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Biomedical subjects

L S Newman

Publications and source records attributed to L S Newman.

At least 19 recordsLinked to original sources
PubMed1999

Beryllium-stimulated in vitro migration of peripheral blood lymphocytes.

Inhalation of beryllium (Be) induces both inflammatory and metal antigen-specific immune responses in the lungs characterized by mononuclear cell infiltration and granuloma formation (chronic beryllium disease, CBD). We tested the hypothesis that Be-salts might increase the in vitro migration of peripheral blood mononuclear cells (PBMC). PBMC are mixed cells, consisting of lymphocytes and monocytes. We compared their responses to populations of both purified blood lymphocytes, and purified blood monocytes. Purified blood monocytes and lymphocytes, isolated by Percoll gradients and centrifugal elutriation from normal human subjects (n = 6), were exposed to graded concentrations (0.01 to 100 microM) of BeSO4 or to the control metal-salt Al2(SO4)3. Migratory responses of stimulated PBMC were measured in Boyden Chambers. As controls, PBMC mixed cells or purified lymphocytes or purified monocytes were unstimulated or stimulated with a positive chemoattractant, Zymosan-A treated pooled, normal human serum (ZAS). The migration index (MI) was defined as the distance (micrometers) that cells migrated through a 5 micron filter. The MI for unstimulated PBMC mixed cells was 75+/-4 whereas the MI for ZAS-stimulated PBMC mixed cells was 124+/-4 (P < or = 0.05, Tukey-Kramer). The MI for BeSO4 -stimulated (100 microM) PBMC mixed cells was 136+/-4. The observed increase in the BeSO4-stimulated PBMC mixed cell migration was significant down to 0.1 microM BeSO4. BeSO4, BeCl2 and BeF2, tested at 100 and 10 microM, were equally effective at inducing PBMC mixed cell migration. Equimolar concentrations of Al2(SO4)3 were not as effective at inducing PBMC mixed cell migration, MI < 100 at 100 microM, and did not induce PBMC mixed cell migration at concentrations below 1 microM. The migration of purified monocytes through filters was not increased in response to either BeSO4 or Al2(SO4)3 compared to controls, but did respond to ZAS (MI = 100+/-4). Purified lymphocytes migrated in response to stimulation with all concentrations of BeSO4 tested (100 microM MI = 133+/-9), and Al2(SO4)3 (100 microM MI = 85+/-8). There were no significant differences in the MI for PBMC mixed cells or for purified lymphocytes at the concentrations of BeSO4 tested. Our data show that Be directly induces the in vitro migration of PBMC mixed cells and purified blood lymphocytes, and not purified blood monocytes, across a broad range of Be concentrations. This induction of migration was independent of the molecular form of the Be-salt. Inhaled Be, by promoting lymphocyte emigration to the lung, may create a microenvironment that favors a Be-antigen-specific T-lymphocyte response, chronic inflammation, and CBD.

Adult↗
PubMed1999

Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease.

Chronic beryllium disease (CBD) provides a human disorder in which to study the delayed type IV hypersensitivity response to persistent Ag that leads to noncaseating pulmonary granuloma formation. We hypothesized that, in CBD, failure of IL-10 to modulate the beryllium-specific, cell-mediated immune response would result in persistent, maximal cytokine production and T lymphocyte proliferation, thus contributing to the development of granulomatous lung disease. To test this hypothesis, we used bronchoalveolar lavage cells from control and CBD subjects to evaluate the beryllium salt-specific production of endogenous IL-10 and the effects of exogenous human rIL-10 (rhIL-10) on HLA expression, on the production of IL-2, IFN-gamma, and TNF-alpha, and on T lymphocyte proliferation. Our data demonstrate that beryllium-stimulated bronchoalveolar lavage cells produce IL-10, and the neutralization of endogenous IL-10 does not increase significantly cytokine production, HLA expression, or T lymphocyte proliferation. Second, the addition of excess exogenous rhIL-10 partially inhibited the beryllium-stimulated production of IL-2, IFN-gamma, and TNF-alpha; however, we measured no change in T lymphocyte proliferation or in the percentage of alveolar macrophages expressing HLA-DP. Interestingly, beryllium salts interfered with an IL-10-stimulated decrease in the percentage of alveolar macrophages expressing HLA-DR. We conclude that, in the CBD-derived, beryllium-stimulated cell-mediated immune response, low levels of endogenous IL-10 have no appreciable effect; exogenous rhIL-10 has a limited effect on cytokine production and no effect on T lymphocyte proliferation or HLA expression.

