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Biomedical subjects

R M Silver

Publications and source records attributed to R M Silver.

At least 55 records · Page 3Linked to original sources
PubMed1997

Autoimmune disease in pregnancy. Systemic lupus erythematosus and antiphospholipid syndrome.

Autoimmune diseases occur most commonly in women of childbearing age. Over 70% of individuals with autoimmune diseases are women, though some conditions (e.g., ankylosing spondylitis) are more common in men. Many authorities have focused on sex hormones as an explanation for the relatively high proportion of females affected by autoimmune diseases. This article covers systemic lupus erythematosus, the prototypical autoimmune disease, and antiphospholipid syndrome, which is associated particularly with pregnancy loss.

Antibodies, Antiphospholipid↗
PubMed1996

Anticardiolipin antibodies: clinical consequences of "low titers".

OBJECTIVE: To clarify the implications of low levels of immunoglobulin (Ig)-G or IgM anticardiolipin antibodies. METHODS: Women who underwent clinically indicated testing for antiphospholipid antibodies were divided into four groups based on results: 1) high-positive (lupus anticoagulant or more than 19 IgG binding units of anticardiolipin antibodies; N = 131), 2) low-positive IgG (fewer than 20 IgG binding units; N 93), 3) IgM only (more than nine IgM binding units; N 97), and 4) negative (N = 153). The development of antiphospholipid antibody-related disorders was assessed for the time interval from initial antibody testing to patient interview. The median study interval for each group was at least 4 years. Forty-five percent of women had repeat testing at the time of interview. RESULTS: Women in the high-positive group were more likely to develop at least one new medical complication than those in the low-positive IgG (odds ratio [OR] 4.49, 95% confidence interval [CI] 2.01-10.03), IgM only (OR 6.00, 95% CI 2.65-13.59), and negative (OR 9.11, 95% CI 3.92-21.2) groups. In contrast, the low-positive IgG, IgM only, and negative groups had similar risks for the development of new disorders. Twelve of 129 (9.3%) women in the low-positive IgG, IgM only, or negative groups had lupus anticoagulant or more than 19 IgG binding units on retesting. Half of these women developed at least one new disorder. CONCLUSION: Women with IgM or low levels of IgG anticardiolipin antibodies comprise distinct populations from those with lupus anticoagulant or moderate to high levels of anticardiolipin antibodies. These women are not at risk for antiphospholipid antibody-related disorders beyond the risk conferred by their medical histories. However, repeat testing is warranted with new or recurrent clinical symptoms.

Adult↗
PubMed1996

Antiphospholipid antibodies and fetal death.

OBJECTIVE: To determine the type of recurrent pregnancy loss associated with antiphospholipid antibodies. METHODS: This was a retrospective analysis of women who had two or more pregnancy losses and who were tested for antiphospholipid antibodies. The specific type of pregnancy losses were determined in patients with and without antiphospholipid antibodies. RESULTS: In our highly selected referral population, 76 of 366 women (21%) tested positive for lupus anticoagulant or anticardiolipin antibodies of 20 or more immunoglobulin-G phospholipid antibody units. Pregnancy loss occurred in 280 of 333 (84%) prior pregnancies in women with and 1240 of 1479 (84%) without antiphospholipid antibodies. However, 50% of pregnancy losses in women with antiphospholipid antibodies were fetal deaths, compared with less than 15% in women who were antiphospholipid antibody-negative. More than 80% of women with antiphospholipid antibodies had at least one fetal death, compared with less than 25% of women without (P < .001). The specificity of fetal death for the presence of antiphospholipid antibodies in patients with recurrent pregnancy loss was 76%. In contrast, two or more early first-trimester losses without fetal death had a specificity of only 6% for antiphospholipid antibodies. CONCLUSION: Fetal death is more characteristic of the type of loss experienced by patients with recurrent pregnancy loss than early first-trimester pregnancy loss in women with antiphospholipid antibodies.

Abortion, Habitual↗
PubMed1996

Cyclosporin A inhibits prostaglandin E2 production by fetal amnion cells in response to various stimuli.

