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Biomedical subjects

R M Silver

Publications and source records attributed to R M Silver.

At least 73 records · Page 4Linked to original sources
PubMed1995

Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma.

OBJECTIVE: Systemic sclerosis (scleroderma, SSc) frequently affects the lungs, and interstitial pulmonary fibrosis is one of its major complications. The pathophysiology of SSc lung disease s poorly understood, but recent studies document an inflammatory process resembling that of idiopathic pulmonary fibrosis with increased numbers of activated alveolar macrophages and granulocytes in bronchoalveolar lavage (BAL) fluid). We determined levels of 2 potentially important mediators of fibroproliferative repair in BAL fluid from patients with SSc. METHODS: Using Western blot and ELISA techniques we measured levels of platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta in BAL fluid from patients with SSc and healthy controls. The mitogenic effect of these cytokines on SSc lung myofibroblasts was determined by [3H]thymidine incorporation. RESULTS: SSc BAL fluid contains significantly elevated levels of PDGF-AA and PDGF-BB. Where TGF-beta 1 was significantly elevated in SSc lavage fluid, the amount of TGF-beta 2 was significantly less than that observed in normal lavage fluid. Myofibroblasts cultured from SSc lavage fluid exhibited enhanced [3H]thymidine incorporation upon exposure to the growth factors present in SSc BAL fluid: PDGF and TGF-beta 1. SSc lung myofibroblasts pretreated with TGF-beta 1 exhibited an enhanced mitogenic effect upon stimulation by PDGF, due in part to the induction of the PDGF alpha receptor. CONCLUSION: Our studies support a role for PDGF and TGF-beta 1 in the pathogenesis of SSc lung disease.

Bronchoalveolar Lavage Fluid↗
PubMed1994

Regulation of intrauterine prostaglandin biosynthesis: interactions between protein kinase C and interleukin 1 beta.

Activation of protein kinase C with phorbol esters stimulates prostaglandin (PG) biosynthesis in many cell types whereas down-regulation of protein kinase C can suppress stimulatory responses. Interleukin-1 beta (IL-1 beta) can stimulate PG production by intrauterine tissues and may play a significant part in the mechanisms of preterm labor associated with intrauterine infection. Hence we have evaluated the effects of staurosporine and H7 (inhibitors of protein kinase C) on IL-1 beta stimulation of amnion, chorion and decidual prostaglandin E2 (PGE2) production. Staurosporine and H7 alone were without effect on PGE2 production by any cell type. However with minor exceptions both protein kinase C inhibitors enhanced the stimulatory actions of IL-1 beta on PGE2 production by all three cell types. Hence we believe that protein kinase C is closely linked to the regulation of intrauterine PG biosynthesis and that these links may have multiple layers of complexity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Lipopolysaccharide-induced fetal death: the role of tumor-necrosis factor alpha.

Lipopolysaccharide (LPS) administration has been known to cause murine fetal death for over 50 years, but the responsible mechanism(s) remains unclear. We used the LPS-hyporesponsive murine strain, C3H/HeJ, to 1) establish whether LPS-induced fetal death is due to a maternal or fetal response to LPS and 2) to investigate the involvement of tumor necrosis factor alpha (TNF alpha) in fetal death caused by LPS. C3H/HeJ (LPS-hyporesponsive) or C3H/HeN (LPS-responsive) females were mated with C57B1/6 or C3H/HeN males (both LPS-responsive). Administration of 10 micrograms LPS caused fetal death in C3H/HeN mothers. However, up to 1000 micrograms LPS did not result in the death of LPS-responsive fetuses when administered to C3H/HeJ mothers. Systemic administration of TNF alpha was able to cause fetal death in both C3H/HeN and C3H/HeJ strains of mice. Pretreatment of pregnant C3H/HeN mice with anti-TNF alpha antibodies significantly reduced fetal death caused by LPS administration. The administration of a sublethal dose of TNF alpha plus 10 micrograms LPS to pregnant C3H/HeJ mice restored abortifacient activity. These results indicate that LPS-induced fetal death is due to a maternal response as opposed to a direct fetal response to LPS and that TNF alpha appears to be an important mediator of fetal death caused by LPS.

