E. Carwile Leroy

TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression

Transforming growth factor-beta (TGF-beta) inhibits the growth of endothelial cells derived from various sources, including human umbilical vein, bovine aorta, and rat heart. Long-term exposure of rat heart endothelial cells to TGF-beta also induces dramatic changes in morphology that are characteristic of senescent cells. These changes are accompanied by a decrease in the number of high-affinity receptors for epidermal growth factor (EGF), with almost no change in total receptor number. Additionally, the EGF-induced expression of specific competence genes (c-myc, JE, KC) is decreased, whereas the induction of c-fos gene expression by EGF is unaltered by TGF-beta treatment. These data suggest that growth inhibitors such as TGF-beta may act by altering the cells response to growth-stimulatory factors.

Increased Factor VIII/von Willebrand Factor Antigen and von Willebrand Factor Activity in Scleroderma and in Raynaud's Phenomenon

Von Willebrand factor activity and factor VIII/von Willebrand factor (fVIII/vWf) antigen concentrations were evaluated in 17 patients with scleroderma, nine patients with Raynauds phenomenon, and eight control volunteers. Higher circulating levels of both activities were seen: von Willebrand factor, 374% +/- 40% (percent of control values) in scleroderma patients, 502% +/- 104% in patients with Raynauds phenomenon and 102% +/- 6% in control subjects (p less than 0.005, scleroderma versus control): fVIII/vWf antigen, 255% +/- 24% in scleroderma patients; 271% +/- 46% in patients with Raynauds phenomenon, and 99% +/- 4% in control subjects (p less than 0.005, scleroderma versus control). Because endothelial cells synthesize and secrete both substances, the role of endothelial injury in vitro was investigated. Wound injury induced a 344% +/- 33% increase in von Willebrand factor and a 115% +/- 5% increases in fVIII/vWf antigen; cold injury induced 644% +/- 66% and 150% +/- 10% increases, and cytotoxic endothelial injury induced 1055% +/- 83% and 185% +/- 20% increases. In five patients with scleroderma, cold exposure led to a further increase in both activities. The observed increase of both activities in scleroderma and Raynauds phenomenon may reflect in-vivo endothelial injury and regeneration in these related conditions.

Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis), Raynaud's syndrome and dermatomyositis

Forty-four study patients with scleroderma (systemic sclerosis) (28 patients), Raynauds syndrome (13 patients) or dermatomyositis (three patients) were observed for skin capillary abnormalities by widefield microscopy and compared with three control groups of 20 subjects each: (1) patients with other rheumatic disease, (2) hospitalized patients with nonrheumatic conditions, and (3) healthy volunteers. The distinctive microvascular pattern (dilated and distorted capillary loops alternating with avascular areas) previously reported in scleroderma and dermatomyositis was observed almost exclusively in the study patients. The severity of capillary abnormalities varied among the diagnostic subgroups, and a positive correlation was found between the degree and extent of abnormal microvascular patterns and multisystem involvement. On this basis, widefield nailfold capillary observations are proposed as a simple, inexpensive, reproducible technic for making an improved early diagnosis and predicting multisystem involvement in scleroderma, Raynauds syndrome and dermatomyositis, presently a group of loosely associated and overlapping connective tissue disorders which often defy early and precise diagnosis.

Pathogenesis of fibrosis: type 1 collagen and the skin.

Abstract This review on the pathogenesis of fibrosis emphasizes the similarities between tissue repair, a tightly regulated salutary biological response, and fibrosis, an unregulated pathological process. It focuses on the transcriptional regulation of type I collagen, the role of cytokines in fibroblast activation, integrins as examples of cell-matrix signaling pathways, and the heterogeneity of fibroblast populations as factors contributing to fibrosis. Tissue remodeling and the role of matrix metalloproteinases and metalloproteinase inhibitors are mentioned briefly. The capacity of extracellular matrix to modulate cellular function is a recurring theme.

