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Biomedical subjects

S M Schwartz

Publications and source records attributed to S M Schwartz.

At least 19 recordsLinked to original sources
PubMed1998

OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40.

We have cloned a TNFR family member from a follicular dendritic cell (FDC)-like cell line, FDC-1. This molecule, FDC-derived receptor-1 (FDCR-1), is identical to osteoprotegerin (OPG), a soluble cytokine that regulates osteoclast differentiation. Recently, OPG/FDCR-1 has been characterized as a second receptor for receptor activator of NF-kappaB ligand (RANKL)/TNF-related activation-induced cytokine (TRANCE), a primarily T-cell restricted TNF family member that augments dendritic cell (DC) function. In this report, we demonstrate that OPG/FDCR-1 is membrane bound on the surface of transfected baby hamster kidney (BHK) and untransfected FDC-1 cells. We also found a restricted OPG/FDCR-1 expression pattern in lymphoid cells, specifically in B cells, DCs and FDC-enriched fractions, which in B cells and DCs is up-regulated by CD40 stimulation. Because OPG/FDCR-1 shares some properties with RANK, the first RANKL/TRANCE receptor, we discuss how the balance between RANK and OPG/FDCR-1 expression could influence immune responses and, ultimately, germinal center formation.

Animals↗
PubMed1998

Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection.

BACKGROUND: Experimental models and analyses of human tumors suggest that oncogenic, sexually transmittable human papillomaviruses (HPVs) are etiologic factors in the development of oral squamous cell carcinoma (SCC). We conducted a population-based, case-control study to determine whether the risk of this cancer is related to HPV infection and sexual history factors. METHODS: Case subjects (n = 284) were 18-65-year-old residents of three counties in western Washington State who were newly diagnosed with oral SCC from 1990 through 1995. Control subjects (n = 477) similar in age and sex were selected from the general population. Serum samples were tested for HPV type 16 capsid antibodies. Exfoliated oral tissue collected from case and control subjects and tumor tissue from case subjects were tested for HPV DNA. Odds ratios (ORs) were calculated after adjusting for age, sex, cigarette smoking, and alcohol consumption. RESULTS: Among males only, oral SCC risk increased with self-reported decreasing age at first intercourse, increasing number of sex partners, and a history of genital warts. Approximately 26% of the tumors in case subjects contained HPV DNA; 16.5% of the tumors contained HPV type 16 DNA. The prevalence of oncogenic HPV types in exfoliated oral tissue was similar in case and control subjects. The ORs for HPV type 16 capsid seropositivity were 2.3 (95% confidence interval [CI] = 1.6-3.3) for all oral SCCs and 6.8 (95% CI = 3.0-15.2) for oral SCCs containing HPV type 16 DNA. The joint association of cigarette smoking and HPV type 16 capsid seropositivity with oral SCC (OR = 8.5; 95% CI = 5.1-14.4) was stronger than predicted from the sum of individual associations with current smoking (OR = 3.2; 95% CI = 2.0-5.2) and seropositivity (OR = 1.7; 95% CI = 1.1-2.6). CONCLUSIONS: HPV type 16 infection may contribute to the development of a small proportion of oral SCCs in this population, most likely in combination with cigarette smoking.

Adult↗
PubMed1998

Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies.

BACKGROUND: Population-based case-control studies to assess the relationship of low-dose oral contraceptive (OC) use with myocardial infarction (MI) were performed at 2 sites in the United States (California and Washington state). The purpose of the present study was to estimate risk of MI in relation to use of low-dose OCs in a pooled analysis combining results from the 2 sites. METHODS AND RESULTS: The study included as cases women aged 18 to 44 years with incident MI who had no prior history of ischemic heart disease or cerebrovascular disease. Women in the case and control groups were interviewed in person regarding OC use and cardiovascular risk factors. The analysis included 271 MI cases and 993 controls. Compared with noncurrent users, the adjusted pooled odds ratio for MI in current OC users was 0.94 (95% CI, 0.44, 2.20) after adjustment for major risk factors and sociodemographic factors. Compared with never users, the adjusted pooled odds ratio for MI was 0.56 (0.21, 1.49) in current OC users and 0.54 (0.31, 0.95) in past OC users. Among past OC users, duration and recency of use were unrelated to MI risk as was current hormone replacement therapy. There was no evidence of interaction between OC use and age, presence of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes), obesity, or smoking. CONCLUSIONS: We conclude that low-dose OCs as used in these populations are safe with respect to risk of MI in women.

