Biomedical subjects

L A Maier

Publications and source records attributed to L A Maier.

16 recordsLinked to original sources

PubMed2001

High beryllium-stimulated TNF-alpha is associated with the -308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease.

Beryllium (Be)-antigen stimulates tumor necrosis factor-alpha (TNF-alpha) from bronchoalveolar lavage (BAL) cells in chronic beryllium disease (CBD). This study tested the hypothesis that high concentrations of Be-stimulated TNF-alpha are related to polymorphisms in the TNF-alpha promoter and clinical markers of disease severity in CBD. Demographic and clinical information was obtained from patients with CBD (n = 20). TNF-alpha concentrations were measured in BAL cell culture supernatant by ELISA. A priori, we categorized CBD subjects as either high or low TNF-alpha producers using a cutoff of 1,500 pg/ml. The TNF-alpha promoter sequence, +64 to -1045, was determined by direct sequencing. Human leukocyte-associated antigen (HLA)-DPB1 and -DRB1 genotyping was determined by polymerase chain reaction (PCR). High Be-stimulated TNF-alpha was associated with TNF2 alleles, Hispanic ethnicity, presence of HLA-DPB1 Glu69, and absence of HLA-DR4. Be-stimulated TNF-alpha concentrations correlated with markers of disease severity, including chest radiograph, beryllium lymphocyte proliferation, and spirometry. We found no novel TNF-alpha promoter polymorphisms. These data suggest that the TNF2 A allele at -308 in the TNF-alpha promoter region is a functional polymorphism, associated with a high level of Be-antigen-stimulated TNF-alpha and that these high TNF-alpha levels indicate disease severity in CBD.

Antigens↗

PubMed2001

Beryllium sensitivity is linked to HLA-DP genotype.

Chronic beryllium disease (CBD) appears to arise from a combination of both exposure and genetic risk factors. A distinguishing feature of CBD is beryllium hypersensitivity, which can be measured in vitro by a lymphocyte proliferation test. The objective of this study was to determine whether certain allelic variations of the HLA-DPB1 gene, which had been observed previously in CBD, could be found in a group of individuals having beryllium hypersensitivity, but no symptoms of CBD. A flow cytometry-based Lymphocyte Proliferation Test combined with immunophenotyping (Immuno-LPT) was used to detect CD4+ and CD8+ T cell proliferation in response to in vitro stimulation with beryllium. The HLA-DPB1 haplotypes of the same individuals were determined by automated DNA sequencing. Twenty-two out of 25 beryllium-sensitive, non-CBD individuals were found to be carriers of the HLA-DPB1 gene having a substitution of a glutamic acid at position 69 in Exon 2 (Glu69), and a significantly high percentage (24%) were Glu69 homozygotes. Most of the CD4+ responders on the Immuno-LPT (10/14) carried rare, non-*0201 Glu69 DPB1 alleles; while most of the non-CD4+ responders (9/11) were common Glu69 carriers (*0201 or *0202) or non-Glu69 individuals (non-Glu69/non-Glu69). This is the first direct evidence that HLA-DP genotype is linked to a phenotypic response that occurs in beryllium sensitization in the absence of clinical CBD.

Berylliosis↗

PubMed2001

Interstitial fibrosis following hydrogen sulfide exposure.

This case report describes a patient with interstitial fibrosis 4 years after poisoning by hydrogen sulfide. Hydrogen sulfide causes pulmonary edema and is also toxic to the nervous system. Long-term pulmonary sequelae of hydrogen sulfide poisoning has not been reported frequently in the literature.

Air Pollutants↗

PubMed2001

Beryllium health effects in the era of the beryllium lymphocyte proliferation test.

The beryllium lymphocyte proliferation test (BeLPT) has revolutionized our approach to the diagnosis, screening, and surveillance of beryllium health effects. Based on the development of a beryllium-specific cell-mediated immune response, the BeLPT has allowed us to define early health effects of beryllium, including beryllium sensitization (BeS), and chronic beryllium disease (CBD) at a subclinical stage. The use of this test as a screening tool has improved our understanding of these health effects. From a number of studies it is apparent that BeS precedes CBD and develops after as little as 9 weeks of beryllium exposure. CBD occurs within 3 months and up to 30 years after initial beryllium exposure. Exposure-response variables have been associated with BeS/CBD, including work as a machinist, chemical or metallurgical operator, laboratory technician, work in ceramics or beryllium metal production, and years of beryllium exposure. Recent studies have found BeS and CBD in workplaces in which the majority of exposures were below the 2 microg/m3 OSHA time-weighted average (TWA). Ideally, the BeLPT would be used in surveillance aimed at defining other risk-related processes, determining exposure variables which predict BeS and CBD, and defining the exposure level below which beryllium health effects do not occur. Unfortunately, the BeLPT can result in false negative tests and still requires an invasive procedure, a bronchoscopy, for the definitive diagnosis of CBD. Thus, research is needed to establish new tests to be used alone or in conjunction with the BeLPT to improve our ability to detect early beryllium health effects.

