Research recommendations of the NORA exposure assessment methods team. National Occupational Research Agenda.
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Biomedical subjects
Publications and source records attributed to M Stenzel.
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Exposure assessment, the first step in risk assessment, has traditionally been performed for a variety of purposes. These include compliance determinations; management of specific programs that are implemented by comparison with an occupational exposure limit (such as medical surveillance, training, and respiratory protection programs); task/source investigations for determination of exposure control strategies; epidemiologic studies; worker compensation/toxic tort cases; health complaint or problem investigations; risk assessment and management; and evaluation of future changes in the workplace (e.g., introduction of a new chemical). Each purpose requires slightly different approaches, but there are also many similarities. The goal of this paper is to identify a general approach to assessing exposures that can be used for all purposes with only slight modifications. Five components of exposure assessments are identified: collection of data, identification of the hazard, selection of exposure metrics, definition of exposure groups and estimation of the exposures. The characteristics of these components for each type of assessment are discussed. From this review, it is clear that there is substantial overlap across the types of assessment. A single exposure assessment program is suggested that encompasses all the needs of these assessments and incorporates assessment of exposures for an entire workforce at a site at minimal cost by using prediction models and validation with measurements.
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Data needs in an epidemiologic study can appear to be substantial in light of the other responsibilities of an industrial hygienist. Many of the data needed for this type of investigation, however, are already collected for other exposure assessment purposes. To increase understanding of this concept, the data needs for the major purposes for conducting an exposure assessment are identified. The purposes include determining compliance; implementing industrial hygiene programs, such as personal protective and respiratory equipment, hazard communication training, and medical surveillance; investigating health complaints and worker concerns; investigating tasks or engineering control effectiveness; investigating toxic tort or worker compensation claims; and conducting epidemiologic studies. A comprehensive exposure assessment system is then described that incorporates the data needs for all these purposes, including epidemiologic studies. The data needs of epidemiologic studies and how the data are used are then described and illustrated with examples taken from published epidemiologic studies.
Within the placenta tumour necrosis factor-alpha (TNF-alpha) and its surface receptors TNF-RI and -RII have been detected on villous cyto- and syncytiotrophoblast and a role in trophoblast function/differentiation and turnover has been suggested. Here, we show for the first time that purified villous trophoblasts and cytotrophoblastic BeWo cells extensively shed TNF receptors, suggesting that release of these soluble proteins is an inherent property of trophoblasts. In supernatants of purified villous trophoblasts, TNF-RI and -RII increased from undetectable levels to 307 pg/ml and 484 pg/ml, respectively, within 12 h of cultivation. In BeWo cells, 26 pg/10(5) cells and 54 pg/10(5) cells of soluble TNF-RI and -RII, respectively, accumulated within 24 h of culturing. While forskolin did not alter TNF-RI expression, TNF-RII mRNA, protein and secretion were selectively up-regulated in these choriocarcinoma cells suggesting that elevation of cAMP levels could modulate cellular events by TNF-RII-mediated signal transduction. Interleukin-1, which greatly enhances TNF-alpha release from trophoblast cells, did not alter shedding of both receptors from villous trophoblasts or BeWo cells. Secretion of TNF receptors from the trophoblast may explain the high levels of soluble TNF-binding proteins in urine of pregnant women and could play a role in regulating TNF-alpha activity in the placental villus or protection against the cytotoxic effects of the cytokine.
The rate of transcription initiation directed by the long terminal repeat (LTR) of HIV-1 increases in response to mitogenic stimuli of T cells. Here we show that the response of the HIV-1 LTR may be governed by two independent sequences located 5' to the site of transcription initiation sequences that bind either NFAT-1 or NF kappa B. The rate of LTR-directed gene expression increased in response to treatment with either a phorbol ester or tumor necrosis factor alpha if either the NFAT-1 or NF kappa B binding sites were deleted, but failed to respond to these mitogenic stimuli if both sequences were absent. The HIV-1 mutant virus containing both NF kappa B and NFAT-1 deletion was able to replicate although at a much decreased growth rate, while the deletion of NFAT-1 alone increased the viral growth rate in Jurkat cells. Neither deletion of NF kappa B nor deletion of NFAT-1 decreased activation of viral replication by phorbol ester.
