Occupational exposure to chrysotile asbestos and cancer risk: a review of the amphibole hypothesis

OBJECTIVES: This article examines the credibility and policy implications of the "amphibole hypothesis," which postulates that (1) the mesotheliomas observed among workers exposed to chrysotile asbestos may be explained by confounding exposures to amphiboles, and (2) chrysotile may have lower carcinogenic potency than amphiboles. METHODS: A critical review was conducted of the lung burden, epidemiologic, toxicologic, and mechanistic studies that provide the basis for the amphibole hypothesis. RESULTS: Mechanistic and lung burden studies do not provide convincing evidence for the amphibole hypothesis. Toxicologic and epidemiologic studies provide strong evidence that chrysotile is associated with an increased risk of lung cancer and mesothelioma. Chrysotile may be less potent than some amphiboles for inducing mesotheliomas, but there is little evidence to indicate lower lung cancer risk. CONCLUSIONS: Given the evidence of a significant lung cancer risk, the lack of conclusive evidence for the amphibole hypothesis, and the fact that workers are generally exposed to a mixture of fibers, we conclude that it is prudent to treat chrysotile with virtually the same level of concern as the amphibole forms of asbestos.     

Adsorption of amyloid beta (1-40) peptide at phospholipid monolayers

The folding of amyloid beta (1-40) peptide into beta-sheet-containing fibrils is thought to play a causative role in Alzheimer's disease. Because of its amphiphilic character, the peptide can interact with phospholipid membranes. Langmuir monolayers of negatively charged DPPS, DPPG, and DMPG, and also of zwitterionic DPPC and DMPC, have been used to study the influence of the peptide on the lipid packing and, vice versa, the influence of phospholipid monolayers on the peptide secondary structure by infrared reflection absorption spectroscopy and grazing incidence X-ray diffraction. The peptide adsorbs at the air/water (buffer) interface, and also inserts into uncompressed phospholipid monolayers. When adsorbed at the interface, the peptide adopts a beta-sheet conformation, with the long axis of these beta-sheets oriented almost parallel to the surface. If the lipid exhibits a condensed monolayer phase, then compression of the complex monolayer with the inserted peptide leads to the squeezing out of the peptide at higher surface pressures (above 30 mN m(-1)). The peptide desorbs completely from zwitterionic monolayers and negatively charged DPPG and DPPS monolayers on buffer, but remains adsorbed in the beta-sheet conformation at negatively charged monolayers on water. This can be explained in terms of electrostatic interactions with the lipid head groups. It also remains adsorbed at, or penetrating into, disordered anionic monolayers on buffer. Additionally, the peptide does not influence the condensed monolayer structure at physiological pH and modest ionic strength.     

Polymorphonuclear neutrophil chemotaxis in Chinese patients with post-juvenile periodontitis and rapidly progressive periodontitis

The purpose of this study was to investigate polymorphonuclear neutrophil (PMN) chemotaxis in Chinese patients with post-juvenile periodontitis (post-JP) and rapidly progressive periodontitis (RPP). Peripheral blood PMNs were isolated from nine post-JP and 13 RPP patients. Eight patients with adult periodontitis (AP) and seven clinically healthy subjects were used for comparison. Clinical data, including the plaque index and gingival index, of each subject were recorded. The "modified Boyden chamber technique" was used for PMN chemotaxis assay. Our results showed that the PMN chemotaxis index in patients with post-JP and RPP were significantly depressed compared to that in healthy subjects or patients with AP. There was no significant difference in PMN chemotaxis between post-JP and RPP, or between AP and healthy subjects. There was also no significant correlation between the plaque index, or gingival index, and PMN chemotaxis in any group. These results suggest that there is a PMN chemotaxis defect in most Chinese patients affected by post-JP or RPP, and that the PMN chemotaxis defect is not associated with clinical parameters such as the plaque index or gingival index.     

Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization

Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells. In mice homozygous for the paucity of lymph node T cell (plt) mutation, naive T cells fail to home to LNs or the lymphoid regions of spleen. Here we demonstrate that expression of SLC is undetectable in plt mice. In addition to the defect in T cell homing, we demonstrate that dendritic cells (DCs) fail to accumulate in spleen and LN T cell zones of plt mice. DC migration to LNs after contact sensitization is also substantially reduced. The physiologic significance of these abnormalities in plt mice is indicated by a markedly increased sensitivity to infection with murine hepatitis virus. The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal. These findings suggest that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.     

