High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso-occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein-kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation. OBJECTIVE: We hypothesize that HK contributes to the hypercoagulable and pro-inflammatory state that causes end-organ damage and early mortality in sickle mice. METHODS: We evaluated the role of HK in the Townes mouse model of SCD. RESULTS/CONCLUSIONS: We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK-deficient background. We found that short-term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long-term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.

Learning with sublexical information from emerging reading vocabularies in exceptionally early and normal reading development.

Predictions from theories of the processes of word reading acquisition have rarely been tested against evidence from exceptionally early readers. The theories of Ehri, Share, and Byrne, and an alternative, Knowledge Sources theory, were so tested. The former three theories postulate that full development of context-free letter sounds and awareness of phonemes are required for normal acquisition, while the claim of the alternative is that with or without such, children can use sublexical information from their emerging reading vocabularies to acquire word reading. Results from two independent samples of children aged 3-5, and 5 years, with mean word reading levels of 7 and 9 years respectively, showed underdevelopment of their context-free letter sounds and phoneme awareness, relative to their word reading levels and normal comparison samples. Despite such underdevelopment, these exceptional readers engaged in a form of phonological recoding that enabled pseudoword reading, at the level of older-age normal controls matched on word reading level. Moreover, in the 5-year-old sample further experiments showed that, relative to normal controls, they had a bias toward use of sublexical information from their reading vocabularies for phonological recoding of heterophonic pseudowords with irregular consistent spelling, and were superior in accessing word meanings independently of phonology, although only if the readers were without exposure to explicit phonics. The three theories were less satisfactory than the alternative theory in accounting for the learning of the exceptionally early readers.