Animals↗
PubMed1994

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

Eosinophilia-myalgia syndrome, a recently described illness, reached epidemic proportions in 1989 and was linked to the ingestion of L-tryptophan containing trace amounts of several contaminants. Eosinophilia-myalgia syndrome shares many clinical and pathologic similarities with toxic-oil syndrome, an epidemic linked to the ingestion of adulterated cooking oil that occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, a condition first described in 1974. Over the past year, much work has been done in understanding the etiology and pathogenesis of eosinophilia-myalgia syndrome and toxic-oil syndrome. Follow-up data detailing the long-term sequelae and mortality rates for these two conditions are becoming available. The results from these studies are reviewed in this paper.

Brassica↗
PubMed1994

Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor.

In addition to its procoagulant properties, the serine protease thrombin increases endothelial permeability, stimulates granulocyte adherence, and serves as a fibroblast mitogen. We demonstrate that thrombin is mitogenic for human lung fibroblasts in vitro. The mitogenic effect of thrombin is associated with an increase in the expression of the ligand PDGF-AA and up-regulation of PDGF alpha-receptor. Since scleroderma (systemic sclerosis; SSc) is characterized by widespread microvascular injury and is frequently complicated by pulmonary fibrosis, we sought to determine the level of thrombin activity in bronchoalveolar lavage (BAL) fluid from SSc patients and normal controls. We report a significantly higher level of thrombin activity in BAL fluid from SSc patients compared with normal controls (P < 0.001). Taken together, the high levels of thrombin in BAL fluid and its demonstrated mitogenicity for lung fibroblasts suggest an important role for thrombin in the pathogenesis of SSc and perhaps other fibrotic lung diseases.

Adult↗
PubMed1994

A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

The eosinophilia-myalgia syndrome (EMS) is a recently described disease that has been associated with the ingestion of L-tryptophan containing trace amounts of several impurities. The first such contaminant to be identified and linked epidemiologically to the EMS epidemic was 1,1'-ethylidenebis(L-tryptophan) (EBT), but its role in the etiology and pathogenesis of the syndrome has been controversial. We report the development of inflammation and fibrosis affecting the dermis and subcutis, including the fascia and perimyseal tissues, after the daily intraperitoneal administration of EBT to female C57BL/6 mice. Such changes are accompanied by increased numbers of mast cells, many of which appear to be degranulating. Plasma levels of quinolinic acid, a metabolic product of L-tryptophan via the kynurenine pathway, are reduced initially, and then become elevated when inflammation and fibrosis are more pronounced. The nature and location of the inflammatory cell infiltrate and fibrosis, as well as the presence of mast cells and alterations of L-tryptophan metabolism, are consistent with findings reported in patients with EMS. This murine model suggests that EBT may have been one of the mediators of EMS and should facilitate studies of the pathogenesis of EMS.

Animals↗
PubMed1994

Unexplained elevations of maternal serum alpha-fetoprotein in women with antiphospholipid antibodies: a harbinger of fetal death.

OBJECTIVE: To determine whether unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) in women with antiphospholipid antibodies are associated with adverse pregnancy outcomes. METHODS: A retrospective cohort study was used to compare pregnancy outcomes between women with second-trimester MSAFP values equal to or greater than 2.5 multiples of the median (MoM) and less than 2.5 MoM. The cohort included 60 pregnancies in 47 women with medium to high positive levels of immunoglobulin (Ig) G anticardiolipin antibodies, lupus anticoagulant, or both. RESULTS: Thirteen pregnancies (22%) had elevated MSAFP values (median 3.6 MoM, range 2.5-12.6). Of these, amniotic fluid AFP was normal in seven and elevated in one. None of the elevated MSAFP levels were explained by fetal anomalies, current fetal death, multiple gestation, incorrect dates, or vaginal bleeding. Pregnancies with elevated MSAFP values had a significantly higher incidence of fetal death (eight of 13, 62%, versus three of 47, 6%) and perinatal loss (ten of 13, 77%, versus seven of 47, 15%) than those with normal MSAFP (P < .001, Fisher exact test). In these women, the sensitivity and specificity of an unexplained elevated MSAFP level in ascertaining fetal death were 73 and 90%, respectively. For perinatal loss, the sensitivity was 59% and the specificity was 93%. Of the placentas studied, infarction occurred in eight of nine (89%) among the women with elevated MSAFP. CONCLUSIONS: Unexplained second-trimester elevations of MSAFP are common in women with antiphospholipid antibodies and are significantly associated with fetal loss. Abnormalities in the fetoplacental barrier are implicated as part of the pathophysiology of antiphospholipid antibody-mediated pregnancy loss.

