Impact of Nutritional Status on Total Brain Tissue Volumes in Preterm Infants.

Preterm infants bypass the crucial in utero period of brain development and are at increased risk of malnutrition. We aimed to determine if their nutritional status is associated with brain tissue volumes at term equivalent age (TEA), applying recently published malnutrition guidelines for preterm infants. We performed a single center retrospective chart review of 198 infants < 30 weeks' gestation between 2018 and 2021. We primarily analyzed the relationship between the manually obtained neonatal MR-based brain tissue volumes with the maximum weight and length z-score. Significant positive linear associations between brain tissue volumes at TEA and weight and length z-scores were found (p < 0.05). Recommended nutrient intake for preterm infants is not routinely achieved despite efforts to optimize nutrition. Neonatal MR-based brain tissue volumes of preterm infants could serve as objective, quantitative and reproducible surrogate parameters of early brain development. Nutrition is a modifiable factor affecting neurodevelopment and these results could perhaps be used as reference data for future timely nutritional interventions to promote optimal brain volume.

Comparing head ultrasounds and susceptibility-weighted imaging for the detection of low-grade hemorrhages in preterm infants.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a complication of prematurity. Grades III and IV IVH lead to significant morbidity, but mounting evidence shows low-grade IVH (grades I-II) may be associated with adverse sequelae. Head ultrasounds (HUS) are used to screen infants for IVH but may miss low-grade IVH. Our study compared the results of HUS around 7 days of age to susceptibility-weighted imaging (SWI) obtained at term-corrected age in infants born at <30 wGA. STUDY DESIGN: Infants <30 weeks gestational age (GA) with an HUS and MRI at admission to UF Health were identified by a retrospective chart review. Images were re-read by a pediatric neuroradiologist. RESULTS: Ninety-four infants with a mean GA of 25.8 weeks were identified. Of those with normal HUS, 50% had low-grade IVH on the term-corrected MRI. CONCLUSIONS: HUS are effective for screening for high-grade IVH. SWI is more sensitive in identifying low-grade IVH.

Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.

KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.

Trafficking-deficient hERG K⁺ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER.

The human ether-a-go-go related gene (hERG) encodes the voltage-gated K(+) channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an "immature" N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.