Increased plasma levels of metalloproteinase-9 are associated with abdominal aortic aneurysms

AbstractPurpose: Previous investigators have identified disease-specific elevations of metalloelastase-9 (MMP-9) in aneurysm tissue biopsies. We hypothesized that circulating MMP-9 might also be elevated in patients with aneurysms. The purpose of this study was to compare plasma and aortic tissue MMP-9 levels in patients with infrarenal aneurysms (AAAs), patients with symptomatic aortoiliac occlusive disease (AOD), and healthy patients. Methods: A sandwich enzyme-linked immunosorbent assay was used to measure plasma MMP-9 in patients with AAA (n = 22; mean age, 72.7 years), with AOD (n = 9; mean age, 60.5 years), and without disease (n = 8; mean age, 35.3 years). The MMP-9 levels also were measured in 48-hour supernatants of organ culture tissue explants from patients with AAA (n = 10; mean age, 66.2 years) and AOD (n = 5; mean age, 50.4 years) and organ donors (n = 7; mean age, 48.1 years). The results were reported as the mean ± the standard error of the mean and analyzed with analysis of variance with multivariate regression. Results: The plasma MMP-9 levels were significantly higher in the patients with AAA (85.66 ng/mL ± 11.64) than in the patients with AOD (25.75 ng/mL ± 4.159; P < .001) or the healthy patients (13.16 ng/mL ± 1.94; P < .001). No significant difference in plasma MMP-9 levels between patients with AOD and healthy patients was identified. The patients with multiple aneurysms had significantly higher levels of plasma MMP-9 than did the patients with an isolated AAA (134.68 ng/mL ± 17.5 vs 71.03 ng/mL ± 10.7; P < .04). In organ culture, AAA and AOD tissue explants produced significantly higher levels of MMP-9 (3218.5 ng/gm ± 1115.2 and 1283.1 ng/gm ± 310.6 aortic tissue) than did disease-free explants (6.14 ng/gm ± 2.3 aortic tissue; P < .0001). No significant difference in MMP-9 production between AAA and AOD explants was identified. Conclusion: Plasma MMP-9 levels are significantly higher in patients with AAA than in patients with AOD or in healthy volunteers. The patients with multiple aneurysms have higher levels than those patients with an isolated AAA. Organ culture studies suggest that diseased aortic tissue is the source of MMP-9. (J Vasc Surg 1999;29:122-9.

Plasminogen activator levels are influenced by location and varicosity in greater saphenous vein

AbstractPurpose: The plasminogen system, which includes tissue type plasminogen activator (tPA), urokinase type plasminogen activator (uPA), and their main inhibitor, plasminogen activator inhibitor type 1 (PAI-1), plays a major role in both fibrinolysis and tissue remodeling. This study compares the levels of tPA, uPA, and PAI-1 at the groin and ankle in normal and varicose greater saphenous vein (GSV).Methods: GSV was collected from patients undergoing varicose vein (VV) removal and from normal vein (NV) from arterial bypass procedures. Portions of the GSV at the groin and the ankle were minced and placed in serum-free media for 48 hours. Assays of the supernatants were obtained for tPA, uPA, and PAI-1 protein by enzyme-linked immunosorbent assay. Cyclohexamide and actinomycin D were also added to the media of the VV tissue explant supernatants to inhibit protein and RNA synthesis, respectively.Results: Levels of tPA were significantly higher at the groin (11 ± 2) than the ankle (5 ± 1) in the VV ( p < 0.005), and this trend was also seen in the NV (groin 10 ± 2 and ankle 7 ± 3). Levels of uPA were significantly higher in the groin VV (14 ± 4.3) than in NV (3.0 ± 0.8, p < 0.05). This difference, although not statistically significant, applied to the ankle as well (VV 14.5 ± 6.3 and NV 5.3 ± 2.7). No significant difference was seen between NV and VV for PAI-1 (NV, groin 155 ± 73 and ankle 113 ± 53, VV, groin 161 ± 20 and ankle 142 ± 38) or tPA. Inhibitor studies revealed no significant difference among control, cyclohexamide, and actinomycin D supernatants for tPA, suggesting release of protein rather than active synthesis. In contrast, inhibitor supernatants were significantly lower for uPA and PAI-1 than control supernatants ( p < 0.05), suggesting that uPA and PAI-1 were actively synthesized.Conclusions: In the tissue explant supernatant model uPA and PAI-1 are actively synthesized, but tPA is not. Levels of PAI-1 were comparable in all four groups. Levels of uPA in the varicose GSV were higher than in NV, suggesting a role for uPA in the pathologic makeup of VV. Levels of tPA were higher at the groin versus the ankle position, potentially explaining the previously described increased fibrinolytic activity seen at the groin. (J Vasc Surg 1996;24:719-24.

