two subjects who had at least one episode of Raynaud's phenomenon per day entered the study. Three patients withdrew from the study because of side effects while taking nifedipine. There was no difference among the subjects' subjective evaluation of the three treatments. Seven of 19 (44 percent) reported a moderate to marked improvement while taking placebo compared with 12 of 19 (63 percent) taking nifedipine and five of 19 (26 percent) taking dazoxiben (p = NS). Similarly, there was no difference in the mean two-week episode rate among the three treatments: placebo 30.4 +/- 4.5, nifedipine 24.7 +/- 5.6, dazoxiben 32.0 +/- 4.9 (p = NS). Twelve of 22 subjects experienced side effects while taking nifedipine as compared with two of 21 taking placebo and eight of 21 taking dazoxiben (p less than 0.005). These data show that dazoxiben is not effective in the treatment of Raynaud's phenomenon and suggest that thromboxane does not cause the vasoconstriction that characterizes this disorder.

Adult↗

PubMed1984

Carbon monoxide diffusing capacity as predictor of outcome in systemic sclerosis.

In order to determine the predictive value of lung function studies for subsequent prognosis in systemic sclerosis, 71 patients with systemic sclerosis were followed up for a mean of five years after pulmonary function testing. A carbon monoxide diffusing capacity less than or equal to 40 percent of the predicted reference value was associated with only a 9 percent five-year cumulative survival rate compared with a 75 percent cumulative five-year survival in patients with a carbon monoxide diffusing capacity greater than 40 percent of predicted. An obstructive ventilatory defect was also associated with increased mortality, and all six patients with obstruction and a diffusing capacity less than 70 percent of the predicted died during the study period. Male gender, independent of abnormalities of pulmonary function, was also associated with a poor prognosis. Although it is not clear whether a severely impaired diffusing capacity is indicative of interstitial pulmonary fibrosis or pulmonary vasculopathy or is a marker of generalized vascular disease, a severely depressed carbon monoxide diffusing capacity is an important predictor of mortality in patients with systemic sclerosis.

Actuarial Analysis↗