Adjuvants, Immunologic↗
PubMed1999

Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles.

Chronic beryllium disease (CBD) is associated with the allelic substitution of a Glu69 in the HLA-DPB1 gene. Although up to 97% of CBD patients may have the Glu69 marker, about 30-45% of beryllium-exposed, unaffected individuals carry the same marker. Because CBD occurs in only 1-6% of exposed workers, the presence of Glu69 does not appear to be the sole genetic factor underlying the disease development. Using two rounds of direct automated DNA sequencing to precisely assign HLA-DPB1 haplotypes, we have discovered highly significant Glu69-containing allele frequency differences between the CBD patients and a beryllium-exposed, nondiseased control group. Individuals with DPB1 Glu69 in both alleles were almost exclusively found in the CBD group (6/20) vs the control group (1/75). Whereas most Glu69 carriers from the control group had a DPB1 allele *0201 (68%), most Glu69 carriers from the CBD group had a non-*0201 DPB1 Glu69-carrying allele (84%). The DPB1 allele *0201 was almost exclusively (29/30) associated with DPA1 *01 alleles, while the non-*0201 Glu69-containing DPB1 alleles were closely associated with DPA1 *02 alleles (26/29). Relatively rare Glu69-containing alleles *1701, *0901, and *1001 had extremely high frequencies in the CBD group (50%), as compared with the control group (6.7%). Therefore, the most common Glu69-containing DPB1 allele, *0201, does not seem to be a major disease allele. The results suggest that it is not the mere presence of Glu69, per se, but specific Glu69-containing alleles and their copy number (homozygous or heterozygous) that confer the greatest susceptibility to CBD in exposed individuals.

Alleles↗
PubMed1999

Identification of pathogenic T cells in patients with beryllium-induced lung disease.

Chronic beryllium disease (CBD) is caused by beryllium exposure and is characterized by granulomatous inflammation with accumulation of CD4+ T cells in the lung. We analyzed TCR beta-chain and alpha-chain genes expressed by these CD4+ T cells. In the lungs of individual patients, as well as among four of five CBD patients studied, different oligoclonal expansions within the Vbeta3 subset were found to express homologous or even identical CDR3 amino acid sequences. These related expansions were specific for CBD patients, were compartmentalized to lung, and persisted at high frequency in patients with active disease. Limiting dilution cloning and analysis of coexpressed TCR alpha-chain genes confirmed that these TCRs were selectively expanded by a common Ag involving beryllium. Overall, homologous TCR beta- and alpha-chains showed identical V regions and invariant charged residues within the CDR3 but considerable variability in TCRJ usage. Remarkably, CBD patients expressing nearly identical TCRs did not share common HLA-DRB1 or DQ alleles. These results implicate particular CD4+ cells in the pathogenesis of CBD and provide insight into how beryllium is recognized in human disease.

Amino Acid Sequence↗
PubMed1999

Beryllium contamination inside vehicles of machine shop workers.

Inhalation of beryllium particles causes a chronic, debilitating lung disease--chronic beryllium disease (CBD)--in immunologically sensitized workers. Evidence that very low concentrations of beryllium may initiate this chronic disease is provided by incidences of the illness in family members exposed to beryllium dust from workers' clothes and residents in neighborhoods surrounding beryllium refineries. This article describes the results of a cross-sectional survey to evaluate potential take-home beryllium exposures by measuring surface concentrations on the hands and in vehicles of workers at a precision machine shop where cases of CBD had recently been diagnosed. Many workers did not change out of their work clothes and shoes at the end of their shift, increasing the risk of taking beryllium home to their families. Wipe samples collected from workers' hands and vehicle surfaces were analyzed for beryllium content by inductively coupled argon plasma-atomic emission spectroscopy (ICP-AES). The results ranged widely, from nondetectable to 40 micrograms/ft2 on workers' hands and up to 714 micrograms/ft2 inside their vehicles, demonstrating that many workers carried residual beryllium on their hands and contaminated the inside of their vehicles when leaving work. The highest beryllium concentrations inside the workers' vehicles were found on the drivers' floor (GM = 19 micrograms/ft2, GSD = 4.9), indicating that workers were carrying beryllium on their shoes into their vehicles. A safe level of beryllium contamination on surfaces is not known, but it is prudent to reduce the potential for workers to carry beryllium away from the work site.