Berylliosis↗

PubMed2001

Efficacy of serial medical surveillance for chronic beryllium disease in a beryllium machining plant.

There is limited information on the use of the blood beryllium lymphocyte proliferation test (BeLPT) at regular intervals in medical surveillance. Employees of a beryllium machining plant were screened with the BeLPT biennially, and new employees were screened within 3 months of hire. Of 235 employees screened from 1995 to 1997, a total of 15 (6.4%) had confirmed abnormal BeLPT results indicating beryllium sensitization; nine of these employees were diagnosed with chronic beryllium disease. Four of the 15 cases were diagnosed within 3 months of first exposure. When 187 of the 235 employees participated in biennial screening in 1997 to 1999, seven more had developed beryllium sensitization or chronic beryllium disease, increasing the overall rate to 9.4% (22 of 235). The blood BeLPT should be used serially in beryllium disease surveillance to capture new or missed cases of sensitization and disease. Beryllium sensitization and chronic beryllium disease can occur within 50 days of first exposure in modern industry.

Adult↗

PubMed2001

Beryllium particulate exposure and disease relations in a beryllium machining plant.

We examined the relationship between exposure to beryllium and the presence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers in a beryllium precision machining facility. Twenty workers with BeS or CBD (cases) were compared with 206 worker-controls in a case-control study. Exposure for each job title was measured using cascade impactors placed in the workers' breathing zone to measure total beryllium exposure and exposure to particles < 6 microns and < 1 micron in aerodynamic diameter. Cumulative exposure was calculated as sigma (job title exposure estimate x years in job title). Individual lifetime-weighted (LTW) exposure was calculated as sigma [(job title exposure x years in job title) divided by total years employment)]. Workers in the case group were more likely to have worked as machinists (odds ratio, 4.4; 95% confidence interval, 1.1 to 17.5) than those in the control group. The median cumulative exposure was consistently greater in the cases compared with the controls for all exposure estimates and particle size fractions, although this was not statistically significant. The median cumulative exposure was 2.9 micrograms/m3-years in the cases versus 1.2 micrograms/m3-years in the controls for total exposure, and 1.7 micrograms/m3-years in the cases versus 0.5 microgram/m3-years in the controls for exposure to particles < 6 microns in diameter. With cumulative exposure categorized into low-, intermediate-, and high-exposure groups, the odds ratios were 2.4 (95% confidence interval, 0.7 to 8.2) for the intermediate-exposure group and 1.2 (95% confidence interval, 0.4 to 4.2) for the high-exposure group compared with the low-exposure group. The median LTW exposure was 0.25 microgram/m3 in both groups. The median LTW exposure to particles < 6 microns was 0.20 microgram/m3 in the cases compared with 0.14 microgram/m3 in the controls. The differences in cumulative and LTW exposure were not statistically significant. None of the 22 workers with LTW exposure < 0.02 microgram/m3 had BeS or CBD. Twelve workers (60%) in the case group had LTW exposures > 0.20. In conclusion, increased cumulative and LTW exposure to total and respirable beryllium was observed in workers with CBD or BeS compared with the controls. These results support efforts to control beryllium exposure in the workplace.

Adult↗

PubMed2001

IL-4 fails to regulate in vitro beryllium-induced cytokines in berylliosis.

