Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant.

OBJECTIVE: To assess sex-specific differences in early brain structure and function of preterm infants after red blood cell (RBC) transfusions. STUDY DESIGN: A single-center subset of infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled from the National Institute of Child Health and Human Development's Neonatal Research Network Transfusion of Prematures Trial. Hemoglobin (Hb) concentration obtained directly before each transfusion (pretransfusion Hb [ptHb]) was obtained longitudinally throughout each infant's neonatal intensive care unit stay and used as a marker of degree of anemia (n = 97). Measures of regional brain volumes using magnetic resonance imaging were obtained at ∼40 weeks postmenstrual age or at hospital discharge, if earlier (n = 29). Measures of brain function were obtained at 12 months corrected age using the Bayley Scales of Infant & Toddler Development, 3rd Edition (n = 34). RESULTS: PtHb was positively correlated with neonatal cerebral white matter volume in males (B = +0.283; P = .006), but not females (B = -0.099; P = .713), resulting in a significant sex interaction (P = .010). Bayley-III gross motor scores and a pooled mean score were significantly lower in association with higher ptHb in females (gross motor score: B = -3.758; P = .013; pooled mean score: B = -1.225; P = .030), but not males (gross motor score: B = +1.758; P = .167; pooled mean score: B = +0.621; P = .359). Higher ptHb was associated with descriptively lower performance on multiple Bayley-III subscales in females, but not in males. CONCLUSIONS: This study demonstrates sex-specific associations between an early marker of anemia and RBC transfusion status (ie, ptHb) with both neonatal white matter volume and early cognitive function at age 12 months in preterm infants.

Sex-specific cytokine responses and neurocognitive outcome after blood transfusions in preterm infants.

BACKGROUND: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. METHODS: Infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months' corrected age. RESULTS: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p = 0.004): monocyte chemoattractant protein-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in males (-0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p = 0.0005) and motor scaled scores (p < 0.0001). CONCLUSIONS: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old. IMPACT: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy. Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes. This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.

Insight into the Phospholipid-Binding Preferences of Kir3.4.

The G-protein-gated inwardly rectifying potassium channel 4 (Kir3.4) subunit forms functional tetramers. Previous studies have established that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is required for Kir3.4 function. However, the binding preferences of Kir3.4 for the headgroup and acyl chains of phosphorylated phosphatidylinositides (PIPs) and other lipids are not well understood. Here, the interactions between full-length, human Kir3.4 and lipids are characterized using native mass spectrometry (MS) in conjunction with a soluble fluorescent lipid-binding assay. Kir3.4 displays binding preferences for PIPs, and, in some cases, the degree of binding is influenced by the type of acyl chains. The interactions between Kir3.4 and PIPs are weaker in comparison to full-length, human Kir3.2. The binding of PI(4,5)P2 modified with a fluorophore to Kir3.2 can be enhanced by other lipids, such as phosphatidylcholine. Introduction of S143T, a mutation that enhances Kir3.4 activity, results in an overall reduction in the channel binding PIPs. In contrast, the D223N mutant of Kir3.4 that mimics the sodium-bound state exhibited stronger binding for PI(4,5)P2, particularly for those with 18:0-20:4 acyl chains. Taken together, these results provide additional insight into the interaction between Kir3.4 and lipids that are important for channel function.

Preliminary evaluation of pre-speech and neurodevelopmental measures in 7-11-week-old infants with isolated oral clefts.

BACKGROUND: The purpose of this research study was to evaluate the earliest markers of vocal functioning and neurological development in infants with isolated oral cleft of the lip and/or palate (iCL/P). METHODS: Participants were recruited through advertisements and clinic visits at a local mid-western university. A total of eight participants (four unaffected and four with iCL/P), ranging in age from 7.29 to 11.57 weeks, were enrolled and completed demographic and pre-speech measures. A subset of six males (four unaffected and two with iCL/P) successfully completed a structural magnetic resonance imaging scan. RESULTS: Patterns of disrupted vocal control and reduced myelinated white matter were found in participants with iCL/P. CONCLUSIONS: The findings of this study provide a foundation from which to build further research on the neuronal development of infants with oral clefts: the need to evaluate measures of cortical development, inclusion of information on anesthesia exposure and airway obstruction, and suggestions for avoiding identified pitfalls/blocks to obtaining data are discussed. IMPACT: Research in children with isolated oral clefts has demonstrated higher rates of learning disorders connected to subtle differences in brain structure. There is no work evaluating the potential impact of exposure to anesthesia on development. This is the first known attempt to evaluate brain structure and function in infants with isolated oral clefts before exposure to anesthesia. Potential trends of early vocal issues and structural brain differences (less myelinated white matter) were identified in infants with isolated oral clefts compared to unaffected controls. Differences in brain structure and function in infants with isolated oral clefts may be present before surgery.

Insight into the Selectivity of Kir3.2 toward Phosphatidylinositides.

