Background: Developmental iodine deficiency results in inadequate thyroid hormone (TH), which damages the hippocampus. Here, we explored the roles of hippocampal doublecortin and neural cell adhesion molecule (NCAM)-180 in developmental iodine deficiency and hypothyroidism. Methods: Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil (PTU)-adulterated water (5 ppm or 15 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day (PN) 28. Silver-stained neurons and protein levels of doublecortin and NCAM-180 in several hippocampal subregions were assessed on PN14, PN21, PN28, and PN42. Results: The results show that nerve fibers in iodine-deficient and 15 ppm PTU-treated rats were injured on PN28 and PN42. Downregulation of doublecortin and upregulation of NCAM-180 were observed in iodine-deficient and 15 ppm PTU-treated rats from PN14 on. These alterations were irreversible by the restoration of serum TH concentrations on PN42. Conclusion: Developmental iodine deficiency and hypothyroidism impair the expression of doublecortin and NCAM-180, leading to nerve fiber malfunction and thus impairments in hippocampal development.

Background: Many patients who survive a myocardial infarction (MI) remain at risk of sudden cardiac death despite revascularization and optimal medical treatment. We used the modified moving average (MMA) method to assess the utility of T-wave alternans (TWA) and heart rate turbulence (HRT) as risk markers in MI patients with or without diabetes mellitus (DM).Methods: We prospectively enrolled 248 consecutive patients: 96 with MI (post-MI patients); 77 MI with DM (post-MI + DM patients); 75 controls without cardiovascular disease (group control). Both TWA and HRT were measured on ambulatory electrocardiograms (AECGs). HRT was assessed by two parameters ─ turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO ≥0% and TS ≤2.5 ms/R-R interval were met. The endpoint was cardiac mortality.Results: TWA values differed significantly between MI and controls. Post-MI + DM patients had higher TWA values than post-MI patients (58 ± 21 μV VS 52 ± 18 μV,P = 0.029). Impaired HRT--increased TO and decreased TS were observed in MI patients with or without DM. During follow-up of 578 ± 146 days, cardiac death occurred in ten patients and three of them suffered sudden cardiac death (SCD). Multivariate analysis determined that a HRT-positive outcome [HR (95% CI): 5.01, 1.33–18.85;P = 0.017], as well as the combination of abnormal TWA (≥47 μV) and positive HRT had significant association with the endpoint [HR (95% CI): 9.08, 2.21–37.2;P = 0.002)].Conclusion: This study indicates that AECGs-based TWA and HRT can predict cardiac mortality in MI patients with or without DM. Combined analysis TWA and HRT may be a convenient and useful method of identifying patients at high risk for cardiovascular death.

Calmodulin (CaM) is well known as an activator of calcium/calmodulin-dependent protein kinase II (CaMKII). Voltage-gated sodium channels (VGSCs) are basic signaling molecules in excitable cells and are crucial molecular targets for nervous system agents. However, the way in which Ca²⁺/CaM/CaMKII cascade modulates Na_V1.1 IQ (isoleucine and glutamine) domain of VGSCs remains obscure. In this study, the binding of CaM, its mutants at calcium binding sites (CaM₁₂, CaM₃₄, and CaM₁₂₃₄), and truncated proteins (N-lobe and C-lobe) to Na_V1.1 IQ domain were detected by pull-down assay. Our data showed that the binding of Ca²⁺/CaM to the Na_V1.1 IQ was concentration-dependent. ApoCaM (Ca²⁺-free form of calmodulin) bound to Na_V1.1 IQ domain preferentially more than Ca²⁺/CaM. Additionally, the C-lobe of CaM was the predominant domain involved in apoCaM binding to Na_V1.1 IQ domain. By contrast, the N-lobe of CaM was predominant in the binding of Ca²⁺/CaM to Na_V1.1 IQ domain. Moreover, CaMKII-mediated phosphorylation increased the binding of Ca²⁺/CaM to Na_V1.1 IQ domain due to one or several phosphorylation sites in T1909, S1918, and T1934 of Na_V1.1 IQ domain. This study provides novel mechanisms for the modulation of Na_V1.1 by the Ca²⁺/CaM/CaMKII axis. For the first time, we uncover the effect of Ca²⁺, lobe-specificity and CaMKII on CaM binding to Na_V1.1.