Use of cyclosporin A as part of an immunosuppressive regimen in pregnant transplant patients is not uncommon. Although successful pregnancies have been reported with the use of various immunosuppressive agents including cyclosporin A, the concern for fetal outcome still remains. Our purpose was to evaluate the effects of immunosuppressive cyclosporin A on prostaglandin E2 (PGE2) production by human fetal amnion. Amnion cells were isolated from term placentae obtained at elective cesarean section before the onset of labor. Cells were grown to confluence and then incubated for 16 hours with cyclosporin A (1-1000 ng/ml) in the presence and absence of interleukin 1 beta (IL-1 beta, 1 ng/ml), phorbol 12-myristate 13-acetate (PMA, 10(-7) M) and ionomycin (0.5 microM). PGE2 was measured by radioimmunoassay and cellular protein determined. IL-1 beta, PMA and ionomycin all stimulated amnion cell PGE2 production as expected. However, these stimulatory actions were attenuated by at least 50% when cells were co-incubated with cyclosporin A (1000 ng/ml). Concentrations of cyclosporin A tested included the therapeutic range (250-1000 ng/ml). Our results indicate that cyclosporin A does not stimulate amnion cell PGE2 production and is probably unrelated to preterm labor and delivery in allograft recipients.

Amnion↗
PubMed1996

Scleroderma. Clinical problems. The lungs.

A recent follow-up study found that patients with pulmonary involvement (with no renal or cardiac involvement) survived a median of 78 +/- 17 months. Another study found death from SSc was most frequently due to pulmonary hypertension. Improved diagnostic modalities and better understanding of the pathophysiology of SSc lung disease are essential, because mortality from this SSc lung disease remains high. During the past decade, advances have been made in the understanding of the alveolitis of SSc lung disease. Although the inciting injury remains uncertain, a cascade of inflammatory and fibrosing mediators culminates in a chronic state of interstitial lung disease. There is increasing evidence that the fibrogenic cytokines PDGF and TGF-beta are major contributors to the pathophysiology of interstitial lung disease, including that of SSc. Future research aimed at modifying the biologic response to such cytokines may yield novel therapeutic approaches to the management of this type of lung disease. Similarly, improved understanding of mediators of vascular tone, such as endothelin and nitric oxide, may yield much-needed treatments for pulmonary hypertension.

Humans↗
PubMed1996

Pathophysiology of the eosinophilia-myalgia syndrome.

Significant morbidity and mortality occur during the acute phase of the eosinophilia-myalgia syndrome (EMS), and many patients still have chronic manifestations of the disease. Although the precise etiologic agent or agents within implicated batches of L-tryptophan remain uncertain, histopathologic studies support a role for a cell mediated immune response underlying the pathophysiology of EMS. The cellular immune response seems to lead to a microangiopathy and release of cytokines that can induce eosinophilia and fibrosis. Such responses are most marked within the dermis, subcutis, fascia, and connective tissue in and around muscles, nerves, and other tissues. The pathophysiology of the chronic symptoms is poorly understood but may involve ischemia, neuropathy, and metabolic abnormalities.

Cardiovascular Diseases↗
PubMed1995

The eosinophilia-myalgia syndrome: status of 205 patients and results of treatment 2 years after onset.

OBJECTIVE: To describe the course of the eosinophilia-myalgia syndrome during a 2-year period. DESIGN: 15 physicians completed a structured review form to describe symptoms, physical findings, laboratory data, and responses to treatments in 205 patients with the eosinophilia-myalgia syndrome at the onset of illness and after 18 to 24 months of follow-up. SETTING: 15 university and private clinical practice settings. PATIENTS: 205 patients for whom follow-up data were available and who met four criteria at diagnosis: eosinophil count of 1000 cells/mm3 or greater; presence of fasciitis, peripheral neuropathy, polyradiculopathy, interstitial pulmonary disease, pulmonary hypertension, or myocardial involvement; history of L-tryptophan consumption; and absence of other conditions that could account for these findings. INTERVENTION: Empirical interventions by the physicians. MEASUREMENTS: Symptoms, physical findings, laboratory test results, biopsy findings, radiographic reports, therapeutic interventions, and responses to these interventions. RESULTS: After 18 to 24 months, all symptoms except cognitive changes were reported to have improved in most patients. Nearly all physical findings were also reported to have improved or resolved in most patients; only peripheral neuropathy was unchanged. No evidence of ongoing inflammatory disease was reported. Prednisone was reported to be helpful in 79% of patients who received it during the acute phase of the syndrome. No other treatment was reported to be consistently beneficial. CONCLUSIONS: 18 to 24 months after the onset of illness, most symptoms and physical findings in most patients with the eosinophilia-myalgia syndrome resolved or improved. Cognitive changes were reported to be worse in 32% of patients. Prednisone was helpful in the acute phase of illness. No treatment was clearly valuable in management of the later phase of the syndrome.

Adult↗
PubMed1995

Maternal thrombocytopenia in pregnancy: time for a reassessment.