The negative regulatory element of human immunodeficiency virus type 1 is a 260-nucleotide-long sequence that decreases the rate of RNA transcription initiation specified by the long terminal repeat. This region has the potential to bind several cellular transcription factors. Here it is shown that sequences which recognize the NFAT-1 and USF cellular transcription factors contribute to this negative regulatory effect. The sequences within the negative regulatory element which resemble the AP-1 site and the URS do not negatively regulate human immunodeficiency virus long terminal repeat transcription initiation.
The effects of deletions within three functional regions of the long terminal repeat of human immunodeficiency virus type 1 upon the ability of the long terminal repeat to direct production of the chloramphenicol acetyltransferase gene product and upon the ability of viruses that carry the mutations to replicate in human cell lines was investigated. The results show that the enhancer and TATAA sequences were required for efficient virus replication. Deletion of the negative regulatory element (NRE) yielded a virus that replicated more rapidly than did an otherwise isogeneic NRE-positive virus. The suppressive effect of the NRE did not depend upon the negative regulatory gene (nef), as both NRE-positive and NRE-negative viruses were defective for nef. We conclude that factors specified by the cell interact with the NRE sequences to retard human immunodeficiency virus type 1 replication.
We present a prospective, unrandomized, uncontrolled series of 1272 patients in whom endoscopic sphincterotomy (ES) was performed, and who had not previously undergone cholecystectomy. These patients were culled from our combined experience of a total of 4177 patients in whom ES was performed over the last 13 yr. Of the group reported here, 1208 patients had demonstrable gallbladder stones, and 64 had acalculous gallbladders. The group included 896 females and 396 males whose mean age was 73.3 yr and who ranged from 17 to 101 yr old. Cholangitis was present in 317 patients (25%), and gallstone pancreatitis in 134 (10.5%) patients. After sphincterotomy, 109 patients (8.6%) developed cholecystitis; 23 developed this within 48 h, and 86 developed this within 10 days of the procedure. Emergency surgery was performed on 25 of these patients, and 84 responded to medical therapy alone. Two deaths occurred within 30 days of sphincterotomy (0.15%), in both cases following emergency surgery in elderly patients. One hundred-eight patients underwent elective cholecystectomy within 3 yr of their sphincterotomy because of recurrent symptoms referrable to the biliary tract. In a subset of 337 patients in whom long-term followup was possible, two patients died of complications related to recurrent cholecystitis, both at approximately 2 yr after sphincterotomy. Although followup was less than optimal in this large series of patients, the data presented here suggest that an intact gallbladder is not a contraindication to ES in the management of common bile duct stones, and that the morbidity and mortality of ES compare favorably over the long and short term with surgical management.
In a prospective series 102 non-variceal upper GI bleeders were studied. An indication for endoscopic injection therapy was seen in 63 patients. In accordance with bleeding intensity, 27 patients were grouped as Forrest Ia, 37 as Forrest Ib, 8 as Forrest II with a "visible vessel" and 13 as Forrest II without one. Definitive hemostasis was achieved in almost 100% of the cases. Within the Forrest Ia group mortality was lowered to 11% as compared with 20% within the emergency surgery group. More than 80% of patients had at least one severe coexistent illness. The aim of endoscopic injection is to avoid surgery in high-risk patients.
We report on the case of a 10-month-old infant with Down's syndrome and acute insulin-dependent diabetes mellitus, who died of hyperosmolar diabetic coma 4 days after admission to the hospital in spite of intensive therapy. Characterizing this disease, a lymphocytic infiltration of the islets of Langerhanns with destruction of the islets was found. The specific localization of the inflammatory infiltrates as well as the histological findings correspond with experimental immune-insulitis in aminals, suggesting that immunological mechanisms play an essential pathogenic role. Virus etiology, diagnostic procedures, and therapeutic approaches are discussed.