Intracerebral Whipple''s disease diagnosed by stereotactic biopsy: a case report and review of the literature

We studied the effects of bile stasis in a guinea pig model of pigment gallstone. The common bile ducts of guinea pigs were partially ligated, and the guinea pigs killed one or two weeks later. Biliary sludge or stones were examined with the Fourier transform infrared spectroscopy and the scanning electromicroscopy. The bile was analyzed for pH, free calcium, bile acids and bilirubin fractions, and the activities of both bacterial and endogenous beta-glucuronidase. After bile duct ligation, calcium bilirubinate precipitates or stones formed in all except one of the animals studied. The bile pH and the proportion of unconjugated bilirubin rose after bile duct ligation, with a concomitant fall of bilirubin monoglucuronide. The activity of bacterial beta-glucuronidase decreased after ligation, while the activity of endogenous beta-glucuronidase rose at week 2. Our results imply that precipitation of calcium bilirubinate in this animal model was induced by an increased bile pH and the nonenzymatic hydrolysis of conjugated bilirubin.     

Resistance to HIV protease inhibitors: a comparison of enzyme inhibition and antiviral potency

Resistance of HIV-1 to protease inhibitors has been associated with changes at residues Val82 and Ile84 of HIV-1 protease (HIV PR). Using both an enzyme assay with a peptide substrate and a cell-based infectivity assay, we examined the correlation between the inhibition constants for enzyme activity (Ki values) and viral replication (IC90 values) for 5 active site mutants and 19 protease inhibitors. Four of the five mutations studied (V82F, V82A, I84V, and V82F/I84V) had been identified as conferring resistance during in vitro selection using a protease inhibitor. The mutant protease genes were expressed in Escherichia coli for preparation of enzyme, and inserted into the HXB2 strain of HIV for test of antiviral activity. The inhibitors included saquinavir, indinavir, nelfinavir, 141W94, ritonavir (all in clinical use), and 14 cyclic ureas with a constant core structure and varying P2, P2' and P3, P3' groups. The single mutations V82F and I84V caused changes with various inhibitors ranging from 0.3- to 86-fold in Ki and from 0.1- to 11-fold in IC90. Much larger changes compared to wild type were observed for the double mutation V82F/I84V both for Ki (10-2000-fold) and for IC90 (0.7-377-fold). However, there were low correlations (r2 = 0.017-0.53) between the mutant/wild-type ratio of Ki values (enzyme resistance) and the mutant/wild-type ratio of viral IC90 values (antiviral resistance) for each of the HIV proteases and the viruses containing the identical enzyme. Assessing enzyme resistance by "vitality values", which adjust the Ki values with the catalytic efficiencies (kcat/Km), caused no significant improvement in the correlation with antiviral resistance. Therefore, our data suggest that measurements of enzyme inhibition with mutant proteases may be poorly predictive of the antiviral effect in resistant viruses even when mutations are restricted to the protease gene.     

Signet-ring cell melanoma mimicking adenocarcinoma. A case report

The fine needle aspiration findings in a lymph node involved by signet-ring cell melanoma, a very rare variant of malignant melanoma, are reported. The patient had a history of superficial spreading melanoma of the right foot, treated 10 years earlier by below-the-knee amputation. He presented with a right groin mass. Fine needle aspiration of the mass yielded poorly cohesive, large cells with eccentric nuclei and abundant, eosinophilic cytoplasm; many of them exhibited a signet-ring appearance. Melanin pigments were identified in a small proportion of tumor cells, and a diagnosis of metastatic melanoma was made. The subsequent lymph node excision revealed a metastatic tumor composed of polygonal and signet-ring cells that were positive for S-100 protein and HMB-45 but not cytokeratin. Nearly all reported cases of signet-ring cell melanoma occurred as metastatic or recurrent disease. It is important not to mistake signet-ring cell melanoma for adenocarcinoma in aspiration cytology, and a constellation of clinical features and of histochemical and immunohistochemical findings enables a correct diagnosis to be reached.     

Survey of the Navy's three-tiered obesity treatment program

The Navy's diverse, three-tiered obesity treatment program is described. Level I (command-directed) programs rely primarily on group exercise to treat obesity; most level II (outpatient counseling) and level III (6-week inpatient) programs are modeled on Overeaters Anonymous and devote substantial amounts of time to group discussion, behavior modification, and nutrition education. Lack of funding or staffing has prevented many level II facilities from conducting a weight-management program, however. Further research might explore the potential for level II to provide a cost-effective middle ground for obesity treatment.