Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor.

Low-density lipoprotein receptor (LDLR) mediates clearance of plasma LDL cholesterol, preventing the development of atherosclerosis. We previously demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) cleaves LDLR and exacerbates the development of atherosclerosis. Here, we investigated determinants in LDLR and MT1-MMP that were critical for MT1-MMP-induced LDLR cleavage. We observed that deletion of various functional domains in LDLR or removal of each of the five predicted cleavage sites of MT1-MMP on LDLR did not affect MT1-MMP-induced cleavage of the receptor. Removal of the hemopexin domain or the C-terminal cytoplasmic tail of MT1-MMP also did not impair its ability to cleave LDLR. On the other hand, mutant MT1-MMP, in which the catalytic domain or the MT-loop was deleted, could not cleave LDLR. Further Ala-scanning analysis revealed an important role for Ile at position 167 of the MT-loop in MT1-MMP's action on LDLR. Replacement of Ile167 with Ala, Thr, Glu, or Lys resulted in a marked loss of the ability to cleave LDLR, whereas mutation of Ile167 to a non-polar amino acid residue, including Leu, Val, Met, and Phe, had no effect. Therefore, our studies indicate that MT1-MMP does not require a specific cleavage site on LDLR. In contrast, an amino acid residue with a hydrophobic side chain at position 167 in the MT-loop is critical for MT1-MMP-induced LDLR cleavage.

The Role of Clinical Pharmacist in Pediatrics' Adherence to Antiepileptic Drugs.

Background: Rate of nonadherence to antiepileptic drugs (AEDs) in children is about 33%. Engaging clinical pharmacists in the management of patients has proved to increase adherence to medications which will improve the outcomes of treatment. Objectives: To investigate the effect of a clinical pharmacist-led education on the adherence to AEDs in pediatric patients with epilepsy. Secondary outcomes include effectiveness and safety of AEDs, satisfaction with information about AEDs provided to the caregivers, and patients quality of life (QoL). Methods: This was an interventional study where pediatric patients were randomly assigned to the intervention (n = 41) or the control (n = 40) group. A 30-minute clinical pharmacist-led educational interview to the parent/caregiver was provided to the first group as add-on to standard medical care received by latter. Outcomes were measured at baseline and after 8-week follow-up. Results: The intervention group had an increase in mean adherence score from 6 ± 1.09 at baseline to 7.6 ± 0.9 at follow-up (P value < 0.001), while the control group had no significant change (P value > 0.05), the difference between the 2 groups at follow-up was significant (P value < 0.0001). No significant difference was observed between groups at follow-up with regard to effectiveness (P value > 0.05), and safety (P value = 0.08). While higher satisfaction with information (P value < 0.0001), and higher QoL (P value < 0.05) was observed in the intervention group. Conclusion and relevance: Clinical pharmacist-led education had a positive outcome on pediatric patients with epilepsy with regard to adherence, effectiveness, safety, satisfaction with information about AEDs, and QoL.