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- Fong, L. G., et al.
(författare)
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Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice
- 2004
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Ingår i: Proc Natl Acad Sci U S A. ; 101:52, s. 18111-18116
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Tidskriftsartikel (refereegranskat)abstract
- Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24(-/-) mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24(-/-) mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24(-/-)Lmna(+/-) mice. As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were significantly reduced. Zmpste24(-/-)Lmna(+/-) mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.
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- Omland, T, et al.
(författare)
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N-Terminal Pro-B-Type Natriuretic Peptide and Long-Term Mortality in Acute Coronary Syndromes
- 2002
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 106:20, s. 2913-2918
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Tidskriftsartikel (refereegranskat)abstract
- ackground— B-type natriuretic peptide (BNP) is a predictor of short- and medium-term prognosis across the spectrum of acute coronary syndromes (ACS). The N-terminal fragment of the BNP prohormone, N-BNP, may be an even stronger prognostic marker. We assessed the relation between subacute plasma N-BNP levels and long-term, all-cause mortality in a large, contemporary cohort of patients with ACS. Methods and Results— Blood samples for N-BNP determination were obtained in the subacute phase in 204 patients with ST-elevation myocardial infarction (MI): 220 with non-ST segment elevation MI and 185 with unstable angina in the subacute phase. After a median follow-up of 51 months, 86 patients (14%) had died. Median N-BNP levels were significantly lower in long-term survivors than in patients dying (442 versus 1306 pmol/L; P<0.0001). The unadjusted risk ratio of patients with supramedian N-BNP levels was 3.9 (95% confidence interval, 2.4 to 6.5). In a multivariate Cox regression model, N-BNP (risk ratio 2.1 [95% confidence interval, 1.1 to 3.9]) added prognostic information above and beyond Killip class, patient age, and left ventricular ejection fraction. Adjustment for peak troponin T levels did not markedly alter the relation between N-BNP and mortality. In patients with no evidence of clinical heart failure, N-BNP remained a significant predictor of mortality after adjustment for age and ejection fraction (risk ratio, 2.4 [95% confidence interval, 1.1 to 5.4]). Conclusions— N-BNP is a powerful indicator of long-term mortality in patients with ACS and provides prognostic information above and beyond conventional risk markers.
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