Biomedical subjects

Barbara White

Publications and source records attributed to Barbara White.

27 records · Page 2Linked to original sources

PubMed2003

Scleroderma patients with combined pulmonary hypertension and interstitial lung disease.

OBJECTIVE: Most studies differentiate scleroderma associated pulmonary hypertension and interstitial lung disease (ILD) as 2 separate pathological processes, concentrating on one or the other; however, many patients have both conditions. We studied the demographics, clinical features, and prognosis of individuals with both vascular and interstitial lung disease. METHODS: A retrospective cross-sectional study of 619 patients with scleroderma who had echocardiograph and pulmonary function testing performed within 6 months of one another. Echocardiography determined the presence of pulmonary hypertension, and pulmonary function testing documented restrictive ventilatory defect (RVD) as a marker of ILD. RESULTS: Among the study group, 139 (22.5%) patients had isolated RVD; 119 (19.2%) isolated pulmonary hypertension; and 112 (18.1%) patients had combined RVD and pulmonary hypertension. The individuals with combined RVD and pulmonary hypertension resembled patients with isolated RVD in that they had a high prevalence of diffuse skin involvement and antitopoisomerase positivity, but they were older at diagnosis and at disease onset (p < 0.01). Among those with mild RVD, 39.2% had pulmonary hypertension compared to those with severe RVD, in whom 51.4% had pulmonary hypertension. Compared to those without pulmonary disease, the mortality risk ratio for patients with isolated pulmonary hypertension, combined RVD and pulmonary hypertension, and isolated RVD was 2.9, 2.4, and 1.61, respectively. CONCLUSION: Patients with combined scleroderma lung disease features are more likely to have diffuse disease, represent older patients, and have a prognosis similar to individuals with isolated pulmonary hypertension, and may represent a distinct subpopulation of scleroderma.

Adult↗

PubMed2002

Deficient Smad7 expression: a putative molecular defect in scleroderma.

Scleroderma is a chronic systemic disease that leads to fibrosis of affected organs. Transforming growth factor (TGF) beta has been implicated in the pathogenesis of scleroderma. Smad proteins are signaling transducers downstream from TGF-beta receptors. Three families of Smads have been identified: (i) receptor-regulated Smad2 and -3 (R-Smads); (ii) common partner Smad4 (Co-Smad); and (iii) inhibitory Smad6 and -7 (I-Smads, part of a negative feedback loop). We have investigated the signaling components for the TGF-beta pathway and TGF-beta activity in scleroderma lesions in vivo and in scleroderma fibroblasts in vitro. Basal level and TGF-beta-inducible expression of Smad7 are selectively decreased, whereas Smad3 expression is increased both in scleroderma skin and in explanted scleroderma fibroblasts in culture. TGF-beta signaling events, including phosphorylation of Smad2 and -3, and transcription of the PAI-1 gene are increased in scleroderma fibroblasts, relative to normal fibroblasts. In vitro adenoviral gene transfer with Smad7 restores normal TGF-beta signaling in scleroderma fibroblasts. These results suggest that alterations in the Smad pathway, including marked Smad7 deficiency and Smad3 up-regulation, may be responsible for TGF-beta hyperresponsiveness observed in scleroderma.

Adult↗

PubMed2002

Synergy between CD40 ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signaling.

Fibrosis can be an undesired consequence of activated cellular immune responses. The purpose of this work was to determine whether CD40 ligation and the pro-fibrotic cytokine IL-4 interact in regulating fibroblast proliferation and collagen production, and, if so, the mechanisms used. This study found that the combination of IL-4 and ligation of CD40 on the fibroblast cell surface had synergistic effects in stimulating fibroblast proliferation. In contrast, CD40 ligation negated the inhibitory effects of IFN-gamma on fibroblast proliferation. Western blotting analyses of fibroblast crude lysates revealed that a potential mechanism of the synergy between CD40 ligation and IL-4 was the phosphorylation of proteins at 130 kDa and, to a lesser degree, at 95, 85, and 75 kDa. Immunoprecipitation-Western blotting experiments showed that phosphorylation levels of IL-4Ralpha, Janus kinase 1, insulin receptor substrate 1, and insulin receptor substrate 2, factors with molecular mass close to the observed 130 kDa major phosphorylation band, increased in response to the combined CD40 ligation and IL-4 action. In contrast, there was no evidence that synergy was mediated by an increased expression of IL-4Ralpha chain, CD40, or the autocrine profibrotic cytokines IL-6 and TGF-beta. These findings suggest that CD40-CD40 ligand contacts between fibroblasts and cells secreting IL-4 may promote the profibrotic effects of IL-4 by affecting signal transduction and reducing the anti-fibrotic effects of IFN-gamma.

