Calcium deposition at sites of inflammation and necrosis is a fundamental but poorly understood element of the response of tissue to injury. It is evident in clinical diseases, including atherosclerosis and cardiac valve sclerosis, in which chronic inflammation or degenerative process with cell death is involved. In the presence of normal calcium and phosphate serum concentrations, such calcification is usually termed dystrophic calcification or calcinosis. Ultrastructural studies have shown that the initial events include cell necrosis and granular calcium deposition in or around the mitochondria (1-3). The pivotal role of intracellular calcium concentrations for cell injury and necrosis has been established (4, 5) and recent data also suggest the involvement of cellular calcium homeostasis in the pathogenesis of chronic myocarditis and cardiomyopathy (6-8).Age-related spontaneous dystrophic cardiac calcinosis (DCC) occurs in several inbred strains of mice, including BALB/c, DBA/2, and C3H; DCC may even lead to congestive heart failure in older animals (9-12). Apart from age and genetic background, other factors including infectious agents (13-15), sex (9, 12), hormonal status (9,(16)(17)(18), and diet (1, 9, 19-21) can markedly influence the time of onset and the severity of DCC. The factors involved in the various etiologies of DCC are different, yet a common element of each is cell injury, necrosis, and subsequent calcium deposition. The typical pattern of susceptibility to DCC was also observed following a standardized myocardial freeze-thaw injury, suggesting a common genetic basis independent from the nature of the etiology (22).We now report the mapping of a major gene determining DCC, designated Dyscalc, on proximal mouse chromosome 7. The locus was identified by quantitative trait locus (QTL) analysis of an F2 intercross between the susceptible strain C3H/HeJ and the resistant strain C57BL/6J using a complete linkage map approach. The significance of the QTL results was tested by permutation analysis and the map position was further confirmed by analysis of a set of recombinant inbred (RI) strains derived from these progenitor strains. The results have implications for the understanding of cell injury and necrosis in myocardial and cardiovascular diseases. MATERIALS AND METHODSAnimals. All mice were obtained from The Jackson Laboratory. An F2 intercross between inbred strains C57BL/6J and C3H/HeJ was constructed in our laboratory; only female progeny (n = 197) were included in the studies to eliminate gender differences as a potential confounder. All animals were maintained in pathogen-free facilities on a 12-hr light/12-hr dark cycle with free access to water and food throughout the experimental period. At 3 months of age, mice were placed on a high-fat, high-cholesterol diet (TD 90221; Harlan-Teklad, Madison, WI) to accelerate DCC (23). After 8 weeks of high-fat diet, mice were sacrificed by cervical dislocation.Histological Analyses. After the mice were killed, the heart and proximal aorta were exci...

AimDysregulation of the activity of the disintegrin/metalloproteinase ADAM10 could contribute to the development of atherosclerosis. Although a number of genetic studies have focused on the association of ADAM10 gene polymorphisms with susceptibility to diseases, no genetic association studies of ADAM10 gene variability with atherosclerotic cerebral infarction (ACI) have been conducted. The aim of this study was to analyze the potential association between ADAM10 promoter polymorphisms and ACI.MethodsThe associations between rs653765 and rs514049 polymorphisms of the ADAM10 promoter and the possible risk of ACI were assessed among 347 patients with ACI and 299 matched healthy individuals in a case–control study.ResultsOverall, there was a significant difference in the genotypes frequencies of rs653765 (P = 0.04) between the ACI and control subjects. In addition, the rs653765 mutated allele of ADAM10 was significantly associated with increased ADAM10 expression in patients with ACI (P = 0.032). In contrast, the allele frequency of rs514049 was not statistically associated with ACI, and the rs514049 variant A > C did not affect the expression of ADAM10 either.ConclusionOur findings indicate a positive association between the rs653765 polymorphism of ADAM10 and ACI, as well as a negative result for rs514049. In addition, a significant increase in ADAM10 expression was observed in patients with ACI carrying the rs653765 C > T mutation. This new knowledge about ADAM10 might be clinically important and confirm a role for ADAM10 in the pathophysiology of ACI, with potentially important therapeutic implications.

ObjectivesWe aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT).DesignAnalysis of a multicentre prospective registry.SettingIn six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively.Participants224 patients with AIS were treated by MT.ResultsOf 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality.ConclusionsWe developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated.Trial registration numberChinese Clinical Trial Registry (ChiCTR-OOC-17013052).

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