Bronchoalveolar lavage (BAL) cells from patients with chronic beryllium disease (CBD) have been used to evaluate the beryllium-specific immune response and potential immunotherapeutics. Beryllium induces interferon-gamma (IFN-gamma), interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10) from BAL cells. An antibody to IL-2 and recombinant human (rHu) IL-10 is able to partially suppress the beryllium-stimulated immune response. To obtain BAL cells, bronchoscopy is required, providing risk to the patient and a limited number of cells to study the immune response. As a result, the objectives of the study were to determine 1) whether CBD peripheral blood mononuclear cells (PBMNs) stimulated with beryllium would produce a similar cytokine pattern as BAL cells, and 2) whether this response could be modulated by interleukin-4 (IL-4), an immunomodulatory cytokine. CBD and normal individuals' PBMN and BAL cells were stimulated with and without beryllium sulfate. To modulate this antigen-stimulated response, we added rHu IL-4 to the unstimulated and beryllium-stimulated cells. IFN-gamma, IL-2, TNF-alpha, IL-6 and IL-10 cytokine concentrations were determined from cell supernatants by enzyme-linked immunosorbent assays (ELISA), while IL-4 messenger ribonucleic acid (mRNA) was assessed using polymerase chain reaction (PCR). Beryllium did not stimulate any of these cytokines from normal PBMNs. Increasing levels of IL-6 and TNF-alpha were produced constituitively by CBD PBMNs over time. Compared to the unstimulated CBD PBMNs, beryllium stimulated significant IFN-gamma, TNF-alpha, IL-2, IL-6 and IL-10 production. This response was similar to that stimulated from CBD BAL cells, although of a much lower magnitude. Low levels of IL-4 mRNA were found in CBD and control PBMNs, which were not increased with beryllium stimulation. The beryllium-stimulated cytokine levels were not decreased by the addition of IL-4. IL-4 was unable to downregulate any of these beryllium-stimulated cytokines from CBD BAL cells or increase IL-4 mRNA from either CBD PBMN or BAL cells, and thus is an unlikely immunomodulatory agent in CBD. From the data, it was concluded that chronic beryllium disease peripheral blood mononuclear cells provide a model to study the beryllium-stimulated immune response. Interleukin-4's inability to downregulate any of the beryllium-stimulated cytokines makes it an unlikely therapeutic candidate in chronic beryllium disease.

Adult↗

PubMed2001

Indirect and direct gas exchange at maximum exercise in beryllium sensitization and disease.

STUDY OBJECTIVES: To determine whether pulse oximetry accurately estimates arterial blood gas measurements during exercise in the assessment of chronic beryllium disease (CBD) and beryllium sensitization (BeS). DESIGN: Participants underwent maximal exercise physiology testing in a clinical-practice setting. Oxygen saturation in the blood was measured through an indwelling arterial line and by pulse oximetry. SETTING: All exercise physiology tests were performed in the pulmonary physiology unit of the National Jewish Medical and Research Center (NJMRC) between December 1985 and November 1998. PATIENTS: We analyzed the exercise physiology data for 168 individuals who were referred to NJMRC for evaluation of possible CBD and underwent exercise testing. On evaluation, they subsequently received diagnoses of either CBD or BeS. RESULTS: In BeS subjects, the percentage of oxygen saturation as measured by pulse oximetry (SpO(2)) often underestimated the percentage of arterial oxygen saturation (SaO(2)) (mean [+/- SD] underestimation, 0.88 +/- 4.6%) at maximum exercise and showed no significant correlation (r = -0.13; p = 0.3). The use of SpO(2) misclassified 14.9% of BeS subjects as having abnormal gas exchange levels (< 90%) that were normal by arterial blood gas measurement. In contrast, SpO(2) and SaO(2) values correlated at maximum exercise in CBD subjects (r = 0.55 [corrected]; p = 0.0001) without exhibiting SpO(2) underestimation of SaO(2), and misclassification occurred in only 5.9%. CONCLUSIONS: These data suggest that pulse oximetry cannot be used reliably to distinguish between CBD and BeS and, thus, is not an adequate substitute for arterial blood gas analysis with exercise.

Adult↗

PubMed2000

Beryllium-stimulated apoptosis in macrophage cell lines.

In vitro stimulation of bronchoalveolar lavage cells from patients with chronic beryllium disease (CBD) induces the production of TNF-alpha. We tested the hypothesis that beryllium (Be)-stimulated TNF-alpha might induce apoptosis in mouse and human macrophage cell lines. These cell lines were selected because they produce a range of Be-stimulated TNF-alpha. The mouse macrophage cell line H36.12j produces high levels of Be-stimulated TNF-alpha. The mouse macrophage cell line P388D.1 produces low, constitutive, levels of TNF-alpha and does not up-regulate Be-stimulated TNF-alpha production. The DEOHS-1 human CBD macrophage cell line does not produce constitutive or Be-stimulated TNF-alpha. Apoptosis was determined by microscopic observation of propidium iodide stained fragmented nuclei in unstimulated and BeSO(4)-stimulated macrophage cell lines. BeSO(4) induced apoptosis in all macrophage cell lines tested. Beryllium-stimulated apoptosis was dose-responsive and maximal after 24 h of exposure to 100 microM BeSO(4). In contrast, unstimulated and Al(2)(SO(4))(3)-stimulated macrophage cell lines did not undergo apoptosis. The general caspase inhibitor BD-fmk inhibited Be-stimulated macrophage cell line apoptosis at concentrations above 50 microM. Our data show that Be-stimulated macrophage cell line apoptosis was caspase-dependent and not solely dependent on Be-stimulated TNF-alpha levels. We speculate that the release of Be-antigen from apoptotic macrophages may serve to re-introduce Be material back into the lung microenvironment, make it available for uptake by new macrophages, and thereby amplify Be-stimulated cytokine production, promoting ongoing inflammation and granuloma maintenance in CBD.