Adolescent↗
PubMed1998

Role of beta1 and beta3 integrins in human smooth muscle cell adhesion to and contraction of fibrin clots in vitro.

The degree of lumen narrowing in advanced lesions correlates poorly with the amount of intimal mass accumulated in the atherosclerotic plaque. As an alternate mechanism of stenosis, we propose that human smooth muscle cells bind to fibrin deposited in the matrix and exert contractile forces to cause a narrowing of the lumen. In the present study we demonstrated in vitro that human newborn aortic smooth muscle cell lines can contract and adhere to fibrin clots composed of either fibronectin-depleted plasma ("plasma") or recombinant fibrin. By using neutralizing antibodies and RGD peptides, we showed that members of the integrin family mediated the interaction between human newborn smooth muscle cells and fibrin. Neutralizing antibodies against the integrin alphavbeta3 (c7E3 Fab and LM609) did not inhibit either plasma clot contraction or recombinant fibrin clot contraction by human newborn smooth muscle cells. In contrast, antibodies against alpha5, beta1, and alpha5/beta1 inhibited contraction of clots composed of either plasma or recombinant fibrin. Anti-alphavbeta3, anti-alphav, anti-alpha5, anti-beta1, and anti-alpha5beta1 antibodies inhibited human newborn smooth muscle cell adhesion to plasma clots; however, only anti-alpha5, anti-beta1, and anti-alpha5beta1 antibodies significantly inhibited adhesion to recombinant fibrin. While the linear RGD peptides had no effect, the cyclic peptide penRGD inhibited adhesion to plasma clots and recombinant fibrin. However, it did not block contraction of recombinant fibrin clots. These results suggest that during the interaction of human newborn smooth muscle cell lines with fibrin, alpha5beta1 plays a significant role. This interaction is of potential interest as a target for efforts to block vascular contraction.

Antibodies↗
PubMed1998

Sequential injury of the rabbit abdominal aorta induces intramural coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition eliminates luminal narrowing.

We hypothesized that activation of the coagulation cascade is involved in arterial remodeling in response to sequential injury. An active site-inhibited recombinant human factor VIIa (FVIIai) was used to inhibit tissue factor, the primary cofactor in the extrinsic pathway of coagulation, in a sequential balloon injury model of the rabbit abdominal aorta. Single balloon injury produced limited intimal thickening at 3 weeks (intimal area, 0.40+/-0.05 mm2) and no loss in luminal area (12.2+/-0.9 mm2 before injury and 12.1+/-0.9 mm2 at 6 weeks after injury). Sequential balloon injury, 3 weeks after the first balloon denudation, produced a progressive loss of lumen, with 22% and 47% loss of luminal area, respectively, at 3 and 6 weeks. Luminal loss could not be accounted for by intimal growth (at 3 weeks after sequential injury, the intimal area was 0.47+/-0.08 mm2, <4% of the initial luminal area). Sequential injury acutely produced extensive mural and intramural fibrin deposition. Treatment with FVIIai inhibited both the fibrin deposition and the chronic loss of lumen. At 3 weeks after sequential injury, luminal cross-sectional areas were 9.8+/-0.6 mm2 for control rabbits and 14.3+/-1.4 mm2 for FVIIai-treated rabbits. Neither neointimal area nor cell proliferation was reduced by FVIIai treatment. The intimal cell proliferation index 3 days after injury was 7.6+/-1.1% in control rabbits versus 5.8+/-1.1% in treated rabbits (P>0.05). These results indicate that tissue factor is an important mediator of coagulation in repeat injury and implicate the extrinsic coagulation cascade in a blood vessel remodeling response that is independent of neointimal growth but leads to extensive loss of lumen.

