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L S Newman

Publications and source records attributed to L S Newman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Beryllium-stimulation does not activate transcription factors in a mouse hybrid macrophage cell line.

We tested the hypothesis that beryllium (Be) could stimulate H36.12j cell (12j) TNF-alpha production by transcription factor-mediated pathways similar to those induced by either LPS- or IFN-gamma stimulation. Unstimulated 12j cells produce constitutive levels of TNF-alpha (175+/-18 pg/ml, mean +/- SEM) detected by ELISA of culture supernatants after 24 h. Beryllium-stimulated (100 microM BeSO4) 12j cell TNF-alpha (724+/-47 pg/ml) was observed after 24 h while LPS-stimulated (1 microg/ml) TNF-alpha (515+/-151 pg/ml) after 6 h. Recombinant-Mu-IFN-gamma (10 U) stimulated 12j cell TNF-alpha at lower levels (284+/-31 pg/ml) while rMu-IFN-gamma + Be-stimulated 12j cells produced 1195+/-225 pg/ml TNF-alpha. Constitutive levels of transcription factors were observed in unstimulated 12j cell nuclei. In LPS-stimulated 12j cells IkappaBalpha was degraded in the cytoplasm and increased levels of NF-kappaB were found in nuclei after 30 min. After 3 h there were increased levels of AP-1 and CREB, with increased amounts of Fos family, Jun B and Jun D transcription factors. In contrast, Be-stimulation failed to increase the levels of any transcription factor tested, NF-kappaB, AP-1, AP-2, CREB, C/EBP, Sp-1, Egr-1, Ets, NF-Y or Oct-1, in 12j cells. A pattern of increased transcription factors, similar to that observed for LPS-stimulation, was found in 12j cell nuclei after stimulation with rMu-IFN-gamma. However, NF-kappaB was increased at 3 h while AP-1 (Jun B and Jun D) and CREB were increased at 15 h. Co-stimulation of 12j cells with rMu-IFN-gamma + Be increased the levels of NF-KB in 12j cell nuclei at 3 h, and the levels of AP-1 and CREB at 15 h, however, only Jun B was increased. Our data show 12j cell TNF-alpha production was associated with increased levels of transcription factors present in nuclei with disparate kinetics and patterns of expression depending on the trigger. We reject our initial hypothesis and conclude that Be-stimulation signals 12j cell TNF-alpha synthesis via a transcription factor-independent pathway. Beryllium may induce novel pathways of macrophage cytokine gene regulation.

Animals↗
PubMed2000

Detection of beryllium sensitivity using a flow cytometric lymphocyte proliferation test: the Immuno-Be-LPT.

Measurement of lymphocyte proliferation to detect hypersensitivity to beryllium (Be-LPT) in vitro is done presently using a method based on tritiated thymidine incorporation. Although this method is sensitive it gives no information on cell viability or responding lymphocyte subsets. We have developed reliable and simple flow cytometric assays for lymphocyte proliferation testing (Immuno-Be-LPT) by combining immunophenotyping with bromodeoxyuridine (BrdU) incorporation or DNA content using propidium iodide (PI) or 4'6'-diimidazolin-2-phenylindole (DAPI). Evaluation of beryllium-induced lymphocyte proliferation in blood cells from seven patients with chronic beryllium disease (CBD) and 120 beryllium workers by both the Bc-LPT and the Immuno-Be-LPT showed agreement between the tests. The Immuno-Bc-LPT provided additional information about the specific type of lymphocytes responding. CD4+ lymphocytes proliferated in response to beryllium in blood samples from all seven CBD individuals and CD8+ lymphocytes proliferated in six of the seven. Four beryllium workers without CBD had positive responses to beryllium primarily in the CD8+ cells. The use of the individual's own plasma supported a greater beryllium or tetanus-induced proliferation of CD4+ lymphocytes when compared to commercial human serum. The response of CD4+ lymphocytes measured in the Immuno-Be-LPT may provide a new marker for the diagnosis of CBD.