Activation of G-protein-gated inwardly rectifying potassium channels (Kir3.x) requires the direct binding of phosphorylated phosphatidylinositides (PIPs). Previous studies have established that PIP isoforms activate Kir channels to varying degrees and the binding affinity between PIPs and Kir3.2 appears to be correlated with the level of activation. However, how individual residues contribute to the selectivity of Kir channels toward PIP isoforms is poorly understood. Here, we employ native mass spectrometry (MS) and fluorescent lipid binding assays to gain insight into the contribution of specific Kir3.2 residues binding to phospholipids. For the wild-type channel, we demonstrate the importance of membrane protein samples devoid of co-purified contaminants for protein-lipid binding studies and show that PIP(4,5)P2 cooperatively binds Kir3.2 with a Hill coefficient of 2.7. We also find lipid binding profiles determined from native MS and solution binding assays are in direct agreement. Point mutations of Kir3.2 residues that interact with PIPs distinctly alter selective lipid binding. The K64Q mutation results in altered binding profiles with the highest binding affinity for PIP(4,5)P2 with specific acyl chains. Mutation of R92 to Pro, a residue found in Kir6.2, results in promiscuous binding of PIP isoforms. Kir3.2 with the K194A mutation results in a distinct binding preference for PIP(3,4,5)P3 over other PIP isoforms. Taken together, our results underscore the utmost importance of protein quality for protein-lipid binding studies and show that a single mutation in Kir3.2 can alter the selectivity toward PIPs.

Sex-specific alterations in preterm brain.

BACKGROUND: The literature on brain imaging in premature infants is mostly made up of studies that evaluate neonates, yet the most dynamic time of brain development happens from birth to 1 year of age. This study was designed to obtain quantitative brain measures from magnetic resonance imaging scans of infants born prematurely at 12 months of age. METHODS: The subject group was designed to capture a wide range of gestational age (GA) from premature to full-term infants. An age-specific atlas generated quantitative brain measures. A regression model was used to predict effects of GA and sex on brain measures. RESULTS: There was a primary effect of sex on: (1) intracranial volume, males > females; (2) proportional cerebral cortical gray matter (females > males), and (3) cerebral white matter (males > females). GA predicted cerebral volume and cerebral spinal fluid. GA also predicted cortical gray matter in a sex-specific manner with GA having a significant effect on cortical volume in the males, but not in females. CONCLUSIONS AND RELEVANCE: Sex differences in brain structure are large early in life. GA had sex-specific effects highlighting the importance evaluating sex effects in neurodevelopmental outcomes of premature infants.

Correction: Sex-specific alterations in preterm brain.

In the original article, the legend within Fig. 3 incorrectly read as '*p < 0.10, **p < 0.05, ***p > 0.01'. This has now been changed to '*p < 0.10, **p < 0.05, ***p < 0.01'. This has been corrected in both the PDF and HTML versions of the Article. The authors would like to apologise for this error.

Asymmetric Synthesis of Hydroxy Esters with Multiple Stereocenters via a Chiral Phosphoric Acid Catalyzed Kinetic Resolution.

The kinetic resolution of hydroxy tert-butyl esters through a Brønsted acid catalyzed lactonization is described. The resulting enantioenriched molecules have cyclic backbones and/or multiple stereocenters. DFT calculations explore how small changes in substrate structure can have a large impact on the selectivity of the process.

Long-term outcome of brain structure in female preterm infants: possible associations of liberal versus restrictive red blood cell transfusions.

BACKGROUND: Preterm infants who receive differential red blood cell (RBC) transfusions at birth may show brain structure differences across development, including abnormalities in white matter (WM) structure and organization. This study investigated long-term outcomes of brain structure in female infants born preterm, at an average age of 13 years old, who received red blood cell (RBC) transfusions in the neonatal period according to a liberal or restrictive approach. Results from this study will increase understanding of the effects of transfusion on the developing brain. STUDY DESIGN AND METHODS: This follow-up study included female preterm infants who participated in a clinical trial and had been randomized at birth to either a liberal or restrictive hematocrit threshold. Brain structures were measured in childhood using structural magnetic resonance imaging (MRI) scans. Due to the low number of females in the restrictive transfusion group at follow-up, additional females were recruited for inclusion. Main outcome measures included cerebral and subcortical brain region volumes. RESULTS: Total intracranial volume was significantly decreased in females who were randomized to higher average hematocrit levels at birth. Infants in the liberal transfusion group had proportionately smaller volumes in all measures of regional cerebral WM and subcortical brain volumes, reaching significance for temporal lobe WM and caudate volumes. CONCLUSION: Female premature infants who received a liberal transfusion threshold at birth had decreased WM volumes, which suggests the potential long-term neurodevelopmental risks associated with liberal transfusion practices.

Facile synthesis of versatile enantioenriched α-substituted hydroxy esters through a Brønsted acid catalyzed kinetic resolution.

An efficient synthesis of enantioenriched α-substituted γ-hydroxy esters via a kinetic resolution event is described. Bulky racemic esters in the presence of a chiral Brønsted acid selectively lactonize to yield a recoverable enantioenriched hydroxy ester and lactone. These esters are highly versatile building blocks that can readily be converted to synthetically useful materials.