Animals↗
PubMed1998

Mitogenic effect of angiotensin II on rat carotid arteries and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous basic fibroblast growth factor.

In this study, anti-basic fibroblast growth factor (anti-bFGF) antibody was used to determine whether the mitogenic effect of angiotensin II in vivo could be blocked by neutralizing bFGF in the vessel wall. Animals, divided into six experimental groups, were given (1) angiotensin II, (2) angiotensin II + anti-bFGF antibody, (3) angiotensin II + normal goat IgG (ngIgG), (4) anti-bFGF antibody, (5) ngIgG, and (6) Ringer's solution. Angiotensin II at 435 ng x kg(-1) x min(-1) was infused into rats continuously for 1 week to induce smooth muscle cell replication, and anti-bFGF antibody or ngIgG was injected intravenously 4 times over the 1-week period at a dose of 60 mg/injection. Bromodeoxyuridine (30 mg/mL) was also continuously infused during the 1-week period. The left carotid artery of all animals was balloon-injured on day 4 of the treatment, and all groups were killed for study on day 7. The results showed that angiotensin II significantly stimulated smooth muscle replication in the balloon-injured carotid artery, intact carotid artery, and three branch levels of the mesenteric vascular tree. Anti-bFGF was able to block the mitogenic effect of angiotensin II in larger vessels but not the smallest (type I) microvessels of the mesenteric arterial tree. This differential response may be attributable to the nature of the lesions in type I vessels versus larger vessels: the type I vascular lesion has a large component of proliferating macrophages, whereas the larger vessels show less injury, few macrophages, and varying levels of smooth muscle replication. Our data suggest that the vessel wall remodeling in the angiotensin II-treated larger vessels involves DNA replication that is dependent on the presence of bFGF.

Angiotensin II↗
PubMed1998

Vitronectin decreases microvascular endothelial cell apoptosis.

Angiogenesis after tissue injury occurs in a matrix environment consisting of fibrin, fibronectin, and vitronectin as the major extracellular matrix (ECM) constituents. ECM-integrin interactions is critical for angiogenesis and failure to bind a ligand to certain integrin receptors (alpha[v]beta3 or alpha[v]beta5) inhibits angiogenesis. The ligand that binds to alpha(v)beta3 or alpha(v)beta5 integrin receptors during microvascular angiogenesis has not been identified. Our hypothesis is that provisional matrix molecules provide the environmental context cues to microvascular endothelial cells and promote angiogenesis by decreased programmed cell death. Using cultured human microvascular endothelial cells, we show that vitronectin, in comparison to growth on alternative provisional matrix molecules (fibronectin, fibrinogen plus thrombin), collagen I, and basement membrane molecules (collagen IV), significantly reduces microvascular endothelial cell death in vitro. This reduction was observed using morphologic criteria, TdT-mediated dUTP nick end labeling (TUNEL) assay, histone release into the cytoplasm, and thymidine release into the supernatant. Though our data confirm that vitronectin may bind to more than one integrin receptor to reduce MEC apoptosis, binding to the alpha(v) component appears to be the critical integrin subcomponent for reducing apoptosis.

Apoptosis↗
PubMed1998

A comparative molecular analysis of four rat smooth muscle cell lines.