Antiphospholipid Syndrome↗
PubMed1994

Fasciitis (not scleroderma) following prolonged exposure to an organic solvent (trichloroethylene).

We describe 2 cases of diffuse fasciitis with eosinophilia (DFE) associated with prolonged exposure to the industrial solvent trichloroethylene (TCE). The medical and personal histories, examinations, and laboratory and pathological investigations were reviewed and summarized. The 2 case reports, representing the first and 2nd cases of DFE associated with TCE, were compared with 8 reported cases of systemic sclerosis associated with TCE and suggest a direct association between TCE exposure and the development of fasciitis (DFE).

Aged↗
PubMed1994

Clinical consequences of antiphospholipid antibodies: an historic cohort study.

OBJECTIVE: To determine the risk of antiphospholipid antibody-related disorders in women with elevated levels of these antibodies. METHODS: We used an historic cohort study design. Surveys of medical and obstetric histories for the interval from initial antibody testing to the time of patient interview were used to calculate age-adjusted rates for the development of medical disorders associated with antiphospholipid antibodies. The cohort included 130 women with lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. RESULTS: The median interval of study was 3.2 years (range 0.7-9.5, mean 3.7). Sixty-three subjects (48%) developed at least one new disorder during the study interval. The age-adjusted rates (per 1000 patient-years; +/- standard error) for the development of the disorders studied were as follows: thrombosis (156.8 +/- 30.0), cerebrovascular accident (93.8 +/- 25.1), amaurosis fugax (57.1 +/- 23.2), transient ischemic attack (170.4 +/- 27.6), systemic lupus erythematosus (9.8 +/- 3.8), and autoimmune thrombocytopenia (56.0 +/- 22.2). Of the 34 thrombotic events that occurred during the study interval, eight were associated with pregnancy and eight occurred while the patients were taking anticoagulant medications. CONCLUSIONS: Our subjects developed complications associated with antiphospholipid antibodies at a substantial rate, and almost half suffered at least one new event during the study interval. The high rate of thrombosis in individuals with antiphospholipid antibodies, especially associated with pregnancy, underscores the need to evaluate long-term anticoagulation in these patients.

Adult↗
PubMed1993

Failure of the circulatory system limits exercise performance in patients with systemic sclerosis.

OBJECTIVE: To determine the mechanisms for exercise impairment in symptomatic patients with systemic sclerosis (SSc) using breath-by-breath expired-gas analysis with incremental exercise testing. DESIGN: Prospective, open trial. PATIENTS AND METHODS: Fifteen consecutive patients with SSc seen at the Medical University Hospital (a tertiary referral center) with complaints of exercise intolerance underwent pulmonary function testing (spirometry, helium dilution lung volumes, and diffusing capacity of carbon monoxide) and incremental exercise testing on a cycle ergometer measuring oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (R), oxygen saturation, blood pressure, and heart rate (HR). Values for oxygen uptake at anaerobic threshold (VO2AT) were derived graphically by blinded clinicians experienced in exercise testing, and the results were averaged. Ventilatory reserve and oxygen pulse were calculated from measured values, and all data were subjected to analysis by standard clinical algorithms. MEASUREMENTS AND MAIN RESULTS: Of 15 patients studied, 14 had either restrictive lung disease or normal results of spirometry on pulmonary function testing. One patient with a history of tobacco use had evidence of airways obstruction. Three patients were unable to exercise maximally (as determined by maximum respiratory exchange ratio [Rmax] greater than 1.09 or maximum heart rate [HRmax] greater than 85% predicted), and exercise testing was terminated in one with Mobitz type II atrioventricular block. The following data (mean +/- SEM) were obtained from 11 maximally exercising patients: VO2max 795 +/- 75 mL oxygen (O2)/min, R 1.34 +/- 0.05, VO2AT/VO2max predicted 0.21 +/- 0.02, O2 pulse 5.1 +/- 0.4 mL O2/beat, ventilatory reserve 0.52 +/- 0.06, and tidal volume/forced vital capacity ratio 0.46 +/- 0.02. Of the 11 patients completing breath-by-breath expired-gas analysis, all had circulatory impairment to exercise, as determined by low O2 pulse and low VO2 at anaerobic threshold, and circulatory impairment was limiting in 9 of 11 patients. Of those nine patients, four had evidence of impaired gas exchange compatible with pulmonary vascular disease. Arterial oxygen desaturation occurred in 2 of 11 patients. CONCLUSION: Circulatory impairment to exercise is common in SSc patients with exercise intolerance. Restrictive lung disease, although also common, does not limit exercise tolerance in patients capable of maximal effort.