Elevated Levels of Circulating Platelet Aggregates and Beta-Thromboglobulin in Scleroderma

Levels of circulating platelet aggregates and plasma beta-thromboglobulin reflect the degree of platelet activation in vascular injury and repair. Both values were evaluated in 38 patients with scleroderma and 18 control subjects matched for age, sex, and race. Circulating platelet aggregates (expressed as percentage of total platelet count) were 7.2 +/- 5.5% (mean +/- SD) in the control group and 31.2 +/- 13% in the scleroderma group (p less than 0.0005). Beta-thromboglobulin levels in the control groups were 20 +/- 10 ng/mL and 72.7 +/- 50 ng/mL in the group with scleroderma (p less than 0.0005). A positive correlation was found between the two values (r = 0.6, p less than 0.0005). Significant reductions in circulating platelet aggregates and beta-thromboglobulin levels were achieved in 10 patients by dipyridamole and aspirin therapy. These results show in-vivo activation of platelets in scleroderma with release of platelet granule constituents. Antiplatelet therapy in adequate doses returned both values to normal; however, its long-term effect on scleroderma is not yet known.

Prevalence of Raynaud phenomenon in the general population: A preliminary study by questionnaire

A short questionnaire inquiring about cold sensitivity of the fingers was administered to 1752 randomly selected subjects in a probability sample drawn from the adult population of the state of South Carolina. The overall prevalence of reported cold sensitivity was approximately 10% and showed no sex or race difference. A female preponderance was revealed only after subjects exposed to vibrating tools were excluded, and then only in the white group. Estimates of the prevalence of Raynaud phenomenon were obtained using the following criteria: cold sensitive subjects reporting white and/or blue color changes: 4.6%; cold sensitivity leading to medical consultation: 3.0%; combination of the two criteria above: 1.9%.

Pericardial disease in scleroderma (systemic sclerosis)

Abstract A review of the records of 210 patients with scleroderma seen between 1952 and 1972 revealed two clinical patterns of pericardial disease in 15 patients: (1) Chronic pericardial effusion (11 patients), confirmed by roentgenography and ultrasound, occurred in association with dyspnea, Raynauds syndrome, cardiomegaly, congestive heart failure and pleural effusion in the absence of renal failure. In three patients hemodynamic signs of pulsus paradoxus, Kussmauls sign or pulsus alternans developed. In six patients with chronic effusion renal failure developed within 6 months, an incidence severalfold higher than expected in the scleroderma population at large. (2) Acute pericarditis (four patients) was associated with dyspnea, chest pain, pericardial friction rub, fever, cardiomegaly and elevated latex fixation titers (in two of four patients). Pericardial disease is a recognizable clinical entity in scleroderma and should be considered in all patients with cardiomegaly, congestive heart failure or chest pain. In 34 autopsy studies, the incidence of pericardial involvement (62 per cent) exceeded the incidence of significant myocardial fibrosis (30 per cent); thus pericardial scleroderma represents a relatively common form of cardiac involvement in this diffuse connective tissue disease.

The management of renal scleroderma: Experience with dialysis, nephrectomy and transplantation☆

In 25 of 100 patients with scleroderma seen over a five year period irreversible renal failure developed; renal support was instituted in 17. Ten of 17 received peritoneal or hemodialysis, one survived. The remaining seven received hemodialysis plus nephrectomy; three survived. Two of these three underwent renal transplantation; one survived. This experience is presented to encourage improvement of these and other technics to increase the survival rate in the otherwise uniformly fatal renal failure associated with scleroderma (systemic sclerosis).

Mast cells and their degranulation in the Tsk mouse model of scleroderma

Abstract The Tsk mouse is a genetically transmitted example of cutaneous fibrosis which has been compared with human scleroderma. During a systematic histopathological study of the Tsk mouse, both an increased number and an increased proportion of degranulated mast cells were observed. The consistent association of mast cells and fibrosis in scleroderma, graft-vs-host reactions (GVHR), and now the Tsk mouse raises the question of a pathogenetic role for mast cells in fibrotic disorders in general.

Primary heart disease in systemic sclerosis (scleroderma): Advances in clinical and pathologic features, pathogenesis, and new therapeutic approaches

Heart disease in SSCL may be primary or secondary. Primary involvement includes pericarditis, myocardial fibrosis, and contraction band necrosis with congestive cardiomyopathy, conduction system fibrosis, intramural coronary artery lesions and, rarely, valvular disease. Symptoms include those of left and right ventricular failure, chest pain, palpitations, syncope, and sudden death. Pathogenesis may be related to functional Raynauds phenomenon of the heart and/or structural small vessel disease. Therapy at present is symptomatic; however, new therapeutic approaches are warranted.