Occupational silica exposure and lung cancer risk: a review of epidemiological studies 1996-2005.

BACKGROUND: In 1997, a Monograph from the International Agency for Research on Cancer (IARC) classified occupational exposure to crystalline silica as carcinogenic to humans. Large amounts of epidemiological data have been published subsequently. METHODS: We conducted a systematic review of epidemiological investigations on silica exposure and lung cancer risk published after the IARC Monograph, including 28 cohort, 15 case-control and two proportionate mortality ratio (PMR) studies. These were identified in the available literature. RESULTS: The pooled RR of lung cancer, calculated using random effects models, from all cohort studies considering occupational exposure to silica was 1.34. The RRs were 1.69 in cohort studies of silicotics only, 1.25 in studies where silicosis status was undefined and 1.19 among non silicotic subjects. The pooled RR was 1.41 for all case-control studies. The RRs were 3.27 in case-control studies of silicotics only, 1.41 in studies where silicosis status was undefined and 0.97 among non silicotic subjects. The RR was 1.24 for PMR studies. CONCLUSIONS: In this re-analysis, the association with lung cancer was consistent for silicotics, but the data were limited for non silicotic subjects and not easily explained for undefined silicosis status workers. This leaves open the issue of dose-risk relation and pathogenic mechanisms and supports the conclusion that the carcinogenic role of silica per se in absence of silicosis is still unclear.     

Kinetic immunodominance: functionally competing antibodies against exposed and cryptic epitopes of Escherichia coli beta-galactosidase are produced in time sequence.

The murine antibody response to Escherichia coli beta-galactosidase (GZ) was analyzed in vivo and in vitro by focusing on two families of antibodies that exert distinct conformational/functional activity on the antigen. Activating antibodies--defined by their capacity to increase the enzymatic activity of defective GZ produced by mutant strains of E. coli--are detected early after secondary challenge. Inhibiting antibodies, which interfere with antibody-mediated enzyme activation, appear later and cause the abrupt fall of activating titer, a scenario suggesting either idiotype/anti-idiotype interaction or opposite pulsions exerted on the antigen molecule. Supporting the latter mechanism, the confrontation of mAbs of the two families produced classical competitive inhibition curves when the readout was enzyme activation, although they recognize two different epitopes of the same molecule: the activating mAb a quaternary conformation-dependent site of wild-type GZ, the inhibiting mAb a sequential determinant exposed only in denatured or in defective enzyme. The different timing of generation of these antibodies during the response may depend on a processing step necessary for unfolding of native antigen and consequent display of certain cryptic epitopes before they can trigger specific B cells. A picture emerges where the response to the various epitopes of a complex antigen is sequentially connected and where the uptake by antigen-presenting cells of antigen complexed with antibodies specific for the exposed epitopes may favor revelation of the cryptic ones.     

Motor neuron disease and optic neuropathy after acute exposure to a methanol-containing solvent mixture.

A 34-years-old floor-layer developed optic neuropathy and motor neuron disease after being accidentally exposed to a solvent mixture containing methanol and other substances. Optic neuropathy is a complication of methanol poisoning, but the onset of a motor neuron disorder resembling amyotrophic lateral sclerosis after the exposure to these substances has not been previously described. The temporal onset of the clinical symptoms, biological plausibility, young age of the patient and absence of neurological disorders in the family history raises suspicion of a possible causative relationship.     

Epitope focus, clonal composition and Th1 phenotype of the human CD4 response to the secretory mycobacterial antigen Ag85

Lymphoproliferation of healthy donors was tested against mycobacterial antigens (PPD, Ag85, Ag85 peptides). All PPD responders recognized the secretory antigen Ag85 and the peptide specificity for Ag85B was defined. Peptide 91-108 was recognized by 85% of donors. In addition, all CD4 T cell lines generated from 12 donors against PPD or Ag85 responded to 91-108. When this peptide was used to generate T cell lines, the cells responded also to tuberculins from atypical mycobacterial species. Thus the cross-reactive peptide behaved as quasi-universal. The analysis of TCR-BV gene usage by cell lines showed that most Ag85-specific T cells correspond to 91-108-specific clonotypes. Intracytoplasmic staining of cell lines after phorbol myristate acetate stimulation resulted in dominance of interferon-gamma (IFN-gamma)-IL-4 double-positive cells, whereas antigen stimulation resulted in production of IFN-gamma only. The data show that peptide 91-108 is the major focus of the CD4 response to mycobacterial antigens in peripheral blood mononuclear cells and in T cell lines from PPD responders.     