Adult↗
PubMed1999

Beryllium copper alloy (2%) causes chronic beryllium disease.

We describe two newly confirmed cases of chronic beryllium disease who presented to our clinic from a facility that only used 2% beryllium copper alloy. These cases illustrate that the 2% beryllium copper alloy continues to cause chronic beryllium disease and that appropriate preventive measures must be taken to control exposures and educate industries and their workers about the hazards of beryllium alloys.

Air Pollutants, Occupational↗
PubMed1999

Angiotensin-1 converting enzyme polymorphisms in chronic beryllium disease.

To test the hypothesis that the angiotensin converting enzyme (ACE) genotype is associated with chronic beryllium disease (CBD) and disease severity, we studied 50 cases of CBD and compared their ACE genotype to that of two different control groups, consisting of: (1) 50 participants from a beryllium machining facility; and (2) 50 participants from a non-beryllium-associated workplace. We found no statistically significant difference in the frequency of the I or D allele or of the DD genotype among cases of CBD and either control group. The odds ratio (OR) for the CBD DD genotype as compared with the non-DD genotype was 1.58 (95% confidence interval [CI]: 0.68 to 3.66, p = 0.12) for the beryllium-exposed control group, and 1.09 (95% CI: 0.48 to 2.46, p = 0.56) for the non-beryllium-exposed controls. We found an association between serum ACE activity and the ACE genotype, with DD cases having the highest median serum ACE activity (p = 0.005). We evaluated the beryllium lymphocyte proliferation test (BeLPT), bronchoalveolar lavage (BAL) cell components, chest radiography, pulmonary function test results, and exercise physiology in our CBD cases. No statistically significant associations with these disease markers were found for the CBD cases with the DD genotype. Although the difference was not statistically significant, the DD cases had a shorter median duration of exposure to beryllium before diagnosis of CBD, and tended to have a weaker response in their blood and BAL BeLPT than did the non-DD cases. These findings may indicate that the ACE genotype is important in the immune response to beryllium and in progression to beryllium disease.

Adult↗
PubMed1998

ATM binds to beta-adaptin in cytoplasmic vesicles.

Inherited mutations in the ATM gene lead to a complex clinical phenotype characterized by neuronal degeneration, oculocutaneous telangiectasias, immune dysfunction, and cancer predisposition. Using the yeast two-hybrid system, we demonstrate that ataxia telangiectasia mutated (ATM) binds to beta-adaptin, one of the components of the AP-2 adaptor complex, which is involved in clathrin-mediated endocytosis of receptors. The interaction between ATM and beta-adaptin was confirmed in vitro, and coimmunoprecipitation and colocalization studies show that the proteins also associate in vivo. ATM also interacts in vitro with beta-NAP, a neuronal-specific beta-adaptin homolog that was identified as an autoantigen in a patient with cerebellar degeneration. Our data describing the association of ATM with beta-adaptin in vesicles indicate that ATM may play a role in intracellular vesicle and/or protein transport mechanisms.

Adaptor Protein Complex 3↗
PubMed1998

Irritant-associated vocal cord dysfunction.

Vocal cord dysfunction (VCD) is a poorly understood entity that is often misdiagnosed as asthma. We report eleven cases of VCD in which there was a temporal association between VCD onset and occupational or environmental exposure. We conducted a case-control study to determine if the characteristics of irritant-exposed VCD (IVCD) cases differed from non-exposed VCD controls. Chart review of VCD patients at the authors' institution produced 11 cases that met IVCD case criteria. Thirty-three control VCD subjects were selected by age matching. There were statistical differences between the groups in ethnicity and chest discomfort. There were no statistical differences between the groups for gender, tobacco, smoking habits, symptoms, or pulmonary function parameters. Varied irritant exposures were associated with IVCD. IVCD should be considered in patients presenting with respiratory symptoms occurring after irritant exposures.

Adult↗
PubMed1998

Morphometric analysis of insulin-like growth factor-I localization in lung tissues of patients with idiopathic pulmonary fibrosis.

