Diffusion Tensor Imaging to Predict Neurodevelopmental Impairment in Infants after Hypoxic-Ischemic Injury.

OBJECTIVE: Magnetic resonance imaging (MRI) is the standard of care for evaluation of brain injury after hypoxic-ischemic encephalopathy (HIE) in term newborns. This study utilizes diffusion tensor imaging (DTI) to (1) identify infants at highest risk of development of cerebral palsy (CP) following HIE and to (2) identify regions of the brain critical to normal fidgety general movements (GMs) at 3 to 4 months of postterm. Absence of these normal, physiological movements is highly predictive of CP. STUDY DESIGN: Term infants treated with hypothermia for HIE from January 2017 to December 2021 were consented for participation and had brain MRI with DTI after rewarming. The Prechtl's General Movements Assessment was performed at 12 to 16 weeks of age. Structural MRIs were reviewed for abnormalities, and DTI data were processed with the FMRIB Software Library. Infants underwent the Bayley Scales of Infant and Toddler Development III test at 24 months. RESULTS: Forty-five infant families were consented; three infants died prior to MRI and were excluded, and a fourth infant was excluded due to diagnosis of a neuromuscular disorder. Twenty-one infants were excluded due to major movement artifact on diffusion images. Ultimately, 17 infants with normal fidgety GMs were compared with 3 infants with absent fidgety GMs with similar maternal and infant characteristics. Infants with absent fidgety GMs had decreased fractional anisotropy of several important white matter tracts, including the posterior limb of the internal capsule, optic radiations, and corpus callosum (p < 0.05). All three infants with absent fidgety GMs and two with normal GMs went on to be diagnosed with CP. CONCLUSION: This study identifies white matter tracts of the brain critical to development of normal fidgety GMs in infants at 3 to 4 months of postterm using advanced MRI techniques. These findings identify those at highest risk for CP among infants with moderate/severe HIE prior to hospital discharge. KEY POINTS: · HIE has devastating impacts on families and infants.. · Diffusion MRI identifies infants at highest risk for developing neurodevelopmental impairment.. · Normal general movements of infancy are generated by key white matter tracts..

Clinical associations of immature breathing in preterm infants: part 1-central apnea.

BACKGROUND: Apnea of prematurity (AOP) is nearly universal among very preterm infants, but neither the apnea burden nor its clinical associations have been systematically studied in a large consecutive cohort. METHODS: We analyzed continuous bedside monitor chest impedance and electrocardiographic waveforms and oxygen saturation data collected on all neonatal intensive care unit (NICU) patients <35 wk gestation from 2009 to 2014 (n = 1,211; >50 infant-years of data). Apneas, with bradycardia and desaturation (ABDs), defined as central apnea ≥10 s associated with both bradycardia <100 bpm and oxygen desaturation <80%, were identified using a validated automated algorithm. RESULTS: Number and duration of apnea events decreased with increasing gestational age (GA) and postmenstrual age (PMA). ABDs were more frequent in infants <31 wk GA at birth but were not more frequent in those with severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or severe intraventricular hemorrhage (IVH) after accounting for GA. In the day before diagnosis of late-onset septicemia and necrotizing enterocolitis, ABD events were increased in some infants. Many infants continued to experience short ABD events in the week prior to discharge home. CONCLUSION: Frequency of apnea events is a function of GA and PMA in infants born preterm, and increased apnea is associated with acute but not with chronic pathologic conditions.

NAVA-synchronized compared to nonsynchronized noninvasive ventilation for apnea, bradycardia, and desaturation events in VLBW infants.