Transcriptional regulation of smooth muscle cell (SMC) differentiation is a rapidly growing area of interest that has relevance for understanding intimal disease. Despite the wealth of data accumulating in vitro, however, no study has compared the cell-specific marker profile, transfectability, promoter activity, and growth characteristics among several SMC culture systems. Accordingly, we performed a comprehensive analysis of the marker profile, growth properties, transfectability, and SMC promoter activity in four rat SMC lines (A7r5, adult and pup aortic, and PAC1). Despite alterations in chromosomal number and structure, A7r5, adult aortic, and PAC1 cells express all SMC markers studied including SM alpha-actin, SM calponin, SM22, tropoelastin, and to a lesser extent, SM myosin heavy chain (SMMHC). In contrast, pup aortic cells express very low or undetectable levels of all the above markers except tropoelastin. Adult aortic, pup, and PAC1 cells display similar growth curves and levels of proto-oncogene transcripts, whereas those in the A7r5 line are comparatively less. All cell lines studied except pup cells show expression of SMC differentiation genes during active growth, indicating that growth and differentiation are not mutually exclusive in cultured smooth muscle. Transfection studies reveal dramatic differences in DNA uptake and SMC-restricted promoter activity between cell lines. Collectively, these results provide detailed information relating to SMC molecular biology in culture that should facilitate the selection of a cell line for studying the transcriptional regulatory mechanisms underlying SMC differentiation.

Actins↗
PubMed1998

Norplant implants and cardiovascular disease.

A 1995 publication on serious adverse events in users of Norplant implants submitted to the Food and Drug Administration's MedWatch Spontaneous Reporting System reported 14 hospitalizations for stroke in Norplant users. This number was higher than expected. This is a report on the association of current use of Norplant implants with stroke and myocardial infarction (MI) based on a pooled analysis of data from two population-based, case-control studies conducted in the US. All data collection for these two studies occurred after approval of Norplant implants for marketing in the US in December 1990. The methods of the individual studies are detailed in prior publications.

Adult↗
PubMed1998

Increased risk of adverse maternal and infant outcomes among women with renal disease.

We conducted a retrospective population-based study to estimate the risk of adverse maternal and neonatal outcomes in women with a diagnosis of renal disease during pregnancy. One hundred and sixty-nine women with renal disease who gave birth to a singleton infant between 1987 and 1993 were identified through linked Washington State hospital discharge and birth certificate databases. For comparison, 506 women without renal disease matched for year of delivery were selected. Women with renal disease were at increased risk of pre-eclampsia [OR = 7.2, 95% CI 4.2-12.5], preterm labour [OR = 7.9, 95% CI 1.9-32.6], dysfunctional labour [OR = 3.6, 95% CI 1.1-11.5], and caesarean section [OR = 3.1, 95% CI 2.0-4.8]. They were also at increased risk of delivering infants who were small for gestational age [OR = 5.3, 95% CI 2.8-10.0], preterm [OR = 6.1, 95% CI 3.3-11.3], and had 5-minute Apgar scores of less than 7 [OR = 3.9, 95% CI 1.1-14.6]. These associations persisted in analyses restricted to women without chronic hypertension. Women with renal disease and their infants also had median hospital charges that were more than twice those of women without renal disease and were more likely to be hospitalised longer. These data demonstrate that, independent of chronic hypertension, women with underlying renal disease are at increased risk of adverse maternal and perinatal outcomes and use more resources than women without renal disease.

Adult↗
PubMed1998

Loss of heterozygosity at 5q21-22 (adenomatous polyposis coli gene region) in oral squamous cell carcinoma is common and correlated with advanced disease.