Antibodies, Monoclonal↗
PubMed2000

Impact of a worker notification program: assessment of attitudinal and behavioral outcomes.

BACKGROUND: Hundreds of worker notification programs are conducted each year to communicate occupational risks to workers. However, few attempts have been made to evaluate their effectiveness and few have described how communication theories are applied in developing notification messages. We developed and assessed the effectiveness of a worker notification program at a beryllium machining plant. METHODS: We compared self-protective attitudinal and behavioral responses among workers in two plants: (1) an intervention plant that received beryllium risk notification and (2) a matched control plant that did not receive notification. RESULTS: Workers receiving notification reported significantly stronger perceptions of threat and efficacy, more positive attitudes toward safety practices, and engaged in more protective behaviors than the workers at the control plant. CONCLUSIONS: This study demonstrates the utility of applying communication theories in the development of notification messages and the results suggest that mass presentations may be just as effective, if not more so, than one-on-one notifications. Am. J. Ind. Med. 37:205-213, 2000. Published 2000 Wiley-Liss, Inc.

Adult↗
PubMed2000

Aerosols generated during beryllium machining.

Some beryllium processes, especially machining, are associated with an increased risk of beryllium sensitization and disease. Little is known about exposure characteristics contributing to risk, such as particle size. This study examined the characteristics of beryllium machining exposures under actual working conditions. Stationary samples, using eight-stage Lovelace Multijet Cascade Impactors, were taken at the process point of operation and at the closest point that the worker would routinely approach. Paired samples were collected at the operator's breathing zone by using a Marple Personal Cascade Impactor and a 35-mm closed-faced cassette. More than 50% of the beryllium machining particles in the breathing zone were less than 10 microns in aerodynamic diameter. This small particle size may result in beryllium deposition into the deepest portion of the lung and may explain elevated rates of sensitization among beryllium machinists.

Aerosols↗
PubMed2000

Mast cell basic fibroblast growth factor in silicosis.

To investigate the role of mast cells (MC) and their fibrogenic growth factors in silicosis, we performed quantitative immunohistochemistry for MC tryptase and for basic fibroblast growth factor (bFGF) in lung tissue from silicotic and control subjects. Anti-bFGF antibody was bound to lung MC, basement membrane, endothelial cells, and smooth-muscle cells. Morphometric analysis revealed that the volume density (V(v)) of MC was increased in silicotic lung and that the V(v) of bFGF-positive (bFGF(+)) cells was significantly higher than normal in silicotic lung. Most MC contained bFGF (rho = 0.88, p < 0.001). The V(v) of collagen/reticulin fibers was increased in silicosis and correlated with the V(v) of bFGF(+) cells (rho = 0.81, p < 0.001). Immature silicotic nodules contained bFGF(+) MC throughout the loose array of collagen/reticulin fibers. In large, mature nodules, the density of collagen/reticulin fibers was higher, and bFGF(+) MC were found only in the nodule periphery. Because of this circumferential MC alignment in silicotic nodules, we observed a negative correlation between the V(v) of bFGF(+) MC and the density of collagen/reticulin fibers in silicotic nodules (rho = -0.80, p < 0.001) and between the V(v) of all other nodule-associated cells and the density of collagen/reticulin fibers in the hypocellular nodule centers (rho = -0.84, p < 0.001). We conclude that MC that produce bFGF may play an important role in the development of silicosis.

Aged↗
PubMed2000

Occupational exposure risks in individuals with PI*Z alpha(1)-antitrypsin deficiency.