Adult↗
PubMed1993

Interleukin-6 levels in amniotic fluid in normal and abnormal pregnancies: preeclampsia, small-for-gestational-age fetus, and premature labor.

OBJECTIVE: Our purpose was to determine if abnormal amniotic fluid interleukin-6 levels correlate with pregnancies complicated by preeclampsia, small-for-gestational-age fetus, and premature labor. STUDY DESIGN: A case control study design was used to compare third-trimester amniotic fluid interleukin-6 levels from women with normal pregnancies (n = 25) and pregnancies complicated by preeclampsia (n = 15), small-for-gestational-age perinates (n = 8), and premature labor (n = 29). RESULTS: Amniotic fluid interleukin-6 levels in women with preeclampsia and small-for-gestational-age perinates were less than in controls (p < 0.01). Interleukin-6 levels in women with preterm labor refractory to tocolysis were higher than those in women with preterm labor responsive to tocolysis (p < 0.01). CONCLUSIONS: Interleukin-6 is normally present in amniotic fluid. In the third trimester of pregnancy low levels correlate with small-for-gestational-age fetuses and preeclampsia, whereas elevated levels correlate with preterm labor and delivery.

Amniotic Fluid↗
PubMed1993

Lung disease in systemic sclerosis (scleroderma).

Scleroderma (SSc) is a disease characterized by skin fibrosis but it is the end-organ effect of microvascular injury and fibrosis that is important prognostically. Pulmonary involvement in SSc patients, either of parenchymal fibrosis and/or pulmonary hypertension, is a major cause of morbidity and mortality. Interstitial lung disease occurs more commonly in patients with diffuse SSc and is associated with a loss of lung volume, as well as a defect of gas exchange. Parenchymal fibrosis may also cause pulmonary hypertension. Isolated pulmonary hypertension occurs exclusively in patients with limited SSc and is detectable by a reduced DCO. The early identification of either manifestation is difficult. Patients may have minimal symptoms, unremarkable physical findings, normal chest radiographs and/or minimally abnormal pulmonary function tests at a time when significant lung pathology is present. It is essential to attempt to identify pulmonary disease early, at a potentially reversible stage. Multiple therapeutic endeavours have yielded only short-term or minimal benefits in symptoms and pulmonary function, and thus a major alteration in SSc pulmonary prognosis has not been achieved. Further study of the pathogenesis of this disease manifestation will be helpful in its earlier identification and intervention.

Humans↗
PubMed1993

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

Eosinophilia-myalgia syndrome reached epidemic proportions in 1989. Its precise etiology remains uncertain, yet virtually all cases were associated with the ingestion of L-tryptophan containing trace amounts of several chemicals. Clinical and pathologic features of eosinophilia-myalgia syndrome are similar to those of the toxic-oil syndrome, which occurred in Spain in 1981 in association with the ingestion of adulterated rapeseed oil. During the past year, the epidemiology of eosinophilia-myalgia syndrome has been better defined, with a second trace contaminant linked to this condition. Knowledge of the clinical and histopathologic features of eosinophilia-myalgia syndrome has also expanded. These and other important advances in the understanding of eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia are presented.

Brassica↗
PubMed1993

Potential agonist action of the interleukin-1 receptor antagonist protein: implications for treatment of women.