Autocrine Communication↗

PubMed2002

Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon.

OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).

Affect↗

PubMed2002

Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

OBJECTIVE: The reported frequency of scleroderma M01-R renal crisis (SRC) in diffuse systemic sclerosis (SSc; scleroderma) is 15-20%. Early use of angiotensin-converting enzyme (ACE) inhibitors has markedly improved outcome. The present analysis reexamines the prognostic factors for and outcome of SRC in a prospective cohort of patients with early diffuse SSc. METHODS: We retrospectively evaluated the cohort of SSc patients who participated in the High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse SSc trial. Patients with diffuse cutaneous scleroderma were enrolled if their disease duration was <18 months. Because the trial failed to show a difference between treatment groups, the data were pooled. RESULTS: One hundred thirty-four SSc patients entered the observation period a mean +/- SD of 0.8 +/- 0.3 years after onset of SSc. SRC occurred in 18 patients a mean +/- SD of 0.9 +/- 1.1 years after entry. During a mean +/- SD 4.0 +/- 1.1 years of followup after entry, 9 of the 18 patients died (mean +/- SD 0.6 +/- 0.9 years after SRC onset). Baseline characteristics that predicted SRC included a modified Rodnan skin thickness score of >or=20 (P < 0.01), enlarged cardiac silhouette on radiograph (P = 0.04), large joint contractures (wrist, elbow, knee) (P = 0.008), and prednisone use at entry (P = 0.01). Baseline characteristics that did not predict SRC included age, sex, race, Health Assessment Questionnaire score, fist closure, handspread, lung involvement, muscle weakness, erythrocyte sedimentation rate, and platelet count. In 5 of 10 subjects for whom at least 2 sequential skin scores were available, skin scores increased significantly (P = 0.012) in the 6 months before onset of SRC. CONCLUSION: SRC occurred in 13% of patients soon (mean 11 months) after entry into the cohort. Predictors of SRC identified in this study included higher than average skin score, prednisone use at study entry, large joint contractures, and heart enlargement. Our data suggest, however, that low-dose prednisone alone was not associated with the onset of SRC, except in the appropriate clinical setting. Although ACE inhibitors and dialysis are now readily available, SRC continues to be associated with poor survival (in this study, 50% of patients with SRC died).

Adult↗

PubMed2002

Evaluation and management of pulmonary fibrosis in scleroderma.

Pulmonary fibrosis causes significant morbidity and mortality in patients with scleroderma. Lung inflammation identifies patients at greater risk for decline in forced vital capacity and diffusing capacity for carbon monoxide. Factors that are increased in patients with scleroderma with lung fibrosis include connective tissue growth factor, KL-6, pulmonary surfactant-D, tissue inhibitor of metalloproteinase 2, monocyte chemotactic protein-1, macrophage inhibitory protein-1 alpha, soluble interleukin-6 receptors, anti-endothelial cell antibodies, and anti-DNA topoisomerase I antibodies. Potential mechanisms of lung damage in scleroderma include increased production of profibrotic type 2 cytokines and abnormal signaling by thrombin of tenascin-C production by lung fibroblasts, with protein kinase C epsilon as an intermediate in the signaling pathway. Treatment of scleroderma lung disease with cyclophosphamide may have a beneficial effect on pulmonary function and survival. Lung transplantation provides a therapeutic option for patients with scleroderma with end-stage lung disease.

Bronchoalveolar Lavage Fluid↗

PubMed2002

The impact of pain and symptoms of depression in scleroderma.