Antiplatelet autoantibodies in women with autoimmune thrombocytopenic purpura can cause fetal thrombocytopenia and serious bleeding problems. Obstetricians have used fetal scalp sampling, cordocentesis, and cesarean delivery in this disorder to avoid fetal complications such as intracranial hemorrhage. Accumulating evidence indicates that the fetal risk of intracranial hemorrhage is much lower than initially reported. Moreover, these invasive tests and treatments are costly, cause morbidity, and have little effect in preventing neonatal bleeding complications. Therefore we suggest these interventions should no longer be used in the management of maternal thrombocytopenia.

Cerebral Hemorrhage↗
PubMed1995

Induction of high levels of anticardiolipin antibodies in mice by immunization with beta 2-glycoprotein I does not cause fetal death.

OBJECTIVE: Our purpose was to determine whether anticardiolipin antibodies induced by immunization with beta 2-glycoprotein I cause fetal death in mice. STUDY DESIGN: Female BALB/c mice were immunized with beta 2-glycoprotein I in a carbohydrate adjuvant or with carbohydrate adjuvant alone. The mice were mated with BALB/c males and killed on day 11 to 13 of pregnancy, and the fetal status was determined. Posttreatment blood samples were obtained for measurement of anticardiolipin and anti-beta 2-glycoprotein I antibodies and platelet counts. RESULTS: Anticardiolipin and anti-beta 2-glycoprotein I antibodies developed in all mice immunized with beta 2-glycoprotein I. Fetal death occurred in 17 of 145 gestational sacs (12%) in 18 mice immunized with beta 2-glycoprotein I compared with 24 of 177 (14%) sacs in 21 control mice. There were no morphometric or histologic differences between gestational tissues, and platelet counts were similar for each group. CONCLUSIONS: The induction of high levels of anticardiolipin antibodies in BALB/c mice by beta 2-glycoprotein I immunizations did not result in fetal death or thrombocytopenia. These nonpathogenic beta 2-glycoprotein I-induced anticardiolipin antibodies should prove useful in the characterization of clinically relevant epitopes for antiphospholipid syndrome.

Animals↗
PubMed1995

Electron probe microanalysis of silicon and the role of the macrophage in proximal (capsule) and distant sites in augmentation mammaplasty patients.

Electron probe x-ray microanalysis was used to locate silicon (Si) within macrophages from 12 women who had previously undergone polymer prosthesis augmentation or reconstruction. Silicon was identified within macrophages and extracellularly in all fibrous breast capsules. In four women with arthritic joint pain and one woman with sclerodermatous skin lesions, silicon also was identified within macrophages residing in joint synovium and skin, respectively. It is suggested that the silicon-laden macrophages observed in the remote lesions may have accumulated silicon from other macrophages that had previously resided in the connective-tissue capsule around the silicone breast implants.

Adult↗
PubMed1995

Eosinophilia-myalgia syndrome: a long-term follow-up study.

In this case-series analysis, of 34 patients originally identified with eosinophilia-myalgia syndrome (EMS), 31 survivors were followed-up by yearly telephone interviews. We ascertained type, duration, and severity of symptoms and whether certain patient characteristics were associated with illness improvement. At a median of 3.6 years after onset, 3 patients (8.8%) had died. Two (5.9%) were well, 7 (20.6%) were improved, and 22 (64.7%) reported either no change or worsening overall condition compared to 1 year prior. Musculoskeletal and neurologic symptoms predominated. The prevalence of several symptoms, including muscle cramps, joint pain, and cognitive symptoms, increased over the course of study. Age, sex, peak eosinophil count, early prednisone use, and usual dose or duration of L-tryptophan use were not associated with significant improvement. We conclude that for the majority of patients, EMS is a chronic illness having a major impact on life-style 3.6 years after onset. The chronic, often worsening pattern of illness suggests an ongoing pathogenetic mechanism.

Adult↗
PubMed1995

Fetal outcome in murine Lyme disease.