Insulin-like growth factor-I (IGF-I) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through its ability to stimulate fibroblast proliferation and collagen synthesis. However, although alveolar macrophages (AM) have been shown to express this growth factor, it is likely to also have other cellular sources. We sought to determine the distribution of cells expressing IGF-I in lung tissues obtained from 10 patients with IPF and 10 control subjects. We evaluated the levels of IGF-I and of a macrophage/monocyte-specific marker, CD68, by immunocytochemistry and quantified by morphometry. In control subjects, IGF-I was localized principally to AM. In contrast, in IPF patients IGF-I was localized to AM, interstitial macrophages, alveolar epithelial cells, and ciliated columnar epithelial cells. The normalized volume density (Vv) of IGF-I-positive (IGF-I+) interstitial macrophages (Vv of IGF-I+ interstitial macrophages/Vv of lung x 100) was increased in patients with IPF as compared with control subjects, and the ratio of Vv of IGF-I+ to CD68(+) interstitial macrophages correlated with: (1) the degree of clinical impairment in patients with IPF as measured by their clinical-radiologic-physiologic (CRP) score; and (2) the degree of collagen deposition in the interstitium. These findings support a role for interstitial macrophages as a source of IGF-I in IPF.

Adult↗
PubMed1998

Expansions of T-cell subsets expressing particular T-cell receptor variable regions in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by the presence of noncaseating granulomas and mononuclear cell inflammation, occurring in 1 to 5% of people exposed to beryllium in the workplace. In the lungs of affected patients, CD4(+) T cells accumulate. Using anti-T-cell receptor (TCR) monoclonal antibodies, we investigated the TCR beta and alpha variable (Vbeta and Valpha, respectively) repertoire in the bronchoalveolar lavage (BAL) and blood of both CBD patients and healthy controls. There was marked heterogeneity within the BAL CD4(+) T-cell repertoire in both patients and controls. However, 11 of the 28 CBD patients demonstrated 16 different T-cell subset expansions within the BAL as compared with only one expansion in ten healthy controls. Five of the 16 expansions in CBD patients expressed Vbeta3. Altered TCR expression within the BAL T-cell repertoire appeared to persist over time in patients who underwent repeat evaluation. After in vitro stimulation of BAL T cells with beryllium sulfate and interleukin-2, we noted further alteration of the BAL TCR repertoire in some individuals. These results provide additional insight into the involvement of CD4(+) T cells in this disease and form the basis for studies to examine the nature of the stimulating antigen.

Adult↗
PubMed1998

"Lifeguard lung": endemic granulomatous pneumonitis in an indoor swimming pool.

OBJECTIVES: Two sequential outbreaks of respiratory disease among lifeguards at an indoor swimming pool with water spray features were investigated. METHODS: Questionnaires were administered to recreation center employees following each outbreak. Respondents reporting 2 or more pool-related symptoms were offered clinical evaluation, including bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Pool air and water were sampled for fungi, bacteria, amoebae, endotoxin, and respirable particulates. RESULTS: Thirty-three lifeguards had noncaseating granulomas on biopsy and/or bronchoalveolar lavage lymphocytosis. Attack rates for the outbreaks were 27% and 65%. Case patients had higher cumulative hours of work and tended to work more hours per week. Analyses indicated increased levels of endotoxin in pool air and water (relative to control pools) and gram-negative bacterial colonization of water sprays. Use of water spray features generated a 5.2-fold increase in the number of respirable particles and up to an 8-fold increase in air endotoxin levels. CONCLUSIONS: Lifeguards in this indoor swimming pool developed granulomatous lung disease associated with endotoxin-containing respirable bioaerosols from water spray features, which ventilation system improvements did not prevent.

Adolescent↗
PubMed1998

Metals that cause sarcoidosis.

Inhalation of metal dust or fume can cause granulomatous lung disease that mimics sarcoidosis. Particular metals that possess antigenic properties which promote granuloma formation include aluminum, barium, beryllium, cobalt, copper, gold, rare earths (lanthanides), titanium, and zirconium. The occupational and environmental exposure history holds the key to linking such metals with seemingly idiopathic disease. We propose clinicians use a systematic approach to investigating the occupational and environmental history and immunologic responses of patients with sarcoidosis, in order to discriminate metal-induced granulomatosis from sarcoidosis.