We determined the frequency of loss of heterozygosity (LOH) at chromosome 5q21-22 (adenomatous polyposis gene region) in oral SCC from 49 patients using PCR-based assays. Of 43 informative (heterozygous) tumors, 41.9% [95% confidence interval (CI)=27.0, 57.9] contained LOH at 5q21-22. LOH at 5q21-22 was strongly associated with stage at diagnosis: 100%, (3/3), 50% (13/26), and 14% (2/14) of tumors from patients with distant metastases, regional spread, and localized disease, respectively, contained this genetic alteration (P=0.01). There were no statistically significant associations between LOH at 5q21-22 and other patient or tumor characteristics, but LOH was more commonly found in the tumors of heavy smokers, infrequent alcohol consumers, and in tumors containing either p53 mutations or HPV-DNA. In univariate analyses, LOH at 5q21-22 was associated with poor prognosis (hazard ratio=1.8, 95%, CI 0.8, 4.5); this relationship did not persist after adjustment for stage of disease (hazard ratio=1.1, 95% CI=0.4, 3.1). These data provide further evidence that inactivation of the APC gene and/or other genes at 5q21-22 is common and may be involved in the development and/or progression of oral SCC. Larger studies are needed to determine whether LOH at 5q21-22 is linked to known oral SCC etiologic factors and/or the prognosis of oral SCC patients, as well as to genetic instability at other loci involved in these malignancies.

Adult↗
PubMed1998

Proliferation and the monoclonal origins of atherosclerotic lesions.

Benditt's observation of the monoclonal origin of the atherosclerotic lesion has been controversial because it appeared to conflict with conventional wisdom. A new method based on a polymerase chain reaction amplification of the DNA of an X-inactivated gene from microdissected tissue confirms that Benditt was correct. However, this monoclonal expansion can also be found in nonatherosclerotic intima and media. These new data suggest that plaque clonality may represent expansion of preexisting patches of cells arising during development of the media. This developmental view does not conflict with other recent evidence that plaque expansion is associated with mutation or viral events. However, if plaques arise from patches, then early developmental mechanisms may be critical to the later evolution of the lesions.

Arteriosclerosis↗
PubMed1998

Angiotensin II induces vascular smooth muscle cell replication independent of blood pressure.

The purpose of this investigation was to evaluate the role of blood pressure in the proliferative response of vascular smooth muscle cells to systemic infusion of angiotensin II (Ang II). Our laboratory has previously shown that infusion of Ang II induces smooth muscle cell proliferation in rat mesenteric vessels and carotid arteries. Ang II, a strong vasopressor, raised systolic blood pressure in rats from 120 to 200 mm Hg at a dose of 435 ng x kg(-1) x min(-1) after 1 week of treatment. The question arises as to whether this development of hypertension is a primary contributor to the replicative activities observed in the arterial wall of the mesenteric arteries or the carotid arteries or whether Ang II alone, without an increase in blood pressure, is sufficient to stimulate proliferation in these vessels. In the previous studies, we found that Ang II stimulated smooth muscle cell replication in the carotid artery and in type III and type I mesenteric microvessels. This study demonstrates that although administration of hydralazine normalizes the animals' blood pressures, it does not suppress the mitogenic effect of Ang II. Thus, it appears that Ang II has a direct effect on cell proliferation.

Angiotensin II↗
PubMed1998

Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two US studies.

BACKGROUND AND PURPOSE: The available data on low-dose oral contraceptive pill (OCP) use and stroke risk in US women are limited by small numbers. We sought more precise estimates by conducting a pooled analysis of data from 2 US population-based case-control studies. METHODS: We analyzed interview data from 175 ischemic stroke cases, 198 hemorrhagic stroke cases, and 1191 control subjects 18 to 44 years of age. RESULTS: For ischemic stroke, the pooled odds ratio (pOR) adjusted for stroke risk factors for current use of low-dose OCPs compared with women who had never used OCP (never users) was 0.66 (95% confidence interval [CI], 0.29 to 1.47) and compared with women not currently using OCPs (nonusers) the pOR was 1.09 (95% CI, 0.54 to 2.21). For hemorrhagic stroke, the pOR for current use of low-dose OCPs compared with never users was 0.95 (95% CI, 0.46 to 1.93) and compared with nonusers the pOR was 1.11 (95% CI, 0.61 to 2.01). The pORs for current low-dose OCP use and either stroke type were not elevated among women who were >/=35 years, cigarette smokers, obese, or not receiving medical therapy for hypertension. pORs for current low-dose OCP use were 2.08 (95% CI, 1. 19 to 3.65) for ischemic stroke and 2.15 (95% CI, 0.85 to 5.45) for hemorrhagic stroke among women reporting a history of migraine but were not elevated among women without such a history. Past OCP use (irrespective of formulation) was inversely related to ischemic stroke but unrelated to hemorrhagic stroke. CONCLUSIONS: Women who use low-dose OCPs are, in the aggregate, not at increased risk of stroke. Studies are needed to clarify the risk of stroke among users who may be susceptible on the basis of age, smoking, obesity, hypertension, or migraine history.

