Quantitative trait analysis of the development of pulmonary tolerance to inhaled zinc oxide in mice

BACKGROUND: Individuals may develop tolerance to the induction of adverse pulmonary effects following repeated exposures to inhaled toxicants. Previously, we demonstrated that genetic background plays an important role in the development of pulmonary tolerance to inhaled zinc oxide (ZnO) in inbred mouse strains, as assessed by polymorphonuclear leukocytes (PMNs), macrophages, and total protein in bronchoalveolar lavage (BAL) phenotypes. The BALB/cByJ (CBy) and DBA/2J (D2) strains were identified as tolerant and non-tolerant, respectively. The present study was designed to identify candidate genes that control the development of pulmonary tolerance to inhaled ZnO. METHODS: Genome-wide linkage analyses were performed on a CByD2F2 mouse cohort phenotyped for BAL protein, PMNs, and macrophages following 5 consecutive days of exposure to 1.0 mg/m(3 )inhaled ZnO for 3 hours/day. A haplotype analysis was carried out to determine the contribution of each quantitative trait locus (QTL) and QTL combination to the overall BAL protein phenotype. Candidate genes were identified within each QTL interval using the positional candidate gene approach. RESULTS: A significant quantitative trait locus (QTL) on chromosome 1, as well as suggestive QTLs on chromosomes 4 and 5, for the BAL protein phenotype, was established. Suggestive QTLs for the BAL PMN and macrophage phenotypes were also identified on chromosomes 1 and 5, respectively. Analysis of specific haplotypes supports the combined effect of three QTLs in the overall protein phenotype. Toll-like receptor 5 (Tlr5) was identified as an interesting candidate gene within the significant QTL for BAL protein on chromosome 1. Wild-derived Tlr5-mutant MOLF/Ei mice were tolerant to BAL protein following repeated ZnO exposure. CONCLUSION: Genetic background is an important influence in the acquisition of pulmonary tolerance to BAL protein, PMNs, and macrophages following ZnO exposure. Promising candidate genes exist within the identified QTL intervals that would be good targets for additional studies, including Tlr5. The implications of tolerance to health risks in humans are numerous, and this study furthers the understanding of gene-environment interactions that are likely to be important factors from person-to-person in regulating the development of pulmonary tolerance to inhaled toxicants

Quantitative in vivo receptor binding IV: Detection of muscarinic receptor down-regulation by equilibrium and by tracer kinetic methods

Newly-developed methods for estimation of in vivo binding to neurotransmitter receptors should enable the detection and quantification of physiologic or pathologic changes in receptor numbers. In the present study, both equilibrium and kinetic experimental strategies for in vivo muscarinic receptor determination were applied to the detection of receptor changes induced by chronic inhibition of acetylcholinesterase in the rat. Following one week of treatment, in vitro receptor autoradiography utilizing [ 3 H]scopolamine revealed significant losses of muscarinic binding in the cerebral cortex, hippocampus, striatum and in cranial nerve motor nuclei. The in vivo distribution of [ 3 H]scopolamine, following infusion to approach equilibrium binding in the brain, revealed reductions in binding which paralleled the pattern and magnitude of changes detected in vitro. A simplified tracer kinetic estimation following bolus injection of the ligand also detected substantial reductions in forebrain muscarinic receptor binding. These results indicate the feasibility of detecting receptor changes underlying neuropathologic conditions in vivo, and suggest that either equilibrium or kinetic experimental approaches may be extended to clinical research applications with the use of positron or single-photon emission tomography.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45405/1/11064_2004_Article_BF00965845.pd

Carcinoembryonic antigen present in human eccrine sweat

Carcinoembryonic antigen is detectable by standard unlabeled peroxidase-antiperoxidase technics in eccrine and apocrine secretory and ductal cells. Carcinoembryonic antigen is also present in the cuticle which lines the duct. In eccrine sweat, carcinoembryonic antigen activities were at least thirty times that in serum, using a radioimmunoassay. Carcinoembryonic antigen may form part of the Schiff-positive cuticle and function in the normal homeostasis of eccrine and apocrine glands

Sinus histiocytosis with massive lymphadenopathy. A case with unusual skin involvement and a therapeutic response to vinblastine‐loaded platelets

A patient with sinus histiocytosis with massive lymphadenopathy had unusual skin lesions and progressive internal involvement. Both aspects responded dramatically to the administration of vinblastine‐loaded platelets. Vinblastine‐loaded, idiopathic thrombocytopenic purpura antibody‐coated platelets are a rationale therapy for a disease characterized by the presence of actively phagocytosing histiocytes

Mechanisms of levamisole‐induced granulocytopenia in breast cancer patients

Five of 39 (13%) women treated with adjuvant combination chemotherapy plus levamisole immunotherapy after mastectomy for Stage II or III breast cancer developed levamisole‐induced granulocytopenia. This complication occurred in each of the women between six and ten weeks after the completion of six months of combination chemoimmunotherapy when they were taking levamisole alone. Although none of the patients had an HLA B‐27 locus and leukoagglutinins could not be demonstrated, complement‐dependent, IgM mediated, peripheral destruction of granulocytes was documented using a microgranulocytotoxicity assay. In addition, a factor(s) present in serum from patients developing levamisole‐induced granulocytopenia caused suppression of bone marrow granulocyte progenitor cells (CFU‐C). The possible relationships between levamisole‐induced peripheral granulocyte destruction and bone marrow CFU‐C suppression are discussed