The interleukin-1 receptor antagonist protein (IRAP) caused a concentration-related increase in prostaglandin production by human decidual cells. The degree and time course of this stimulatory action were identical to those induced by interleukin 1 beta (IL-1 beta). IRAP had no inhibitory action on IL-1 beta stimulation of decidual prostaglandin production and at high concentrations had an additive effect. We believe that this represents the first description of a potential agonist action of IRAP and suggests caution in treatment of women with this substance.

Cells, Cultured↗
PubMed1993

Chest CT in patients with scleroderma: prevalence of asymptomatic esophageal dilatation and mediastinal lymphadenopathy.

OBJECTIVE: The high-resolution CT findings of chronic diffuse interstitial lung disease associated with scleroderma have been reported previously. This study determined the prevalence of esophageal dilatation and mediastinal adenopathy on high-resolution CT scans in patients with this disease. MATERIALS AND METHODS: We retrospectively reviewed the high-resolution CT scans of 25 patients with scleroderma who had diffuse interstitial lung disease. Esophageal dilatation was diagnosed if the esophagus below the aortic arch had a single, large, nonloculated collection of intraluminal air on four or more consecutive axial images and if the luminal diameter of such an air-filled esophagus exceeded 10 mm in the coronal plane. The presence of fluid or an air-fluid level was also considered abnormal. For mediastinal adenopathy, we used the American Thoracic Society lymph node mapping scheme and the size criteria described previously. RESULTS: Asymptomatic esophageal dilatation was detected in 20 patients (80%) and mediastinal adenopathy was present in 15 (60%). CONCLUSION: Our results suggest that CT is useful in the detection of mediastinal adenopathy and asymptomatic esophageal involvement in patients with scleroderma. These findings can be used to narrow the differential diagnosis in patients in whom CT shows diffuse interstitial lung disease. Furthermore, the early detection of esophageal involvement in these patients shows the need for treatment to forestall the complications of esophageal dysmotility and accompanying chronic gastroesophageal reflux.

Adult↗
PubMed1993

Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease.

Fourteen patients with systemic sclerosis (SSc, scleroderma) and interstitial lung disease were treated with oral cyclophosphamide (1-2 mg/kg/day) and low dose prednisone (< 10 mg/day). There was a significant improvement in FVC after 6 months compared to entry values (2.21 +/- 0.19 l vs. 2.03 +/- 0.15 l, p < 0.02). Improvement was maintained at 12 months (2.27 +/- 0.27 l, p < 0.05) and 18-24 months (2.60 +/- 0.28 l, p < 0.001). In 12 cases followed for 18-24 months, FVC was stable or improved. No significant improvement or decline was noted for the DLCO. Side effects included cytopenia (2), infection (1), and hemorrhagic cystitis (2), and one possible related malignancy. A controlled prospective trial of cyclophosphamide is warranted in patients with SSc and active interstitial lung disease.

Adult↗
PubMed1993

Demonstration of silicon in sites of connective-tissue disease in patients with silicone-gel breast implants.

BACKGROUND AND DESIGN: Silica, Silastic, and silicone (any organic compound in which silicon replaces carbon) have been associated with a number of connective-tissue diseases, most commonly systemic sclerosis (scleroderma). Silicone is known to leak from breast implants and spread to surrounding tissues, including lymph nodes, but silicone's role in the origin and pathogenesis of the inflammation and fibrosis related to such conditions remains controversial. Synovial tissue, alveolar macrophages, and skin, each from three different patients with silicone-gel implants, plus the breast implant capsules from each of the three patients, were examined by light microscopy, transmission electron microscopy, and electron probe microanalysis for the presence of silicon-containing material. RESULTS: Silicon was identified within the fibrous breast capsule of each case, associated with a chronic inflammatory cell infiltrate. Silicon was also identified within tissues involved by chronic inflammation and fibrosis, namely, synovium, skin, and alveolar macrophages, in association with clinical, serologic, and histologic evidence of connective tissue disease. All three patients improved after removal of the silicone-gel breast implants. CONCLUSIONS: The presence of silicon-containing material within sites of connective-tissue disease supports a role for silicon in the origin or pathogenesis of such conditions in patients with silicone-gel breast implants. All patients with connective-tissue disease should be questioned about exposure to various forms of silicon. In those patients with known exposure, tissue specimens should be examined carefully for silicon-containing material and, if found, the source should be removed.

Adult↗