Systemic sclerosis (scleroderma) is a rare connective tissue disease that can affect multiple organ systems. Case reports and small treatment studies suggest that pain is significant in scleroderma, but few data speak of the frequency or impact of pain. This study sought to determine the frequency and impact of pain, symptoms of depression, and social network characteristics on physical functioning and social adjustment in patients with scleroderma. One hundred and forty-two scleroderma patients completed measures of pain, depressive symptoms, social network characteristics, physical functioning, and social adjustment. Sixty-three percent reported at least mild pain and 50% reported at least mild levels of depressive symptomatology. Hierarchical regression analyses revealed that pain, depressive symptoms, and employment status (disabled/unemployed vs. not) were significant, independent predictors of physical functioning, together accounting for 37% of the total variance. Pain was the single strongest predictor of physical function, accounting for 20% of the variance. Depressive symptoms, physical functioning, diversity of social network, and employment status were significant independent predictors of social adjustment, together accounting for 63% of the variance. Depressive symptoms were the single strongest predictor of social adjustment, accounting for 26% of the variance. The effects of pain and physical function on social adjustment became non-significant when depressive symptoms were entered into the model, suggesting that symptoms of depression mediate the effect of pain and physical function on social adjustment. These findings indicate that pain is common in scleroderma and that pain and depressive symptoms are significant determinants of physical functioning and social adjustment, two important components of health-related quality of life. Increased attention to effective management of pain and symptoms of depression in scleroderma will likely lead to improved functioning and quality of life.

Adult↗

PubMed2002

Gene expression in bronchoalveolar lavage cells from scleroderma patients.

The hypothesis of this study is that activation of cell-mediated immunity with associated macrophage activation occurs in the lungs of scleroderma patients with lung inflammation. Gene expression profiles were determined in bronchoalveolar lavage (BAL) cells from scleroderma patients with and without lung inflammation and control subjects, using DNA array technology. Enzyme-linked immunosorbent assay was used to measure proteins in BAL fluids. Gene expression profiles were similar in BAL cells from patients without lung inflammation and control subjects. Gene expression profiles in patients with lung inflammation showed increased expression of chemokines and chemokine receptor genes, which would lead to migration of T cells, especially type 2 T cells, and phagocytic cells. Protein levels of pulmonary and activated-response chemokine and monocyte chemoattractant protein-1 were elevated. Other changes in gene expression suggested alterations in gene transcription, cell cycle control, vesicle transport, antigen-presenting function, and intracellular signaling. Two anti-inflammatory cytokines, interleukin-1 receptor antagonist and transforming growth factor-beta1, had increased expression, consistent with other human fibrotic lung diseases and animal models of lung fibrosis. These findings suggest recruitment of T cells and chronic macrophage activation in scleroderma patients at greater risk for lung fibrosis, but differ from typical delayed-type hypersensitivity responses, without prominence of type 1 T cells and inflammatory cytokines.

Bronchoalveolar Lavage↗

PubMed2002

Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation.

OBJECTIVE: To determine whether circulating concentrations of the counteradhesive proteins SPARC (secreted protein acidic and rich in cysteine) and thrombospondin-1 (TSP-1) are elevated in scleroderma (systemic sclerosis, SSc). The relationship of these counteradhesive proteins to measures of platelet and endothelial cell activation was examined. METHODS: Plasma from 45 patients with SSc (26 limited form, 19 diffuse) and 22 age and sex matched controls was assayed for SPARC, TSP-1, beta-thromboglobulin (betaTG), and platelet factor 4 (PF4), 2 distinct platelet a-granule products, and soluble E-selectin, a marker of endothelial cell activation. RESULTS: The mean (+/- SE) SPARC concentration was greater in patients with limited SSc (124.0 +/- 9.6 ng/ml) compared to controls (66.8 +/- 8.0 ng/ml) (p = 0.0005), whereas in patients with diffuse SSc (74.1 +/- 7.9 ng/ml) it was not. Elevated SPARC concentrations in the limited SSc group could not be ascribed to either platelet or endothelial cell activation. TSP-1 concentrations were also increased in SSc patients (n = 29) compared to controls (n = 11) (2.98 +/- 0.12 vs 2.4 +/- 0.21 log transformed ng/ml; p < 0.02). Unlike SPARC, TSP-1 concentrations correlated with both betaTG (r = 0.57, p = 0.0014) and PF4 (r = 0.41, p = 0.026) levels, indicating that increased TSP-1 could, in part, be explained through elevated platelet a-granule release in SSc patients. Plasma levels of betaTG, PF4, and E-selectin were each similarly elevated (p < 0.003) in patients with both limited and diffuse SSc compared to controls. CONCLUSION: That circulating SPARC and TSP-1 are elevated in patients with SSc raises the possibility that counteradhesive proteins, which regulate vascular organization and remodeling, might contribute to the pathogenesis of SSc vasculopathy.

Adult↗