Diagnosis, Differential↗
PubMed1997

Sarcoidosis.

Explore the source record for details and available documents.

Adrenal Cortex Hormones↗
PubMed1997

Beryllium induces IL-2 and IFN-gamma in berylliosis.

Chronic beryllium disease (CBD) provides a model for study of the Ag-stimulated, cell-mediated immune response that, over time, progresses to granulomatous lung disease. Using cells obtained with bronchoalveolar lavage from patients with CBD and normal individuals, we evaluated beryllium salt-stimulated T lymphocyte proliferation and production of proinflammatory cytokines. Our findings demonstrate that beryllium sulfate stimulates production of both IL-2 and IFN-gamma, not IL-4 and IL-7. We observed a brief time course for IL-2 protein (6-48 h after BeSO4 stimulation) and mRNA production (3-6 h) and a protracted time course for IFN-gamma protein (24-168 h) and mRNA (0.25-168 h). Beryllium-stimulated T lymphocyte proliferation and IFN-gamma release were only partially inhibited by neutralization of IL-2. On the basis of these findings, we hypothesized that IFN-gamma and the IL-2/IFN-gamma-inducible alpha subunit of the soluble IL-2 receptor were elevated in serum and bronchoalveolar lavage fluid of individuals with disease and were molecular markers of granulomatous disease. The data demonstrate that levels of the alpha subunit of the soluble IL-2 receptor, but not IFN-gamma, are elevated in the serum (median = 1428 U/ml; interquartile range = 823-2137 U/ml) and bronchoalveolar lavage fluid (median = 1.56 U/ml, interquartile range = 1.04-4.22 U/ml) of patients with CBD and correlate with the degree of pulmonary lymphocytosis and clinical measures of disease severity. We conclude that IL-2 and IFN-gamma are produced in the beryllium-stimulated, cell-mediated immune response with different time courses and that the alpha subunit of the soluble IL-2 receptor may serve as a biomarker of disease progression.

Adult↗
PubMed1997

Serum neopterin in chronic beryllium disease.

We evaluated serum neopterin as a biomarker of chronic beryllium disease (CBD), for use in conjunction with the beryllium lymphocyte proliferation test (BeLPT) in workplace screening. Serum neopterin levels were determined by radioimmunoassay, and we compared levels in three groups: CBD (n = 86), beryllium sensitized (BeS) (n = 22), and normal (Nor) (n = 20). Those in the diseased group underwent pulmonary function tests, bronchoalveolar lavage (BAL), and maximal exercise testing. We correlated neopterin levels with results of these clinical parameters of disease severity. To evaluate the optimum sensitivity, specificity, and neopterin cut-off value, receiver operator characteristic (ROC) curves were generated. The median serum neopterin level in CBD was significantly higher than in BeS or in Nor [median 1.45, 25th, 75th percentiles (1.00, 2.7) ng/ml, 0.82 (0.67, 1.16) ng/ml, and 0.92 (0.86, 1.16) ng/ml, respectively] (P < 0.05). In CBD, we observed statistically significant associations between neopterin and measures of gas exchange and BAL cellularity. Using a neopterin value of 1.27 ng/ml, test specificity is 88%. In those workers with an abnormal BeLPT, serum neopterin has high positive predictive value (92%), and can identify disease, helping to distinguish it from BeS without the risks of biopsy.

Adult↗
PubMed1997

A new look at defensive projection: thought suppression, accessibility, and biased person perception.

It has long been assumed that people perceive in others qualities that they wish to deny in themselves, but empirical evidence for defensive projection is limited and controversial. A new model for projection is presented in this article. People might try to actively suppress thoughts about the possibility that they have undesirable personality traits, but it was hypothesized that this response to threat ultimately causes thoughts about the unwanted traits to become chronically accessible. As a result, those trait concepts will be used to interpret others' behavior. Studies 1-4 showed that those people who both avoid thinking about having threatening personality traits and deny possessing them (repressors) also readily infer those traits from others' behavior. Studies 5-6 provided experimental support for the model. Unfavorable traits were attributed to participants, who, when they were asked or predisposed to not think about the traits, subsequently projected them onto someone else.

Adult↗