Leg strength in peripheral arterial disease: associations with disease severity and lower-extremity performance

AbstractObjectiveThe purpose of this study was to determine relationships between lower-extremity arterial obstruction, leg strength, and lower-extremity functioning.DesignThe study design was cross-sectional. A total of 514 outpatients (269 with ankle-brachial index [ABI] <0.90), aged 55 and older, were identified from three Chicago-area hospitals. Individuals with history of lower-extremity revascularization were excluded.Main outcome measuresStrength in each leg, 6-minute walk, 4-meter walking velocity, accelerometer-measured physical activity, and a summary performance score were measured. The summary performance score is a composite measure of lower-extremity functioning, ranging from 0 to 12 (12 = best). The leg with the lower ABI was defined as the “index” leg, and the leg with higher ABI was defined as the “contralateral” leg.ResultsIndex leg ABI levels were associated linearly and significantly with strength for hip extension (P < .001), hip flexion (P < .001), knee extension (P = .066), and knee flexion (P = .003), adjusting for known and potential confounders. In adjusted analyses, the index ABI was also associated linearly and significantly with strength in the contralateral leg. Adjusting for confounders, including ABI, knee extension strength, was associated independently with functional measures.ConclusionAmong patients without prior leg revascularization, strength in each leg is highly correlated with the lower-leg ABI. Leg strength is associated independently with functional performance. Further study is needed to determine whether lower-extremity resistance training improves functioning in patients with peripheral arterial disease

A North Atlantic tephrostratigraphical framework for 130-60 ka b2k:new tephra discoveries, marine-based correlations, and future challenges

Building chronological frameworks for proxy sequences spanning 130–60 ka b2k is plagued by difficulties and uncertainties. Recent developments in the North Atlantic region, however, affirm the potential offered by tephrochronology and specifically the search for cryptotephra. Here we review the potential offered by tephrostratigraphy for sequences spanning 130–60 ka b2k. We combine newly identified cryptotephra deposits from the NGRIP ice-core and a marine core from the Iceland Basin with previously published data from the ice and marine realms to construct the first tephrostratigraphical framework for this time-interval. Forty-three tephra or cryptotephra deposits are incorporated into this framework; twenty three tephra deposits are found in the Greenland ice-cores, including nine new NGRIP tephras, and twenty separate deposits are preserved in various North Atlantic marine sequences. Major, minor and trace element results are presented for the new NGRIP horizons together with age estimates based on their position within the ice-core record. Basaltic tephras of Icelandic origin dominate the framework with only eight tephras of rhyolitic composition found. New results from marine core MD99-2253 also illustrate some of the complexities and challenges of assessing the depositional integrity of marine cryptotephra deposits. Tephra-based correlations in the marine environment provide independent tie-points for this time-interval and highlight the potential of widening the application of tephrochronology. Further investigations, however, are required, that combine robust geochemical fingerprinting and a rigorous assessment of tephra depositional processes, in order to trace coeval events between the two depositional realms

Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management