Lyme disease is an inflammatory syndrome caused by infection with Borrelia burgdorferi. Although this syndrome has important implications for human pregnancy, little is known about gestational infection with B. burgdorferi. Fetal death occurred in 33 of 280 gestational sacs (12%) in 39 C3H/HeN female mice infected by intradermal injection of B. burgdorferi 4 days after mating (acute infection), compared with 0 of 191 sacs in 25 control mice (P = 0.0001). Forty-six percent of acutely infected mice suffered at least one fetal death, compared with none of the control animals (P = 0.0002). There were no fetal deaths in 18 C3H/HeN mice infected 3 weeks prior to mating (chronic infection). A sensitive PCR technique detected B. burgdorferi DNA in the uteri of acutely infected mice but did not detect DNA in the uteri of controls or chronically infected mice. Spirochete DNA was only rarely detected in fetal tissues, and its presence was not required for fetal death. The inclusion of an internal competitive PCR target indicated that the lack of B. burgdorferi sequences in fetal DNA was not due to the presence of a PCR inhibitor. Histologic analysis of gestational tissues from infected animals demonstrated nonspecific pathology consistent with fetal death. These findings indicate an association between murine fetal death and acute infection with B. burgdorferi early in gestation but not with chronic infection. Our data suggest that fetal death is due to a maternal response to infection rather than fetal infection. These findings could provide an explanation for observations in humans in which sporadic cases of fetal death in women infected with B. burgdorferi during pregnancy have been reported, while previous infection has not been associated with fetal death.

Animals↗
PubMed1995

Bacterial lipopolysaccharide-mediated fetal death. Production of a newly recognized form of inducible cyclooxygenase (COX-2) in murine decidua in response to lipopolysaccharide.

Maternal infection is a cause of spontaneous abortion and preterm labor in humans, but the pathophysiology is unclear. We hypothesized that eicosanoids play an important role in infection-driven pregnancy loss. To investigate this hypothesis, we administered lipopolysaccharide (LPS) to pregnant C3H/HeN mice and found that LPS administration caused fetal death in a dose-dependent fashion. Pretreatment with indomethacin significantly decreased the proportion of fetal death from 83% to < 25% in mice injected with 10 micrograms of LPS. Also, decidual explants from LPS-treated mice produced significantly more inflammatory eicosanoids, including prostaglandins E2 and F2 alpha and thromboxane B2, than controls. We investigated the regulatory mechanisms responsible for increased decidual prostanoid production in response to LPS. Western and Northern blots demonstrated that decidual protein and mRNA levels of a recently recognized highly inducible form of cyclooxygenase, COX-2, were substantially increased in mice treated with LPS. Induction of COX-2 was rapid: mRNA was detected 30 min after LPS injection. In contrast, another form of cyclooxygenase, COX-1, was only minimally induced in response to LPS. Our data indicate that LPS induces decidual prostanoid production via increased COX-2 expression. Since LPS-mediated fetal death is markedly diminished by pretreatment with indomethacin, COX-2-mediated eicosanoid production is likely a key pathophysiologic event in LPS-mediated fetal death.

Abortion, Spontaneous↗
PubMed1995

Interstitial lung disease of systemic sclerosis.

Fibrosis of the pulmonary parenchyma is a frequent and serious complication of scleroderma (systemic sclerosis, SSc), resulting in significant morbidity and mortality. During the past decade data have accumulated in support of an inflammatory process affecting the alveoli and distal airways that culminates in irreversible fibrosis in many SSc patients. Recent findings indicate the presence of lung fibroblasts with altered phenotype and biologic activity (myofibroblasts), perhaps arising from the influence of cytokines on resident lung fibroblasts. Acute-phase inflammatory cytokines such as IL-1 alpha, TNF-alpha, MIP-1 alpha, IL-8 and RANTES are increased in SSc bronchoalveolar lavage (BAL) fluid, as is thrombin, a potent mitogen for lung fibroblasts. Chronic-phase inflammatory and fibrogenic cytokines such as PDGF and TGF-beta are also present in increased amounts in SSc BAL fluid. The inciting event(s) and the process(es) leading to the perpetuation of fibrosis in SSc are unknown. Treatment of SSc lung disease has been empiric and generally disappointing, and it is likely that effective treatment awaits a better understanding of the biological events that regulate collagen and other extracellular matrix synthesis.

Bronchoalveolar Lavage Fluid↗
PubMed1995

Systemic sclerosis (scleroderma). Clinical management of its major complications.

Systemic sclerosis (scleroderma) is a disease of unknown cause whose pathogenesis involves interaction between the vasculature, the immune system, and connective tissue cells. Although specific therapy awaits a better understanding of its pathogenesis, proper management may enhance not only the duration, but the quality of life for most scleroderma patients. Presently, controlled prospective trials of therapeutic agents are lacking. Published reports of drug therapy for skin, kidney, cardiac, pulmonary, and gastrointestinal complications, as well as management of Raynaud's phenomenon, are critically reviewed in this article, and the authors' approach to management of difficult clinical problems is presented.

Gastrointestinal Diseases↗