We obtained questionnaire and spirometry data from 128 alpha(1)-antitrypsin (alpha(1)AT)-deficient individuals with phenotype PI*Z to examine the relationship between chronic respiratory symptoms, airflow limitation, treatment requirements, and semiquantitative estimates of occupational exposure to dust, fumes, smoke, and gas. After adjusting for age, smoking, and prior lower respiratory tract infections, increased prevalence of chronic cough (OR = 4.69, 95% CI = 1.57-13.74, p = 0.006) and having left a job due to breathlessness (OR = 2.72, 95% CI = 1.07-6.92, p = 0.036) were seen in individuals reporting high mineral dust exposure compared with those with no exposure. Subjects reporting high mineral dust exposure also had significantly lower FEV(1) (31% predicted for high exposure versus 36% for low and 40% for unexposed, p = 0.032). The excess risk of chronic cough seen with occupational fumes or smoke exposure disappeared after adjusting for mineral dust exposure, but the association with lower FEV(1)/FVC ratio persisted (p = 0.022). Personal tobacco use was a significant risk factor for most outcome measures, but no interaction with occupational exposure was seen. These results suggest that occupational inhalational exposures are independently associated with respiratory symptoms and airflow limitation in severely alpha(1)AT-deficient individuals.

Cross-Sectional Studies↗
PubMed2000

Inorganic dust pneumonias: the metal-related parenchymal disorders.

In recent years the greatest progress in our understanding of pneumoconioses, other than those produced by asbestos, silica, and coal, has been in the arena of metal-induced parenchymal lung disorders. Inhalation of metal dusts and fumes can induce a wide range of lung pathology, including airways disorders, cancer, and parenchymal diseases. The emphasis of this update is on parenchymal diseases caused by metal inhalation, including granulomatous disease, giant cell interstitial pneumonitis, chemical pneumonitis, and interstitial fibrosis, among others. The clinical characteristics, epidemiology, and pathogenesis of disorders arising from exposure to aluminum, beryllium, cadmium, cobalt, copper, iron, mercury, and nickel are presented in detail. Metal fume fever, an inhalation fever syndrome attributed to exposure to a number of metals, is also discussed. Advances in our knowledge of antigen-specific immunologic reactions in the lung are particularly evident in disorders secondary to beryllium and nickel exposure, where immunologic mechanisms have been well characterized. For example, current evidence suggests that beryllium acts as an antigen, or hapten, and is presented by antigen-presenting cells to CD4+ T cells, which possess specific surface antigen receptors. Other metals such as cadmium and mercury induce nonspecific damage, probably by initiating production of reactive oxygen species. Additionally, genetic susceptibility markers associated with increased risk have been identified in some metal-related diseases such as chronic beryllium disease and hard metal disease. Future research needs include development of biologic markers of metal-induced immunologic disease, detailed characterization of human exposure, examination of gene alleles that might confer risk, and association of exposure data with that of genetic susceptibility.

Air Pollutants↗
PubMed2000

Bronchoalveolar lavage macrophage-lymphocyte clusters in granulomatous disease are linked to lymphocytosis.

BACKGROUND AND AIM OF THE WORK: Clusters of macrophages associated with lymphocytes (ML clusters) have been observed among the bronchoalveolar lavage (BAL) cells of patients with pulmonary disease. We tested the hypothesis that ML clusters might be found among the BAL cells from patients with granulomatous disease. METHODS: We measured the number of ML clusters among the BAL cells from normal controls (n = 13), sarcoidosis patients (n = 18), beryllium-sensitized (BeS) patients (n = 21) and chronic beryllium disease (CBD) patients (n = 15). RESULTS: ML clusters were observed in the BAL cells of all groups, but at different frequencies: normal 8.5% (median, range 2-15%); BeS 7% (range 2-31%); sarcoidosis 14% (range 4-50%); and CBD 17% (range 6-73%). This data suggested that ML clusters were increased in granulomatous lung disease. However, the percentage of ML clusters strongly correlated with the BAL lymphocyte percentage (rho = 0.79). Cohort analysis showed that increases in macrophages having 2, 3 or > 3 associated lymphocytes correlated with an increase in lymphocyte percentage. CONCLUSIONS: An increase in ML clusters in BAL cells is not specific for granulomatous disease and is associated with the increase in BAL lymphocytes.

Adult↗
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↗