Telomere dysfunction provokes regional amplification and deletion in cancer genomes

Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.     

Pulmonary manifestations of intentionally released chemical and biological agents

Recent events have underscored the importance of knowledge and understanding of biological and chemical agents that are intentionally released on civilian populations. Preparedness of the medical community to recognize and manage the resulting clinical syndromes will be a major determinant in the outcome of such attack, or a community's 'prognosis' for survival. The biological and chemical agents that have been weaponized produce diseases and toxidromes that are not commonly seen by clinicians in most parts of the United States. Patients or clusters of patients who present with febrile syndromes that are unusual for the geographic or seasonal setting should trigger notification of public health authorities and the use of state or national reference lab systems for augmented diagnostic support. In many cases, early, empiric therapy, administered before definitive diagnosis, is required for survival. The basic principles in the management of exposure to chemical agents include containment, prevention of secondary exposure, rapid decontamination, implementation of supportive and symptomatic care, and specific antidotes as indicated and available.     

Comparison of two methods used to assess first-ray mobility

Mobility of the first-ray is associated with several common lower extremity disorders. However, the reliability and validity of clinical measurement remains unclear. In this study we examined first-ray mobility by using one hand to stabilize the lesser metatarsals while the clinician's other hand applied a displacement force to the head of the first metatarsal. The amount of mobility was graded as stiff, normal or hypermobile. We then used a well-validated mechanical device to perform similar tests and assessed validity, intrarater reliability and interrater reliability. Three clinicians having varied levels of experience graded first-ray mobility on 15 subjects. A separate investigator measured dorsal mobility with a mechanical device. Both methods of testing were repeated to assess measurement reliability. Reliability was estimated by kappa (K) statistics. Spearman correlation assessed the relationship between mobility graded manually and dorsal mobility measured by device. Manual examination intrarater K values ranged from 0.50 to 0.85, and interrater agreement from 0.09 to 0.16. Manual grading was not related (r = -0.21) to the absolute measure of total dorsal mobility made by device. This brings into question the validity and reliability of manual estimates of first-ray mobility.     

Temporal changes in collagen composition and metabolism during rodent palatogenesis

Cleft lip and palate is a common craniofacial malformation in man. The aetiology is multifactorial and not known. Since collagen is a major structural component of the developing palate, we studied its composition and metabolism during palate shelf formation and elevation in the rat. Palatal shelves were harvested at embryonic days (E) 15, 16 and 17 as well as post-partum. Palatal collagen increased threefold from E15 to E17 and tenfold from E17 to 5-day-old pups. Palatal calcification was seen in the main, post-partum. Collagen cross-linking, which may be important in shelf elevation and union, varied. The concentration of hydroxylysyl-pyridinolone cross-links was greatest prior to shelf elevation, declining thereafter. Similarly, the highest concentration of dihydroxylysinononorleucine was seen at E16 and this supports the concept of a compliant mesenchymal shelf responding to an intrinsic elevating force. We then determined if enzymes responsible for matrix degradation, matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMPs) altered over the same time periods. MMP-2, and TIMP-1 and TIMP-2 were identified by gelatin zymography and reverse zymography, respectively. MMP-3 activity was determined with a fluorogenic substrate assay. TIMP-1, TIMP-2 and MMP-3 levels remained constant from E15 to E17. The MMP-2 levels showed a significant elevation from E15 to E16 and E16 to E17. This suggests the regulation of extracellular matrix is likely to be of importance in palate morphogenesis.     

Demonstration of increased proteoglycan turnover in cartilage explants from dogs with experimental osteoarthritis

The turnover of proteoglycans (assessed by the release into the medium of newly synthesised [35S]-proteoglycan) in explant cultures of articular cartilage from various anatomical sites of the knee joints (stifle) of mature beagles with experimental osteoarthritis has been studied with the following findings: (a) The proportion of newly synthesised proteoglycans released from cartilage explants maintained in vitro was generally increased for cartilage from operated compared with nonoperated control joints. (b) At 3 weeks after surgery there was a significant increase in the release of [35S]-proteoglycans from explants of the lateral and medial tibial plateaux of operated joints compared with sham-operated joints but not from other sites. On the other hand, when this comparison was made at 3 to 6 months after surgery, significant increases in the release of [35S]-proteoglycans were observed from cartilage of all anatomical areas except the patellar groove. (c) The release of [35S]-proteoglycan from cartilage explant cultures was dependent on live chondrocytes, since freeze-thawing the tissue immediately after labelling markedly reduced the release from both normal and osteoarthritic cartilage.