Biomedical subjects
Publications and source records attributed to R Devlin.
Struvite stones are caused by urea-splitting, usually gram-negative, organisms. A case of aggressive struvite stone production caused by Corynebacterium group F1 is reported that responded to the appropriate antibiotic treatment. To our knowledge this organism has never been associated previously with struvite stone formation.
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This study was performed to determine if genes for tissue factor and factor VII proteins are expressed and regulated in vivo in lung macrophages during inflammation. Human alveolar macrophages and alveolar fluids were obtained 18 hours after healthy male adults were exposed, for 2 hours during intermittent exercise, to either air or air with 0.4 ppm ozone, added as a model toxic respiratory agent. Messenger RNA (mRNA) for both tissue factor and factor VII were demonstrated in macrophages isolated after subjects were exposed to unpolluted control air. With the same subjects examined after breathing ozone, the following changes were observed: tissue factor mRNA concentration in macrophages increased 2.6 +/- 0.47-fold. Factor VII mRNA concentration was reduced 0.64 +/- 0.24-fold. Total numbers of macrophages recovered did not change significantly. Ratios of nuclear:cytoplasmic areas of cytocentrifuged macrophages were augmented by 24.8% +/- 3%, giving morphometric evidence that immature cell forms increased in the population. In the lavage, tissue factor activity was increased 2.1 +/- 0.3-fold, while amounts of lipid phosphorous, which estimate total membrane lipids, and estimated volumes of alveolar fluid were not significantly changed. Factor VII activity and fibrinopeptide A levels in lavage were increased approximately twofold. These results using rapidly isolated, noncultured cells indicate that tissue factor and factor VII mRNA are synthesized in the alveolar macrophage population in vivo. In addition, evidence was found that as a result of breathing ozone, a shift in alveolar macrophage maturity occurred in association with tissue factor mRNA, tissue factor activity, and factor VII activity increases, and with formation of fibrinopeptide A in alveolar fluids.
Lipoprotein lipase (LPL) plays a crucial role in the regulation of lipoprotein metabolism by hydrolysing the core triglycerides of circulating chylomicrons and VLDL. Human, bovine, mouse, and guinea pig complementary DNA clones have recently been isolated and the organization of the human LPL gene is now known to comprise 10 exons spanning approximately 30 kb. Here we report a similar mutation on 21 alleles from 13 unrelated affected probands with LPL deficiency of French Canadian, English, Polish, German, Dutch, and East Indian ancestry. We show that an identical missense mutation within exon 5, resulting in an amino acid substitution of glutamic acid for glycine at position 188, is responsible for LPL deficiency in 21 of 88 LPL alleles assessed. This mutation alters an Ava II restriction site in exon 5 and will allow a rapid screening test for this mutation in patients with LPL deficiency. This mutation has occurred on the same haplotype in all the unrelated affected persons suggesting a common origin. The amino acid substitution lies within the longest segment of homology for LPL in different species and results in a protein that is catalytically defective.
Several mutations in the human lipoprotein lipase (LPL) gene have been shown to underlie LPL deficiency. These mutations occur in patients who are mainly of European descent, and comprise a single base transition causing a premature stop codon, four separate amino acid substitutions and two large gene rearrangements. Together they account for approximately 40% of the LPL alleles in a cohort of 50 patients whose DNA has been examined in this laboratory. We now report on a new mutation in exon 3 of the LPL gene from a South African subject of South-east Asian extraction. This mutation comprises a six base-pair insertion at the site of a single base deletion. The net insertion of five base-pairs at amino acid positions 102 to 103 causes a shift in the reading frame, generating 44 amino acid residues of random sequence and a premature stop codon within exon 4. This mutation is predicted to result in the synthesis of a markedly truncated protein and is the cause of the enzyme deficiency in our patient.
Clotting factors synthesized by monocytes and macrophages may initiate coagulation reactions during inflammation. Functional vitamin K-dependent coagulation factors have been found to be associated with human monocytes/macrophages, but there are no reports identifying mRNA coding for vitamin K-dependent proteins in these cells. In the present studies, factor VII mRNA was found in total RNA extracted from freshly isolated human alveolar macrophages using hybridization with a complementary DNA probe. On the other hand, vitamin K-dependent carboxylase activity which is required for postribosomal modification of the protein, was not detectable in the macrophages before or after culture, and human blood mononuclear leukocytes also lacked this enzyme activity. Control human and rat hepatoma cells exhibited high levels of carboxylase activity within the same experiments. Using sensitive kinetic assays, no increase in factor VII activity was detected during culture of alveolar macrophages under conditions promoting 1.78 +/- .24 (n = 8) fold increases of tissue factor activity. These findings with freshly isolated cells demonstrate that alveolar macrophages synthesize factor VII mRNA in vivo. However, the mRNA was found in the absence of evidence for gamma-carboxylase activity or processing of the factor into a functional clotting enzyme. The results imply that functional expression of any synthesized coagulation factor VII in alveolar macrophages may be limited or prevented due to a cellular deficiency at the level of postribosomal processing.
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Several clones containing alpha tropomyosin sequences were isolated from cDNA libraries prepared from quail skeletal or smooth muscle RNA. All of these clones contain identical sequences coding for amino acids 81-257 of alpha skeletal muscle tropomyosin where they overlap, strongly indicating they are derived from the same gene. However, there are differences among these clones in sequences coding for the final 27 amino acids, as well as 3' untranslated sequences. In addition, S1 nuclease and Northern analyses indicate that coding sequences at the 5' end of the tropomyosin mRNA are also differentially expressed in smooth and skeletal muscle. These data point to the likelihood that differential splicing at both the 5' and 3' ends of a single tropomyosin gene results in the appearance of multiple tissue-specific transcripts.
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