Neurally adjusted ventilatory assistance (NAVA) can overcome technical difficulties with synchronizing noninvasive ventilation breaths with the patient, a modality often used in very low birthweight infants (VLBW) with apnea of prematurity (AOP). This study is a retrospective single-center investigation into whether NAVA-synchronized noninvasive (niNAVA) ventilation is better than nonsynchronized (nasal intermittent positive pressure ventilation [nIPPV]) for symptomatic apnea in VLBW infants. Nursing records of apnea, bradycardia, and/or desaturations were abstracted from the electronic medical records of 108 VLBW infants admitted to the neonatal intensive care unit (NICU) from 2015 to 2017 who received either of the two modalities, 61 epochs of niNAVA totaling 488 days and 103 epochs of nIPPV totaling 886.5 days. niNAVA was associated with a significant reduction in the number of isolated bradycardic events/day (0.48 ± 0.14 vs 1.35 ± 0.27; P = .019) and overall bradycardias/day (2.42 ± 0.47 vs 4.02 ± 0.53; P = .042) and there were more epochs with no events with niNAVA compared with nIPPV (23.0% vs 6.8%; P = .004). These results justify a prospective trial of NAVA-synchronized noninvasive ventilation for VLBW infants with caffeine-resistant AOP.

Impact of Caffeine Boluses and Caffeine Discontinuation on Apnea and Hypoxemia in Preterm Infants.

Background: Apnea of prematurity often occurs during and following caffeine therapy. We hypothesized that number of apnea events would be impacted by adjustments in caffeine therapy. Materials and Methods: An automated algorithm was used in all infants ≤32 weeks gestation admitted to a level IV Neonatal Intensive Care Unit from 2009 to 2014 to analyze chest impedance, electrocardiogram, and oxygen saturation data around the time of serum caffeine levels, caffeine boluses while on maintenance therapy, and caffeine discontinuation. Episodes of central apnea/bradycardia/desaturation (ABDs), and percent time with SpO2 <88% and <75% were measured. Results: ABDs were analyzed in 302 preterm infants (mean gestational age 27.6 weeks) around the time of 485 serum caffeine levels, 90 caffeine boluses, and 273 episodes of caffeine discontinuation. Higher serum caffeine levels were not associated with fewer ABDs or higher heart rate. For caffeine boluses given due to clinically recognized spells, hypoxemia and algorithm-detected ABDs decreased day 1-2 after the bolus compared to the day before and day of the bolus (mean 4.4 events/day after vs. 6.6 before, p = 0.004). After caffeine discontinuation, there was no change in hypoxemia and a small increase in ABDs (2 events/day 3-5 days after discontinuation vs. 1 event/day before and >5 days after, p < 0.01). This increase in ABDs occurred irrespective of gestational age, respiratory support, or postmenstrual age at the time caffeine was stopped. Conclusions: In this retrospective analysis, caffeine boluses and caffeine discontinuation were associated with a small change in the number of ABD events in preterm infants.

Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254).

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Discovery of novel vitamin D receptor interacting proteins that modulate 1,25-dihydroxyvitamin D3 signaling.

The nuclear vitamin D receptor (VDR) modulates gene transcription in 1,25-dihydroxyvitamin D(3) (1,25D) target tissues such as kidney, intestine, and bone. VDR is also expressed in heart, and 1,25D deficiency may play a role in the acceleration of cardiovascular disease. Employing a yeast two-hybrid system and a human heart library, using both a 1,25D-independent and 1,25D-dependent screen, we discovered six candidate VDR interacting proteins (VIPs). These novel VIPs include CXXC5, FASTK, NR4A1, TPM2, MYL3 and XIRP1. Mammalian two-hybrid assays as well as GST pull-downs were used to confirm VIP-VDR interaction, and the combination of these two assays reveals that CXXC5, XIRP1, FASTK and NR4A1 interactions with VDR may be modulated by 1,25D. The functional effects of these VIPs on 1,25D-mediated gene expression were explored in transcriptional assays employing three separate and distinct 1,25D-responsive element (VDRE)-driven luciferase reporter genes in transfected Caco-2 and HEK-293 cells, and in a C2C12 myoblast line. FASTK and TPM2 activated expression in all cell line and promoter contexts, while CXXC5 and XIRP1 exhibited differing effects depending on the cell line and promoter employed, suggesting promoter and cell-specific effects of these unique VIPs on VDR signaling. Further evaluation of the interaction between CXXC5 and VDR revealed that CXXC5 acts in a dose-dependent manner to stimulate VDR-mediated transcription on select VDREs. Identification of novel heart VIPs and their influence on VDR activity may increase our understanding of how vitamin D impacts cardiac physiology and may facilitate development of VDR/VIP drug analogs to combat heart disease.