Adolescent↗
PubMed1998

Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A)

BACKGROUND AND PURPOSE: Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age. METHODS: We conducted a case-control study in western Washington state. Case patients were women aged 18 to 44 years with a first stroke (n = 106). Control subjects were women without stroke recruited from the same region by use of random-digit telephone dialing (n = 391). All were interviewed and provided blood specimens, which were genotyped for these mutations. RESULTS: Factor V Leiden was found in 0.9% of case patients, a single patient with a subarachnoid hemorrhage, and in 4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2 (95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant was found in 1.9% of case patients, 1 with a venous stroke and 1 with an ischemic stroke, and in 1.6% of control subjects. The OR for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types were also not statistically significant. CONCLUSIONS: In this study, neither factor V Leiden nor the prothrombin variant (G20210A) was an important risk factor for stroke in young women. In this setting, screening for these mutations cannot be recommended. Unanswered by this study is whether screening would be useful in select patients, such as those with a strong family history of thrombophilia or those with venous strokes.

Adult↗
PubMed1998

Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants.

Platelet-derived growth factor (PDGF) plays an important role in renal disease. We have recently demonstrated that in healthy mature human kidney, PDGF alpha-receptor expression is largely restricted to interstitial cells. The study presented here assesses the expression of PDGF alpha-receptor in 18 mature adult kidneys with arteriosclerosis from individuals with no clinically evident history of renal disease other than localized neoplasia, in 13 kidneys with irreversible transplant rejection, and in a series of renal transplant biopsies composed of examples of both severe and absent rejection, by in situ hybridization and immunocytochemistry. Strong focal or diffuse expression of PDGF alpha-receptor mRNA and protein was noted in some intimal cells of intrarenal arterial vessels exhibiting signs of arteriosclerosis and/or vascular rejection. By double immunostaining, it could be shown that these cells were neither endothelial cells nor infiltrating leukocytes. The cells were most often identified as smooth muscle by colabeling for the smooth muscle cell-specific protein SM22alpha and less commonly for alpha-smooth muscle actin. There was also a population of PDGF alpha-receptor-expressing cells that failed to colabel with any of these markers, and hence remain of uncertain histogenesis. These intimal cells were generally negative for several other markers of differentiated smooth muscle cells, i.e., calponin and desmin. Near these PDGF alpha-receptor-positive intimal cells, expression of PDGF A-chain, an alpha-receptor ligand, was demonstrated in endothelial, intimal, and/or medial cells. Prominent PDGF alpha-receptor mRNA and protein expression also was noted in areas of interstitial fibrosis and in some glomeruli, in particular those with segmental glomerulosclerosis or fibrotic crescents. Double immunolabeling for PDGF alpha-receptor and alpha-smooth muscle actin confirmed that most of these latter PDGF alpha-receptor-positive cells were interstitial myofibroblasts or mesangial cells, or both. In summary, these data demonstrate widespread expression of PDGF alpha-receptor in renal cell types involved in fibrotic and sclerosing processes. The data also show that PDGF alpha-receptor expression identifies a unique population of phenotypically altered vascular smooth muscle cells, which appear to be involved in the vascular response to injury.

Adult↗