Animals↗

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↗

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

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↗

PubMed1997

Sarcoidosis.

Explore the source record for details and available documents.

Adrenal Cortex Hormones↗

PubMed1992

A combination of two immunotoxins exerts synergistic cytotoxic activity against human breast-cancer cell lines.

In previous studies, combinations of immunotoxins reactive with different cell-surface antigens have exerted additive cytotoxicity against tumor cells in culture. In this report we describe a combination of 2 immunotoxins that produce synergistic cytotoxic activity. Recombinantly derived ricin A chain (RTA) was conjugated with murine monoclonal antibodies (MAbs) 317G5, 260F9, 454A12 and 741F8 that bound to cell-surface determinants of 42, 55, 180 (transferrin receptor) and 185 kDa (HER-2/neu) expressed by the SKBr3 human breast-cancer cell line. When inhibition of clonogenic growth was measured in a limiting dilution assay, the combination of 260F9-RTA and 454A12-RTA produced synergistic cytotoxic activity against SKBr3 and 2 other breast-cancer cell lines. All other combinations produced only additive inhibition of clonogenic growth. Simultaneous binding of 260F9 and 454A12 was not supra-additive, but sub-populations of cells which lacked one or the other antigen could be detected. Kinetic studies of internalization, using antibodies conjugated with gold particles, indicated that 454A12 remained within peripheral endosomes for a longer interval in the presence of 260F9. This change in the traffic of the transferrin receptor may contribute to synergy between 260F9-RTA and 454A12-RTA.

Antibodies, Monoclonal↗

PubMed1991

Requirements for the internalization of a murine monoclonal antibody directed against the HER-2/neu gene product c-erbB-2.

A murine monoclonal antibody, TA1, is directed against an epitope on the extracellular domain of the HER-2/neu (c-erbB-2) gene product. Requirements for TA1-induced internalization of c-erbB-2 have been studied using the SKBr3 human breast cancer cell line and several rat fibroblast cell lines that express either wild-type or mutant human c-erbB-2. Internalization of TA1 was monitored by assaying protease-resistant uptake of 125I-labeled TA1, by electron microscopy of gold-labeled TA1, and by inhibition of clonogenic growth of cells incubated with TA1 that had been conjugated with blocked ricin. Similar rates of internalization of TA1 were observed in SKBr3 and in rat fibroblasts that expressed human c-erbB-2. The route of endocytosis was the same as that observed with antibodies against other membrane receptors. Anti-c-erbB-2 and anti-transferrin receptor cointernalized through clathrin-coated pits, coated vesicles, endosomes, and multivesicular bodies. Products of mutant c-erbB-2 that lacked a portion of the tyrosine kinase domain or that lacked most of the cytoplasmic domain were endocytosed in the presence of TA1 as promptly as the wild-type c-erbB-2 product. Slightly more rapid internalization of TA1 was observed in rat cells that expressed c-erbB-2 with a single point mutation in the transmembrane domain. Taken together, our data suggest that neither the intracytoplasmic domain nor receptor phosphorylation is required for antibody-mediated endocytosis of c-erbB-2.

Animals↗

PubMed1990

Anticipatory immune suppression and nausea in women receiving cyclic chemotherapy for ovarian cancer.

Nausea and immune function were assessed in 20 cancer patients in the hospital prior to chemotherapy and compared with assessments conducted at home. Proliferative responses to T-cell mitogens were lower for cells isolated from hospital blood samples than for home samples obtained several days earlier. Patients also experienced increased nausea in the hospital. Hierarchical multiple regression analyses indicated that decreased immune function in the hospital was not related to increased anxiety. The observed anticipatory immune suppression is consistent with the hypothesis that chemotherapy patients may develop conditioned immune suppression as well as conditioned nausea after repeated pairings of hospital stimuli with the emetic and immunosuppressive effects of chemotherapy.

Adult↗