High-density lipoprotein cholesterol subfractions in chronic uremia

Cholesterol content in high-density lipoprotein (HDL) subfractions has been studied in 108 patients at different evolutive stages of chronic renal failure (CRF) under conservative treatment. Results have been compared with healthy control subjects, patients receiving hemodialysis, and renal graft recipients. Significant low levels of total HDL and HDL2 cholesterol are observed in men with CRF. The more severe the CRF, the more likely that total HDL and HDL2 cholesterol will be low. Moreover, a significant inverse correlation is found between HDL2 cholesterol and serum creatinine levels. In women, although a decrease in total and HDL2 subfraction is observed, no significant differences are found across the severity of CRF. Serum HDL2 cholesterol levels are decreased in men and women receiving hemodialysis, while raised total HDL and HDL2 cholesterol levels are observed in normally functioning renal grafts. These results indicate that according to the "HDL hypothesis," despite other associated risk factors, the high cardiovascular mortality rates noted mainly in men with CRF under conservative treatment and in patients receiving hemodialysis could be explained, at least in part, by the sustained and progressive decrease in total HDL and HDL2 values. From this point of view, our study suggests the need to promote early kidney transplantation.     

Mortality among workers in the geothermal power plants at Larderello, Italy

BACKGROUND: Since the early 1990s various European electricity companies have set up a research program, named EURELEX, devoted to the development of a comprehensive and validated title-occupation--job-exposure matrix (i.e., an instrument to assess exposures from occupations and jobs), in order to estimate and quantify past exposure to a number of potentially carcinogenic agents plus a few selected other toxic substances. The EURELEX program was first applied in Italy to a cohort of geothermal workers in Larderello, Tuscany. METHODS: The cohort mortality study comprised 4,237 men who had worked at the geothermal power plant between 1950 and 1990. Vital status and death certificates were obtained from registration offices in the municipality of birth or death. Particular attention was paid to neoplastic effects of exposure to asbestos, largely used in the past for pipeline insulating purposes. The matrix allowed the workers to be subdivided into several categories according to estimated absestos exposure. Smoking information was not available. RESULTS: No excess mortality was found for all causes and total cancer mortality. A small excess of pleural cancer (2 obs. vs. 1.4 exp.) was not statistically significant. The effect of other agents included in the matrix was also examined: the small excess of leukemia among those exposed to solvents prior to 1963 (year of benzene ban in Italy) did not reach the level of statistical significance. No cases of leukemia were found among the workers presumed to have been exposed to important ELF electromagnetic fields. CONCLUSION: The study provides reassuring information on a large cohort of a unique geothermal power plant since no significant excess mortality for asbestos related cancers was observed. Furthermore, it represents a useful application and validation of a comprehensive job-exposure matrix for the electric industry in Europe.     

Time Trends in Outcomes After Aneurysmal Subarachnoid Hemorrhage Over the Past 30 Years

Objective

To analyze trends in mortality rates, functional outcomes, and treatment in patients with aneurysmal subarachnoid hemorrhage (aSAH) over the past 3 decades.

High throughput functional microdissection of pathogen-specific T-cell immunity using antigen and lymphocyte arrays

The analysis of the human T-cell response specific for relevant pathogens is useful for diagnostic purposes and for research. Several methods enumerate antigen specific T-cells and measure their functions. Since screening of numerous antigens from pathogens is often needed to evaluate immunocompetence, lymphocytes, labor and cost are limiting factors. To examine pathogen-specific T-cell immunity, we have miniaturized the analysis of T-cell responses using an array approach in 384- and 1536-well plates with as few as 10 x 10(3) PBMC per well instead of the 500 x 10(3) PBMC used for current assays. Secreted cytokines were detected in the same wells used for lymphocyte cultures. The method can detect about ten CMV specific T-cells diluted into 50 x 10(3) PBMC (0.02%), and can quantify secreted cytokines. The microarray approach allowed evaluation of T-cell immunity in children with a sensitivity higher than current methods. When applied to CMV epitope mapping, the data obtained with conventional methods were confirmed. The assay could be automated, allowing high throughput processing. The assay provides quantitative information on cytokines induced by antigen stimulation and can be applied in a simplified format as a field test to monitor T-cell immunity in vaccine trials or in veterinary medicine.     

Helper function of cytolytic lymphocytes: switching roles in the immune response

T helper (Th) cells and cytolytic T lymphocytes (CTL) play defined roles in the cellular immune response. This distinction wavered when Th lymphocytes were shown to kill antigen-presenting cells displaying the relevant antigen. Here we demonstrate that also the opposite can be true: CTL can exert helper functions. We noticed that certain CMV-specific CTL lines grew after antigen activation also without exogenous IL-2. These lines produced their own IL-2, which supported the expansion of other CTL and Th cell lines. High levels of helper cytokines like IL-4, IL-5 and IL-6 were detected in the culture supernatants. Thus, we set up a helper assay to study the functional interactions between T cells (or their supernatants) and B cells. Conditioned media from helper CTL lines induced secretion of antigen-specific antibodies by B cells pulsed with antigen as first signal. We conclude that it is possible to isolate CTL lines that exhibit helper functions for T cells and B cells. If this possibility is proven also in vivo, we should revise some of our views on the pathogenesis of diseases in which CD8 cells are key players, such as in viral infections, graft rejection and GVHD.